query: carcinogens

positive: IP6: a novel anti-cancer agent. Inositol hexaphosphate (InsP6 or IP6) is ubiquitous. At 10 microM to 1 mM concentrations, IP6 and its lower phosphorylated forms (IP(1-5)) as well as inositol (Ins) are contained in most mammalian cells, wherein they are important in regulating vital cellular functions such as signal transduction, cell proliferation and differentiation. A striking anti-cancer action of IP6 has been demonstrated both in vivo and in vitro, which is based on the hypotheses that exogenously administered IP6 may be internalized, dephosphorylated to IP(1-5), and inhibit cell growth. There is additional evidence that Ins alone may further enhance the anti-cancer effect of IP6. Besides decreasing cellular proliferation, IP6 also causes differentiation of malignant cells often resulting in a reversion to normal phenotype. These data strongly point towards the involvement of signal transduction pathways, cell cycle regulatory genes, differentiation genes, oncogenes and perhaps, tumor suppressor genes in bringing about the observed anti-neoplastic action of IP6.

positive: The role of phytic acid in legumes: antinutrient or beneficial function? This review describes the present state of knowledge about phytic acid (phytate), which is often present in legume seeds. The antinutritional effects of phytic acid primarily relate to the strong chelating associated with its six reactive phosphate groups. Its ability to complex with proteins and particularly with minerals has been a subject of investigation from chemical and nutritional viewpoints. The hydrolysis of phytate into inositol and phosphates or phosphoric acid occurs as a result of phytase or nonenzymatic cleavage. Enzymes capable of hydrolysing phytates are widely distributed in micro-organisms, plants and animals. Phytases act in a stepwise manner to catalyse the hydrolysis of phytic acid. To reduce or eliminate the chelating ability of phytate, dephosphorylation of hexa- and penta-phosphate forms is essential since a high degree of phosphorylation is necessary to bind minerals. There are several methods of decreasing the inhibitory effect of phytic acid on mineral absorption (cooking, germination, fermentation, soaking, autolysis). Nevertheless, inositol hexaphosphate is receiving increased attention owing to its role in cancer prevention and/or therapy and its hypocholesterolaemic effect.

positive: Effect of IP6 on human neutrophil cytokine production and cell morphology. Inositol hexaphosphate (IP6) has anti-cancer properties, but recently other extracellular functions have been observed for IP6, including enhancing superoxide production and phagocytosis by neutrophils in the presence of microbial stimuli. This study investigated other inflammatory functions of IP6 on adherent neutrophils. The effect of IP6 on the release of IL-8, tumour necrosis factor (TNF-alpha) and IL-6 by neutrophils attached to either plastic or laminin for up to 6 hours in response to stimulation with lipopolysaccharide or N-formyl-Met-Leu-Phe (fMLP) was investigated. An increase in IL-8 secretion by stimulated cells occurred in the presence of IP6. The incubation of cells attached to laminin with IP6 alone (100-250 BM) did not effect cell morphology, but in the presence of 10(-7) M fMLP altered cell shape. A direct effect of IP6 on cell function was to trigger a sustained assembly of F-actin. Thus, exposure of neutrophils to low levels of IP6 appears to modulate selective neutrophil functions.

positive: Phytate in foods and significance for humans: food sources, intake, processing, bioavailability, protective role and analysis. The article gives an overview of phytic acid in food and of its significance for human nutrition. It summarises phytate sources in foods and discusses problems of phytic acid/phytate contents of food tables. Data on phytic acid intake are evaluated and daily phytic acid intake depending on food habits is assessed. Degradation of phytate during gastro-intestinal passage is summarised, the mechanism of phytate interacting with minerals and trace elements in the gastro-intestinal chyme described and the pathway of inositol phosphate hydrolysis in the gut presented. The present knowledge of phytate absorption is summarised and discussed. Effects of phytate on mineral and trace element bioavailability are reported and phytate degradation during processing and storage is described. Beneficial activities of dietary phytate such as its effects on calcification and kidney stone formation and on lowering blood glucose and lipids are reported. The antioxidative property of phytic acid and its potentional anticancerogenic activities are briefly surveyed. Development of the analysis of phytic acid and other inositol phosphates is described, problems of inositol phosphate determination and detection discussed and the need for standardisation of phytic acid analysis in foods argued.

positive: In vitro investigations of the potential health benefits of Australian-grown faba beans (Vicia faba L.): chemopreventative capacity and inhibitory ... The functional properties, including antioxidant and chemopreventative capacities as well as the inhibitory effects on angiotensin-converting enzyme (ACE), α-glucosidase and pancreatic lipase, of three Australian-grown faba bean genotypes (Nura, Rossa and TF(Ic*As)*483/13) were investigated using an array of in vitro assays. Chromatograms of on-line post column derivatisation assay coupled with HPLC revealed the existence of active phenolics (hump) in the coloured genotypes, which was lacking in the white-coloured breeding line, TF(Ic*As)*483/13. Roasting reduced the phenolic content, and diminished antioxidant activity by 10-40 % as measured by the reagent-based assays (diphenylpicrylhydrazyl, 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) and oxygen radical absorbance capacity) in all genotypes. Cell culture-based antioxidant activity assay (cellular antioxidant activity) showed an increase of activity in the coloured genotypes after roasting. Faba bean extracts demonstrated cellular protection ability against H₂O₂-induced DNA damage (assessed using RAW264.7 cells), and inhibited the proliferation of all human cancer cell lines (BL13, AGS, Hep G2 and HT-29) evaluated. However, the effect of faba bean extracts on the non-transformed human cells (CCD-18Co) was negligible. Flow cytometric analyses showed that faba bean extracts successfully induced apoptosis of HL-60 (acute promyelocytic leukaemia) cells. The faba bean extracts also exhibited ACE, α-glucosidase and pancreatic lipase inhibitory activities. Overall, extracts from Nura (buff-coloured) and Rossa (red-coloured) were comparable, while TF(Ic*As)*483/13 (white-coloured) contained the lowest phenolic content and exhibited the least antioxidant and enzyme inhibition activities. These results are important to promote the utilisation of faba beans in human diets for various health benefits.

positive: Anti-angiogenic activity of inositol hexaphosphate (IP6). A significant anticancer activity of the naturally occurring carbohydrate inositol hexaphosphate (IP(6)) has been reported against numerous cancer models. Since tumors require angiogenesis for growth and metastasis, we hypothesize that IP(6) reduces tumor growth by inhibiting angiogenesis. Because angiogenesis depends on the interaction between endothelial and tumor cells, we investigated the effect of IP(6) on both. IP(6) inhibited the proliferation and induced the differentiation of endothelial cells in vitro; the growth of bovine aortic endothelial cells (BAECs) evaluated by MTT proliferation assay was inhibited in a dose-dependent manner (IC(50) = 0.74 mM). The combination of IP(6) and vasostatin, a calreticulin fragment with anti-angiogenic activity, was synergistically superior in growth inhibition than either compound. IP(6) inhibited human umbilical vein endothelial cell (HUVEC) tube formation (in vitro capillary differentiation) on a reconstituted extracellular matrix, Matrigel, and disrupted pre-formed tubes. IP(6) significantly reduced basic fibroblast growth factor (bFGF)-induced vessel formation (P < 0.01) in vivo in Matrigel plug assay. Exposure of HepG2, a human hepatoma cell line, to IP(6) for 8 h, resulted in a dose-dependent decrease in the mRNA levels of vascular endothelial growth factor (VEGF), as assessed by RT-PCR. IP(6) treatment of HepG2 cells for 24 h also significantly reduced the VEGF protein levels in conditioned medium, in a concentration-dependent manner (P = 0.012). Thus, IP(6) has an inhibitory effect on induced angiogenesis.

positive: Protection against cancer by dietary IP6 and inositol. Inositol hexaphosphate (IP(6)) is a naturally occurring polyphosphorylated carbohydrate, abundantly present in many plant sources and in certain high-fiber diets, such as cereals and legumes. In addition to being found in plants, IP(6) is contained in almost all mammalian cells, although in much smaller amounts, where it is important in regulating vital cellular functions such as signal transduction, cell proliferation, and differentiation. For a long time IP(6) has been recognized as a natural antioxidant. Recently IP(6) has received much attention for its role in cancer prevention and control of experimental tumor growth, progression, and metastasis. In addition, IP(6) possesses other significant benefits for human health, such as the ability to enhance immune system, prevent pathological calcification and kidney stone formation, lower elevated serum cholesterol, and reduce pathological platelet activity. In this review we show the efficacy and discuss some of the molecular mechanisms that govern the action of this dietary agent. Exogenously administered IP(6) is rapidly taken up into cells and dephosphorylated to lower inositol phosphates, which further affect signal transduction pathways resulting in cell cycle arrest. A striking anticancer action of IP(6) was demonstrated in different experimental models. In addition to reducing cell proliferation, IP(6) also induces differentiation of malignant cells. Enhanced immunity and antioxidant properties also contribute to tumor cell destruction. Preliminary studies in humans show that IP(6) and inositol, the precursor molecule of IP(6), appear to enhance the anticancer effect of conventional chemotherapy, control cancer metastases, and improve quality of life. Because it is abundantly present in regular diet, efficiently absorbed from the gastrointestinal tract, and safe, IP(6) + inositol holds great promise in our strategies for cancer prevention and therapy. There is clearly enough evidence to justify the initiation of full-scale clinical trials in humans.

positive: Cancer inhibition by inositol hexaphosphate (IP6) and inositol: from laboratory to clinic. Inositol hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate that is present in substantial amounts in almost all plant and mammalian cells. It was recently recognized to possess multiple biological functions. A striking anticancer effect of IP6 was demonstrated in different experimental models. Inositol is also a natural constituent possessing moderate anticancer activity. The most consistent and best anticancer results were obtained from the combination of IP6 plus inositol. In addition to reducing cell proliferation, IP6 increases differentiation of malignant cells, often resulting in a reversion to normal phenotype. Exogenously administered IP6 is rapidly taken into the cells and dephosphorylated to lower-phosphate inositol phosphates, which further interfere with signal transduction pathways and cell cycle arrest. Enhanced immunity and antioxidant properties can also contribute to tumor cell destruction. However, the molecular mechanisms underlying this anticancer action are not fully understood. Because it is abundantly present in regular diet, efficiently absorbed from the gastrointestinal tract, and safe, IP6 holds great promise in our strategies for the prevention and treatment of cancer. IP6 plus inositol enhances the anticancer effect of conventional chemotherapy, controls cancer metastases, and improves the quality of life, as shown in a pilot clinical trial. The data strongly argue for the use of IP6 plus inositol in our strategies for cancer prevention and treatment. However, the effectiveness and safety of IP6 plus inositol at therapeutic doses needs to be determined in phase I and phase II clinical trials in humans.

positive: Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upre... Curcumin exhibits anti-inflammatory and antitumor activities. Although its functional mechanism has not been elucidated so far, numerous studies have shown that curcumin induces apoptosis in cancer cells. In the present study, we show that subtoxic concentrations of curcumin sensitize human renal cancer cells to the tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. This apoptosis induced by the combination of curcumin and TRAIL is not interrupted by Bcl-2 overexpression. We found that treatment with curcumin significantly induces death receptor 5 (DR5) expression both at its mRNA and protein levels, accompanying the generation of the reactive oxygen species (ROS). Not only the pretreatment with N-acetylcystine but also the ectopic expression of peroxiredoxin II, an antioxidative protein, dramatically inhibited the apoptosis induced by curcumin and TRAIL in combination, blocking the curcumin-mediated DR5 upregulation. Taken together, the present study demonstrates that curcumin enhances TRAIL-induced apoptosis by ROS-mediated DR5 upregulation.

positive: New perspectives of curcumin in cancer prevention Numerous natural compounds have been extensively investigated for their potential for cancer prevention over decades. Curcumin, from Curcuma longa, is a highly promising natural compound that can be potentially used for chemoprevention of multiple cancers. Curcumin modulates multiple molecular pathways involved in the lengthy carcinogenesis process to exert its chemopreventive effects through several mechanisms: promoting apoptosis, inhibiting survival signals, scavenging reactive oxidative species (ROS), and reducing the inflammatory cancer microenvironment. Curcumin fulfills the characteristics for an ideal chemopreventive agent with its low toxicity, affordability, and easy accessibility. Nevertheless, the clinical application of curcumin is currently compromised by its poor bioavailability. Here we review the potential of curcumin in cancer prevention, its molecular targets, and action mechanisms. Finally, we suggest specific recommendations to improve its efficacy and bioavailability for clinical applications.

positive: Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of p53. In this study, we investigated the molecular pathways targeted by curcumin during apoptosis of human melanoma cell lines. We found that curcumin caused cell death in eight melanoma cell lines, four with wild-type and four with mutant p53. We demonstrate that curcumin-induced apoptosis is both dose- and time-dependent. We found that curcumin did not induce p53, suggesting that curcumin activates other apoptosis pathways. Our data show that curcumin activates caspases-3 and -8 but not caspase-9, supporting the rationale that apoptosis occurs via a membrane-mediated mechanism. Both a caspase-8 and broad-based caspase inhibitor, but not a caspase-9 specific inhibitor, suppressed curcumin-induced cell death. To further support our hypothesis that curcumin induces activation of a death receptor pathway, we show that curcumin induces Fas receptor aggregation in a FasL-independent manner and that low-temperature incubation, previously shown to inhibit receptor aggregation, prevented curcumin-induced cell death. Moreover, we demonstrate that expression of dominant negative FADD significantly inhibited curcumin-induced cell death. In addition, our results indicate that curcumin also blocks the NF-kappaB cell survival pathway and suppresses the apoptotic inhibitor, XIAP. Since melanoma cells with mutant p53 are strongly resistant to conventional chemotherapy, curcumin may overcome the chemoresistance of these cells and provide potential new avenues for treatment.

positive: FADD: a regulator of life and death. FAS-associated protein with death domain (FADD) is the key adaptor protein transmitting apoptotic signals mediated by the main death receptors (DRs). Besides being an essential instrument in cell death, FADD is also implicated in proliferation, cell cycle progression, tumor development, inflammation, innate immunity, and autophagy. Recently, many of these new functions of FADD were shown to be independent of DRs. Moreover, FADD function is dictated by protein localization and phosphorylation state. Thus, FADD is a crucial and unique controller of many essential cellular processes. The full understanding of the networks dictating the ultimate function of FADD may provide a new paradigm for other multifaceted proteins. Copyright 2010 Elsevier Ltd. All rights reserved.

positive: Curcumin-induced apoptosis of human colon cancer colo 205 cells through the production of ROS, Ca2+ and the activation of caspase-3. Curcumin (diferuloylmethane), the yellow pigment in turmeric (Curcuma longa), is known to inhibit proliferation of cancer cells by arresting them at various phases of the cell cycle and to induce apoptosis in tumor cells. Curcumin-induced apoptosis mainly involves the activation of caspase-3 and mitochondria-mediated pathway in various cancer cells of different tissue origin. In the present study, the induction of apoptosis and cytotoxicity by curcumin in colon cancer colo 205 cells was investigated by using flow cytometry. The results demonstrated that curcumin induced cytotoxicity and apoptosis dose- and time-depedently. Curcumin induced the production of reactive oxygen species (ROS) and Ca+2, decreased the levels of mitochondria membrane potential and induced caspase-3 activity. Curcumin also promoted the expression of Bax, cytochrome C, p53 and p21 but inhibited the expression of Bcl-2. These observations suggest that curcumin may have a possible therapeutic potential in colon cancer patients.

positive: Curcumin and Cancer Cells: How Many Ways Can Curry Kill Tumor Cells Selectively? Cancer is a hyperproliferative disorder that is usually treated by chemotherapeutic agents that are toxic not only to tumor cells but also to normal cells, so these agents produce major side effects. In addition, these agents are highly expensive and thus not affordable for most. Moreover, such agents cannot be used for cancer prevention. Traditional medicines are generally free of the deleterious side effects and usually inexpensive. Curcumin, a component of turmeric (Curcuma longa), is one such agent that is safe, affordable, and efficacious. How curcumin kills tumor cells is the focus of this review. We show that curcumin modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK). How curcumin selectively kills tumor cells, and not normal cells, is also described in detail.

positive: Effect of turmeric on urinary mutagens in smokers. Curcumin, the active principle of turmeric, is known to act as an anti-oxidant, anti-mutagen and anti-carcinogen in experimental animals. In the present study, anti-mutagenic effects of turmeric were assessed in 16 chronic smokers. It was observed that turmeric, given in doses of 1.5 g/day for 30 days, significantly reduced the urinary excretion of mutagens in smokers. In contrast, in six non-smokers, who served as control, there was no change in the urinary excretion of mutagens after 30 days. Turmeric had no significant effect on serum aspartate aminotransferase and alanine aminotransferase, blood glucose, creatinine and lipid profile. These results indicate that dietary turmeric is an effective anti-mutagen and it may be useful in chemoprevention.

positive: In vitro antimutagenicity of curcumin against environmental mutagens. The effects of curcumin, the yellow pigment of the spice, turmeric (Curcuma longa) on the mutagenicity of several environmental mutagens were investigated in the Salmonella/microsome test with or without Aroclor 1254-induced rat-liver homogenate (S-9 mix). With Salmonella typhimurium strain TA98 in the presence of S-9 mix, curcumin inhibited the mutagenicity of bidi and cigarette smoke condensates, tobacco and masheri extracts, benzo[a]pyrne and dimethyl benzo[a]anthracene in a dose-dependent manner. Curcumin did not influence the mutagenicity without S-9 mix of sodium azide, monoacetylhydrazine and streptozocin in strain TA100 nor of 4-nitrophenylenediamine in strain TA98. Our observations indicate that curcumin may alter the metabolic activation and detoxification of mutagens.

positive: Plant-derived health: the effects of turmeric and curcuminoids. Plants contain numerous polyphenols, which have been shown to reduce inflammation and hereby to increase resistance to disease. Examples of such polyphenols are isothiocyanates in cabbage and broccoli, epigallocatechin in green tee, capsaicin in chili peppers, chalones, rutin and naringenin in apples, resveratrol in red wine and fresh peanuts and curcumin/curcuminoids in turmeric. Most diseases are maintained by a sustained discreet but obvious increased systemic inflammation. Many studies suggest that the effect of treatment can be improved by a combination of restriction in intake of proinflammatory molecules such as advanced glycation end products (AGE), advanced lipoperoxidation end products (ALE), and rich supply of antiinflammatory molecules such as plant polyphenols. To the polyphenols with a bulk of experimental documentation belong the curcuminoid family and especially its main ingredient, curcumin. This review summarizes the present knowledge about these turmericderived ingredients, which have proven to be strong antioxidants and inhibitors of cyclooxigenase-2 (COX-2), lipoxygenase (LOX) and nuclear factor kappa B (NF-kappaB) but also AGE. A plethora of clinical effects are reported in various experimental diseases, but clinical studies in humans are few. It is suggested that supply of polyphenols and particularly curcuminoids might be value as complement to pharmaceutical treatment, but also prebiotic treatment, in conditions proven to be rather therapy-resistant such as Crohn's, long-stayed patients in intensive care units, but also in conditions such as cancer, liver cirrhosis, chronic renal disease, chronic obstructive lung disease, diabetes and Alzheimer's disease.

positive: Maternal meat and fat consumption during pregnancy and suspected atopic eczema in Japanese infants aged 3-4 months: the Osaka Maternal and Child He... Interest has increased in the possibility that maternal dietary intake during pregnancy might influence the development of allergic disorders in children. The present prospective study examined the association of maternal intake of selected foods high in fatty acids and specific types of fatty acids during pregnancy with the risk of suspected atopic eczema among Japanese infants aged 3-4 months. Subjects were 771 mother-child pairs. Information on maternal dietary intake during pregnancy was assessed with a validated self-administered diet history questionnaire. The term 'suspected atopic eczema' was used to define an outcome based on results of our questionnaire completed by mothers 3-4 months postpartum. The risk of suspected atopic eczema was 8.4% (n = 65). Higher maternal intake of meat during pregnancy was significantly associated with an increased risk of suspected atopic eczema in the offspring: the multivariate odds ratio (OR) for the highest vs. lowest quartile was 2.59 [95% confidence interval (CI): 1.15-6.17, p for trend = 0.01]. The positive association was strengthened when the definition of the outcome was confined to a definite physician's diagnosis of atopic eczema (n = 35): the multivariate OR between extreme quartiles was 3.53 (95% CI: 1.19-12.23, p for trend = 0.02). No material exposure-response relationships were observed between maternal intake of eggs, dairy products, fish, total fat, saturated fatty acids, monounsaturated fatty acids, n-3 polyunsaturated fatty acids, alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, n-6 polyunsaturated fatty acids, linoleic acid, arachidonic acid and cholesterol and the ratio of n-3 to n-6 polyunsaturated fatty acid consumption and the risk of suspected atopic eczema. Higher maternal meat intake may increase the risk of infantile atopic eczema, whereas we found no evidence that maternal intake of fish and n-3 polyunsaturated fatty acids are preventive against infantile atopic eczema. (c) 2009 John Wiley & Sons A/S

positive: Endocrine-Disrupting Chemicals: Associated Disorders and Mechanisms of Action The incidence and/or prevalence of health problems associated with endocrine-disruption have increased. Many chemicals have endocrine-disrupting properties, including bisphenol A, some organochlorines, polybrominated flame retardants, perfluorinated substances, alkylphenols, phthalates, pesticides, polycyclic aromatic hydrocarbons, alkylphenols, solvents, and some household products including some cleaning products, air fresheners, hair dyes, cosmetics, and sunscreens. Even some metals were shown to have endocrine-disrupting properties. Many observations suggesting that endocrine disruptors do contribute to cancer, diabetes, obesity, the metabolic syndrome, and infertility are listed in this paper. An overview is presented of mechanisms contributing to endocrine disruption. Endocrine disruptors can act through classical nuclear receptors, but also through estrogen-related receptors, membrane-bound estrogen-receptors, and interaction with targets in the cytosol resulting in activation of the Src/Ras/Erk pathway or modulation of nitric oxide. In addition, changes in metabolism of endogenous hormones, cross-talk between genomic and nongenomic pathways, cross talk with estrogen receptors after binding on other receptors, interference with feedback regulation and neuroendocrine cells, changes in DNA methylation or histone modifications, and genomic instability by interference with the spindle figure can play a role. Also it was found that effects of receptor activation can differ in function of the ligand.

positive: Reduction in penis size and plasma testosterone concentrations in juvenile alligators living in a contaminated environment. The development of the male reproductive ducts and external genitalia in vertebrates is dependent on elevated androgen concentrations during embryonic development and the period of postnatal growth. We have observed that a population of juvenile alligators living on Lake Apopka exhibit significantly smaller penis size (24% average decrease) and lower plasma concentrations of testosterone (70% lower concentrations) when compared to animals of similar size on Lake Woodruff. In addition to smaller phalli, no relationship exists between plasma testosterone concentrations and penile size in males from Lake Apopka, whereas a positive relationship exists for males from Lake Woodruff. The alligators on Lake Apopka are known to have elevated concentrations of the antiandrogenic DDT breakdown product p.p'-DDE stored in their fat. We suggest a number of hypotheses that could explain the modification in the phenotype of the juvenile male living in Lake Apopka. These modifications in phenotype include a smaller penis size, lower plasma androgen concentrations, and lack of responsiveness of the penis to the plasma androgens present.

positive: Effects of intestinal microflora and the environment on the development of asthma and allergy. The aim of previous research into the causes of allergic diseases, including asthma was mostly to identify potential risk factors in the environment. No major risk factors have been identified, however. Over the past 10 years, focus has, therefore, more been directed towards protective factors that could enhance the development of tolerance to allergens which were previously encountered early in life, but are now lost in modern affluent societies. In particular, the role of childhood infections has been discussed, but so far these studies have not been conclusive. Recent epidemiological studies and experimental research suggest that the microbial environment and exposure to microbial products in infancy modifies immune responses and enhances the development of tolerance to ubiquitous allergens. The intestinal microflora may play a particular role in this respect, as it is the major external driving force in the maturation of the immune system after birth, and animal experiments have shown it to be a prerequisite for normal development of oral tolerance. Recent studies have shown differences in the composition of the microflora between healthy and allergic infants in countries with a high and low prevalence of allergies and between healthy and allergic infants within such countries. These differences are apparent within the first week of life and thus precede clinical symptoms. The use of live microorganisms that might be beneficial to health has a long tradition and the safety is well documented. Very recently, several prospective intervention studies, modifying the gut flora from birth have yielded encouraging results and may suggest a new mode of primary prevention of allergy in the future.

positive: Increasing prevalence of Japanese cedar pollinosis: a meta-regression analysis. BACKGROUND: Japanese cedar pollinosis, caused by the pollen of the Japanese cedar tree (Cryptomeria japonica), is the commonest seasonal allergic disease in Japan. A number of epidemiological surveys have been reported on Japanese cedar pollinosis, but it has never been assessed systematically or quantitatively. To confirm the increasing prevalence of Japanese cedar pollinosis and related factors, we conducted a meta-regression analysis on population-based surveys in Japan. METHODS: We searched for data from population-based surveys in which serological methods were used to test all participants. Weighted regression of logit-transformed prevalence and sensitization rates were used to evaluate the effects of the year of survey, age, and degree of urbanization. We also analyzed the relationship between prevalence and sensitization rate. RESULTS: Thirty-eight reports with 27 subgroups for prevalence and 134 subgroups for sensitization rate were selected from the literature published in the years between 1986 and 2000. The Japanese cedar pollen sensitization rate was found to be significantly correlated with the year of survey, age, and degree of urbanization (adjusted R(2) = 0.55). The coefficient for the correlation between the prevalence and the sensitization rate revealed a statistically significant correlation (Pearson's r = 0.70, p < 0.001). CONCLUSIONS: The prevalence of Japanese cedar pollinosis among adolescents was predicted to be 28.7% in metropolitan areas and 24.5% in the general population in urban areas in the year 2004, derived from the estimated sensitization rate and the relationship between sensitization rate and prevalence. The prevalence of Japanese cedar pollinosis increased 2.6-fold between 1980 and 2000, and the prevalence differed considerably according to age and degree of urbanization. Copyright (c) 2005 S. Karger AG, Basel

positive: Alkylphenols--potential modulators of the allergic response. The prevalence of allergic diseases has increased in recent decades. Allergic diseases, particularly asthma, are complex diseases with strong gene-environment interactions. Epidemiological studies have identified a variety of risk factors for the development of allergic diseases. Among them, endocrine-disrupting chemicals (EDCs) play an important role in triggering or exacerbating these diseases. 4-Nonylphenol (NP) and 4-octylphenol (OP)--two major alkylphenols--have been recognized as common toxic and xenobiotic endocrine disrupters. Due to their low solubility, high hydrophobicity, and low estrogenic activity, they tend to accumulate in the human body and may be associated with the adverse effects of allergic diseases. Recently, new evidence has supported the importance of alkylphenols in the in vitro allergic response. This review focuses on the effects of alkylphenols on several key cell types in the context of allergic inflammation. Copyright © 2012. Published by Elsevier B.V.

positive: Trends in nutritional intake and serum cholesterol levels over 40 years in Tanushimaru, Japanese men. BACKGROUND: Rapid socioeconomic development in Japan since the beginning of the Seven Countries Study in 1958 has brought remarkable changes in lifestyle and dietary patterns. We investigated the relationship between time trends in nutrient intake and serum cholesterol levels in a Japanese cohort of the Seven Countries Study, in Tanushimaru, a typical farming town on Kyushu Island. METHODS: Subjects totaled 628 in 1958, 539 in 1977, 602 in 1982, 752 in 1989, and 402 in 1999, and all of the subjects were men aged 40-64 years. Eating patterns were evaluated by 24-hour dietary recall from 1958 through 1989, and by a food frequency questionnaire in 1999. We also measured serum cholesterol levels in each health examination. RESULTS: The total daily energy intake decreased from 2837 kcal in 1958 to 2202 kcal in 1999. The carbohydrate intake in percentage of total daily energy intake decreased markedly, from 84% in 1958 to 62% in 1999, in contrast to large increases during this period in protein intake (from 11% to 18%) and fat intake (from 5% to 20%). In proportion to the dramatic change in protein and fat intake, serum cholesterol levels showed large increases (from 152.5mg/dl to 194.2 mg/ dL). CONCLUSIONS: In spite of such big dietary changes toward a westernized diet, the incidence of coronary artery disease in a rural Japanese area remains low. However, careful surveillance is needed in the future because of the remarkably increasing intake of fats, especially saturated fatty acids.

positive: Dietary meat and fat intake and prevalence of rhinoconjunctivitis in pregnant Japanese women: baseline data from the Kyushu Okinawa Maternal and Child Health Study Background Dietary fat exerts numerous complex effects on proinflammatory and immunologic pathways. Several epidemiological studies have examined the relationships between intake of fatty acids and/or foods high in fat and allergic rhinitis, but have provided conflicting findings. The current cross-sectional study investigated such relationships in Japan. Methods Study subjects were 1745 pregnant women. The definition of rhinoconjunctivitis was based on criteria from the International Study of Asthma and Allergies in Childhood. Information on dietary factors was collected using a validated self-administered diet history questionnaire. Adjustment was made for age; gestation; region of residence; number of older siblings; number of children; smoking; secondhand smoke exposure at home and at work; family history of asthma, atopic eczema, and allergic rhinitis; household income; education; and body mass index. Results The prevalence of rhinoconjunctivitis in the past 12 months was 25.9%. Higher meat intake was significantly associated with an increased prevalence of rhinoconjunctivitis: the adjusted odds ratio between extreme quartiles was 1.71 (95% confidence interval: 1.25-2.35, P for trend = 0.002). No measurable association was found between fish intake and rhinoconjunctivitis. Intake of total fat, saturated fatty acids, monounsaturated fatty acids, n-3 polyunsaturated fatty acids, α-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, n-6 polyunsaturated fatty acids, linoleic acid, arachidonic acid, and cholesterol and the ratio of n-3 to n-6 polyunsaturated fatty acid intake were not evidently related to the prevalence of rhinoconjunctivitis. Conclusions The current results suggest that meat intake may be positively associated with the prevalence of rhinoconjunctivitis in young adult Japanese women.

positive: Comparison of the cytotoxic and mutagenic potential of liquid smoke food flavourings, cigarette smoke condensate and wood smoke condensate. Although products of pyrolysis are often cytotoxic and mutagenic, the relationship between the type of material pyrolysed and the toxicity of the resulting pyrolysis products is poorly understood. The objective of this study was to evaluate and compare the cytotoxicity and mutagenicity of several types of common pyrolysis products. The cytotoxicity and mutagenicity of these products were assessed by using neutral red uptake and Ames mutagenicity assays, respectively. The biological activities of four liquid smoke food flavourings (LSF) were compared with two other pyrolysis-derived materials; cigarette smoke condensate (CSC) and a wood smoke condensate (WSC). Results indicated all of the mixtures exhibited a concentration-dependent cytotoxic response. The CSC and WSC were less cytotoxic than three of the LSFs, but more cytotoxic than one of the brands. The CSC was mutagenic in two Salmonella strains; however, none of the LSFs or WSC was mutagenic using TA98, and only three of the LSFs were positive with TA100. The six pyrolysis-derived materials evaluated in this study showed differing patterns and magnitudes of cytotoxicity and mutagenicity. These results indicate that the cytotoxicity and mutagenicity of complex mixtures derived from pyrolysis products are affected by the type of material pyrolysed and/or the method used to prepare the mixture. The cytotoxic potential of some commercial smoke flavourings is greater than cigarette smoke condensate and several of the food flavourings are mutagenic in one Salmonella strain.

positive: Mutagenicity testing in the Salmonella typhimurium assay of phenolic compounds and phenolic fractions obtained from smokehouse smoke condensates. Smokehouse smoke, which is used for flavouring meat products, was investigated for its mutagenic activity in the Salmonella typhimurium assay. We were chiefly concerned with the fractions free of polycyclic aromatic hydrocarbons but containing phenol compounds, which are responsible for the preservative and aromatizing properties of the smoke. The most abundantly occurring phenol compounds (phenol, cresols, 2,4-dimethylphenol, brenzcatechine, syringol, eugenol, vanilline and guaiacol) gave negative results when they were tested for mutagenicity at five concentrations up to 5000 micrograms/plate, with and without S-9 mix, using five strains of S. typhimurium. Even when phenol was further investigated in a variety of test conditions, no induction of his+ revertants was observed. When smokehouse smoke was condensed and fractionated the majority of the various phenolic fractions also gave negative results when tested at five concentrations using five strains of S. typhimurium. However there was a slight increase in the number of revertants in a few cases. The presence in the phenolic fractions of very small amounts of mutagenic impurities, the nature of which needs further investigation, cannot be excluded. These results support the further development of non-hazardous smoke-aroma preparations, based on the phenolic components of smokehouse smoke.

positive: Biological Clues to Potent DNA-Damaging Activities in Food and Flavoring Population differences in age-related diseases and cancer could stem from differences in diet. To characterize DNA strand-breaking activities in selected foods/beverages, flavorings, and some of their constituent chemicals, we used p53R cells, a cellular assay sensitive to such breaks. Substances testing positive included reference chemicals: quinacrine (peak response, 51X) and etoposide (33X); flavonoids: EGCG (19X), curcumin (12X), apigenin (9X), and quercetin (7X); beverages: chamomile (11X), green (21X), and black tea (26X) and coffee (3 to 29X); and liquid smoke (4 to 28X). Damage occurred at dietary concentrations: etoposide near 5 μg/ml produced responses similar to a 1:1000 dilution of liquid smoke, a 1:20 dilution of coffee, and a 1:5 dilution of tea. Pyrogallol-related chemicals and tannins are present in dietary sources and individually produced strong activity: pyrogallol (30X), 3-methoxycatechol (25X), gallic acid (21X), and 1,2,4-benzenetriol (21X). From structure-activity relationships, high activities depended on specific orientations of hydroxyls on the benzene ring. Responses accompanied cellular signals characteristic of DNA breaks such as H2AX phosphorylation. Breaks were also directly detected by comet assay. Cellular toxicological effects of foods and flavorings could guide epidemiologic and experimental studies of potential disease risks from DNA strand-breaking chemicals in diets.

positive: Polycyclic aromatic hydrocarbons in smoked food products and commercial liquid smoke flavourings. Smoked foods including turkey, pork, chicken, beef and fish products were screened for the presence of carcinogenic and non-carcinogenic polycyclic aromatic hydrocarbons (PAHs). Eighteen commercial liquid smoke flavourings and seasonings were also analysed. Total PAH concentrations in smoked meat products ranged from 2.6 micrograms/kg in a cooked ham sample to 29.8 micrograms/kg in grilled pork chops, while those in fish products ranged from 9.3 micrograms/kg in smoked shrimp to 86.6 micrograms/kg in smoked salmon. Total concentrations of the carcinogenic PAHs (benzo[a]anthracene, benzo[b]fluoranthene, benzo[a]pyrene, dibenzo[a,h]anthracene, and indeno[1,2,3-c,d]pyrene) ranged from non-detectable in several meat products to 7.4 micrograms/kg in grilled pork chops, and from 0.2 micrograms/kg in trout to 16.0 micrograms/kg in salmon. In liquid smoke flavourings and seasonings, total PAH concentrations ranged from 6.3 to 43.7 micrograms/kg, with the carcinogenic PAHs ranging from 0.3 to 10.2 micrograms/kg.

positive: Commercial hickory-smoke flavouring is a human lymphoblast mutagen but does not induce lung adenomas in newborn mice. Commercial aqueous wood-smoke flavouring induced significant increases in the 6-thioguanine resistance mutation frequency of TK6 human lymphoblasts at 0.1 microliter flavouring/ml of cell suspension. This corresponds to 6 micrograms/ml of dissolved 'solids' as determined by fully drying the aqueous flavouring in a vacuum desiccator. In AHH-1 human lymphoblasts, which contain a cytochrome P-450 monooxygenase system, mutations were induced at 0.3 microliter/ml, corresponding to 18 microliters/ml of dissolved 'solids'. The flavouring did not induce 8-azaguanine resistant mutations in Salmonella typhimurium at concentrations up to 1.5 microliter/ml. At higher concentrations the flavouring was toxic to bacteria. The flavouring did not induce lung adenomas or other tumours in newborn mice when injected ip with total doses of up to 26 microliters over a 3-wk period. Toxicity to the kidney, colon and rectum was observed in some mice at 15 wk of age.

positive: TOXICITY AND CARCINOGENICITY STUDIES OF 4-METHYLIMIDAZOLE IN F344/N RATS AND B6C3F1 MICE 4-Methylimidazole (4MI) is used in the manufacture of pharmaceuticals, photographic chemicals, dyes and pigments, cleaning and agricultural chemicals, and rubber. It has been identified as a by-product of fermentation in foods and has been detected in mainstream and side stream tobacco smoke. 4MI was studied because of its high potential for human exposure. Groups of 50 male and 50 female F344/N rats were fed diets containing 0-, 625-, 1,250-, or 2,500-ppm 4MI (males) or 0-, 1,250-, 2,500-, or 5,000-ppm 4MI (females) for 106 weeks. Based on the food consumption the calculated average daily doses were approximately 30, 55, or 115 mg 4MI/kg body weight to males and 60, 120, or 250 mg 4MI/kg to females. Survival of all exposed groups of males and females was similar to that of the control groups. Mean body weights of males in the 1,250- and 2,500-ppm groups and females in the 2,500- and 5,000-ppm groups were less than those of the control groups throughout the study. Feed consumption by 5,000-ppm females was less than that by the controls. Clonic seizures, excitability, hyperactivity, and impaired gait were observed primarily in 2,500- and 5,000-ppm females. The incidence of mononuclear cell leukemia in the 5,000-ppm females was significantly greater than that in the controls. The incidences of hepatic histiocytosis, chronic inflammation, and focal fatty change were significantly increased in all exposed groups of male and female rats. The incidences of hepatocellular eosinophilic and mixed cell foci were significantly increased in 2,500-ppm males and 5,000-ppm females. Groups of 50 male and 50 female B6C3F1 mice were fed diets containing 0-, 312-, 625-, or 1,250-ppm 4MI for 106 weeks. Based on the food consumption the calculated average daily doses were approximately 40, 80, or 170 mg 4MI/kg body weight to males and females. Survival of all exposed groups of males and females was similar to that of the control groups. Mean body weights of males and females in the 1,250-ppm groups and that in the 312- and 625-ppm females were less than those of the control groups. Feed consumption by exposed groups of male and female mice was similar to that by the controls. The incidences of alveolar/bronchiolar adenoma in all exposed groups of females, alveolar/bronchiolar carcinoma in 1,250-ppm males, and alveolar/bronchiolar adenoma or carcinoma (combined) in 1,250-ppm males and 625- and 1,250-ppm females were significantly greater than those in the control groups. The incidence of alveolar epithelial hyperplasia was significantly increased in the 1,250-ppm females. 4MI is carcinogenic inducing alveolar/bronchiolar adenoma and carcinoma in male and female mice. 4MI may also induce mononuclear cell leukemia in female rats.

positive: Carcinogenicity and regulation of caramel colorings. 2- and 4-methylimidazoles are present as contaminants in caramel colorings manufactured with ammonia catalysts. Both contaminants have been shown to induce cancer in animals and may be present in caramel colorings in amounts that exceed federal guidelines. California requires warning notices on products that could lead to consumption of more than 30 micrograms per day. The US Food and Drug Administration should bar the use of excessively contaminated caramel coloring in food.

positive: Detection of increased choline compounds with proton nuclear magnetic resonance spectroscopy subsequent to malignant transformation of human prosta... In this study, a panel of normal human prostate cells (HPCs) and tumor cells derived from metastases were studied by (1)H NMR spectroscopy to determine whether the malignant transformation of HPCs results in the elevation of choline compounds. Although an elevated choline signal has been observed previously in clinical studies, the contribution of the different Cho compounds to this elevation, as well as their quantification, has not been established until now. Here we have shown that HPCs derived from metastases exhibit significantly higher phosphocholine as well as glycerophosphocholine levels compared with normal prostate epithelial and stromal cells. Thus the elevation of the choline peak observed clinically in prostate cancer is attributable to an alteration of phospholipid metabolism and not simply to increased cell density, doubling time, or other nonspecific effects. Androgen deprivation of the androgen receptor-positive cell lines resulted in a significant increase of choline compounds after chronic androgen deprivation of the LNCaP cell line and in a decrease of choline compounds after a more acute androgen deprivation of the LAPC-4 cell line. These data strongly support the use of proton magnetic resonance spectroscopic imaging to detect the presence of prostate cancer for diagnosis, to detect response subsequent to androgen ablation therapy, and to detect recurrence.

positive: Choline intake and risk of lethal prostate cancer: incidence and survival Background: Meat, milk, and eggs have been inconsistently associated with the risk of advanced prostate cancer. These foods are sources of choline—a nutrient that may affect prostate cancer progression through cell membrane function and one-carbon metabolism. No study has examined dietary choline and the risk of lethal prostate cancer. Objective: Our objective was to examine whether dietary choline, choline-containing compounds, and betaine (a choline metabolite) increase the risk of lethal prostate cancer. Design: We prospectively examined the intake of these nutrients and the risk of lethal prostate cancer among 47,896 men in the Health Professionals Follow-Up Study. In a case-only survival analysis, we examined the postdiagnostic intake of these nutrients and the risk of lethal prostate cancer among 4282 men with an initial diagnosis of nonmetastatic disease during follow-up. Diet was assessed with a validated questionnaire 6 times during 22 y of follow-up. Results: In the incidence analysis, we observed 695 lethal prostate cancers during 879,627 person-years. Men in the highest quintile of choline intake had a 70% increased risk of lethal prostate cancer (HR: 1.70; 95% CI: 1.18, 2.45; P-trend = 0.005). In the case-only survival analysis, we observed 271 lethal cases during 33,679 person-years. Postdiagnostic choline intake was not statistically significantly associated with the risk of lethal prostate cancer (HR for quintile 5 compared with quintile 1: 1.69; 95% CI: 0.93, 3.09; P-trend = 0.20). Conclusion: Of the 47,896 men in our study population, choline intake was associated with an increased risk of lethal prostate cancer.

positive: Intakes of meat, fish, poultry, and eggs and risk of prostate cancer progression Background: Processed meat and fish have been shown to be associated with the risk of advanced prostate cancer, but few studies have examined diet after prostate cancer diagnosis and risk of its progression. Objective: We examined the association between postdiagnostic consumption of processed and unprocessed red meat, fish, poultry, and eggs and the risk of prostate cancer recurrence or progression. Design: We conducted a prospective study in 1294 men with prostate cancer, without recurrence or progression as of 2004–2005, who were participating in the Cancer of the Prostate Strategic Urologic Research Endeavor and who were followed for an average of 2 y. Results: We observed 127 events (prostate cancer death or metastases, elevated prostate-specific antigen concentration, or secondary treatment) during 2610 person-years. Intakes of processed and unprocessed red meat, fish, total poultry, and skinless poultry were not associated with prostate cancer recurrence or progression. Greater consumption of eggs and poultry with skin was associated with 2-fold increases in risk in a comparison of extreme quantiles: eggs [hazard ratio (HR): 2.02; 95% CI: 1.10, 3.72; P for trend = 0.05] and poultry with skin (HR: 2.26; 95% CI: 1.36, 3.76; P for trend = 0.003). An interaction was observed between prognostic risk at diagnosis and poultry. Men with high prognostic risk and a high poultry intake had a 4-fold increased risk of recurrence or progression compared with men with low/intermediate prognostic risk and a low poultry intake (P for interaction = 0.003). Conclusions: Our results suggest that the postdiagnostic consumption of processed or unprocessed red meat, fish, or skinless poultry is not associated with prostate cancer recurrence or progression, whereas consumption of eggs and poultry with skin may increase the risk.

positive: Egg, red meat, and poultry intake and risk of lethal prostate cancer in the prostate specific antigen-era: incidence and survival Red and processed meat may increase risk of advanced prostate cancer. Data on post-diagnostic diet and prostate cancer are sparse, but post-diagnostic intake of poultry with skin and eggs may increase risk of disease progression. Therefore, we prospectively examined total, unprocessed, and processed red meat, poultry, and eggs in relation to risk of lethal prostate cancer (e.g. men without cancer at baseline who developed distant organ metastases or died from prostate cancer during follow-up) among 27, 607 men followed from 1994–2008. We also performed a case-only survival analysis to examine post-diagnostic consumption of these foods and risk of lethal prostate cancer among the 3,127 men initially diagnosed with non-metastatic prostate cancer during follow-up. In the incidence analysis, we observed 199 events during 306,715 person-years. Men who consumed 2.5 or more eggs per week had an 81% increased risk of lethal prostate cancer compared to men who consumed less than 0.5 eggs per week (HR: 1.81; 95% confidence interval (CI): 1.13, 2.89; p-trend: 0.01). In the case-only survival analysis, we observed 123 events during 19,354 person-years. There were suggestive, but not statistically significant, positive associations between post-diagnostic poultry (HR ≥3.5 vs. <1.5 servings per week: 1.69; 95%CI: 0.96, 2.99; p-trend: 0.07) and post-diagnostic processed red meat (HR ≥3 vs. <0.5 servings per week: 1.45; 95%CI: 0.73, 2.87; p-trend: 0.08) and risk of progression of localized prostate cancer to lethal disease. In conclusion, consumption of eggs may increase risk of developing a lethal-form of prostate cancer among healthy men.

positive: Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk Context Multiple studies have linked alcohol consumption to breast cancer risk, but the risk of lower levels of consumption has not been well quantified. In addition, the role of drinking patterns (i.e. frequency of drinking and “binge” drinking) and consumption at different times of adult life are not well understood. Objective To evaluate the association of breast cancer with alcohol consumption during adult life, including quantity, frequency, and age at consumption. Design, Setting, and Participants Prospective observational study of 105,986 women enrolled in the Nurses’ Health Study followed from 1980 until 2008 with early adult and eight updated alcohol assessments during this time. Main Outcome Measures Relative risks of developing invasive breast cancer. Results 7690 cases developed during 2.4 million person-years of follow-up. Increasing alcohol consumption was associated with increased breast cancer risk that was statistically significant at levels as low as 5.0-9.9 gm/day, equivalent to 3-6 drinks/week (RR 1.15 (95% CI 1.06-1.24) 332 cases/100,000 person-years). After controlling for cumulative alcohol intake, binge drinking, but not frequency of drinking, was associated with breast cancer risk. Alcohol intake both earlier and later in adult life was independently associated with risk. Conclusion Low levels of alcohol consumption were associated with a small increase in breast cancer risk, with the most consistent measure being cumulative alcohol intake throughout adult life. Alcohol intake both earlier and later in adult life was independently associated with risk.

positive: A single sip of a strong alcoholic beverage causes exposure to carcinogenic concentrations of acetaldehyde in the oral cavity. The aim of this study was to explore oral exposure to carcinogenic (group 1) acetaldehyde after single sips of strong alcoholic beverages containing no or high concentrations of acetaldehyde. Eight volunteers tasted 5 ml of ethanol diluted to 40 vol.% with no acetaldehyde and 40 vol.% calvados containing 2400 μM acetaldehyde. Salivary acetaldehyde and ethanol concentrations were measured by gas chromatography. The protocol was repeated after ingestion of ethanol (0.5 g/kg body weight). Salivary acetaldehyde concentration was significantly higher after sipping calvados than after sipping ethanol at 30s both with (215 vs. 128 μmol/l, p<0.05) and without (258 vs. 89 μmol/l, p<0.05) alcohol ingestion. From 2 min onwards there were no significant differences in the decreasing salivary acetaldehyde concentration, which remained above the level of carcinogenicity still at 10 min. The systemic alcohol distribution from blood to saliva had no additional effect on salivary acetaldehyde after sipping of the alcoholic beverages. Carcinogenic concentrations of acetaldehyde are produced from ethanol in the oral cavity instantly after a small sip of strong alcoholic beverage, and the exposure continues for at least 10 min. Acetaldehyde present in the beverage has a short-term effect on total acetaldehyde exposure. Copyright © 2011 Elsevier Ltd. All rights reserved.

positive: Salivary acetaldehyde increase due to alcohol-containing mouthwash use: a risk factor for oral cancer. Increasing evidence suggests that acetaldehyde, the first and genotoxic metabolite of ethanol, mediates the carcinogenicity of alcoholic beverages. Ethanol is also contained in a number of ready-to-use mouthwashes typically between 5 and 27% vol. An increased risk of oral cancer has been discussed for users of such mouthwashes; however, epidemiological evidence had remained inconclusive. This study is the first to investigate acetaldehyde levels in saliva after use of alcohol-containing mouthwashes. Ready-to-use mouthwashes and mouthrinses (n = 13) were rinsed in the mouth by healthy, nonsmoking volunteers (n = 4) as intended by the manufacturers (20 ml for 30 sec). Saliva was collected at 0.5, 2, 5 and 10 min after mouthwash use and analyzed using headspace gas chromatography. The acetaldehyde content in the saliva was 41 +/- 15 microM, range 9-85 microM (0.5 min), 52 +/- 14 microM, range 11-105 microM (2 min), 32 +/- 7 microM, range 9-67 microM (5 min) and 15 +/- 7 microM, range 0-37 microM (10 min). The contents were significantly above endogenous levels and corresponding to concentrations normally found after alcoholic beverage consumption. A twice-daily use of alcohol-containing mouthwashes leads to a systemic acetaldehyde exposure of 0.26 microg/kg bodyweight/day on average, which corresponds to a lifetime cancer risk of 3E-6. The margin of exposure was calculated to be 217,604, which would be seen as a low public health concern. However, the local acetaldehyde contents in the saliva are reaching concentrations associated with DNA adduct formation and sister chromatid exchange in vitro, so that concerns for local carcinogenic effects in the oral cavity remain.

positive: Environmental exposure to pesticides and cancer risk in multiple human organ systems. There is growing evidence on the association between long-term exposure to pesticides in occupational settings and an elevated rate of chronic diseases, including different types of cancer. However, data on non-occupational exposures are scarce to draw any conclusion. The objective of this study was to investigate the putative associations of environmental pesticide exposures in the general population with several cancer sites and to discuss potential carcinogenic mechanisms by which pesticides develop cancer. A population-based case-control study was conducted among people residing in 10 Health districts from Andalusia (South Spain) to estimate the risk of cancer at different sites. Health districts were categorized into areas of high and low environmental pesticide exposure based on two quantitative criteria: number of hectares devoted to intensive agriculture and pesticide sales per capita. The study population consisted of 34,205 cancer cases and 1,832,969 age and health district matched controls. Data were collected by computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of cancer at most organ sites were significantly higher in districts with greater pesticide use related to those with lower pesticide use. Conditional logistic regression analyses showed that the population living in areas with high pesticide use had an increased risk of cancer at all sites studied (odds ratios between 1.15 and 3.45) with the exception of Hodgkin's disease and non-Hodgkin lymphoma. The results of this study support and extend previous evidence from occupational studies indicating that environmental exposure to pesticides may be a risk factor for different types of cancer at the level of the general population. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

positive: Organic food: buying more safety or just peace of mind? A critical review of the literature. Consumer concern over the quality and safety of conventional food has intensified in recent years, and primarily drives the increasing demand for organically grown food, which is perceived as healthier and safer. Relevant scientific evidence, however, is scarce, while anecdotal reports abound. Although there is an urgent need for information related to health benefits and/or hazards of food products of both origins, generalized conclusions remain tentative in the absence of adequate comparative data. Organic fruits and vegetables can be expected to contain fewer agrochemical residues than conventionally grown alternatives; yet, the significance of this difference is questionable, inasmuch as actual levels of contamination in both types of food are generally well below acceptable limits. Also, some leafy, root, and tuber organic vegetables appear to have lower nitrate content compared with conventional ones, but whether or not dietary nitrate indeed constitutes a threat to human health is a matter of debate. On the other hand, no differences can be identified for environmental contaminants (e.g. cadmium and other heavy metals), which are likely to be present in food from both origins. With respect to other food hazards, such as endogenous plant toxins, biological pesticides and pathogenic microorganisms, available evidence is extremely limited preventing generalized statements. Also, results for mycotoxin contamination in cereal crops are variable and inconclusive; hence, no clear picture emerges. It is difficult, therefore, to weigh the risks, but what should be made clear is that 'organic' does not automatically equal 'safe.' Additional studies in this area of research are warranted. At our present state of knowledge, other factors rather than safety aspects seem to speak in favor of organic food.

positive: Pesticides and human chronic diseases: evidences, mechanisms, and perspectives. Along with the wide use of pesticides in the world, the concerns over their health impacts are rapidly growing. There is a huge body of evidence on the relation between exposure to pesticides and elevated rate of chronic diseases such as different types of cancers, diabetes, neurodegenerative disorders like Parkinson, Alzheimer, and amyotrophic lateral sclerosis (ALS), birth defects, and reproductive disorders. There is also circumstantial evidence on the association of exposure to pesticides with some other chronic diseases like respiratory problems, particularly asthma and chronic obstructive pulmonary disease (COPD), cardiovascular disease such as atherosclerosis and coronary artery disease, chronic nephropathies, autoimmune diseases like systemic lupus erythematous and rheumatoid arthritis, chronic fatigue syndrome, and aging. The common feature of chronic disorders is a disturbance in cellular homeostasis, which can be induced via pesticides' primary action like perturbation of ion channels, enzymes, receptors, etc., or can as well be mediated via pathways other than the main mechanism. In this review, we present the highlighted evidence on the association of pesticide's exposure with the incidence of chronic diseases and introduce genetic damages, epigenetic modifications, endocrine disruption, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress and unfolded protein response (UPR), impairment of ubiquitin proteasome system, and defective autophagy as the effective mechanisms of action. Copyright © 2013 Elsevier Inc. All rights reserved.

positive: Formation of dioxins during exposure of pesticide formulations to sunlight. Chlorinated pesticides can contain impurities of dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), and their precursors, as a result of various manufacturing processes and conditions. As precursor formation of PCDD/Fs can also be mediated by ultraviolet light (UV), this study investigated whether PCDD/Fs are formed when currently used pesticides are exposed to natural sunlight. Formulations containing pentachloronitrobenzene (PCNB; n=2) and 2,4-dichlorophenoxyacetic acid (2,4-D; n=1) were exposed to sunlight in quartz tubes, and the concentration of 93 PCDD/F congeners were monitored over time. Considerable formation of PCDD/Fs was observed in both PCNB formulations (by up to 5600%, to a maximum concentration of 57000 μg ∑PCDD/F kg(-1)) as well as the 2,4-D formulation (by 3000%, to 140 μg ∑PCDD/F kg(-1)). TEQ also increased by up to 980%, to a maximum concentration of 28 μg kg(-1) in PCNB, but did not change in the 2,4-D formulation. Assuming similar yields as observed in the present study as a worst case scenario the use of PCNB in Australia may result in the formation of 155 g TEQ annum(-1), contributed primarily by OCDD formation. This warrants detailed evaluations on the contemporary release of PCDD/Fs to the environment after the use of pesticides. Changes in congener profiles (including the ratio of PCDDs to PCDFs (DF ratio)) suggest that pesticide sources of PCDD/Fs after sunlight exposure may not be recognized based on matching source fingerprints established from manufacturing impurities. These changes also provide preliminary insights into the possible formation routes and types of precursors involved. Copyright © 2012 Elsevier Ltd. All rights reserved.

positive: Risk perceptions and food choice: an exploratory analysis of organic- versus conventional-produce buyers. Consumer choice between organically (without pesticides) and conventionally grown produce is examined. Exploratory focus-group discussions and questionnaires (N = 43) suggest that individuals who purchase organically grown produce believe it is substantially less hazardous than the conventional alternative and are willing to pay significant premiums to obtain it (a median 50% above the cost of conventional produce). The value of risk reduction implied by this incremental willingness to pay is not high relative to estimates for other risks, since the perceived risk reduction is relatively large. Organic-produce consumers also appear more likely than conventional-produce consumers to mitigate other ingestion-related risks (e.g., contaminated drinking water) but less likely to use automobile seatbelts.

positive: Perceived risks of conventional and organic produce: pesticides, pathogens, and natural toxins. Public risk perceptions and demand for safer food are important factors shaping agricultural production practices in the United States. Despite documented food safety concerns, little attempt has been made to elicit consumers' subjective risk judgments for a range of food safety hazards or to identify factors most predictive of perceived food safety risks. In this study, over 700 conventional and organic fresh produce buyers in the Boston area were surveyed for their perceived food safety risks. Survey results showed that consumers perceived relatively high risks associated with the consumption and production of conventionally grown produce compared with other public health hazards. For example, conventional and organic food buyers estimated the median annual fatality rate due to pesticide residues on conventionally grown food to be about 50 per million and 200 per million, respectively, which is similar in magnitude to the annual mortality risk from motor vehicle accidents in the United States. Over 90% of survey respondents also perceived a reduction in pesticide residue risk associated with substituting organically grown produce for conventionally grown produce, and nearly 50% perceived a risk reduction due to natural toxins and microbial pathogens. Multiple regression analyses indicate that only a few factors are consistently predictive of higher risk perceptions, including feelings of distrust toward regulatory agencies and the safety of the food supply. A variety of factors were found to be significant predictors of specific categories of food hazards, suggesting that consumers may view food safety risks as dissimilar from one another. Based on study findings, it is recommended that future agricultural policies and risk communication efforts utilize a comparative risk approach that targets a range of food safety hazards.

positive: Higher antioxidant and lower cadmium concentrations and lower incidence of pesticide residues in organically grown crops: a systematic literature review and meta-analyses Demand for organic foods is partially driven by consumers' perceptions that they are more nutritious. However, scientific opinion is divided on whether there are significant nutritional differences between organic and non-organic foods, and two recent reviews have concluded that there are no differences. In the present study, we carried out meta-analyses based on 343 peer-reviewed publications that indicate statistically significant and meaningful differences in composition between organic and non-organic crops/crop-based foods. Most importantly, the concentrations of a range of antioxidants such as polyphenolics were found to be substantially higher in organic crops/crop-based foods, with those of phenolic acids, flavanones, stilbenes, flavones, flavonols and anthocyanins being an estimated 19 (95 % CI 5, 33) %, 69 (95 % CI 13, 125) %, 28 (95 % CI 12, 44) %, 26 (95 % CI 3, 48) %, 50 (95 % CI 28, 72) % and 51 (95 % CI 17, 86) % higher, respectively. Many of these compounds have previously been linked to a reduced risk of chronic diseases, including CVD and neurodegenerative diseases and certain cancers, in dietary intervention and epidemiological studies. Additionally, the frequency of occurrence of pesticide residues was found to be four times higher in conventional crops, which also contained significantly higher concentrations of the toxic metal Cd. Significant differences were also detected for some other (e.g. minerals and vitamins) compounds. There is evidence that higher antioxidant concentrations and lower Cd concentrations are linked to specific agronomic practices (e.g. non-use of mineral N and P fertilisers, respectively) prescribed in organic farming systems. In conclusion, organic crops, on average, have higher concentrations of antioxidants, lower concentrations of Cd and a lower incidence of pesticide residues than the non-organic comparators across regions and production seasons.

positive: Estimation of cancer risks and benefits associated with a potential increased consumption of fruits and vegetables. The current paper provides an analysis of the potential number of cancer cases that might be prevented if half the U.S. population increased its fruit and vegetable consumption by one serving each per day. This number is contrasted with an upper-bound estimate of concomitant cancer cases that might be theoretically attributed to the intake of pesticide residues arising from the same additional fruit and vegetable consumption. The cancer prevention estimates were derived using a published meta-analysis of nutritional epidemiology studies. The cancer risks were estimated using U.S. Environmental Protection Agency (EPA) methods, cancer potency estimates from rodent bioassays, and pesticide residue sampling data from the U.S. Department of Agriculture (USDA). The resulting estimates are that approximately 20,000 cancer cases per year could be prevented by increasing fruit and vegetable consumption, while up to 10 cancer cases per year could be caused by the added pesticide consumption. These estimates have significant uncertainties (e.g., potential residual confounding in the fruit and vegetable epidemiologic studies and reliance on rodent bioassays for cancer risk). However, the overwhelming difference between benefit and risk estimates provides confidence that consumers should not be concerned about cancer risks from consuming conventionally-grown fruits and vegetables. Copyright © 2012 Elsevier Ltd. All rights reserved.

positive: Cadmium in organic and conventional pig production. The main sources of cadmium (Cd) input to soils have been phosphate fertilizers and deposition from air. In organic farming, phosphate fertilizers are not used, which may in the long term result in lower Cd levels. In the present study, feed, kidney, liver, and manure from growing/finishing pigs raised conventionally and organically on the same farm were microwave-digested and analyzed for Cd by graphite furnace atomic absorption spectrometry. Cd was also analyzed in soil and water. A quality control program was included. The organic pigs (n = 40) were raised outdoors and fed an organic feed; the conventional pigs (n = 40) were raised indoors and given a conventional feed. The Cd levels in organic and conventional feed were 39.9 microg/kg and 51.8 microg/kg, respectively. Organic feed contained 2% potato protein, which contributed 17% of the Cd content. Conventional feed contained 5% beet fiber, which contributed 38% of total Cd content. Both feeds contained vitamin-mineral mixtures with high levels of Cd: 991 microg/kg in organic and 589 microg/kg in conventional feed. There was a significant negative linear relationship between Cd concentration in kidney and kidney weight. There was no significant difference in liver Cd levels between organic and conventional pigs and the mean +/- SD was 15.4 +/- 3.0. In spite of the lower level of Cd in the organic feed, the organic pigs had significantly higher levels in kidneys than the conventional pigs, 96.1 +/- 19.5 microg/kg wet weight (mean +/- SD; n = 37) and 84.0 +/- 17.6 microg/kg wet weight (n = 40), respectively. Organic pigs had higher Cd levels in manure, indicating a higher Cd exposure from the environment, such as ingestion of soil. Differences in feed compositions and bioavailability of Cd from the feed components may also explain the different kidney levels of Cd.

positive: The sensitivity of the child to sex steroids: possible impact of exogenous estrogens. The current trends of increasing incidences of testis, breast and prostate cancers are poorly understood, although it is assumed that sex hormones play a role. Disrupted sex hormone action is also believed to be involved in the increased occurrence of genital abnormalities among newborn boys and precocious puberty in girls. In this article, recent literature on sex steroid levels and their physiological roles during childhood is reviewed. It is concluded that (i) circulating levels of estradiol in prepubertal children are lower than originally claimed; (ii) children are extremely sensitive to estradiol and may respond with increased growth and/or breast development even at serum levels below the current detection limits; (iii) no threshold has been established, below which no hormonal effects can be seen in children exposed to exogenous steroids or endocrine disruptors; (iv) changes in hormone levels during fetal and prepubertal development may have severe effects in adult life and (v) the daily production rates of sex steroids in children estimated by the Food and Drug Administration in 1999 and still used in risk assessments are highly overestimated and should be revised. Because no lower threshold for estrogenic action has been established, caution should be taken to avoid unnecessary exposure of fetuses and children to exogenous sex steroids and endocrine disruptors, even at very low levels.

positive: Occurrence of estrogen hormones in biosolids, animal manure and mushroom compost. The presence of natural estrogen hormones as trace concentrations in the environment has been reported by many researchers and is of growing concern due to its possible adverse effects on the ecosystem. In this study, municipal biosolids, poultry manure (PM) and cow manure (CM), and spent mushroom compost (SMC) were analyzed for the presence of seven estrogen hormones. 17α-estradiol, 17β-estradiol, 17α-dihydroequilin, and estrone were detected in the sampled biosolids and manures at concentrations ranging from 6 to 462 ng/g of dry solids. 17α-estradiol, 17β-estradiol, and estrone were also detected in SMC at concentrations ranging from 4 to 28 ng/g of dry solids. Desorption experiments were simulated in the laboratory using deionized water (milli-Q), and the aqueous phase was examined for the presence of estrogen hormones to determine their desorption potential. Very low desorption of 0.4% and 0.2% estrogen hormones was observed from municipal biosolids and SMC, respectively. An estimate of total estrogen contribution from different solid waste sources is reported. Animal manures (PM and CM) contribute to a significant load of estrogen hormones in the natural environment.

positive: Oestrogen levels in serum and urine of premenopausal women eating low and high amounts of meat. OBJECTIVE: Based on the hypothesis that high-meat diets may increase breast cancer risk through hormonal pathways, the present analysis compared oestrogens in serum and urine by meat-eating status. DESIGN: Intervention with repeated measures. SETTING: Two randomized soya trials (BEAN1 and BEAN2) among premenopausal healthy women. SUBJECTS: BEAN1 participants completed seven unannounced 24 h dietary recalls and donated five blood and urine samples over 2 years. BEAN2 women provided seven recalls and three samples over 13 months. Serum samples were analysed for oestrone (E₁) and oestradiol (E₂) using RIA. Nine oestrogen metabolites were measured in urine by LC-MS. Semi-vegetarians included women who reported consuming <30 g of red meat, poultry and fish daily, and pescatarians those who reported consuming <20 g of meat/poultry but >10 g of fish daily. All other women were classified as non-vegetarians. We applied mixed models to compute least-square means by vegetarian status adjusted for potential confounders. RESULTS: The mean age of the 272 participants was 41·9 (SD 4·5) years. Serum E₁ (85 v. 100 pg/ml, P = 0·04) and E₂ (140 v. 154 pg/ml, P = 0·04) levels were lower in the thirty-seven semi-vegetarians than in the 235 non-vegetarians. The sum of the nine urinary oestrogen metabolites (183 v. 200 pmol/mg creatinine, P = 0·27) and the proportions of individual oestrogens and pathways did not differ by meat-eating status. Restricting the models to the samples collected during the luteal phase strengthened the associations. CONCLUSIONS: Given the limitations of the study, the lower levels of serum oestrogens in semi-vegetarians than non-vegetarians need confirmation in larger populations.

positive: Occurrence, fate, and biodegradation of estrogens in sewage and manure. The estrogens estrone (E1), 17alpha-estradiol (E2alpha), 17beta-estradiol (E2beta), and estriol (E3) are natural sex hormones produced by humans and animals. In addition, there are some synthetic estrogens, such as 17alpha-ethinylestradiol (EE2), used for contraception purposes. These compounds are able to produce endocrine disruption in living organisms at nanogram-per-liter levels. In both humans and animals, estrogens are excreted in urine and feces, reaching the natural environment through discharge from sewage treatment plants (STP) and manure disposal units. In STPs, hormone removal depends on the type of treatment process and on different parameters such as the hydraulic and sludge retention times. Thus, hormone elimination rates vary from 0% to 90% in different STPs. Animals are also an important source of estrogens in the environment. Indeed, animals produce high concentrations of hormones which will end up in manure which is typically spread on land. Hence, waste-borne animal hormones may transfer these pollutants to the soil. The purpose of this review is to highlight the significance for both health and the environment of pollution by estrogens and critically review the existing knowledge on their fate and removal in different treatment processes. Relevant information on the microbial degradation of hormones and metabolic pathways is also included.

positive: Development of an LC-MS/MS method to quantify sex hormones in bovine milk and influence of pregnancy in their levels. Hormones work in harmony in the body, and this status must be maintained to avoid metabolic disequilibrium and the subsequent illness. Besides, it has been reported that exogenous steroids (presence in the environment and food products) influence the development of several important illnesses in humans. Endogenous steroid hormones in food of animal origin are unavoidable as they occur naturally in these products. The presence of hormones in food has been connected with several human health problems. Bovine milk contains considerable quantities of hormones and it is of particular concern. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, based on hydroxylamine derivatisation, has been developed and validated for the quantification of six sex hormones in milk [pregnenolone (P₅), progesterone (P₄), estrone (E₁), testosterone (T), androstenedione (A) and dehydroepiandrosterone (DHEA)]. This method has been applied to real raw milk samples and the existence of differences between milk from pregnant and non-pregnant cows has been statistically confirmed. Basing on a revision of existing published data, it could be concluded that maximum daily intakes for hormones are not reached through milk ingestion. Although dairy products are an important source of hormones, other products of animal origin must be considered as well for intake calculations.

positive: Are oral contraceptives a significant contributor to the estrogenicity of drinking water? Recent observed feminization of aquatic animals has raised concerns about estrogenic compounds in water supplies and the potential for these chemicals to reach drinking water. Public perception frequently attributes this feminization to oral contraceptives (OCs) in wastewater and raises concerns that exposure to OCs in drinking water may contribute to the recent rise in human reproductive problems. This paper reviews the literature regarding various sources of estrogens, in surface, source and drinking water, with an emphasis on the active molecule that comes from OCs. It includes discussion of the various agricultural, industrial, and municipal sources and outlines the contributions of estrogenic chemicals to the estrogenicity of waterways and estimates that the risk of exposure to synthetic estrogens in drinking water on human health is negligible. This paper also provides recommendations for strategies to better understand all the potential sources of estrogenic compounds in the environment and possibilities to reduce the levels of estrogenic chemicals in the water supply.

positive: An Assessment of Potential Exposure and Risk from Estrogens in Drinking Water Background Detection of estrogens in the environment has raised concerns in recent years because of their potential to affect both wildlife and humans. Objectives We compared exposures to prescribed and naturally occurring estrogens in drinking water to exposures to naturally occurring background levels of estrogens in the diet of children and adults and to four independently derived acceptable daily intakes (ADIs) to determine whether drinking water intakes are larger or smaller than dietary intake or ADIs. Methods We used the Pharmaceutical Assessment and Transport Evaluation (PhATE) model to predict concentrations of estrogens potentially present in drinking water. Predicted drinking water concentrations were combined with default water intake rates to estimate drinking water exposures. Predicted drinking water intakes were compared to dietary intakes and also to ADIs. We present comparisons for individual estrogens as well as combined estrogens. Results In the analysis we estimated that a child’s exposures to individual prescribed estrogens in drinking water are 730–480,000 times lower (depending upon estrogen type) than exposure to background levels of naturally occurring estrogens in milk. A child’s exposure to total estrogens in drinking water (prescribed and naturally occurring) is about 150 times lower than exposure from milk. Adult margins of exposure (MOEs) based on total dietary exposure are about 2 times smaller than those for children. Margins of safety (MOSs) for an adult’s exposure to total prescribed estrogens in drinking water vary from about 135 to > 17,000, depending on ADI. MOSs for exposure to total estrogens in drinking water are about 2 times lower than MOSs for prescribed estrogens. Depending on the ADI that is used, MOSs for young children range from 28 to 5,120 for total estrogens (including both prescribed and naturally occurring sources) in drinking water. Conclusions The consistently large MOEs and MOSs strongly suggest that prescribed and total estrogens that may potentially be present in drinking water in the United States are not causing adverse effects in U.S. residents, including sensitive subpopulations.

positive: Cigarette Smoke Toxins Deposited on Surfaces: Implications for Human Health Cigarette smoking remains a significant health threat for smokers and nonsmokers alike. Secondhand smoke (SHS) is intrinsically more toxic than directly inhaled smoke. Recently, a new threat has been discovered – Thirdhand smoke (THS) – the accumulation of SHS on surfaces that ages with time, becoming progressively more toxic. THS is a potential health threat to children, spouses of smokers and workers in environments where smoking is or has been allowed. The goal of this study is to investigate the effects of THS on liver, lung, skin healing, and behavior, using an animal model exposed to THS under conditions that mimic exposure of humans. THS-exposed mice show alterations in multiple organ systems and excrete levels of NNAL (a tobacco-specific carcinogen biomarker) similar to those found in children exposed to SHS (and consequently to THS). In liver, THS leads to increased lipid levels and non-alcoholic fatty liver disease, a precursor to cirrhosis and cancer and a potential contributor to cardiovascular disease. In lung, THS stimulates excess collagen production and high levels of inflammatory cytokines, suggesting propensity for fibrosis with implications for inflammation-induced diseases such as chronic obstructive pulmonary disease and asthma. In wounded skin, healing in THS-exposed mice has many characteristics of the poor healing of surgical incisions observed in human smokers. Lastly, behavioral tests show that THS-exposed mice become hyperactive. The latter data, combined with emerging associated behavioral problems in children exposed to SHS/THS, suggest that, with prolonged exposure, they may be at significant risk for developing more severe neurological disorders. These results provide a basis for studies on the toxic effects of THS in humans and inform potential regulatory policies to prevent involuntary exposure to THS.

positive: Exposure to nitrosamines in thirdhand tobacco smoke increases cancer risk in non-smokers. In addition to passive inhalation, non-smokers, and especially children, are exposed to residual tobacco smoke gases and particles that are deposited to surfaces and dust, known as thirdhand smoke (THS). However, until now the potential cancer risks of this pathway of exposure have been highly uncertain and not considered in public health policy. In this study, we estimate for the first time the potential cancer risk by age group through non-dietary ingestion and dermal exposure to carcinogen N-nitrosamines and tobacco-specific nitrosamines (TSNAs) measured in house dust samples. Using a highly sensitive and selective analytical approach we have determined the presence of nicotine, eight N-nitrosamines and five tobacco-specific nitrosamines in forty-six settled dust samples from homes occupied by both smokers and non-smokers. Using observations of house dust composition, we have estimated the cancer risk by applying the most recent official toxicological information. Calculated cancer risks through exposure to the observed levels of TSNAs at an early life stage (1 to 6years old) exceeded the upper-bound risk recommended by the USEPA in 77% of smokers' and 64% of non-smokers' homes. The maximum risk from exposure to all nitrosamines measured in a smoker occupied home was one excess cancer case per one thousand population exposed. The results presented here highlight the potentially severe long-term consequences of THS exposure, particularly to children, and give strong evidence of its potential health risk and, therefore, they should be considered when developing future environmental and health policies. Copyright © 2014 Elsevier Ltd. All rights reserved.

positive: Beyond celery and starter culture: advances in natural/organic curing processes in the United States. Over the past 10years there has been ongoing development of curing processes with natural ingredients designed to meet consumer demand and regulatory requirements for natural and organic processed meats. Initially, these processes utilized celery concentrates with a high nitrate content combined with a nitrate-reducing starter culture. Subsequent advances included celery concentrates with the nitrate converted to nitrite by suppliers. Further, as questions developed concerning reduced concentration of preservatives and the microbiological safety of these processed meats, additional advances have resulted in a wide variety of ingredients and processes designed to provide supplementary antimicrobial effects for improved product safety. Copyright © 2012 Elsevier Ltd. All rights reserved.

positive: Survey of naturally and conventionally cured commercial frankfurters, ham, and bacon for physio-chemical characteristics that affect bacterial growth. Natural and organic food regulations preclude the use of sodium nitrite/nitrate and other antimicrobials for processed meat products. Consequently, processors have begun to use natural nitrate/nitrite sources, such as celery juice/powder, sea salt, and turbinado sugar, to manufacture natural and organic products with cured meat characteristics but without sodium nitrite. The objective of this study was to compare physio-chemical characteristics that affect Clostridium perfringens and Listeria monocytogenes growth in naturally cured and traditionally cured commercial frankfurters, hams, and bacon. Correlations of specific product characteristics to pathogen growth varied between products and pathogens, though water activity, salt concentration, and product composition (moisture, protein and fat) were common intrinsic factors correlated to pathogen growth across products. Other frequently correlated traits were related to curing reactions such as % cured pigment. Residual nitrite and nitrate were significantly correlated to C. perfringens growth but only for the ham products. Copyright © 2012 Elsevier Ltd. All rights reserved.

positive: Dietary intake of nitrate and nitrite and risk of renal cell carcinoma in the NIH-AARP Diet and Health Study Background: Nitrate and nitrite are present in many foods and are precursors of N-nitroso compounds, known animal carcinogens and potential human carcinogens. We prospectively investigated the association between nitrate and nitrite intake from dietary sources and risk of renal cell carcinoma (RCC) overall and clear cell and papillary histological subtypes in the NIH-AARP Diet and Health Study. Methods: Nitrate and nitrite intakes were estimated from a 124-item food frequency questionnaire. Over a mean follow-up of 9 years, we identified 1816 RCC cases (n=498, clear cell; n=115, papillary cell) among 491 841 participants. Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Individuals in the highest quintile of nitrite intake from animal sources compared with those in the lowest quintile, had an increased risk of total RCC and clear cell subtype (HR=1.28, 95% CI, 1.10–1.49 and HR=1.68, 95% CI, 1.25–2.27, respectively). Nitrite from processed meats and other animal sources were associated with increased clear cell adenocarcinoma risk (HR=1.33, 95% CI, 1.01–1.76 and HR=1.78, 95% CI, 1.34–2.36, respectively). We found no association for nitrite intake from plant sources or nitrate intake overall. Conclusion: Our findings suggest that nitrite from animal sources may increase the risk of RCC, particularly clear cell adenocarcinomas.

positive: Thirdhand cigarette smoke in an experimental chamber: evidence of surface deposition of nicotine, nitrosamines and polycyclic aromatic hydrocarbons... BACKGROUND: A growing body of evidence shows that secondhand cigarette smoke undergoes numerous chemical changes after it is released into the air: it can adsorb to indoor surfaces, desorb back into the air and undergo chemical changes as it ages. OBJECTIVES: To test the effects of aging on the concentration of polycyclic aromatic hydrocarbons (PAHs), nicotine and tobacco-specific nitrosamines in cigarette smoke. METHODS: We generated sidestream and mainstream cigarette smoke with a smoking machine, diluted it with conditioned filtered air, and passed it through a 6 m(3) flow reactor with air exchange rates that matched normal residential air exchange rates. We tested the effects of 60 min aging on the concentration of 16 PAHs, nicotine, cotinine and tobacco-specific nitrosamines. We also measured sorption and deposition of nicotine, cotinine and tobacco-specific nitrosamines on materials placed within the flow reactor. RESULTS: We observed mass losses of 62% for PAHs, 72%, for nicotine, 79% for N-nitrosonornicotine and 80% for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Extraction of cotton cloth exposed to smoke yielded nicotine and NNK. The ratio of NNK:nicotine on the exposed cloth was 10-fold higher than that in aerosol samples. CONCLUSIONS: Our data suggest that the majority of the PAHs, nicotine, cotinine and tobacco-specific nitrosamines that are released during smoking in homes and public places deposit on room surfaces. These data give an estimate of the potential for accumulation of carcinogens in thirdhand cigarette smoke. Exposure to PAHs and tobacco-specific nitrosamines, through dermal absorption and inhalation of contaminated dust, may contribute to smoking-attributable morbidity and mortality.

positive: Cruciferous vegetables consumption and risk of renal cell carcinoma: a meta-analysis. Previous cohort and case-control studies on the association between cruciferous vegetables consumption and risk of renal cell carcinoma have illustrated conflicting results so far. To demonstrate the potential association between them, a meta-analysis was performed. Eligible studies were retrieved via both computerized searches and review of references. The summary relative risks (RRs) with 95% confidence interval (CI) for the highest vs. the lowest consumption of cruciferous vegetables were calculated. Heterogeneity and publication bias were also evaluated. Stratified analyses were performed as well. Three cohort and 7 case-control studies were included. A significantly decreased risk with renal cell carcinoma was observed in overall cruciferous vegetables consumption group (RR = 0.73; 95% CI, 0.63-0.83) and subgroup of case-control studies (RR = 0.69; 95% CI, 0.60-0.78), but not in cohort studies (RR = 0.96; 95% CI, 0.71-1.21). No heterogeneity and publication bias were detected across studies. Our findings supported that cruciferous vegetables consumption was related to the decreased risk of renal cell carcinoma. Because of the limited number of studies, further well-designed prospective studies and researches need to be conducted to better clarify the protective effect of cruciferous vegetables on renal cell carcinoma and potential mechanism.

positive: It is time to regulate carcinogenic tobacco-specific nitrosamines in cigarette tobacco The Family Smoking Prevention and Tobacco Control Act gives the Food and Drug Administration power to regulate tobacco products. This commentary calls for immediate regulation of the carcinogenic tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N’-nitrosonornicotine (NNN) in cigarette tobacco as a logical path to cancer prevention. NNK and NNN, powerful carcinogens in laboratory animals, have been evaluated as “carcinogenic to humans” by the International Agency for Research on Cancer. NNK and NNN are present in the tobacco of virtually all marketed cigarettes; levels in cigarette smoke are directly proportional to the amounts in tobacco. The NNK metabolite NNAL, itself a strong carcinogen, is present in the urine of smokers and non-smokers exposed to secondhand smoke. Some of the highest levels of NNK and NNN are found in U.S. products. It is well established that factors such as choice of tobacco blend, agricultural conditions, and processing methods influence levels of NNK and NNN in cigarette tobacco and cigarette smoke. Therefore, it is time to control these factors and produce cigarettes with 100 ppb or less each of NNK and NNN in tobacco, which would result in an approximate 15-20 fold reduction of these carcinogens in the mainstream smoke of popular cigarettes sold in the United States.

positive: Intake of fiber and fiber-rich plant foods is associated with a lower risk of renal cell carcinoma in a large US cohort Background: Plant-based and fiber-rich diets high in vegetables, fruit, and whole grains are recommended to prevent cancer and chronic conditions associated with renal cell carcinoma (RCC), such as obesity, hypertension, and diabetes. Diet may play a role in the etiology of RCC directly and/or indirectly. Objective: In a large prospective cohort of US men and women, we comprehensively investigated dietary intake and food sources of fiber in relation to RCC risk. Design: Participants of the NIH-AARP Diet and Health Study (n = 491,841) completed a self-administered questionnaire of demographics, diet, lifestyle, and medical history. Over 9 (mean) years of follow-up we identified 1816 incident cases of RCC. HRs and 95% CIs were estimated within quintiles by using multivariable Cox proportional hazards regression. Results: Total dietary fiber intake was associated with a significant 15–20% lower risk of RCC in the 2 highest quintiles compared with the lowest (P-trend = 0.005). Intakes of legumes, whole grains, and cruciferous vegetables were also associated with a 16–18% reduced risk of RCC. Conversely, refined grain intake was positively associated with RCC risk in a comparison of quintile 5 with quintile 1 (HR: 1.19; 95% CI: 1.02, 1.39; P-trend = 0.04). The inverse association between fiber intake and RCC was consistent among participants who never smoked, had a body mass index [BMI (in kg/m2)] <30, and did not report a history of diabetes or hypertension. Conclusions: Intake of fiber and fiber-rich plant foods was associated with a significantly lower risk of RCC in this large US cohort. This trial was registered at clinicaltrials.gov as NCT00340015.

positive: Long-term dietary sodium, potassium and fluid intake; exploring potential novel risk factors for renal cell cancer in the Netherlands Cohort Study on diet and cancer Background: As sodium, potassium and fluid intake are related to hypertension, an established risk factor for renal cell cancer (RCC), they may be independent risk factors for RCC. Methods: The Netherlands Cohort Study (NLCS) with case-cohort design included 120 852 participants aged 55–69 years. At baseline, diet and lifestyle were assessed with questionnaires. After 17.3 years of follow-up, 485 RCC cases and 4438 subcohort members were available for analyses. Results: Sodium intake increased RCC risk (P-trend=0.03), whereas fluid and potassium intake did not. For high sodium and low fluid intake, the RCC risk additionally increased (P-interaction=0.02). Conclusion: Sodium intake is a potential risk factor for RCC, particularly if fluid consumption is low.

positive: Determination of total N-nitroso compounds and their precursors in frankfurters, fresh meat, dried salted fish, sauces, tobacco, and tobacco smoke ... Total N-nitroso compounds (NOC) and NOC precursors (NOCP) were determined in extracts of food and tobacco products. Following Walters' method, NOC were decomposed to NO with refluxing HBr/HCl/HOAc/EtOAc and NO was measured by chemiluminescence. NOC were determined after sulfamic acid treatment to destroy nitrite, and NOCP were determined after treatment with 110 mM nitrite and then sulfamic acid. Analysis without HBr gave results < or =20% of those with HBr. This NOC method was efficient for nitrosamines but not nitrosoureas. The standard nitrosation for determining NOCP gave high yields for readily nitrosated amines, including 1-deoxy-1-fructosylvaline, but not for simple amines, dipeptides, and alkylureas. Mean NOC and NOCP results were (respectively, in micromol/kg of product) 5.5 and 2700 for frankfurters, 0.5 and 660 for fresh meat, 5.8 and 5800 for salted, dried fish, and 660 and 2900 for chewing tobacco (all for aqueous extracts) and 220 and 20000 nmol/cigarette for MeCN extracts of cigarette smoke filter pads.

positive: A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin) in cancer patients. BACKGROUND: A growing number of preclinical studies have demonstrated that curcumin could be a promising anticancer drug; however, poor bioavailability has been the major obstacle for its clinical application. To overcome this problem, we developed a new form of curcumin (Theracurmin) and reported high plasma curcumin levels could be safely achieved after a single administration of Theracurmin in healthy volunteers. In this study, we aimed to evaluate the safety of repetitive administration of Theracurmin in cancer patients. METHODS: Pancreatic or biliary tract cancer patients who failed standard chemotherapy were eligible for this study. Based on our previous pharmacokinetic study, we selected Theracurmin containing 200 mg of curcumin (Level 1) as a starting dose, and the dose was safely escalated to Level 2, which contained 400 mg of curcumin. Theracurmin was orally administered every day with standard gemcitabine-based chemotherapy. In addition to safety and pharmacokinetics data, NF-κB activity, cytokine levels, efficacy, and quality-of-life score were evaluated. RESULTS: Ten patients were assigned to level 1 and six were to level 2. Peak plasma curcumin levels (median) after Theracurmin administration were 324 ng/mL (range, 47-1,029 ng/mL) at Level 1 and 440 ng/mL (range, 179-1,380 ng/mL) at Level 2. No unexpected adverse events were observed and 3 patients safely continued Theracurmin administration for >9 months. CONCLUSIONS: Repetitive systemic exposure to high concentrations of curcumin achieved by Theracurmin did not increase the incidence of adverse events in cancer patients receiving gemcitabine-based chemotherapy.

positive: Dietary habits and past medical history as related to fatal pancreas cancer risk among Adventists. Epidemiologic studies of diet and pancreas cancer are few, and include ecologic comparisons and a limited number of prospective and case-control studies. Foods and/or nutrients that have been suggested to be associated with increased risk of this cancer include total fat intake, eggs, animal protein, sugar, meat, coffee and butter. Consumption of raw fruits and vegetables has been consistently associated with decreased risk. Dietary habits and medical history variables were evaluated in a prospective study of fatal pancreas cancer among 34,000 California Seventh-day Adventists between 1976 and 1983. Forty deaths from pancreas cancer occurred during the follow-up period. Compared to all US whites, Adventists experienced decreased risk from pancreas cancer death (standardized mortality ratio [SMR] = 72 for men; 90 for women), which was not statistically significant. Although there was a suggestive relationship between increasing meat, egg, and coffee consumption and increased pancreatic cancer risk, these variables were not significantly related to risk after controlling for cigarette smoking. However, increasing consumption of vegetarian protein products, beans, lentils, and peas as well as dried fruit was associated with highly significant protective relationships to pancreas cancer risk. A prior history of diabetes was associated with increased risk of subsequent fatal pancreas cancer, as was a history of surgery for peptic or duodenal ulcer. A history of tonsillectomy was associated with a slight, nonsignificant protective relationship as was history of various allergic reactions. These findings suggest that the protective relationships associated with frequent consumption of vegetables and fruits high in protease-inhibitor content are more important than any increase in pancreas cancer risk attendant on frequent consumption of meat or other animal products. Furthermore, the previously reported positive associations between diabetes and abdominal surgery and pancreas cancer risk are supported in these data.

positive: Phase II trial of curcumin in patients with advanced pancreatic cancer. PURPOSE: Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration-approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients. We evaluated the clinical biological effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-kappaB (NF-kappaB) and tumor inhibitory properties, against advanced pancreatic cancer. EXPERIMENTAL DESIGN: Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-kappaB and cyclooxygenase-2 were monitored. RESULTS: Twenty-five patients were enrolled, with 21 evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for >18 months; interestingly, one additional patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4- to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed. Curcumin down-regulated expression of NF-kappaB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41 ng/mL and remained relatively constant over the first 4 weeks. CONCLUSIONS: Oral curcumin is well tolerated and, despite its limited absorption, has biological activity in some patients with pancreatic cancer.

positive: Dietary patterns and risk of pancreatic cancer in a large population-based case-control study in the San Francisco Bay Area Pancreatic cancer is highly lethal, and identifying modifiable risk factors could have substantial public health impact. In this population-based case-control study (532 cases, 1701 controls), we used principal component analysis and multivariable unconditional logistic regression models to examine whether a particular dietary pattern was associated with risk of pancreatic cancer, adjusting for other known risk factors. A Prudent dietary pattern, characterized by greater intake of vegetables, fruit, fish, poultry, whole grains, and low-fat dairy, was associated with an approximate 50% reduction in pancreatic cancer risk among men (OR=0.51, 95% CI 0.31-0.84, p-trend=0.001) and women (OR=0.51, 95% CI 0.29-0.90, p-trend=0.04). A Western dietary pattern, characterized by higher intake of red and processed meats, potato chips, sugary beverages, sweets, high fat dairy, eggs, and refined grains, was associated with a 2.4-fold increased risk of pancreatic cancer among men (95% CI 1.3-4.2, p-trend=0.008); but was not associated with risk among women. Among men, those in the upper quintiles of the Western diet and lower quintiles of the Prudent diet had a 3-fold increased risk. Consistent with what has been recommended for several other chronic diseases, consuming a diet rich in plant-based foods, whole grains, and white meat, might reduce risk of pancreatic cancer.

positive: Dietary Mutagen Exposure and Risk of Pancreatic Cancer To investigate the association between dietary exposure to food mutagens and risk of pancreatic cancer, we conducted a hospital-based case-control study at the University of Texas M. D. Anderson Cancer Center during June 2002 to May 2006. Atotal of 626 cases and 530 noncancer controls were frequency matched for race, sex and age (±5 years). Dietary exposure information was collected via personal interview using a meat preparation questionnaire. A significantly greater portion of the cases than controls showed a preference to well-done pork, bacon, grilled chicken, and pan-fried chicken, but not to hamburger and steak. Cases had a higher daily intake of food mutagens and mutagenicity activity (revertants per gram of daily meat intake) than controls did. The daily intakes of 2-amino-3,4,8-trimethylimidazo[4,5—f]quinoxaline (DiMeIQx) and benzo(a)pyrene (BaP), as well as the mutagenic activity, were significant predictors for pancreatic cancer (P = 0.008, 0.031, and 0.029, respectively) with adjustment of other confounders. A significant trend of elevated cancer risk with increasing DiMeIQx intake was observed in quintile analysis (Ptrend= 0.024). Ahigher intake of dietary mutagens (those in the two top quintiles) was associated with a 2-fold increased risk of pancreatic cancer among those without a family history of cancer but not among those with a family history of cancer. Apossible synergistic effect of dietary mutagen exposure and smoking was observed among individuals with the highest level of exposure (top 10%) to PhIP and BaP, Pinteraction= 0.09 and 0.099, respectively. These data support the hypothesis that dietary mutagen exposure alone and in interaction with other factors contribute to the development of pancreatic cancer.

positive: Dietary Fatty Acids and Pancreatic Cancer in the NIH-AARP Diet and Health Study Background Previous research relating dietary fat, a modifiable risk factor, to pancreatic cancer has been inconclusive. Methods We prospectively analyzed the association between intakes of fat, fat subtypes, and fat food sources and exocrine pancreatic cancer in the National Institutes of Health–AARP Diet and Health Study, a US cohort of 308 736 men and 216 737 women who completed a 124-item food frequency questionnaire in 1995–1996. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models, with adjustment for energy intake, smoking history, body mass index, and diabetes. Statistical tests were two-sided. Results Over an average follow-up of 6.3 years, 865 men and 472 women were diagnosed with exocrine pancreatic cancer (45.0 and 34.5 cases per 100 000 person-years, respectively). After multivariable adjustment and combination of data for men and women, pancreatic cancer risk was directly related to the intakes of total fat (highest vs lowest quintile, 46.8 vs 33.2 cases per 100 000 person-years, HR = 1.23, 95% CI = 1.03 to 1.46; Ptrend  = .03), saturated fat (51.5 vs 33.1 cases per 100 000 person-years, HR = 1.36, 95% CI = 1.14 to 1.62; Ptrend < .001), and monounsaturated fat (46.2 vs 32.9 cases per 100 000 person-years, HR = 1.22, 95% CI = 1.02 to 1.46; Ptrend = .05) but not polyunsaturated fat. The associations were strongest for saturated fat from animal food sources (52.0 vs 32.2 cases per 100 000 person-years, HR = 1.43, 95% CI = 1.20 to 1.70; Ptrend < .001); specifically, intakes from red meat and dairy products were both statistically significantly associated with increased pancreatic cancer risk (HR = 1.27 and 1.19, respectively). Conclusion In this large prospective cohort with a wide range of intakes, dietary fat of animal origin was associated with increased pancreatic cancer risk.

positive: Meat and fish consumption and risk of pancreatic cancer: results from the European Prospective Investigation into Cancer and Nutrition. Pancreatic cancer is the fourth most common cause of cancer death worldwide with large geographical variation, which implies the contribution of diet and lifestyle in its etiology. We examined the association of meat and fish consumption with risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 477,202 EPIC participants from 10 European countries recruited between 1992 and 2000 were included in our analysis. Until 2008, 865 nonendocrine pancreatic cancer cases have been observed. Calibrated relative risks (RRs) and 95% confidence intervals (CIs) were computed using multivariable-adjusted Cox hazard regression models. The consumption of red meat (RR per 50 g increase per day = 1.03, 95% CI = 0.93-1.14) and processed meat (RR per 50 g increase per day = 0.93, 95% CI = 0.71-1.23) were not associated with an increased pancreatic cancer risk. Poultry consumption tended to be associated with an increased pancreatic cancer risk (RR per 50 g increase per day = 1.72, 95% CI = 1.04-2.84); however, there was no association with fish consumption (RR per 50 g increase per day = 1.22, 95% CI = 0.92-1.62). Our results do not support the conclusion of the World Cancer Research Fund that red or processed meat consumption may possibly increase the risk of pancreatic cancer. The positive association of poultry consumption with pancreatic cancer might be a chance finding as it contradicts most previous findings. Copyright © 2012 UICC.

positive: Nutrient-based dietary patterns and pancreatic cancer risk. PURPOSE: Few data are available on the role of combinations of foods and/or nutrients on pancreatic cancer risk. To add further information on dietary patterns potentially associated to pancreatic cancer, we applied an exploratory principal component factor analysis on 28 major nutrients derived from an Italian case-control study. METHODS: Cases were 326 incident pancreatic cancer cases and controls 652 frequency-matched controls admitted to hospital for non-neoplastic diseases. Dietary information was collected through a validated and reproducible food frequency questionnaire. Multiple logistic regression models adjusted for sociodemographic variables and major recognized risk factors for pancreatic cancer were used to estimate the odds ratios (OR) of pancreatic cancer for each dietary pattern. RESULTS: We identified four dietary patterns-named "animal products," "unsaturated fats," "vitamins and fiber," and "starch rich," that explain 75% of the total variance in nutrient intake in this population. After allowing for all the four patterns, positive associations were found for the animal products and the starch rich patterns, the OR for the highest versus the lowest quartiles being 2.03 (95% confidence interval [CI], 1.29-3.19) and 1.69 (95% CI, 1.02-2.79), respectively; an inverse association emerged for the vitamins and fiber pattern (OR, 0.55; 95% CI, 0.35-0.86), whereas no association was observed for the unsaturated fats pattern (OR, 1.13; 95% CI, 0.71-1.78). CONCLUSIONS: A diet characterized by a high consumption of meat and other animal products, as well as of (refined) cereals and sugars, is positively associated with pancreatic cancer risk, whereas a diet rich in fruit and vegetables is inversely associated. Copyright © 2013 Elsevier Inc. All rights reserved.

positive: Potentiation of gemcitabine by Turmeric Force in pancreatic cancer cell lines. Gemcitabine is a first line cancer drug widely used for the treatment of pancreatic cancer. However, its therapeutic efficiency is significantly limited by resistance of pancreatic cancer cells to this and other chemotherapeutic drugs. We have investigated the cytotoxic effect of Turmeric Force (TF), a supercritical and hydroethanolic extract of turmeric, alone and in combination with gemcitabine in two pancreatic carcinoma cell lines (BxPC3 and Panc-1). TF is highly cytotoxic to BxPC3 and Panc-1 cell lines with IC50 values of 1.0 and 1.22 microg/ml, respectively with superior cytotoxicity than curcumin. Gemcitabine IC50 value for both of these cell line is 0.03 microg/ml; however, 30-48% of the pancreatic cancer cells are resistant to gemcitabine even at concentrations >100 microg/ml. In comparison, TF induced cell death in 96% of the cells at 50 microg/ml. The combination of gemcitabine and TF was synergistic with IC90 levels achieved in both pancreatic cancer cell lines at lower concentrations. CalcuSyn analysis of cytotoxicity data showed that the Gemcitabine + Turmeric Force combination has strong synergism with combination index (CI) values of 0.050 and 0.183 in BxPC3 and Panc-1 lines, respectively at IC50 level. This synergistic effect is due to the increased inhibitory effect of the combination on nuclear factor-kappaB activity and signal transducer and activator of transcription factor 3 expression as compared to the single agent.

positive: Gemcitabine Plus Erlotinib for Advanced Pancreatic Cancer: A Systematic Review with Meta-Analysis Background This study aims to comprehensively summarize the currently available evidences on the efficacy and safety of gemcitabine plus erlotinib for treating advanced pancreatic cancer. Methodology/Principal Findings PubMed, EMBASE, The Cochrane Library and abstracts of recent major conferences were systematically searched to identify relevant publications. Studies that were conducted in advanced pancreatic cancer patients treated with gemcitabine plus erlotinib (with or without comparison with gemcitabine alone) and reporting objective response rate, disease control rate, progression-free survival, time-to-progression, overall survival, 1-year survival rate and/or adverse events were included. Data on objective response rate, disease control rate, 1-year survival rate and adverse events rate, respectively, were combined mainly by using Meta-Analyst software with a random-effects model. Data on progression-free survival, time-to-progression and overall survival were summarized descriptively. Sixteen studies containing 1,308 advanced pancreatic cancer patients treated with gemcitabine plus erlotinib were included. The reported median progression-free survival (or time-to-progression), median overall survival, 1-year survival rates, objective response rates and disease control rates were 2–9.6 months, 5–12.5 months, 20%–51%, 0%–28.6% and 25.0%–83.3%, respectively. The weighted 1-year survival rate, objective response rate and disease control rate based on studies reporting robust results were 27.9%, 9.1% and 57.0%, respectively. According to the studies with relevant data, the incidences of total and severe adverse events were 96.3% and 62.9%, respectively. The most frequently reported adverse events were leucopenia, rash, diarrhea, vomitting, neutropenia, thrombocytopenia, anaemia, stomatitis, drug-induced liver injury, fatigue and fever. Compared with gemcitabine alone, the progression-free survival and overall survival with gemcitabine plus erlotinib were significantly longer, but there were also more deaths and interstitial lung disease-like syndrome related to this treatment. Conclusions/Significance Gemcitabine plus erlotinib represent a new option for the treatment of advanced pancreatic cancer, with mild but clinically meaningful additive efficacy compared with gemcitabine alone. Its safety profile is generally acceptable, although careful management is needed for some specific adverse events.

positive: The medicalisation of 'tall' girls: A discourse analysis of medical literature on the use of synthetic oestrogen to reduce female height. Endocrine research in the 1930s increased and extended the use of sex hormones as medical therapies in an unprecedented way, especially for female ailments. In the 1950s the therapeutic use of sex hormones extended to the treatment of 'tall' girls. Ambiguity in the definition of the 'tall' girl, the arbitrary nature of the treatment decision, and diversity in the therapeutic regimes highlight the problematic nature of this medical practice. Using linguistic repertoires to study the political and ideological implications found in the patterned use of language, this paper reports on a discourse analysis of the medical literature on treatment of tall girls between the 1950s and 1990s, when this treatment was at its peak. Three linguistic repertoires emerged: the institutional authority of medicine to determine the 'abnormality' of tall stature in females; the clinical knowledge and experience in the diagnosis of medical risk associated with tall stature in women; and using hormones as cosmetic therapy to (re)produce femininity in tall girls. All three related to the maintenance of the cultural representations and social expectations of femininity. With no evidence of psychological harm associated with tall stature in women, and no long-term studies of either effectiveness or benefit, over five decades clinicians persuaded themselves and their patients that tall stature required therapeutic intervention. The treatment of tall girls with high dose oestrogen must be viewed as the medicalisation of a normal physical attribute adversely related to the social construction of gender. Copyright 2010 Elsevier Ltd. All rights reserved.

positive: Diethylstilboestrol--a long-term legacy. Diethylstilboestrol (DES) is an endocrine disrupter which causes cancer in rodents. It was prescribed in large amounts to treat women with gynaecological problems; some of the daughters of these women subsequently developed a rare cancer (vaginal clear cell adenocarcinoma) while genital abnormalities were found in some of the sons. It was used for decades in livestock feed and this may have contaminated the food chain leading to the exposure of the more general population. DES appears to cause epigenetic effects in animals and there is some evidence that this also occurs in man. The mechanisms of carcinogenesis are complex and the effects are difficult to prove due to the background of dietary and environmental phyto- and xenooestrogens. It has been suggested that, like other endocrine disrupters, DES may have acted as an obesogen in the human population. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

positive: Arsenic species in poultry feather meal. Organoarsenical drugs are widely used in the production of broiler chickens in the United States. Feathers from these chickens are processed into a meal product that is used as an animal feed additive and as an organic fertilizer. Research conducted to date suggests that arsenical drugs, specifically roxarsone, used in poultry production result in the accumulation of arsenic in the keratinous material of poultry feathers. The use of feather meal product in the human food system and in other settings may result in human exposures to arsenic. Consequently, the presence and nature of arsenic in twelve samples of feather meal product from six US states and China were examined. Since arsenic toxicity is highly species-dependent, speciation analysis using HPLC/ICPMS was performed to determine the biological relevance of detected arsenic. Arsenic was detected in all samples (44-4100 μg kg(-1)) and speciation analyses revealed that inorganic forms of arsenic dominated, representing 37 - 83% of total arsenic. Roxarsone was not detected in the samples (<20 μg As kg(-1)). Feather meal products represent a previously unrecognized source of arsenic in the food system, and may pose additional risks to humans as a result of its use as an organic fertilizer and when animal waste is managed. Copyright © 2011 Elsevier B.V. All rights reserved.

positive: In vitro binding capacities of three dietary fibers and their mixture for four toxic elements, cholesterol, and bile acid. Water-soluble dietary fibers from apple peels and water-insoluble dietary fibers from wheat bran and soybean-seed hull were used to evaluate their binding capacities for four toxic elements (Pb, Hg, Cd, and As), lard, cholesterol, and bile acids. The water-soluble dietary fibers showed a higher binding capacity for three toxic cations, cholesterol, and sodium cholate; and a lower binding capacity for lard, compared to the water-insoluble ones. A mixture of the dietary fibers from all samples - apple peels, wheat bran, and soybean-seed hull - in the ratio 2:4:4 (w/w) significantly increased the binding capacity of water-insoluble dietary fibers for the three toxic cations, cholesterol, and sodium cholate; moreover, the mixture could lower the concentrations of Pb(2+) and Cd(+) in the tested solutions to levels lower than those occurring in rice and vegetables grown in polluted soils. However, all the tested fibers showed a low binding capacity for the toxic anion, AsO(3)(3-). Copyright © 2010. Published by Elsevier B.V.

positive: Cytological abnormalities in nipple aspirates of breast fluid from women with severe constipation. The relation between epithelial dysplasia in nipple aspirates of breast fluid and frequency of bowel movements was studied in 1481 white women. There was a significant positive association with dysplasia (risk ratio 4.5; 95% confidence interval 1.9-11.9) in women reporting severe constipation, i.e., two or fewer bowel movements weekly, which was not seen in women reporting more than one bowel movement daily. Women who had one bowel movement daily or one every other day had increased risk ratios. Cytological abnormalities in breast epithelium associated with severe constipation may be relevant to studies of diet and breast disease since the intestinal flora has been reported to metabolism bile salts and oestrogens secreted by the liver into the gastrointestinal tract-a process which may be enhanced by severe constipation.

positive: Breast-gut connection: origin of chenodeoxycholic acid in breast cyst fluid. The notion that a breast-gut connection might modulate the microenvironment of breast tissue was supported by the finding that breast cyst fluid contains bile acids that are characteristically found in the intestines. To establish that the gut, rather than circulating steroid precursors, is the source of bile acids in breast cyst fluid, we gave two patients deuterium-labelled chenodeoxycholic acid (three 200 mg doses by mouth), starting 9 days before aspiration of breast cysts. The chenodeoxycholic acid concentration of seven samples of aspirated cyst fluid ranged from 42 to 94 mumol/L. The corresponding serum concentrations of chenodeoxycholic acid on the same day were 0.8 and 2.9 mumol/L, of which the labelled compound comprised 13.0% (0.38 mumol/L) and 28.2% (0.23 mumol/L). The deuterated chenodeoxycholic acid concentrations in cyst fluid were 0.79 and 1.26 mumol/L in two samples from patient 1 and 3.22 mumol/L in patient 2; these values are equivalent to 11-17% of the serum concentrations [corrected]. This study shows that intestinal bile acids rapidly gain access to cyst fluid. Further studies should investigate the mechanisms that govern the exchange processes and the maintenance of the high cyst fluid to plasma concentration gradients, and the biological half-lives of individual constituents.

positive: Bile acids influence the growth, oestrogen receptor and oestrogen-regulated proteins of MCF-7 human breast cancer cells. The effects of the major human serum bile acid, glycochenodeoxycholic acid (GCDC), as well as unconjugated chenodeoxycholic acid (CDC), on the MCF-7 human breast cancer cell line have been studied in vitro under oestrogen and bile acid deprived culture conditions. GCDC increased the growth of the breast cancer cells over the range 10-300 microM. At concentrations in excess of the bile acid binding capacity of the medium cell growth was prevented. In contrast 10 microM CDC tended to reduce cell growth. Oestrogen (ER) and progesterone (PgR) receptors, pS2 and total cathepsin D were quantified by monoclonal antibody based immunoassays. Ten to 100 microM GCDC and 10 microM CDC down-regulated ER protein and this was accompanied by induction of the oestrogen-regulated proteins PgR, pS2 and possibly cathepsin D, including increased secretion of the latter two proteins into the culture medium. All these changes were quantitatively similar to those observed with 10 nM oestradiol. The bile acid effects on ER and PgR were not due to interference with the assay procedures. Cells incubated with 50 microM GCDC or 10 microM CDC had higher pmolar concentrations of the bile acids than controls. This study suggests that naturally occurring bile acids influence the growth and steroid receptor function of human breast cancer cells.

positive: Plasma deoxycholic acid concentration is elevated in postmenopausal women with newly diagnosed breast cancer. OBJECTIVE: High concentrations of plasma deoxycholic acid (DCA) are found in human breast cyst fluid and it has been hypothesised that this may be related to risk of breast cancer. The aim of this pilot study was to ascertain whether plasma bile acid concentrations were greater in women with breast cancer. DESIGN: A case-control study comparing postmenopausal women with breast cancer with healthy controls was conducted. SUBJECTS: Twenty Caucasian postmenopausal breast cancer patients were recruited at the time of diagnosis together with 20 healthy controls matched for age and body mass index. Exclusion criteria included any treatment for breast cancer, use of hormone replacement therapy in the last 12 months, diabetes mellitus, a history of liver or gall bladder disease or abnormal liver function. MEASUREMENTS: Fasting plasma bile acid concentrations were determined by gas-liquid chromatography/mass spectrometry. RESULTS: The mean plasma DCA concentration was 52% higher (P=0.012) in patients with breast cancer compared with controls. CONCLUSION: These results support the hypothesis that DCA may be involved in the aetiology of breast cancer.

positive: Effect of a very-high-fiber vegetable, fruit, and nut diet on serum lipids and colonic function. We tested the effects of feeding a diet very high in fiber from fruit and vegetables. The levels fed were those, which had originally inspired the dietary fiber hypothesis related to colon cancer and heart disease prevention and also may have been eaten early in human evolution. Ten healthy volunteers each took 3 metabolic diets of 2 weeks duration. The diets were: high-vegetable, fruit, and nut (very-high-fiber, 55 g/1,000 kcal); starch-based containing cereals and legumes (early agricultural diet); or low-fat (contemporary therapeutic diet). All diets were intended to be weight-maintaining (mean intake, 2,577 kcal/d). Compared with the starch-based and low-fat diets, the high-fiber vegetable diet resulted in the largest reduction in low-density lipoprotein (LDL) cholesterol (33% +/- 4%, P <.001) and the greatest fecal bile acid output (1.13 +/- 0.30 g/d, P =.002), fecal bulk (906 +/- 130 g/d, P <.001), and fecal short-chain fatty acid outputs (78 +/- 13 mmol/d, P <.001). Nevertheless, due to the increase in fecal bulk, the actual concentrations of fecal bile acids were lowest on the vegetable diet (1.2 mg/g wet weight, P =.002). Maximum lipid reductions occurred within 1 week. Urinary mevalonic acid excretion increased (P =.036) on the high-vegetable diet reflecting large fecal steroid losses. We conclude that very high-vegetable fiber intakes reduce risk factors for cardiovascular disease and possibly colon cancer. Vegetable and fruit fibers therefore warrant further detailed investigation. Copyright 2001 by W.B. Saunders Company

positive: Recent Perspectives on the Relations between Fecal Mutagenicity, Genotoxicity, and Diet DNA damage is an essential component of the genesis of colonic cancer. Gut microbial products and food components are thought to be principally responsible for the damage that initiates disease progression. Modified Ames tests and Comet assays have been developed for measuring mutagenicity and genotoxicity. Their relevance to oncogenesis remains to be confirmed, as does the relative importance of different mutagenic and genotoxic compounds present in fecal water and the bacteria involved in their metabolism. Dietary intervention studies provide clues to the likely risks of oncogenesis. High-protein diets lead to increases in N-nitroso compounds in fecal water and greater DNA damage as measured by the Comet assay, for example. Other dietary interventions, such as non-digestible carbohydrates and probiotics, may lead to lower fecal genotoxicity. In order to make recommendations to the general public, we must develop a better understanding of how genotoxic compounds are formed in the colon, how accurate the Ames and Comet assays are, and how diet affects genotoxicity.

positive: Bile acids as carcinogens in human gastrointestinal cancers. Bile acids were first proposed to be carcinogens in 1939 and 1940. On the basis of later work with rodent models, bile acids came to be regarded as cancer promoters rather than carcinogens. However, considerable indirect evidence, obtained more recently, supports the view that bile acids are carcinogens in humans. At least 15 reports, from 1980 through 2003, indicate that bile acids cause DNA damage. The mechanism is probably indirect, involving induction of oxidative stress and production of reactive oxygen species that then damage DNA. Repeated DNA damage likely increases the mutation rate, including the mutation rate of tumor suppressor genes and oncogenes. Additional reports, from 1994 through 2002, indicate that bile acids, at the increased concentrations accompanying a high fat diet, induce frequent apoptosis. Those cells within the exposed population with reduced apoptosis capability tend to survive and selectively proliferate. That bile acids cause DNA damage and may select for apoptosis-resistant cells (both leading to increased mutation), indicates that bile acids are likely carcinogens. In humans, an increased incidence of cancer of the laryngopharyngeal tract, esophagus, stomach, pancreas, the small intestine (near the Ampulla of Vater) and the colon are associated with high levels of bile acids. The much larger number of cell generations in the colonic (and, likely, other gastrointestinal) epithelia of humans compared to rodents may allow time for induction and selection of mutations leading to cancer in humans, although not in rodents.

positive: The metabolic consequences of slow colonic transit. Intestinal transit has a substantial influence on the enterohepatic circulation of bile acids and steroid hormones, on colonic pH, and on short chain fatty acid concentrations in the distal colon. Slow transit is likely to favor disease processes that are related to over-efficient enterohepatic recirculation and to lack of short chain fatty acid in the distal colon. These include gallstones, large bowel cancer, and possibly breast cancer. The best-documented influence of slow colonic transit is on bile acid metabolism. Slowing colonic transit increases deoxycholate and raises cholesterol saturation of bile, making gallstone formation more likely. In this review, we also examine the evidence that slow colonic transit may be important in the etiology of large bowel and breast cancer. There is a lack of data pertaining to the relationship between colonic transit and diseases such as colon and breast cancer. Should slow colonic transit prove to be a significant factor in the etiology of such diseases, then the health of the population might benefit from dietary and lifestyle changes that speed up intestinal transit.

positive: Diet, nutrition intake, and metabolism in populations at high and low risk for colon cancer. Nutrient intake. A 3-day diary with portion sizes weighed by the subject and a 24-h recall were obtained on 50 sets of subjects: Seventh-day Adventist lacto-ovo-vegetarians and nonvegetarians, and general population nonvegetarians, matched on age (+/- 5 yr), sex, marital status, education, type of milk preferred, and an index of the frequency of dairy and egg product use. An additional 18 unmatched persons who follow a pure vegetarian dietary pattern (use no meat, fish, fowl, dairy, or egg products) were recruited into the study. The rational for the dietary methods used is presented and details of each of the methods used are given. The results of the nutrient analysis of the 24-h recall and 3-day diary are presented. The 3-day nutrient intake means for the four groups are compared to the sex-specific recommended daily allowance both with and without supplements. The contribution of nutritional supplements to the nutrient intake is discussed. All groups show adequate or excess intake levels of calories, protein, and fat when either the 24-h recall or the 3-day diary values are considered. The higher intake of calories noted among nonvegetarians can be explained by a higher intake of both fat and protein in these groups. A, B, and C vitamin levels (3-day dairy estimates) are adequate both with and without supplements. Calcium intake is much below recommended levels for pure vegetarian females. Iron intake is low for all females. A heme iron source does not improve the intake levels for nonvegetarian females. A comparison of these results with prior reports of nutrient intake among Seventh-day Adventists is presented.

positive: Microstructure and in vitro beta carotene bioaccessibility of heat processed orange fleshed sweet potato. Orange fleshed sweet potato (OFSP) has been identified as a good source of beta-carotene but the beta-carotene bioaccessibility is affected by processing. In this study, the effect of traditional heat processing methods on the microstructure and in vitro bioaccessibility of beta-carotene from OFSP were investigated. Bioaccessibility was determined using simulated in vitro digestion model followed by membrane filtration to separate the micellar fraction containing bioaccessible beta-carotene. Processing led to decrease in the amount of all-trans-beta-carotene and increase in 13-cis-beta-carotene. Processed OFSP had significantly higher (P < 0.05) bioaccessible beta-carotene compared to the raw forms. Bioaccessibility varied with processing treatments in the order; raw < baked < steamed/boiled < deep fried. Light microscopy showed that the microstructure of OFSP was disrupted by the processing methods employed. The cell walls of OFSP were sloughed by the traditional heat processing methods applied. The findings show that heat processing improves bioaccessibility of beta-carotene in OFSP and this was probably due to disruption of the tissue microstructure.

positive: Diet and gallbladder cancer: a case-control study. Cancer of the gallbladder is rare but fatal, and has an unusual geographic and demographic distribution. Gallstones and obesity have been suggested as possible risk factors. As diet is known to influence both these factors, we carried out the present study to evaluate the possible role of diet in gallbladder carcinogenesis. A case-control study involving 64 newly diagnosed cases of gallbladder cancer and 101 cases of gallstones was carried out. The dietary evaluation was carried out by the dietary recall method based on a preset questionnaire developed specifically for the present study, keeping in mind the common dietary habits prevailing in this part of the world. Odds ratios (OR) and 95% confidence interval (CI) were calculated for various dietary items. A significant reduction in odds ratio was seen with the consumption of radish (OR 0.4; 95% CI 0.17-0.94), green chilli (OR 0.45; 95% CI 0.21-0.94) and sweet potato (OR 0.33; 95% CI 0.13-0.83) among vegetables, and mango (OR 0.4; 95% CI 0.16-0.99), orange (OR; 0.45; 95% CI 0.22-0.93), melon (OR 0.3; 95% CI 0.14-0.64) and papaya (OR 0.44; 95% 0.2-0.64) among fruits. A reduction in odds was also seen with the consumption of cruciferous vegetables, beans, onion and turnip, however the difference was not statistically significant. On the other hand, an increase in the odds was observed with consumption of capsicum (OR 2.2), beef (OR 2.58), tea (OR 1.98), red chilli (OR 1.29) and mutton (OR 1.2), however the difference was statistically not significant. In conclusion, the results of the present study show a protective effect of vegetables and fruits on gallbladder carcinogenesis, but red meat (beef and mutton) was found to be associated with increased risk of gallbladder cancer.

positive: New metrics of affordable nutrition: which vegetables provide most nutrients for least cost? Measuring food prices per gram, rather than per calorie, is one way to make healthful vegetables appear less expensive. However, a better measure of affordability would take the nutrient content of vegetables into account. This study, based on analyses of US Department of Agriculture datasets, aimed to identify which vegetables, including juices and soups, provided the most nutrients per unit cost. Nutrient density was measured using the Nutrient Rich Foods (NRF) index, based on nine nutrients to encourage: protein; fiber; vitamins A, C, and E; calcium; iron; magnesium; and potassium; and on three nutrients to limit: saturated fat, added sugar, and sodium. Food cost in dollars was calculated per 100 g, per 100 kcal, per serving, and per nutrient content. One-way analyses of variance with post hoc tests were used to determine statistical significance. Results showed that tomato juices and tomato soups, dark green leafy and nonleafy vegetables, and deep yellow vegetables, including sweet potatoes, had the highest NRF scores overall. Highest NRF scores per dollar were obtained for sweet potatoes, white potatoes, tomato juices and tomato soups, carrots, and broccoli. Tomato sauces, raw tomatoes, and potato chips were eaten more frequently than were many other vegetables that were both more affordable and more nutrient-rich. These new measures of affordable nutrition can help foodservice and health professionals identify those vegetables that provide the highest nutrient density per unit cost. Processed vegetables, including soups and juices, can contribute to the quality and the affordability of the diet. Copyright © 2013 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.

positive: Stability of carotenoids, total phenolics and in vitro antioxidant capacity in the thermal processing of orange-fleshed sweet potato (Ipomoea batat... Intervention strategies regarding the biofortification of orange-fleshed sweet potato, which is a rich source of carotenoids for combating vitamin A deficiency, are being developed in Brazil. This study was conducted to evaluate the concentrations of individual carotenoids, total phenolic compounds and antioxidant capacity in the roots of four biofortified sweet potato cultivars that were raw or processed by four common heat treatments. HPLC, Folin-Ciocalteu, DPPH and ABTS assays were used. All cultivars showed high levels of carotenoids in raw roots, predominantly all-trans-β-carotene (79.1-128.5 mg.100 g(-1) DW), suggesting a high estimated vitamin A activity. The CNPH 1194 cultivar reported carotenoids values highest than those of other cultivars (p < 0.05). The total phenolic compounds varied among cultivars and heat treatments (0.96-2.05 mg.g(-1) DW). In most cases, the heat treatments resulted in a significant decrease in the carotenoids and phenolic compounds contents as well as antioxidant capacity. Processing of flour presented the greatest losses of major carotenoids and phenolics. The phenolic compounds showed more stability than carotenoids after processing. There were significant correlations between the carotenoids and phenolic compounds and the antioxidant capacity.

positive: Anticancer effects of sweet potato protein on human colorectal cancer cells AIM: To investigate the effects of proteins purified from sweet potato storage roots on human colorectal cancer cell lines. METHODS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Hoechst 33258 nuclear staining and Boyden transwell chamber methods were used to determine whether purified sweet potato protein (SPP) from fresh sweet potato roots affected proliferation, migration and invasion, respectively, of human colorectal cancer SW480 cells in vitro. The inhibitory effects of SPP on growth of human colorectal cancer HCT-8 cells intraperitoneally xenografted in nude mice and spontaneous lung metastasis of murine Lewis lung carcinoma 3LL cells subcutaneously transplanted in C57 BL/6 mice were also investigated in vivo. RESULTS: SPP inhibited the proliferation of SW480 cells in a dose-dependent manner, with an IC50 value of 38.732 μmol/L (r2 = 0.980, P = 0.003) in the MTT assay. Hoechst 33258 nuclear staining further revealed inhibition of cell viability and induction of apoptosis by SPP. The transwell assay disclosed significant reduction in migrated cells/field by 8 μmol/L SPP (8.4 ± 2.6 vs 23.3 ± 5.4, P = 0.031) and invaded cells/field through the ECMatrix by 0.8 μmol/L SPP, compared with the control (25.2 ± 5.2 vs 34.8 ± 6.1, P = 0.038). Both intraperitoneal (ip) and intragastric (ig) administration of SPP led to significant suppression of growth of intraperitoneally inoculated HCT-8 cells in nude mice to 58.0% ± 5.9% (P = 0.037) and 43.5% ± 7.1% (P = 0.004) of the controls, respectively, after 9 d treatment. Bloody ascites additionally disappeared after ip injection of trypsin inhibitor. Notably, ig and ip administration of SPP induced a significant decrease in spontaneous pulmonary metastatic nodule formation in C57 BL/6 mice (21.0 ± 12.3 and 27.3 ± 12.7 nodules/lung vs 42.5 ± 4.5 nodules/lung in controls, respectively, P < 0.05) after 25 d treatment. Moreover, the average weight of primary tumor nodules in the hind leg of mice decreased from 8.2 ± 1.3 g/mice in the control to 6.1 ± 1.4 g/mice in the ip group (P = 0.035). CONCLUSION: SPP exerts significant antiproliferative and antimetastatic effects on human colorectal cancer cell lines, both in vitro and in vivo.

positive: Sweet potato: a review of its past, present, and future role in human nutrition. The overall objective of this chapter is to review the past, present, and future role of the sweet potato (Ipomoea batatas [L.] Lam) in human nutrition. Specifically, the chapter describes the role of the sweet potato in human diets; outlines the biochemical and nutritional composition of the sweet potato with emphasis on its beta-carotene and anthocyanin contents; highlights sweet potato utilization, and its potential as value-added products in human food systems; and demonstrates the potential of the sweet potato in the African context. Early records have indicated that the sweet potato is a staple food source for many indigenous populations in Central and South Americas, Ryukyu Island, Africa, the Caribbean, the Maori people, Hawaiians, and Papua New Guineans. Protein contents of sweet potato leaves and roots range from 4.0% to 27.0% and 1.0% to 9.0%, respectively. The sweet potato could be considered as an excellent novel source of natural health-promoting compounds, such as beta-carotene and anthocyanins, for the functional food market. Also, the high concentration of anthocyanin and beta-carotene in sweet potato, combined with the high stability of the color extract make it a promising and healthier alternative to synthetic coloring agents in food systems. Starch and flour processing from sweet potato can create new economic and employment activities for farmers and rural households, and can add nutritional value to food systems. Repositioning sweet potato production and its potential for value-added products will contribute substantially to utilizing its benefits and many uses in human food systems. Multidisciplinary, integrated research and development activities aimed at improving production, storage, postharvest and processing technologies, and quality of the sweet potato and its potential value-added products are critical issues, which should be addressed globally.

positive: Effects of baking and boiling on the nutritional and antioxidant properties of sweet potato [Ipomoea batatas (L.) Lam.] cultivars. The effects of baking and boiling on the nutritional and antioxidant properties of three sweet potato cultivars (Beniazuma, Koganesengan, Kotobuki) cultivated in Turkey were investigated. The samples were analyzed for proximate composition, total phenolic content, ascorbic acid, β-carotene, antiradical activity, and free sugars. The dry matter, protein, and starch contents of the sweet potatoes were significantly changed by the treatments while the ash and crude fiber contents did not differ as significantly. The β-carotene contents of baked and boiled sweet potatoes were lower than those of fresh sweet potatoes; however, the total phenolic and ascorbic acid contents of the baked and boiled sweet potatoes were higher than those of the fresh samples. Generally, the antiradical activity of the sweet potatoes increased with the treatments. Sucrose, glucose, and fructose were quantified as free sugars in all fresh sweet potatoes; however, maltose was determined in the treated samples. In terms of the analyzed parameters, there were no explicit differences among the sweet potato cultivars.

positive: The effect of a sweet potato, footbath, and acupressure intervention in preventing constipation in hospitalized patients with acute coronary syndro... Constipation is a common health problem that adversely affects quality of life and the prognosis of hospitalized patients with acute coronary syndromes (ACS). The purpose of this study was to develop and test the sweet potato/footbath/acupressure massage (SFA) intervention as a safe treatment for prevention of constipation and to increase satisfaction with bowel emptying in hospitalized patients with ACS. The study was a prospective, randomized controlled trial with a sample of 93 patients (SFA group, n = 44; usual care group, n = 49). Patients in the SFA group received SFA intervention combined with usual care. The results showed that there were statistical differences between the two groups in terms of (1) the incidence of constipation; (2) the use of laxatives and enemas; (3) patients' subjective satisfaction with their bowel emptying during hospitalization; and (4) sensation of incomplete evacuation and anorectal obstruction/blockade. The SFA intervention was more effective, economical, and practical than usual care alone in managing constipation and satisfaction with defecation in patients hospitalized with ACS.

positive: Multiple biological functions of sporamin related to stress tolerance in sweet potato (Ipomoea batatas Lam). The initial investigation of the nature of the proteins in the tuber of sweet potato (Ipomoea batatas Lam.) revealed a globulin-designated "ipomoein," which was reported by Jones and Gersdorff, (1931). Later, "ipomoein" was renamed "sporamin" and was found to be a major storage protein that accounted for over 80% of the total protein in the tuberous root. To date, sporamin has been studied by a series of biochemical and molecular approaches. The first purification of sporamin into two major fractions, A and B, was successfully completed in 1985. Several characteristics of the protein, such as the diversification of the nucleotide sequences in the gene family, the protein structure, the biological functions of storage, defense, inhibitory activity and ROS scavenging, were identified. In the past decade, sporamin was classified as a Kunitz-type trypsin inhibitor, and its insect-resistance capability has been examined in transgenic tobacco and cauliflower plants, indicating the multiple functions of this protein has evolved to facilitate the growth and development of sweet potato. Sporamin is constitutively expressed in the tuberous root and is not normally expressed in the stem or leaves. However, this protein is expressed systemically in response to wounding and other abiotic stresses. These dual expression patterns at the transcriptional level revealed that the complex regulatory mechanism of sporamin was modulated by environmental stresses. The versatile functions of sporamin make this storage protein a good research model to study molecular evolution, regulatory mechanisms and physiological functions in plants. This review summarizes and discusses recent approaches and future perspectives in agricultural biotechnology. Copyright © 2012 Elsevier Inc. All rights reserved.

positive: Role of Anthocyanin-enriched Purple-fleshed Sweet Potato P40 in Colorectal Cancer Prevention Scope Anthocyanins, the natural pigments in plant foods, have been associated with cancer prevention. However, the content of anthocyanins in staple foods is typically low and the mechanisms by which they exert anti-cancer activity is not yet fully defined. Methods and results We selected an anthocyanin-enriched purple-fleshed sweet potato clone, P40, and investigated its potential anti-cancer effect in both in vitro cell culture and in vivo animal model. In addition to a high level of total phenolics and antioxidant capacity, P40 possesses a high content of anthocyanins at 7.5 mg/g dry matter. Treatment of human colonic SW480 cancer cells with P40 anthocyanin extracts at 0–40 μM of peonidin-3-glucoside equivalent resulted in a dose-dependent decrease in cell number due to cytostatic arrest of cell cycle at G1 phase but not cytotoxicity. Furthermore, dietary P40 at 10–30% significantly suppressed azoxymethane-induced formation of aberrant crypt foci in the colons of CF-1 mice in conjunction with, at least in part, a lesser proliferative PCNA and a greater apoptotic caspase-3 expression in the colon mucosal epithelial cells. Conclusion These observations, coupled with both in vitro and in vivo studies reported here, suggest anthocyanin-enriched sweet potato P40 may protect against colorectal cancer by inducing cell cycle arrest, anti-proliferative and apoptotic mechanisms.

positive: The influence of deep frying using various vegetable oils on acrylamide formation in sweet potato (Ipomoea batatas L. Lam) chips. The objective of this study was to evaluate the precursors of acrylamide formation in sweet potato (SP) (Ipomoea batatas L. Lam) chips and to determine the effect of different types of vegetable oils (VOs), that is, palm olein, coconut oil, canola oil, and soya bean oil, on acrylamide formation. The reducing sugars and amino acids in the SP slices were analyzed, and the acrylamide concentrations of SP chips were measured. SP chips that were fried in a lower degree of unsaturation oils contained a lower acrylamide concentration (1443 μg/kg), whereas those fried with higher degree of unsaturated oils contained a higher acrylamide concentration (2019 μg/kg). SP roots were found to contain acrylamide precursors, that is, 4.17 mg/g glucose and 5.05 mg/g fructose, and 1.63 mg/g free asparagine. The type of VO and condition used for frying, significantly influenced acrylamide formation. This study clearly indicates that the contribution of lipids in the formation of acrylamide should not be neglected. © 2013 Institute of Food Technologists®

positive: Therapeutic efficacy of once-daily oral administration of a Kunitz-type protease inhibitor, bikunin, in a mouse model and in human cancer. BACKGROUND: Bikunin, a Kunitz-type protease inhibitor, specifically inhibits tumor invasion and metastasis. METHODS: The authors initially evaluated the therapeutic efficacy of once-daily oral administration of different doses of bikunin against human ovarian carcinoma HRA cells growing in the peritonea of nude mice. For the in vivo studies, female 7-week-old nude mice were randomized to 1 of 4 groups: bikunin-treated groups (n = 9 in each group) received 3, 10, or 30 microg/g body weight per day bikunin for 7 days via gastrointestinal gavage, and a control group (n = 9) received the vehicle solution (phosphate-buffered saline) via gastrointestinal gavage. On Day 9, the abdominal cavity was examined by two observers who were blinded to treatment. RESULTS: After oral administration, intact bikunin was detectable in mouse serum specimens at 3 and 6 hours. This was followed by a decline at 12 hours. The mice given bikunin at the highest dose level had a 40% decrease in tumor load. The highest uptake in the tumor was obtained with [125I]bikunin 12 hours postadministration. No effect on either food intake or body weight was observed in the treated versus sham groups. The current study was the first to report the potent activity of once-daily oral administration of bikunin against ovarian carcinoma. Next, the authors performed a Phase I trial to determine the maximum-tolerated dose (MTD) and safety of a once-daily oral administration schedule. The indication was locally advanced uterine cervical carcinoma after definitive treatment. An escalating dose (3, 10, and 30 mg/kg per day) of bikunin was administered orally to nine patients for 7 days. There were no dose-limiting toxicities and the MTD of the bikunin schedule was not defined. The authors also obtained preliminary data on its effect on urokinase-type plasminogen activator expression at the highest dose level. CONCLUSIONS: Once-daily oral administration of bikunin was found to be safe in humans and exhibited signs of biologic activity. Copyright 2004 American Cancer Society.

positive: Growth inhibition and induction of apoptosis in NB4 promyelocytic leukemia cells by trypsin inhibitor from sweet potato storage roots. The objective of this study was to investigate the antiproliferative effect and the mechanism of trypsin inhibitor (TI) from sweet potato [Ipomoea batatas (L.) Lam. 'Tainong 57'] storage roots on NB4 promyelocytic leukemia cells. The results showed that TI inhibited cellular growth of NB4 promyelocytic leukemia cells in a time-dependent and dose-dependent manner, and treatment for 72 h induced a marked inhibition of cellular growth, showing an IC50 of 57.1 +/- 8.26 microg/mL. TI caused cell cycle arrest at the G1 phase as determined by flow cytometric analysis and apoptosis as shown by DNA laddering. TI-induced cell apoptosis involved p53, Bcl-2, Bax, and cytochrome c protein in NB4 cells. P53 and Bax proteins were accumulated, and antiapoptotic molecule Bcl-2 was decreased in the tested cells in a time-dependent manner during TI treatment. TI also induced a substantial release of cytochrome c from the mitochondria into the cytosol. Hence, TI induced apoptosis in NB4 cells through a mitochondria-dependent pathway, which was associated with the activation of caspase-3 and -8. These results demonstrated that TI induces NB4 cell apoptosis through the inhibition of cell growth and the activation of the pathway of caspase-3 and -8 cascades.

positive: Relationship between Processing Method and the Glycemic Indices of Ten Sweet Potato (Ipomoea batatas) Cultivars Commonly Consumed in Jamaica This study investigated the effect of different traditional cooking methods on glycemic index (GI) and glycemic response of ten Sweet potato (Ipomoea batatas) cultivars commonly eaten in Jamaica. Matured tubers were cooked by roasting, baking, frying, or boiling then immediately consumed by the ten nondiabetic test subjects (5 males and 5 females; mean age of 27 ± 2 years). The GI varied between 41 ± 5–93 ± 5 for the tubers studied. Samples prepared by boiling had the lowest GI (41 ± 5–50 ± 3), while those processed by baking (82 ± 3–94 ± 3) and roasting (79 ± 4–93 ± 2) had the highest GI values. The study indicates that the glycemic index of Jamaican sweet potatoes varies significantly with the method of preparation and to a lesser extent on intravarietal differences. Consumption of boiled sweet potatoes could minimize postprandial blood glucose spikes and therefore, may prove to be more efficacious in the management of type 2 diabetes mellitus.

positive: Sporamin induce apoptosis in human tongue carcinoma cells by down-regulating Akt/GSK-3 signaling. We investigated the effects of sporamin, the major soluble protein with a kunitz-type trypsin inhibitory activity in the root tuber of the sweet potato, on cell proliferation, apoptosis, Akt/GSK-3 signaling and its related genes to provide more insights in the mechanism behind the inhibitory effects of sporamin in a human tongue cancer line Tca8113. In this study, sporamin inhibited cell proliferation and induced apoptosis in Tca8113 cells in a concentration-dependent and time-dependent manner. Consistently, Bax was up-regulated and Bcl-2 was down-regulated in sporamin-treated cells. Furthermore, Akt/GSK-3 signaling was down-regulated in sporamin-treated cells. Consistently, the phosphorylated Bad was significantly declined in sporamin-treated Tca8113 cells. These results suggest the antiproliferative effects of sporamin in Tca8113 cells might result partly from induction of apoptosis by down-regulating Akt/GSK-3 pathway. © 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique.

positive: Review of epidemiologic studies of dietary acrylamide intake and the risk of cancer. Conjectured associations between dietary acrylamide intake and cancer have been evaluated in more than 15 epidemiologic studies examining almost every major cancer site. We have critically reviewed the epidemiologic studies of estimated dietary acrylamide exposure and cancer. As substantially greater acrylamide exposure occurs through tobacco smoke than dietary exposure, we present the results separately for never smokers or adjusted statistically for smoking status, where possible. After an extensive examination of the published literature, we found no consistent or credible evidence that dietary acrylamide increases the risk of any type of cancer in humans, either overall or among nonsmokers. In particular, the collective evidence suggests that a high level of dietary acrylamide intake is not a risk factor for breast, endometrial, or ovarian cancers, which have generated particular interest because of a conjectured hormonal mechanism of acrylamide. Moreover, the absence of a positive association between smoking and ovarian and endometrial cancers suggests that any association of these cancers with the much lower, more sporadic dietary acrylamide intake is unlikely. In conclusion, epidemiologic studies of dietary acrylamide intake have failed to demonstrate an increased risk of cancer. In fact, the sporadically and slightly increased and decreased risk ratios reported in more than two dozen papers examined in this review strongly suggest the pattern one would expect to find for a true null association over the course of a series of trials. Therefore, continued epidemiologic investigation of acrylamide and cancer risk appears to be a misguided research priority.

positive: Intake of fried meat and risk of cancer: a follow-up study in Finland. It has been suggested that mutagens in fried meat may be involved in the cancer process. Therefore the relationships between intake of fried meat and subsequent risk of cancers at different sites were studied among 9,990 Finnish men and women, 15-99 years of age and initially free of cancer. The baseline study was carried out in 1966-1972, and cases of cancer were identified through data linkage with the Finnish Cancer Registry. During a 24-year follow-up, 853 cancer cases were diagnosed. The intake of fried meat was estimated from a dietary history interview covering the total diet of the participants during the previous year. There was a positive association between fried meat intake and the risk of female-hormone-related cancers, i.e., cancer of the breast, endometrium and ovary combined. The relative risk of these cancers combined between persons in the highest and lowest tertiles of daily intake of fried meat adjusted for age, personal characteristics and intake of other main food groups was 1.77 (95% confidence interval = 1.11-2.84). Pancreatic and nervous system cancers also presented non-significant suggestive associations. No associations were observed with respect to other single cancer sites studied or to all sites of cancer combined. Further epidemiological efforts are needed to ascertain the potential link between fried-food mutagens and cancer risk.

positive: Chronic intake of potato chips in humans increases the production of reactive oxygen radicals by leukocytes and increases plasma C-reactive protein... BACKGROUND: Relatively high concentrations of acrylamide in commonly ingested food products, such as French fries, potato chips, or cereals, may constitute a potential risk to human health. OBJECTIVE: The objective of this pilot study was to investigate the possible connection between chronic ingestion of acrylamide-containing potato chips and oxidative stress or inflammation. DESIGN: Fourteen healthy volunteers (mean age: 35 y; 8 women and 6 smokers of >20 cigarettes/d) were given 160 g of potato chips containing 157 microg [corrected] acrylamide daily for 4 wk. RESULTS: An increase in acrylamide-hemoglobin adducts in blood was found in all the study subjects, with a mean of 43.1 pmol x L(-1) x g(-1) hemoglobin (range: 27-76; P < 0.01) in nonsmokers and 59.0 pmol x L(-1) x g(-1) hemoglobin (range: 43-132; P < 0.05) in smokers. Concurrently, a significant increase (P < 0.01) in the oxidized LDL, high-sensitivity interleukin-6, high-sensitivity C-reactive protein, and gamma-glutamyltransferase concentrations was observed in both smokers and nonsmokers. A significant increase in reactive oxygen radical production by monocytes, lymphocytes, and granulocytes and an increase in CD14 expression in macrophages (P < 0.001) were found after intake of potato chips. Twenty-eight days from the discontinuation of the experiment, the variables under study decreased to some extent. It has been shown also that acrylamide increases the production of reactive oxygen species in isolated human monocyte-macrophages in vitro and decreases the cellular glutathione concentration. CONCLUSION: These novel findings seem to indicate that chronic ingestion of acrylamide-containing products induces a proinflammatory state, a risk factor for progression of atherosclerosis.

positive: Empirically derived dietary patterns and risk of postmenopausal breast cancer in a large prospective cohort study. BACKGROUND: Inconsistent associations have been reported between diet and breast cancer. OBJECTIVE: We prospectively examined the association between dietary patterns and postmenopausal breast cancer risk in a US-wide cohort study. DESIGN: Data were analyzed from 40 559 women who completed a self-administered 61-item Block food-frequency questionnaire in the Breast Cancer Detection Demonstration Project, 1987-1998; 1868 of those women developed breast cancer. Dietary patterns were defined by using principal components factor analysis. Cox proportional hazard regression was used to assess breast cancer risk. RESULTS: Three major dietary patterns emerged: vegetable-fish/poultry-fruit, beef/pork-starch, and traditional southern. The vegetable-fish/poultry-fruit pattern was associated with higher education than were the other patterns, but was similar in nutrient intake to the traditional southern pattern. After adjustment for confounders, there was no significant association between the vegetable-fish/poultry-fruit and beef/pork-starch patterns and breast cancer. The traditional southern pattern, however, was associated with a nonsignificantly reduced breast cancer risk among all cases (in situ and invasive) that was significant for invasive breast cancer (relative hazard = 0.78; 95% CI = 0.65, 0.95; P for trend = 0.003). This diet was also associated with a reduced risk in women without a family history of breast cancer (P = 0.05), who were underweight or normal weight [body mass index (in kg/m(2)) < 25; P = 0.02], or who had tumors positive for estrogen receptor (P = 0.01) or progesterone receptor (P = 0.003). Foods in the traditional southern pattern associated with reduced breast cancer risk were legumes, low mayonnaise-salad dressing intake, and possibly cabbage. CONCLUSIONS: The traditional southern diet or its components are associated with a reduced risk of invasive breast cancer in postmenopausal women.

positive: Consumption of deep-fried foods and risk of prostate cancera,b Background Evidence suggests that high-heat cooking methods may increase the risk of prostate cancer (PCa). The addition of oil/fat, as in deep-frying, may be of particular concern, and has not specifically been investigated in relation to PCa. Potential mechanisms include the formation of potentially carcinogenic agents such as aldehydes, acrolein, heterocyclic amines, polycyclic aromatic hydrocarbons, and acrylamide. Methods We estimated odds ratios (OR) and 95% confidence intervals (CI) for the association between tertiles of intake of deep-fried foods from a food frequency questionnaire (French fries, fried chicken, fried fish, doughnuts and snack chips) and PCa risk, adjusted for potential confounders, among 1,549 cases and 1,492 controls. We additionally examined associations with more aggressive PCa (defined as regional/distant stage, elevated Gleason score or prostate specific antigen level). Results Compared with <1/week, there was a positive association with PCa risk for intake ≥ 1/week of French fries (OR=1.37; 95% CI, 1.11–1.69), fried chicken (OR=1.30; 95% CI, 1.04–1.62), fried fish (OR=1.32; 95% CI, 1.05–1.66), and doughnuts (OR=1.35; 95% CI, 1.11–1.66). There was no association for snack chips (OR=1.08; 95% CI, 0.89–1.32). Most of the estimates were slightly stronger for more aggressive disease (OR=1.41; 95% CI, 1.04–1.92 for fried fish). Conclusion Regular consumption of select deep-fried foods is associated with increased PCa risk. Whether this risk is specific to deep-fried foods, or whether it represents risk associated with regular intake of foods exposed to high heat and/or other aspects of the Western lifestyle, such as fast food consumption, remains to be determined.

positive: Dietary acrylamide exposure of the French population: results of the second French Total Diet Study. Acrylamide is a heat-induced carcinogen compound that is found in some foods consequently to cooking or other thermal processes. In the second French Total Diet Study (TDS), acrylamide was analysed in 192 food samples collected in mainland France to be representative of the population diet and prepared "as consumed". Highest mean concentrations were found in potato chips/crisps (954 μg/kg), French fries and other fried potatoes (724 μg/kg), and salted biscuits other than potato chips (697 μg/kg). Exposure of general adult and child populations was assessed by combining analytical results with national consumption data. Mean acrylamide exposure was assessed to be 0.43±0.33 μg/kg of body weight (bw) per day for adults and 0.69±0.58 μg/kg bw/day for children. Although the exposure assessed is lower than in previous evaluations, the calculated margins of exposure, based on benchmark dose limits defined for carcinogenic effects, remain very low especially for young children (below 100 at the 95th percentile of exposure), indicating a health concern. It is therefore advisable to continue efforts in order to reduce dietary exposure to acrylamide. Copyright Â© 2012 Elsevier Ltd. All rights reserved.

positive: Acrylamide in foods: a review of the science and future considerations. Acrylamide occurs in foods commonly consumed in diets worldwide. It is formed from the reaction of reducing sugars (e.g., glucose or fructose) with the amino acid asparagine via the Maillard reaction, which occurs during heat processing of foods, primarily those derived from plant origin, such as potato and cereal products, above 120°C (248°F). The majority of epidemiological studies concerning potential relationships between acrylamide consumption and different types of cancer have indicated no increased risk, except with a few types that warrant further study. Efforts to reduce the formation of acrylamide in food products have resulted in some successes, but there is no common approach that works for all foods. Reduction in some foods is probably not possible. The results from a major toxicological study (aqueous intake of acrylamide by rats and mice) are in the process of being released. The status of current knowledge in these areas is reviewed.

positive: Birth Weight, Head Circumference, and Prenatal Exposure to Acrylamide from Maternal Diet: The European Prospective Mother–Child Study (NewGeneris) Background: Acrylamide is a common dietary exposure that crosses the human placenta. It is classified as a probable human carcinogen, and developmental toxicity has been observed in rodents. Objectives: We examined the associations between prenatal exposure to acrylamide and birth outcomes in a prospective European mother–child study. Methods: Hemoglobin (Hb) adducts of acrylamide and its metabolite glycidamide were measured in cord blood (reflecting cumulated exposure in the last months of pregnancy) from 1,101 singleton pregnant women recruited in Denmark, England, Greece, Norway, and Spain during 2006–2010. Maternal diet was estimated through food-frequency questionnaires. Results: Both acrylamide and glycidamide Hb adducts were associated with a statistically significant reduction in birth weight and head circumference. The estimated difference in birth weight for infants in the highest versus lowest quartile of acrylamide Hb adduct levels after adjusting for gestational age and country was –132 g (95% CI: –207, –56); the corresponding difference for head circumference was –0.33 cm (95% CI: –0.61, –0.06). Findings were similar in infants of nonsmokers, were consistent across countries, and remained after adjustment for factors associated with reduced birth weight. Maternal consumption of foods rich in acrylamide, such as fried potatoes, was associated with cord blood acrylamide adduct levels and with reduced birth weight. Conclusions: Dietary exposure to acrylamide was associated with reduced birth weight and head circumference. Consumption of specific foods during pregnancy was associated with higher acrylamide exposure in utero. If confirmed, these findings suggest that dietary intake of acrylamide should be reduced among pregnant women.

positive: A statistical regression model for the estimation of acrylamide concentrations in French fries for excess lifetime cancer risk assessment. Human exposure to acrylamide (AA) through consumption of French fries and other foods has been recognized as a potential health concern. Here, we used a statistical non-linear regression model, based on the two most influential factors, cooking temperature and time, to estimate AA concentrations in French fries. The R(2) of the predictive model is 0.83, suggesting the developed model was significant and valid. Based on French fry intake survey data conducted in this study and eight frying temperature-time schemes which can produce tasty and visually appealing French fries, the Monte Carlo simulation results showed that if AA concentration is higher than 168 ppb, the estimated cancer risk for adolescents aged 13-18 years in Taichung City would be already higher than the target excess lifetime cancer risk (ELCR), and that by taking into account this limited life span only. In order to reduce the cancer risk associated with AA intake, the AA levels in French fries might have to be reduced even further if the epidemiological observations are valid. Our mathematical model can serve as basis for further investigations on ELCR including different life stages and behavior and population groups. Copyright © 2012 Elsevier Ltd. All rights reserved.

positive: Dietary patterns and breast cancer risk among women. OBJECTIVE: Breast cancer is the most common type of cancer in women worldwide. Several studies have examined the role of single nutrients and food groups in breast cancer pathogenesis but fewer investigations have addressed the role of dietary patterns. Our main objective was to identify the relationship between major dietary patterns and breast cancer risk among Iranian women. DESIGN: Hospital-based case-control study. SETTING: Shohada Teaching Hospital, Tehran, Iran. SUBJECTS: Overall, 100 female patients aged 30-65 years with breast cancer and 174 female hospital controls were included in the present study. Dietary intake was assessed using a valid and reliable semi-quantitative FFQ consisting of 168 food items. RESULTS: Two dietary patterns were identified explaining 24·31 % of dietary variation in the study population. The 'healthy' food pattern was characterized by the consumption of vegetables, fruits, low-fat dairy products, legumes, olive and vegetable oils, fish, condiments, organ meat, poultry, pickles, soya and whole grains; while the 'unhealthy' food pattern was characterized by the consumption of soft drinks, sugars, tea and coffee, French fries and potato chips, salt, sweets and desserts, hydrogenated fats, nuts, industrial juice, refined grains, and red and processed meat. Compared with the lowest tertile, women in the highest tertile of the 'healthy' dietary pattern score had 75 % decreased risk of breast cancer (OR = 0·25, 95 % CI 0·08, 0·78), whereas women in the highest tertile of the 'unhealthy' dietary pattern had a significantly increased breast cancer risk (OR = 7·78, 95 % CI 2·31, 26·22). CONCLUSIONS: A healthy dietary pattern may be negatively associated with breast cancer risk, while an unhealthy dietary pattern is likely to increase the risk among Iranian women.

positive: Preschool diet and adult risk of breast cancer. Events before puberty may affect adult risk of breast cancer. We examined whether diet during preschool age may affect a woman's risk of breast cancer later in life. We conducted a case-control study including 582 women with breast cancer and 1,569 controls free of breast cancer selected from participants in the Nurses' Health Study and the Nurses' Health Study II. Information concerning childhood diet of the nurses at ages 3-5 years was obtained from the mothers of the participants with a 30-item food-frequency questionnaire. An increased risk of breast cancer was observed among woman who had frequently consumed French fries at preschool age. For one additional serving of French fries per week, the odds ratio (OR) for breast cancer adjusted for adult life breast cancer risk factors was 1.27 (95% confidence interval [CI] = 1.12-1.44). Consumption of whole milk was associated with a slightly decreased risk of breast cancer (covariate-adjusted OR for every additional glass of milk per day = 0.90; 95% CI = 0.82-0.99). Intake of none of the nutrients calculated was related to the risk of breast cancer risk in this study. These data suggest a possible association between diet before puberty and the subsequent risk of breast cancer. Differential recall of preschool diet by the mothers of cases and controls has to be considered as a possible explanation for the observed associations. Further studies are needed to evaluate whether the association between preschool diet and breast cancer is reproducible in prospective data not subject to recall bias. Copyright 2005 Wiley-Liss, Inc.

positive: Heterocyclic amines: Mutagens/carcinogens produced during cooking of meat and fish. Research leading to the discovery of a series of mutagenic and carcinogenic heterocyclic amines (HCAs) was inspired by the idea that smoke produced during cooking of food, especially meat or fish, might be carcinogenic. More than ten kinds of HCAs, actually produced by cooking or heating of meat or fish, have now been isolated and their structures determined, most being previously unregistered compounds. They are highly mutagenic towards Salmonella typhimurium in the presence of S9 mix and are also mutagenic in vitro and in vivo toward mammalian cells. HCAs have now been chemically synthesized in quantity and subjected to long-term animal testing. When HCAs were fed in the diet, rodents developed cancers in many organs, including the colon, breast and prostate, and one HCA produced hepatomas in monkeys. The lesions exhibited alteration in genes including Apc, beta-catenin and Ha-ras, and these changes provide clues to the induction mechanisms. The HCAs are oxidized to hydroxyamino derivatives by cytochrome P450s, and further converted to ester forms by acetyltransferase and sulfotransferase. Eventually, they produce DNA adducts through the formation of N-C bonds at guanine bases. There are HCA-sensitive and resistant strains of rodents and a search for the responsible genes is now under way. While the content of HCAs in dishes consumed in ordinary life is low and not sufficient in itself to explain human cancer, the coexistence of many other mutagens/carcinogens of either autobiotic or xenobiotic type and the possibility that HCAs induce genomic instability and heightened sensitivity to tumor promoters suggest that avoidance of exposure to HCAs or reduction of HCAs' biological effects as far as possible are to be highly recommended. Usage of microwave ovens for cooking and supplementation of the diet, for example with soy-isoflavones, which have been found to suppress the occurrence of HCA-induced breast cancers, should be encouraged. Advice to the general public about how to reduce the carcinogenic load imposed by HCAs would be an important contribution to cancer prevention.

positive: Pre-diagnostic acrylamide exposure and survival after breast cancer among postmenopausal Danish women. Acrylamide is a probable human carcinogen, with industrial contact, tobacco smoking and foods processed at high temperatures as the main routes of exposure. In animal studies oral intake of acrylamide has been related to cancer development, with indications that the increased cancer occurrence especially regards endocrine related tumors. In human epidemiological studies, dietary exposure to acrylamide has also been suggested related to higher risk of endocrine related tumors, like estrogen sensitive breast cancer. The aim of the present study was to evaluate if pre-diagnostic acrylamide exposure, measured by acrylamide and glycidamide hemoglobin adducts (AA-Hb and GA-Hb), were associated to mortality in breast cancer cases. Among 24,697 postmenopausal women included into a Danish cohort between 1993 and 1997, 420 developed breast cancer before 2001 and 110 died before 2009. AA-Hb and GA-Hb concentrations measured in blood samples were related to mortality by Cox proportional hazard models. Estimates are given per 25 pmol/g globin higher levels. Among non-smokers, higher concentrations of GA-Hb were associated to a higher hazard rate of breast cancer specific mortality (HR (95% CI): 1.63 (1.06-2.51)), the hazard rate among women diagnosed with estrogen receptor positive tumors was (HR (95% CI): 2.23 (1.38-3.61)). For AA-Hb the tendency was similar, but only statistically significant among those with estrogen receptor positive tumors (HR (95% CI): 1.31 (1.02-1.69)). In conclusion, the present study indicates that pre-diagnostic exposure to acrylamide may be related to mortality among breast cancer patients and that this may especially concern the most endocrine related type of breast cancer. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

positive: Vegetarian diet ameliorates symptoms of atopic dermatitis through reduction of the number of peripheral eosinophils and of PGE2 synthesis by monocy... Many patients with atopic dermatitis are dissatisfied with conventional treatments based on topical steroids and have experienced some traditional remedies and alternative therapies. However, most of such therapies have not been evaluated scientifically and clinically by specialists. This study was designed to assess whether a certain vegetarian diet might be effective for atopic dermatitis and if so, to identify the mechanisms of this remedy through analyses of immunological parameters. An open-trial study was carried out in twenty patients with atopic dermatitis. An improvement of dermatitis was evaluated by SCORAD index and serological and immunological parameters were monitored. After a two-month treatment, the severity of dermatitis was strikingly inhibited, as assessed by SCORAD index and serological parameters including LDH5 activity and a number of peripheral eosinophils. A sharp reduction in eosinophils and neutrophils was observed prior to improvement in the skin inflammation. In addition, PGE2 production by peripheral blood mononuclear cells was reduced by this treatment. In contrast, serum IgE levels did not change during the same period. Although this study is an open-trial one, it suggests that this treatment may be useful for the treatment of adult patients with severe atopic dermatitis.

positive: Double-blind, controlled, crossover study of cyclosporin in adults with severe refractory atopic dermatitis. A few patients remain severely affected by atopic dermatitis into adult life despite treatment with systemic steroids, azathioprine, and photochemotherapy. 33 patients took part in a double-blind, placebo-controlled, crossover study to assess the efficacy and safety of cyclosporin (5 mg/kg per day) in adults with severe refractory atopic dermatitis. Treatments were given for eight weeks each with one group (n = 16) receiving placebo followed by cyclosporin and another (n = 17) receiving cyclosporin and then placebo. Disease activity, extent of disease, sleep and itch, topical steroid use, and adverse events were assessed every two weeks. Both extent and activity of dermatitis were significantly improved (p less than 0.001) as were subjective measures of disease. 20 patients receiving cyclosporin reported adverse events compared with 8 taking placebo, although no patient required withdrawal from the study. Cyclosporin therapy led to an increase in the mean serum urea, creatinine, and bilirubin concentrations, although only the rise in bilirubin was significant (p = 0.001). Our results confirm that cyclosporin is a safe and effective short-term treatment for severe, refractory atopic dermatitis.

positive: Vegan regimen with reduced medication in the treatment of bronchial asthma. Thirty-five patients who had suffered from bronchial asthma for an average of 12 yr, all receiving long-term medication, 20 including cortisone, were subject to therapy with vegan food for 1 yr. In almost all cases, medication was withdrawn or drastically reduced. There was a significant decrease in asthma symptoms. Twenty-four patients (69%) fulfilled the treatment. Of these, 71% reported improvement at 4 months and 92% at 1 yr. There was a significant improvement in a number of clinical variables; for example, vital capacity, forced expiratory volume at one sec and physical working capacity, as well as a significant change in various biochemical indices as haptoglobin, IgM, IgE, cholesterol, and triglycerides in blood. Selected patients, with a fear of side-effects of medication, who are interested in alternative health care, might get well and replace conventional medication with this regimen.

positive: Side-effect profile of cyclosporin A in patients treated for psoriasis. This is a review of the side-effects of cyclosporin A (CyA) in patients with severe psoriasis; renal dysfunction and hypertension are discussed elsewhere. In particular, paraesthesia, hypertrichosis, gingival hyperplasia and gastrointestinal disorders may occur, but are generally transient, mild-to-moderate in severity and only rarely require discontinuation of CyA. Infections are not a problem. As expected with an immunosuppressive drug, there is the possible risk of tumour development, particularly squamous cell carcinomas. However, these skin malignancies developed almost exclusively in patients previously treated with PUVA and/or methotrexate. The few lymphoproliferative disorders regressed spontaneously on discontinuation of the drug. Whether the isolated cases of solid tumours were CyA-related is not known. Apart from a raised serum creatinine, an important indicator of renal dysfunction, the laboratory abnormalities included hypomagnesaemia, hyperkalaemia, increased uric acid, changes in liver function tests, and fluctuations in the serum cholesterol and triglyceride levels. Although most of these changes were not clinically relevant, laboratory monitoring of patients with psoriasis treated with CyA is essential.

positive: Arsenic, Organic Foods, and Brown Rice Syrup Background: Rice can be a major source of inorganic arsenic (Asi) for many sub-populations. Rice products are also used as ingredients in prepared foods, some of which may not be obviously rice based. Organic brown rice syrup (OBRS) is used as a sweetener in organic food products as an alternative to high-fructose corn syrup. We hypothesized that OBRS introduces As into these products. Objective: We determined the concentration and speciation of As in commercially available brown rice syrups and in products containing OBRS, including toddler formula, cereal/energy bars, and high-energy foods used by endurance athletes. Methods: We used inductively coupled plasma mass spectrometry (ICP-MS) and ion chromatography coupled to ICP-MS to determine total As (Astotal) concentrations and As speciation in products purchased via the Internet or in stores in the Hanover, New Hampshire, area. Discussion: We found that OBRS can contain high concentrations of Asi and dimethyl-arsenate (DMA). An “organic” toddler milk formula containing OBRS as the primary ingredient had Astotal concentrations up to six times the U.S. Environmental Protection Agency safe drinking water limit. Cereal bars and high-energy foods containing OBRS also had higher As concentrations than equivalent products that did not contain OBRS. Asi was the main As species in most food products tested in this study. Conclusions: There are currently no U.S. regulations applicable to As in food, but our findings suggest that the OBRS products we evaluated may introduce significant concentrations of Asi into an individual’s diet. Thus, we conclude that there is an urgent need for regulatory limits on As in food.

positive: Arsenic and lead in juice: apple, citrus, and apple-base. Exposure limits for arsenic and lead in drinking water have long been established by the U.S. Environmental Protection Agency and new regulations regarding the presence of these contaminants in bottled water went into effect in California in 2009. No comparable exposure limits or regulations are available, however, for juices and other beverages that may contain arsenic and lead. In the study described in this article, 20 apple juices (or ciders), 15 apple-containing juices, one grape, and one citrus juice were analyzed for arsenic and lead. Arsenic was detected in all juices while lead was detected in more than 94% of juices analyzed. Twelve samples (32%) demonstrated arsenic levels nearly at or above the drinking water exposure limit of 10 parts per billion. No juices contained lead above drinking water exposure limits. Expanding drinking water limits to include juices (and other frequently consumed beverages) would better protect consumers while regular testing of these juices would better inform consumers of the risks posed by specific juices and brands.

positive: Roxarsone, Inorganic Arsenic, and Other Arsenic Species in Chicken: A U.S.-Based Market Basket Sample Background: Inorganic arsenic (iAs) causes cancer and possibly other adverse health outcomes. Arsenic-based drugs are permitted in poultry production; however, the contribution of chicken consumption to iAs intake is unknown. Objectives: We sought to characterize the arsenic species profile in chicken meat and estimate bladder and lung cancer risk associated with consuming chicken produced with arsenic-based drugs. Methods: Conventional, antibiotic-free, and organic chicken samples were collected from grocery stores in 10 U.S. metropolitan areas from December 2010 through June 2011. We tested 116 raw and 142 cooked chicken samples for total arsenic, and we determined arsenic species in 65 raw and 78 cooked samples that contained total arsenic at ≥ 10 µg/kg dry weight. Results: The geometric mean (GM) of total arsenic in cooked chicken meat samples was 3.0 µg/kg (95% CI: 2.5, 3.6). Among the 78 cooked samples that were speciated, iAs concentrations were higher in conventional samples (GM = 1.8 µg/kg; 95% CI: 1.4, 2.3) than in antibiotic-free (GM = 0.7 µg/kg; 95% CI: 0.5, 1.0) or organic (GM = 0.6 µg/kg; 95% CI: 0.5, 0.8) samples. Roxarsone was detected in 20 of 40 conventional samples, 1 of 13 antibiotic-free samples, and none of the 25 organic samples. iAs concentrations in roxarsone-positive samples (GM = 2.3 µg/kg; 95% CI: 1.7, 3.1) were significantly higher than those in roxarsone-negative samples (GM = 0.8 µg/kg; 95% CI: 0.7, 1.0). Cooking increased iAs and decreased roxarsone concentrations. We estimated that consumers of conventional chicken would ingest an additional 0.11 µg/day iAs (in an 82-g serving) compared with consumers of organic chicken. Assuming lifetime exposure and a proposed cancer slope factor of 25.7 per milligram per kilogram of body weight per day, this increase in arsenic exposure could result in 3.7 additional lifetime bladder and lung cancer cases per 100,000 exposed persons. Conclusions: Conventional chicken meat had higher iAs concentrations than did conventional antibiotic-free and organic chicken meat samples. Cessation of arsenical drug use could reduce exposure and the burden of arsenic-related disease in chicken consumers.

positive: Efficacy of IP6 + inositol in the treatment of breast cancer patients receiving chemotherapy: prospective, randomized, pilot clinical study Background Prospective, randomized, pilot clinical study was conducted to evaluate the beneficial effects of inositol hexaphosphate (IP6) + Inositol in breast cancer patients treated with adjuvant therapy. Patients and methods Patients with invasive ductal breast cancer where polychemotherapy was indicated were monitored in the period from 2005-2007. Fourteen patients in the same stage of ductal invasive breast cancer were involved in the study, divided in two randomized groups. One group was subjected to take IP6 + Inositol while the other group was taking placebo. In both groups of patients the same laboratory parameters were monitored. When the treatment was finished, all patients have filled questionnaires QLQ C30 and QLQ-BR23 to determine the quality of life. Results Patients receiving chemotherapy, along with IP6 + Inositol did not have cytopenia, drop in leukocyte and platelet counts. Red blood cell counts and tumor markers were unaltered in both groups. However, patients who took IP6 + Inositol had significantly better quality of life (p = 0.05) and functional status (p = 0.0003) and were able to perform their daily activities. Conclusion IP6 + Inositol as an adjunctive therapy is valuable help in ameliorating the side effects and preserving quality of life among the patients treated with chemotherapy.

positive: Traditional non-Western diets. In traditional cultures, balancing health with a balanced lifestyle was a core belief. The diseases of modern civilization were rare. Indigenous people have patterns of illness very different from Western civilization; yet, they rapidly develop diseases once exposed to Western foods and lifestyles. Food and medicine were interwoven. All cultures used special or functional foods to prevent disease. Food could be used at different times either as food or medicine. Foods, cultivation, and cooking methods maximized community health and well-being. With methods passed down through generations, cooking processes were utilized that enhanced mineral and nutrient bioavailability. This article focuses on what researchers observed about the food traditions of indigenous people, their disease patterns, the use of specific foods, and the environmental factors that affect people who still eat traditional foods.

positive: The effect of inositol hexaphosphate on the expression of selected metalloproteinases and their tissue inhibitors in IL-1β-stimulated colon cancer cells Introduction Matrix metalloproteinases (MMPs) have repeatedly been shown to play a very active role in extracellular matrix degradation associated with tumor invasion and metastasis. Tissue inhibitors of MMPs (TIMPs) are well-known for their ability to inhibit MMP activity thereby inhibiting malignant progression. Inositol hexaphosphate (IP6 phytic acid) has been recognized to have both preventive and therapeutic effects against various cancers including that of colon. In in vitro studies, IP6 has been demonstrated to inhibit cancer cell adhesion and migration. In the present study, the effect of IP6 on the expression of MMP and TIMP genes was evaluated in unstimulated and IL-1β-stimulated colon cancer cell line Caco-2. Materials and methods Real-time QRT-PCR was used to validate the transcription level of selected MMP and TIMP genes in Caco-2 cells after treatment with 1 ng/ml of IL-1β, 2.5 mM of IP6, and both for 6, 12, and 24 h. Results Stimulation of cells with IL-1β only resulted in an overexpression of MMP and their TIMP mRNAs. A significant decrease in MMP-13, MMP-3, MMP-2, and TIMP-1 basal expression was achieved by IP6. IP6 was also an efficient downregulator of MMP-1, MMP-9, and TIMP-2 genes transcription stimulated by IL-1β in 6 h lasting culture. After 12 h, IL-1β-induced MMP-2 mRNA expression was significantly reduced by IP6. Conclusion Proinflammatory cytokine IL-1β upregulates MMP and TIMP mRNAs expression in colon cancer epithelial cells Caco-2. IP6 (2.5 mM) influences constitutive expression of both MMP and TIMP genes and downregulates IL-1β stimulated transcription of some of these genes. IP6 exerts its anti-metastatic activity through modulation of MMP and TIMP genes expression to prevent cancer cell migration and invasion.

positive: Diet and colorectal cancer: a case-control study in Greece. A case-control study probing the role of diet on the incidence of colorectal cancer was undertaken in Athens, Greece, in a population characterized by ethnic homogeneity but substantial heterogeneity with respect to dietary habits. The case series consisted of 100 consecutive patients with histologically confirmed colorectal cancer admitted to two large hospitals of Athens during a 16-month period; the control series consisted of orthopaedic patients, admitted to the same hospitals during the same time period, individually matched to the index cases by age and sex. Dietary histories concerning the frequency of consumption (per month or per week) of about 80 food items were obtained by the same interviewer. Cases reported significantly less frequent consumption of vegetables (particularly beets, spinach, lettuce and cabbage) and, independently, significantly more frequent consumption of meat (notably lamb and beef). Between the two extremes (high-vegetable, low-meat diet versus high-meat, low-vegetable diet) a risk ratio of about 8 appears to exist, sufficient (in size and direction) to explain a substantial part of the international variation in the incidence of colorectal cancer. Significant associations were not found with beer or other alcoholic beverages, and significant interactions were not noted with respect to age, sex and anatomic localization (colon vs. rectum).

positive: Dietary suppression of colonic cancer. Fiber or phytate? The incidence of colonic cancer differs widely between various human populations. It has been suggested that dietary fiber content is of utmost importance and is inversely related to the occurrence of colonic cancer. However, high-fiber diets are not always correlated with low frequency of colonic cancer, suggesting the involvement of additional dietary constituents. Inositol hexaphosphate (phytic acid) is an abundant plant seed component present in many, but not all, fiber-rich diets. The authors have found that phytic acid is a potent inhibitor of iron-mediated generation of the hazardous oxidant, hydroxyl radical. Herein, the authors propose that inhibition of intracolonic hydroxyl radical generation, via the chelation of reactive iron by phytic acid, may help explain the suppression of colonic carcinogenesis and other inflammatory bowel diseases by diets rich in phytic acid.

positive: Prostate cancer and inositol hexaphosphate: efficacy and mechanisms. There are now extensive scientific data suggesting the potential role of dietary and non-dietary phytochemicals in the prevention and control of prostate cancer (PCA) growth and progression. PCA is a disease of elderly male populations with a relatively slower rate of growth and progression as compared to most other cancers and, therefore, is a candidate disease for preventive intervention. Overall, PCA growth and progression involve aberrant mitogenic and survival signaling and deregulated cell cycle progression, accompanied by gradual accumulation of genetic and epigenetic changes over a period of years. Several mechanisms, including overexpression of growth, survival and angiogenic factors and their receptors, together with a loss/decrease of tumor suppressor p53, retinoblastoma and cyclin-dependent kinase inhibitor, have been implicated in PCA growth and progression. Therefore, phytochemicals targeting these molecular events could have a promising role in PCA prevention and/or therapy. Inositol hexaphosphate (IP6) is a major constituent of most cereals, legumes, nuts, oil seeds and soybean. Taken orally as an over-the-counter dietary/nutrient supplement, and is recognised as offering several health benefits without any known toxicity. In vitro anticancer efficacy of IP6 has been observed in many human, mouse and rat prostate cancer cells. Completed studies also show that oral feeding of IP6 inhibits human PCA xenograft growth in nude mice without toxicity. In a recently completed pilot study, we observed similar preventive effects of IP6 on prostate tumorigenesis in the TRAMP model. Mechanistic studies indicate that IP6 targets mitogenic and survival signaling, as well as cell cycle progression, in PCA cells. IP6 is also shown to target molecular events associated with angiogenesis. Moreover, IP6 has pleiotropic molecular targets for its overall efficacy against PCA and, therefore, could be a suitable candidate agent for preventive intervention of this malignancy in humans.

positive: High Dry Bean Intake and Reduced Risk of Advanced Colorectal Adenoma Recurrence among Participants in the Polyp Prevention Trial Adequate fruit and vegetable intake was suggested to protect against colorectal cancer and colorectal adenomas; however, several recent prospective studies reported no association. We examined the association between fruits and vegetables and adenomatous polyp recurrence in the Polyp Prevention Trial (PPT). The PPT was a low-fat, high-fiber, high-fruit, and vegetable dietary intervention trial of adenoma recurrence, in which there were no differences in the rate of adenoma recurrence in participants in the intervention and control arms of the trial. In this analysis of the entire PPT trial–based cohort, multiple logistic regression analysis was used to estimate the odds ratio (OR) of advanced and nonadvanced adenoma recurrence within quartiles of baseline and change (baseline minus the mean over 3 y) in fruit and vegetable intake, after adjustment for age, total energyy intake, use of nonsteroidal anti-inflammatory drugs, BMI, and gender. There were no significant associations between nonadvanced adenoma recurrence and overall change in fruit and vegetable consumption; however, those in the highest quartile of change in dry bean intake (greatest increase) compared with those in the lowest had a significantly reduced OR for advanced adenoma recurrence (OR = 0.35; 95% CI, 0.18–0.69; P for trend = 0.001). The median in the highest quartile of change in dry bean intake was 370% higher than the baseline intake. The PPT trial–based cohort provides evidence that dry beans may be inversely associated with advanced adenoma recurrence.

positive: Colorectal cancer and diet in an Asian population--a case-control study among Singapore Chinese. A hospital-based case-control study of diet and colorectal cancer was conducted among Chinese in Singapore (who constitute 77% of the population). A total of 203 cases and 425 controls were included. A history of the usual dietary intake one year prior to interview was taken using a quantitative food frequency questionnaire. Daily intakes of nutrients and selected food items were computed and stratified by tertiles of the control range, to assess risk in low-, medium- and high-intake categories. Effects were adjusted in analysis for age, sex, Chinese dialect group and occupation. For cancers of colon and rectum combined, significant observations were a protective effect of high cruciferous vegetable intake (OR = 0.50, p less than 0.01) and a predisposing effect of a high meat/vegetable consumption ratio (OR = 1.77, p less than 0.05). Similar results were observed for colon cancer alone. For rectal cancer alone (only 71 cases), significant (p less than 0.05) protective effects were observed for high intakes of protein (OR = 0.61), fibre (OR = 0.46), beta-carotene (OR = 0.54), cruciferous vegetables (OR = 0.51) and total vegetables (OR = 0.51). When further assessed by multiple logistic regression, tests for trend and assessment of risk in the extreme highest and lowest quintiles of the control range, the factors consistently significant were cruciferous vegetable intake and the meat/vegetable ratio. A particularly high relative risk was also noted in association with low coffee consumption (OR = 1.59, with p less than 0.05 for trend). No consistent trends were noted for fat or fibre intakes. For non-dietary variables investigated, a history of cholecystectomy increased the risk of both cancers combined (OR = 3.43, p less than 0.05) and colon cancer alone (OR = 4.39, p less than 0.01). This study in an Asian population of countries of Southern and Eastern Asia newly undergoing industrialization and in which rapid economic change is reflected in changing cancer patterns, suggests that the protective effects of certain dietary constituents, notably the cruciferous vegetables, may be more important than the hitherto stressed carcinogenic potential of fat and protein.

positive: Effect of inositol hexaphosphate (IP(6)) on human normal and leukaemic haematopoietic cells. Inositol hexaphosphate (IP(6)), a naturally polyphosphorylated carbohydrate, has been reported to have significant in vivo and in vitro anticancer activity against numerous tumours, such as colon, prostate, breast, liver and rhabdomyosarcomas. To confirm this activity in haematological malignancies and to characterize some of the mechanisms of IP(6) action, we analysed its effects on human leukaemic cell lines and fresh chronic myelogenous leukaemia (CML) progenitor cells using a combined cellular and molecular approach. IP(6) had a dose-dependent cytotoxic effect on all of the evaluated cell lines, with accumulation in the G2M phase in two out of five cell lines tested. At the molecular level, cDNA microarray analysis after IP(6) exposure showed an extensive downmodulation of genes involved in transcription and cell cycle regulation and a coherent upregulation of cell cycle inhibitors. Furthermore, IP(6) treatment of fresh leukaemic samples of bone marrow CD34+ CML progenitor cells significantly inhibited granulocyte-macrophage colony-forming unit (CFU-GM) formation (P = 0.0062) in comparison to normal bone marrow specimens, which were not affected. No differentiating effect on HL60 cells was observed. Taken together, our results confirm the antiproliferative activity of IP(6) and suggest that it may have a specific antitumour effect also in chronic myeloid leukaemias, via active gene modulation.

positive: Dietary risk factors for colon cancer in a low-risk population. In a 6-year prospective study, the authors examined the relation between diet and incident colon cancer among 32,051 non-Hispanic white cohort members of the Adventist Health Study (California, 1976-1982) who, at baseline, had no documented or reported history of cancer. The risk of colon cancer was determined from proportional hazards regression with adjustment for age and other covariates. The authors found a positive association with total meat intake (risk ratio (RR) for > or =1 time/week vs. no meat intake = 1.85, 95% confidence interval (CI) 1.19-2.87; p for trend = 0.01) and, among subjects who favored specific types of meat, positive associations with red meat intake (RR for > or =1 time/week vs. no red meat intake = 1.90, 95% CI 1.16-3.11; p for trend = 0.02) and white meat intake (RR for > or =1 time/week vs. no white meat intake = 3.29, 95% CI 1.60-6.75; p for trend = 0.006). An inverse association with legume intake (RR for >2 times/week vs. <1 time/week = 0.53, 95% CI 0.33-0.86; p for trend = 0.03) was observed. Among men, a positive association with body mass index was observed (relative to the RR for tertile III (>25.6 kg/m2) vs. tertile I (<22.5 kg/m2) = 2.63, 95% CI 1.12-6.13; p for trend = 0.05). A complex relation was identified whereby subjects exhibiting a high red meat intake, a low legume intake, and a high body mass experienced a more than threefold elevation in risk relative to all other patterns based on these variables. This pattern of putative risk factors would likely contribute to increases in both insulin resistance (high body mass, high red meat intake) and glycemic load (low legume intake), a synergism that, if causal, implicates hyperinsulinemic exposure in colon carcinogenesis. The overall findings from this cohort identify both red meat intake and white meat intake as important dietary risk factors for colon cancer and raise the possibility that the risk due to red meat intake reflects a more complex etiology.

positive: Apoptosis induced by death receptors. Death receptors belong to the TNF receptor family and are characterised by an intracellular death domain that serves to recruit adapter proteins such as TRADD and FADD and cysteine proteases such as Caspase-8. Activation of Caspase-8 on the aggregated receptor leads to apoptosis. Triggering of death receptors is mediated through the binding of specific ligands of the TNF family, which are homotrimeric type-2 membrane proteins displaying three receptor binding sites. There are various means of modulating the activation of death receptors. The status of the ligand (membrane-bound vs. soluble) is critical in the activation of Fas and of TRAIL receptors. Cleavage of membrane-bound FasL to a soluble form (sFasL) does not affect its ability to bind to Fas but drastically decreases its cytotoxic activity. Conversely, cross-linking epitope-tagged sFasL with anti-tag antibodies to mimic membrane-bound ligand results in a 1000-fold increase in cytotoxicity. This suggests that more than three Fas molecules need to be aggregated to efficiently signal apoptosis. Death receptors can also be regulated by decoy receptors. The cytotoxic ligand TRAIL interacts with five receptors, only two of which (TRAIL-R1 and -R2) have a death domain. TRAIL-R3 is anchored to the membrane by a glycolipid and acts as a dominant negative inhibitor of TRAIL-mediated apoptosis when overexpressed on TRAIL-sensitive cells. Intracellular proteins interacting with the apoptotic pathway are potential modulators of death receptors. FLIP resembles Caspase-8 in structure but lacks protease activity. It interacts with both FADD and Caspase-8 to inhibits the apoptotic signal of death receptors and, at the same time, can activate other signalling pathways such as that leading to NF-kappa B activation.

positive: Curcumin induces apoptosis in human non-small cell lung cancer NCI-H460 cells through ER stress and caspase cascade- and mitochondria-dependent pat... It has been reported that curcumin inhibited various types of cancer cells in vitro and in vivo. However, mechanisms of curcumin-inhibited cell growth and -induced apoptosis in human non-small cell lung cancer cells (NCI-H460) still remain unclear. In this study, NCI-H460 cells were treated with curcumin to determine its anticancer activity. Different concentrations of curcumin were used for different durations in NCI-H460 cells and the subsequent changes in the cell morphology, viability, cell cycle, mRNA and protein expressions were determined. Curcumin induced apoptotic morphologic changes in NCI-H460 cells in a dose-dependent manner. After curcumin treatment, BAX and BAD were up-regulated, BCL-2, BCL-X(L) and XIAP were down-regulated. In addition, reactive oxygen species (ROS), intracellular Ca(2+) and endoplasmic reticulum (ER) stress were increased in NCI-H460 cells after exposure to curcumin. These signals led to a loss of mitochondrial membrane potential (Delta Psi(m)) and culminated in caspase-3 activation. Curcumin-induced apoptosis was also stimulated through the FAS/caspase-8 (extrinsic) pathway and ER stress proteins, growth arrest- and DNA damage-inducible gene 153 (GADD153) and glucose-regulated protein 78 (GRP78) were activated in the NCI-H460 cells. Apoptotic cell death induced by curcumin was significantly reversed by pretreatment with ROS scavenger or caspase-8 inhibitor. Furthermore, the NCI-H460 cells tended to be arrested at the G(2)/M cell cycle stage after curcumin treatment and down-regulation of cyclin-dependent kinase 1 (CDK1) may be involved. In summary, curcumin exerts its anticancer effects on lung cancer NCI-H460 cells through apoptosis or cell cycle arrest.

positive: Molecular mechanisms of curcumin action: gene expression. Curcumin derived from the tropical plant Curcuma longa has a long history of use as a dietary agent, food preservative, and in traditional Asian medicine. It has been used for centuries to treat biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism, and sinusitis. The preventive and therapeutic properties of curcumin are associated with its antioxidant, anti-inflammatory, and anticancer properties. Extensive research over several decades has attempted to identify the molecular mechanisms of curcumin action. Curcumin modulates numerous molecular targets by altering their gene expression, signaling pathways, or through direct interaction. Curcumin regulates the expression of inflammatory cytokines (e.g., TNF, IL-1), growth factors (e.g., VEGF, EGF, FGF), growth factor receptors (e.g., EGFR, HER-2, AR), enzymes (e.g., COX-2, LOX, MMP9, MAPK, mTOR, Akt), adhesion molecules (e.g., ELAM-1, ICAM-1, VCAM-1), apoptosis related proteins (e.g., Bcl-2, caspases, DR, Fas), and cell cycle proteins (e.g., cyclin D1). Curcumin modulates the activity of several transcription factors (e.g., NF-κB, AP-1, STAT) and their signaling pathways. Based on its ability to affect multiple targets, curcumin has the potential for the prevention and treatment of various diseases including cancers, arthritis, allergies, atherosclerosis, aging, neurodegenerative disease, hepatic disorders, obesity, diabetes, psoriasis, and autoimmune diseases. This review summarizes the molecular mechanisms of modulation of gene expression by curcumin. Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.

positive: p-Nonyl-phenol: an estrogenic xenobiotic released from "modified" polystyrene. Alkylphenols are widely used as plastic additives and surfactants. We report the identification of an alkylphenol, nonylphenol, as an estrogenic substance released from plastic centrifuge tubes. This compound was extracted with methanol, purified by flash chromatography and reverse-phase high performance liquid chromatography, and identified by gas chromatography-mass spectrometry. Nonylphenol induced both cell proliferation and progesterone receptor in human estrogen-sensitive MCF7 breast tumor cells. Nonylphenol also triggered mitotic activity in rat endometrium; this result confirms the reliability of the MCF7 cell proliferation bioassay. The estrogenic properties of alkylphenols, specifically nonylphenols, indicate that the use of plasticware containing these chemicals in experimental and diagnostic tests may lead to spurious results, and these compounds as well as alkylphenol polyethoxylates may also be potentially harmful to exposed humans and the environment at large.

positive: Do fast foods cause asthma, rhinoconjunctivitis and eczema? Global findings from the International Study of Asthma and Allergies in Childhood (ISAA... BACKGROUND: Certain foods may increase or decrease the risk of developing asthma, rhinoconjunctivitis and eczema. We explored the impact of the intake of types of food on these diseases in Phase Three of the International Study of Asthma and Allergies in Childhood. METHODS: Written questionnaires on the symptom prevalence of asthma, rhinoconjunctivitis and eczema and types and frequency of food intake over the past 12 months were completed by 13-14-year-old adolescents and by the parents/guardians of 6-7-year-old children. Prevalence ORs were estimated using logistic regression, adjusting for confounders, and using a random (mixed) effects model. RESULTS: For adolescents and children, a potential protective effect on severe asthma was associated with consumption of fruit ≥3 times per week (OR 0.89, 95% CI 0.82 to 0.97; OR 0.86, 95% CI 0.76 to 0.97, respectively). An increased risk of severe asthma in adolescents and children was associated with the consumption of fast food ≥3 times per week (OR 1.39, 95% CI 1.30 to 1.49; OR 1.27, 95% CI 1.13 to 1.42, respectively), as well as an increased risk of severe rhinoconjunctivitis and severe eczema. Similar patterns for both ages were observed for regional analyses, and were consistent with gender and affluence categories and with current symptoms of all three conditions. CONCLUSIONS: If the association between fast foods and the symptom prevalence of asthma, rhinoconjunctivitis and eczema is causal, then the findings have major public health significance owing to the rising consumption of fast foods globally.

positive: Dietary exposure to xenoestrogens in New Zealand. Continuing evidence of the feminising effects of xenoestrogens on a range of wildlife species increases the need to assess the human health risk of these estrogen mimics. We have estimated the exposure of New Zealand males, females and young men to a range of naturally occurring and synthetic xenoestrogens found in food. Only estrogenic compounds that act by interaction with the estrogen receptor have been included. Theoretical plasma estrogen activity levels were derived from estrogen exposure estimates and estrogenic potency data. Theoretical plasma levels were compared with published data for specific xenoestrogens. There was surprisingly close agreement. Xenoestrogenicity from dietary intake was almost equally attributed to naturally occurring and synthetic xenoestrogens. Relative contributions for a male, for example were isoflavones (genistein and daidzein) (36%) and bisphenol A (34%) with smaller contributions from alkyl phenols (18%) and the flavonoids (phloretin and kaempferol) (12%). It is suggested that dietary xenoestrogens might have a pharmacological effect on New Zealand males and postmenopausal women, but are unlikely to be significant for pre-menopausal women.

positive: Comparison of Short-Term Estrogenicity Tests for Identification of Hormone-Disrupting Chemicals The aim of this study was to compare results obtained by eight different short-term assays of estrogenlike actions of chemicals conducted in 10 different laboratories in five countries. Twenty chemicals were selected to represent direct-acting estrogens, compounds with estrogenic metabolites, estrogenic antagonists, and a known cytotoxic agent. Also included in the test panel were 17beta++-estradiol as a positive control and ethanol as solvent control. The test compounds were coded before distribution. Test methods included direct binding to the estrogen receptor (ER), proliferation of MCF-7 cells, transient reporter gene expression in MCF-7 cells, reporter gene expression in yeast strains stably transfected with the human ER and an estrogen-responsive reporter gene, and vitellogenin production in juvenile rainbow trout. 17beta-Estradiol, 17alpha-ethynyl estradiol, and diethylstilbestrol induced a strong estrogenic response in all test systems. Colchicine caused cytotoxicity only. Bisphenol A induced an estrogenic response in all assays. The results obtained for the remaining test compounds--tamoxifen, ICI 182.780, testosterone, bisphenol A dimethacrylate, 4-n-octylphenol, 4-n-nonylphenol, nonylphenol dodecylethoxylate, butylbenzylphthalate, dibutylphthalate, methoxychlor, o,p'-DDT, p,p'-DDE, endosulfan, chlomequat chloride, and ethanol--varied among the assays. The results demonstrate that careful standardization is necessary to obtain a reasonable degree of reproducibility. Also, similar methods vary in their sensitivity to estrogenic compounds. Thus, short-term tests are useful for screening purposes, but the methods must be further validated by additional interlaboratory and interassay comparisons to document the reliability of the methods.

positive: Inadvertent exposure to xenoestrogens. Over the last 40 years there have been constant reports concerning environmental chemicals with hormone-like effects in wildlife. An endocrine disruptor is an exogenous substance that causes adverse health effects in an intact organism or its progeny, secondary to changes in endocrine function. Endocrine disruptors of widely diverse chemical structures that have oestrogenic properties are known as oestrogenic xenobiotics or xenoestrogens. Some of these substances, such as phytoestrogens and mycoestrogens, can come from diet or from the environment. Although the oestrogenic activity of these substances is weaker than that of oestradiol, new chemicals with endocrine disrupting potential continue to be discovered, inadvertent forms of exposure are constantly being identified, and there is increasing concern about cumulative effects. Studies in the 1960s and 1970s characterized the oestrogenicity of a number of industrial compounds and the pesticides o,p-DDT, kepone, methoxychlor, phenolic derivatives and polychlorinated biphenyls (PCBs). In the last 5 years, several environmental chemicals have been added to the list of xenoestrogens, including the pesticides toxaphene, dieldrin and endosulphan, and several different compounds used in the food industry, antioxidants such a t-butylhydroxyanisole; plasticizers such as benzylbutylphthalate and 4-OH-alkylphenols; and substances used in dental restorations, such as bisphenol-A. The relevance of these newly discovered endocrine disruptors to human health is now starting to emerge. The few studies that have investigated their effect in humans point in the same direction: if there is indeed an association between exposure to substances with hormone-disruptive activity and certain disorders of endocrine organs, the incidence of such disorders would be greater in areas where exposure to agents with this activity is high. A closer scrutiny is required to determine whether these newly discovered endocrine disrupting chemicals contribute, together with oestrogenic pesticides, to the exposure of humans to xenoestrogens.

positive: Alkylphenols in human milk and their relations to dietary habits in central Taiwan. The aims of this study were to determine the concentrations of 4-nonylphenol (NP) and 4-octylphenol (OP) in 59 human milk samples and to examine related factors including mothers' demographics and dietary habits. Women who consumed over the median amount of cooking oil had significantly higher OP concentrations (0.98 ng/g) than those who consumed less (0.39 ng/g) (P < 0.05). OP concentration was significantly associated with the consumption of cooking oil (beta = 0.62, P < 0.01) and fish oil capsules (beta = 0.39, P < 0.01) after adjustment for age and body mass index (BMI). NP concentration was also significantly associated with the consumption of fish oil capsules (beta = 0.38, P < 0.01) and processed fish products (beta = 0.59, P < 0.01). The food pattern of cooking oil and processed meat products from factor analysis was strongly associated with OP concentration in human milk (P < 0.05). These determinations should aid in suggesting foods for consumption by nursing mothers in order to protect their infants from NP/OP exposure. 2010 Elsevier Ltd. All rights reserved.

positive: Xeno-estrogenic compounds in precipitation. The exposure to some chemicals can lead to hormone disrupting effects. Presently, much attention is focused on so-called xeno-estrogens, synthetic compounds that interact with hormone receptors causing a number of reactions that eventually lead to effects related to reproduction and development. The current study was initiated to investigate the presence of a number of such compounds in precipitation as a follow-up on a previous study in which pesticide concentrations in air and precipitation were determined. Rainwater samples were collected at about 50 locations in The Netherlands in a four week period. The samples were analysed for bisphenol-A, alkylphenols and alkylphenol ethoxylates, phthalates, flame retardants and synthetic musk compounds. The results clearly indicated the presence of these compounds in precipitation. The concentrations ranged from the low ng l(-1) range for flame retardants to several thousands of ng l(-1) for the phthalates. Bisphenol-A was found in 30% of the samples in concentrations up to 130 ng l(-1), while alkylphenols and alkylphenol ethoxylates were found in virtually all locations in concentrations up to 920 ng l(-1) for the individual compounds. Phthalates were by far the most abundant xeno-estrogens in the precipitation samples and were found in every sample. Di-isodecyl phthalate was found in a surprisingly high concentration of almost 100 000 ng l(-1). Polybrominated flame retardants were found in the low ng l(-1) range and generally in less than 20% of the samples. Noticeable was the finding of hexabromocyclododecane, a replacement for the polybrominted diphenyl ethers at one location in a concentration of almost 2000 ng l(-1). Finally, as expected, synthetic musk compounds were detected in almost all samples. This is especially true for the polycyclic musks HHCB and AHTN. Nitro musks were found, but only on a few locations. Kriging techniques were used to calculate precipitation concentrations in between actual sampling locations to produce contour plots for a number of compounds. These plots clearly show located emission sources for a number of compounds such as bisphenol-A, nonylphenol ethoxylate, phthalates and AHTN. On the contrary, the results for HHCB and some phthalates indicated diffuse emission patterns, probably as the result of the use of consumer products containing these compounds.

positive: Nonylphenol and octylphenol in human breast milk. Human milk is the most important form of nourishment for newborn children. Its consumption is strongly recommended by health authorities also for other important advantages. Unfortunately, in the last three decades a great number of investigations have shown the occurrence of several environmental contaminants in human milk, especially those with lipophilic properties. This study investigates the presence of nonylphenol, octylphenol (OP), nonylphenol monoethoxylate (NP1EO) and two octylphenol ethoxylates (OPEOs) (namely OP1EO and OP2EO), in human breast milk of Italian women. NP was the contaminant found at the highest levels with mean concentrations of 32 ng/mL, about two orders of magnitude higher than OP (0.08 ng/mL), OP1EO (0.07 ng/mL) and OP2EO (0.16 ng/mL). In the group of study a positive correlation among fish consumption and levels of NP in the milk was observed, in accordance with the evidence that seafood represents one of the most important sources of exposure to this group of contaminants in Italy. On the basis of the concentrations found in the breast milk samples, a maximum NP daily intake of 3.94 microg/kg/day can be calculated, which is close to the Tolerable Daily Intake (TDI) of 5 microg/kg body weight (bw) proposed by the Danish Institute of Safety and Toxicology. In the cases of OP no TDI is available, but its intake is at least six orders of magnitude lower than the NOAEL of 10 mg/kg/day derived from a two generation study on rats.

positive: Endocrine disrupting nonylphenols are ubiquitous in food. 4-Nonylphenols (NPs) are common products of biodegradation of a widely used group of nonionic surfactants, the nonylphenol ethoxylates (NPEs). These compounds are known to be persistent, toxic, and estrogen active. There is a worldwide scientific and public discussion on the potential consequences of human long term dietary exposure to such endocrine disrupters. Despite numerous determinations of NPs in environmental samples no systematical reports exist relating to concentrations of NPs in food. We analyzed NPs in 60 different foodstuff commercially available in Germany. The results indicate that NPs are ubiquitous in food. The concentrations of NPs on a fresh weight basis varied between 0.1 and 19.4 microg/kg regardless of the fat content of the foodstuff. Based on data on German food consumption rates and these first analyses of NPs in food, the daily intake for an adult was calculated to be 7.5 microg/day NPs. For infants exclusively fed with breast milk or infant formulas daily intakes of 0.2 microg/day and 1.4 microg/day NPs, respectively, can be estimated.

positive: Association of dietary soy genistein intake with lung function and asthma control: a post-hoc analysis of patients enrolled in a prospective multicentre clinical trial Background Broad dietary patterns have been linked to asthma but the relative contribution of specific nutrients is unclear. Soy genistein has important anti-inflammatory and other biological effects that might be beneficial in asthma. A positive association was previously reported between soy genistein intake and lung function but not with asthma exacerbations. Aims To conduct a post-hoc analysis of patients with inadequately controlled asthma enrolled in a prospective multicentre clinical trial to replicate this association. Methods A total of 300 study participants were included in the analysis. Dietary soy genistein intake was measured using the Block Soy Foods Screener. The level of soy genistein intake (little or no intake, moderate intake, or high intake) was compared with baseline lung function (pre-bronchodilator forced expiratory volume in 1 second (FEV1)) and asthma control (proportion of participants with an episode of poor asthma control (EPAC) and annualised rates of EPACs over a 6-month follow-up period. Results Participants with little or no genistein intake had a lower baseline FEV1 than those with a moderate or high intake (2.26L vs. 2.53L and 2.47L, respectively; p=0.01). EPACs were more common among those with no genistein intake than in those with a moderate or high intake (54% vs. 35% vs. 40%, respectively; p<0.001). These findings remained significant after adjustment for patient demographics and body mass index. Conclusions In patients with asthma, consumption of a diet with moderate to high amounts of soy genistein is associated with better lung function and better asthma control.

positive: European bans on surfactant trigger transatlantic debate. U.S. and European regulators and researchers disagree over risks of a common class of surfactants.

positive: Alkylphenols and alkylphenol ethoxylates contamination of crustaceans and fishes from the Adriatic Sea (Italy). This paper presents the results of an investigation on the occurrence of alkylphenols (APs) and their ethoxylates (APEs) in 8 edible marine species from the Adriatic Sea and tries to estimate the corresponding intake for the Italian population. Two crustaceans, Nephrops norvegicus (Norway lobster) and Squilla mantis (spottail mantis shrimp), plus six fish species, Engraulis enchrascicolus (anchovy), Scomber scombrus (Atlantic mackerel), Merluccius merluccius (European hake), Mullus barbatus (red mullet), Solea vulgaris (common sole) and Lophius piscatorius (angler) were analyzed for their content of nonylphenol (NP), octylphenol (OP) and octylphenol polyethoxylates (OPEs). These compounds were found in all analysed samples. NP was detected at the highest concentrations: 118-399 and 9.5-1431 ng g(-1) fresh weight (fw) respectively in crustaceans and fish. OP was found at respective levels of 2.7-4.7 and 0.3-3.8 ng g(-1) fw in crustaceans and fish, whereas OPE was determined at respective concentrations of 1.2-16.8 and 0.2-21.1 ng g(-1) fw in the same species. These results, together with those from a previous study on 4 edible mollusc, allow to estimate respective daily intakes for NP, OP, and OPE of about 12, 0.1, and 0.1 microg day(-1) for an Italian adult living along the Adriatic Coast. In relation to NP and OP, these intakes are much lower than the doses associated with toxic effects in laboratory animals (9 mg kg(-1) bw for rats). Nevertheless, data of exposure from other sources to these chemicals and others with similar biological characteristics are needed.

positive: Effects of xenoestrogenic environmental pollutants on the proliferation of a human breast cancer cell line (MCF-7). A human breast cancer cell line (MCF-7) was used to develop an in vitro screening assay for the detection of xenoestrogenic environmental pollutants. MCF-7 cells were cultured in DMEM containing 5% fetal bovine serum (FBS). An estrogenic response was defined as an increase in the frequency of proliferating MCF-7 cells, and was measured using a thymidine analog, bromodeoxyuridine, and flow cytometry. Di-2-ethylhexyl phthalate (DEHP) and 4-n-nonylphenol (4-n-NP) were used as model chemicals. The proliferation rate of S-phase cells after 24 h of exposure to various concentrations of 17beta-estradiol and to model compounds was compared with a positive and a negative control, containing 1 nM 17beta-estradiol and 0.1% ethanol, respectively. DEHP and 4-n-NP increased the frequency of proliferating MCF-7 cells in a dose-dependent manner. The lowest concentration that significantly increased the proliferation of MCF-7 cells was 10 microM for DEHP and 1 microM for 4-n-NP. The results showed that the assay is accurate and quick to perform. It may prove a valuable tool for screening potential estrogen-mimicking environmental pollutants.

positive: p53: guardian of the genome and policeman of the oncogenes. The process of malignant transformation universally entails genetic damage and oncogenic signaling, two stresses that are signaled to p53 through different genetic pathways. Based on this, it is possible to distinguish two jobs for p53: "guardian of the genome" that consists in sensing and reacting to DNA damage through the ATM/ATR and Chk1/Chk2 kinases, and "policeman of the oncogenes" that, correspondingly, consists in responding to oncogenic signaling through the p53-stabilizing protein ARF. Contrary to expectation, recent genetic evidence in mice indicates that the response of p53 to DNA damage has little or no impact on cancer protection. In contrast, ARF-dependent activation of p53 is critical for p53-mediated tumor suppression. Here, we discuss the mechanistic implications of these observations and their relevance for cancer therapy.

positive: Does 4-methylimidazole have tumor preventive activity in the rat? 4-Methylimidazole (4-MEI) is found in a wide array of food products. The National Toxicology Program (NTP) recently conducted a two-year feeding cancer bioassay of 4-MEI in B6C3F(1) mice and F344/N rats. In rats, NTP found "equivocal evidence of carcinogenic activity" in females based on increased incidences of mononuclear cell leukemia and "no evidence of carcinogenic activity" in males. However, dose-related, statistically significant decreases in multiple tumors were observed in both male and female rats exposed to 4-MEI in the NTP bioassay. For example, 4-MEI was associated with a 25-fold decrease in the incidence of mammary tumors among high dose females. NTP noted briefly that the decreases in certain tumors, including mammary tumors, were greater than could be attributed to body weight alone. The present paper provides a more detailed evaluation of the evidence that 4-MEI exhibits tumor preventive activity in the rat based upon the results of the NTP bioassay. Reduced body weight offers a partial explanation for the reduction in tumors, but does not appear to be the primary cause of the decreased tumor incidences, indicating that 4-MEI itself may possess an ability to prevent tumor formation. Copyright © 2010 Elsevier Ltd. All rights reserved.

positive: 11C-choline vs. 18F-FDG PET/CT in assessing bone involvement in patients with multiple myeloma Background Multiple Myeloma (MM) is a B cell neoplasm causing lytic or osteopenic bone abnormalities. Whole body skeletal survey (WBSS), Magnetic resonance (MR) and 18F-FDG PET/CT are imaging techniques routinely used for the evaluation of bone involvement in MM patients. Aim As MM bone lesions may present low 18F-FDG uptake; the aim of this study was to assess the possible added value and limitations of 11C-Choline to that of 18F-FDG PET/CT in patients affected with MM. Methods Ten patients affected with MM underwent a standard 11C-Choline PET/CT and an 18F-FDG PET/CT within one week. The results of the two scans were compared in terms of number, sites and SUVmax of lesions. Results Four patients (40%) had a negative concordant 11C-Choline and 18F-FDG PET/CT scans. Two patients (20%) had a positive 11C-Choline and 18F-FDG PET/CT scans that identified the same number and sites of bone lesions. The remaining four patients (40%) had a positive 11C-Choline and 18F-FDG PET/CT scan, but the two exams identified different number of lesions. Choline showed a mean SUVmax of 5 while FDG showed a mean SUVmax of 3.8 (P = 0.042). Overall, 11C-Choline PET/CT scans detected 37 bone lesions and 18F-FDG PET/CT scans detected 22 bone lesions but the difference was not significant (P = 0.8). Conclusion According to these preliminary data, 11C-Choline PET/CT appears to be more sensitive than 18F-FDG PET/CT for the detection of bony myelomatous lesions. If these data are confirmed in larger series of patients, 11C-Choline may be considered a more appropriate functional imaging in association with MRI for MM bone staging.

positive: One-carbon metabolism and prostate cancer risk: prospective investigation of seven circulating B vitamins and metabolites. PURPOSE: Components of one-carbon metabolism are believed to influence cancer development with suggested mechanisms, including DNA methylation and DNA repair mechanisms. However, few prospective studies have investigated one-carbon metabolism in relation to prostate cancer risk, and the results have been conflicting. The aim of this study was to do a comprehensive investigation of the components of one-carbon metabolism in relation to prostate cancer risk. A panel of seven circulating B vitamins and related metabolites was selected, most of which have not been studied before. MATERIALS AND METHODS: We analyzed plasma concentrations of betaine, choline, cysteine, methionine, methylmalonic acid (MMA), vitamin B2, and vitamin B6 in 561 cases and 1,034 controls matched for age and recruitment date, nested within the population-based Northern Sweden Health and Disease Cohort. Relative risks of prostate cancer were estimated by conditional logistic regression. RESULTS: Positive associations with prostate cancer risk were observed for choline and vitamin B2, and an inverse association was observed for MMA. The relative risks for a doubling in concentrations were 1.46 [95% confidence interval (95% CI), 1.04-2.05; P(trend) = 0.03] for choline, 1.11 (95% CI, 1.00-1.23; P(trend) = 0.04) for vitamin B2, and 0.78 (95% CI, 0.63-0.97; P(trend) = 0.03) for MMA. Concentrations of betaine, cysteine, methionine, and vitamin B6 were not associated with prostate cancer risk. CONCLUSION: The results of this large prospective study suggest that elevated plasma concentrations of choline and vitamin B2 may be associated with an increased risk of prostate cancer. These novel findings support a role of one-carbon metabolism in prostate cancer etiology and warrant further investigation.

positive: 210Po in the marine environment with emphasis on its behaviour within the biosphere. The distribution and behaviour of the natural-series alpha-emitter polonium-210 in the marine environment has been under study for many years primarily due to its enhanced bioaccumulation, its strong affinity for binding with certain internal tissues, and its importance as a contributor to the natural radiation dose received by marine biota as well as humans consuming seafoods. Results from studies spanning nearly 5 decades show that (210)Po concentrations in organisms vary widely among the different phylogenic groups as well as between the different tissues of a given species. Such variation results in (210)Po concentration factors ranging from approximately 10(3) to over 10(6) depending upon the organism or tissue considered. (210)Po/(210)Pb ratios in marine species are generally greater than unity and tend to increase up the food chain indicating that (210)Po is preferentially taken up by organisms compared to its progenitor (210)Pb. The effective transfer of (210)Po up the food chain is primarily due to the high degree of assimilation of the radionuclide from ingested food and its subsequent strong retention in the organisms. In some cases this mechanism may lead to an apparent biomagnification of (210)Po at the higher trophic level. Various pelagic species release (210)Po and (210)Pb packaged in organic biodetrital particles that sink and remove these radionuclides from the upper water column, a biogeochemical process which, coupled with scavenging rates of this radionuclide pair, is being examined as a possible proxy for estimating downward organic carbon fluxes in the sea. Data related to preferential bioaccumulation in various organisms, their tissues, resultant radiation doses to these species, and the processes by which (210)Po is transferred and recycled through the food web are discussed. In addition, the main gaps in our present knowledge and proposed areas for future studies on the biogeochemical behaviour of (210)Po and its use as a tracer of oceanographic processes are highlighted in this review. Copyright © 2010 Elsevier Ltd. All rights reserved.

positive: Pacific bluefin tuna transport Fukushima-derived radionuclides from Japan to California The Fukushima Dai-ichi release of radionuclides into ocean waters caused significant local and global concern regarding the spread of radioactive material. We report unequivocal evidence that Pacific bluefin tuna, Thunnus orientalis, transported Fukushima-derived radionuclides across the entire North Pacific Ocean. We measured γ-emitting radionuclides in California-caught tunas and found 134Cs (4.0 ± 1.4 Bq kg−1) and elevated 137Cs (6.3 ± 1.5 Bq kg−1) in 15 Pacific bluefin tuna sampled in August 2011. We found no 134Cs and background concentrations (∼1 Bq kg−1) of 137Cs in pre-Fukushima bluefin and post-Fukushima yellowfin tunas, ruling out elevated radiocesium uptake before 2011 or in California waters post-Fukushima. These findings indicate that Pacific bluefin tuna can rapidly transport radionuclides from a point source in Japan to distant ecoregions and demonstrate the importance of migratory animals as transport vectors of radionuclides. Other large, highly migratory marine animals make extensive use of waters around Japan, and these animals may also be transport vectors of Fukushima-derived radionuclides to distant regions of the North and South Pacific Oceans. These results reveal tools to trace migration origin (using the presence of 134Cs) and potentially migration timing (using 134Cs:137Cs ratios) in highly migratory marine species in the Pacific Ocean.

positive: Radioactive fallout in the United States due to the Fukushima nuclear plant accident. The release of radioactivity into the atmosphere from the damaged Fukushima Daiichi nuclear power plant started on March 12th, 2011. Among the various radionuclides released, iodine -131 ((131)I) and cesium isotopes ((137)Cs and (134)Cs) were transported across the Pacific Ocean and reached the United States on 17-18 March 2011. Consequently, an elevated level of fission products (131)I, (132)I, (132)Te, (134)Cs and (137)Cs were detected in air, water, and milk samples collected across the United States between March 17 and April 4, 2011. The continuous monitoring of activities over a period of 25 days and spatial variations across more than 100 sampling locations in the United States made it possible to characterize the contaminated air masses. For the entire period, the highest detected activity values ranged from less than 1 m Bq m(-3) to 31 m Bq m(-3) for the particulate (131)I, and up to 96 m Bq m(-3) for the gaseous (131)I fraction.

positive: Increase of 210Po levels in human semen fluid after mussel ingestion. Polonium-210 ((210)Po) radioactive concentrations were determined in human semen fluid of vasectomized non-smoker volunteers. The (210)Po levels ranged from 0.10 to 0.39 mBq g(-1) (mean: 0.23 ± 0.08 mBq g(-1)). This value decreased to 0.10 ± 0.02 mBq g(-1) (range from 0.07 to 0.13 mBq g(-1)) after two weeks of a controlled diet, excluding fish and seafood. Then, volunteers ate during a single meal 200 g of the cooked mussel Perna perna L., and (210)Po levels were determined again, during ten days, in semen fluid samples collected every morning. Volunteers continued with the controlled diet and maintained sexual abstinence through the period of the experiment. A 300% increase of (210)Po level was observed the day following mussel consumption, with a later reduction, such that the level returned to near baseline by day 4. Copyright © 2011 Elsevier Ltd. All rights reserved.

positive: An unexpected mortality increase in the United States follows arrival of the radioactive plume from Fukushima: is there a correlation? The multiple nuclear meltdowns at the Fukushima plants beginning on March 11, 2011, are releasing large amounts of airborne radioactivity that has spread throughout Japan and to other nations; thus, studies of contamination and health hazards are merited. In the United States, Fukushima fallout arrived just six days after the earthquake, tsunami, and meltdowns. Some samples of radioactivity in precipitation, air, water, and milk, taken by the U.S. government, showed levels hundreds of times above normal; however, the small number of samples prohibits any credible analysis of temporal trends and spatial comparisons. U.S. health officials report weekly deaths by age in 122 cities, about 25 to 35 percent of the national total. Deaths rose 4.46 percent from 2010 to 2011 in the 14 weeks after the arrival of Japanese fallout, compared with a 2.34 percent increase in the prior 14 weeks. The number of infant deaths after Fukushima rose 1.80 percent, compared with a previous 8.37 percent decrease. Projecting these figures for the entire United States yields 13,983 total deaths and 822 infant deaths in excess of the expected. These preliminary data need to be followed up, especially in the light of similar preliminary U.S. mortality findings for the four months after Chernobyl fallout arrived in 1986, which approximated final figures.

positive: Semen quality of male idiopathic infertile smokers and nonsmokers: an ultrastructural study. This retrospective study was aimed at evaluating the effects of cigarette consumption on semen parameters in a group of men with idiopathic infertility. The semen quality of 2 groups of men with idiopathic infertility, smokers (n = 118) and nonsmokers (n = 153), were compared. Conventional semen analysis was performed and sperm morphology was assessed by transmission electron microscopy (TEM). TEM data were elaborated by means of a mathematical formula based on a Bayesian technique able to furnish a fertility index (FI), and the percentages of sperm apoptosis, necrosis, and immaturity. Values of normality recommended by World Health Organization guidelines were used as a control for conventional semen analysis, and values from sperm of 25 men of proven fertility were used for TEM indices. Infertile smoker and nonsmoker patients showed similar sperm parameters, although sperm motility and TEM analysis values in both groups were significantly impaired compared with controls. Smoker patients were then classified as mild (>or=1 and <or=10 cigarettes/d), moderate (>10 and <20 cigarettes/day), or heavy smokers (>or=20 cigarettes/d). Sperm concentration and FI were significantly (P < .05) different among the 3 considered smoker classes. Comparing the pairs of smoker classes, sperm concentration and FI in heavy smokers were significantly lower (P < .05) than that observed in mild smoker and nonsmoker groups. Although semen quality in males with idiopathic infertility seems not to be dramatically affected by cigarette consumption, heavy smokers show significantly lower sperm concentration and FI: another strong reason to stop smoking.

positive: Cigarette smoke radioactivity and lung cancer risk. INTRODUCTION: To determine the tobacco industry's policy and action with respect to radioactive polonium 210 ((210)Po) in cigarette smoke and to assess the long-term risk of lung cancer caused by alpha particle deposits in the lungs of regular smokers. METHODS: Analysis of major tobacco industries' internal secret documents on cigarette radioactivity made available online by the Master Settlement Agreement in 1998. RESULTS: The documents show that the industry was well aware of the presence of a radioactive substance in tobacco as early as 1959. Furthermore, the industry was not only cognizant of the potential "cancerous growth" in the lungs of regular smokers but also did quantitative radiobiological calculations to estimate the long-term (25 years) lung radiation absorption dose (rad) of ionizing alpha particles emitted from the cigarette smoke. Our own calculations of lung rad of alpha particles match closely the rad estimated by the industry. According to the Environmental Protection Agency, the industry's and our estimate of long-term lung rad of alpha particles causes 120-138 lung cancer deaths per year per 1,000 regular smokers. Acid wash was discovered in 1980 to be highly effectively in removing (210)Po from the tobacco leaves; however, the industry avoided its use for concerns that acid media would ionize nicotine converting it into a poorly absorbable form into the brain of smokers thus depriving them of the much sought after instant "nicotine kick" sensation. CONCLUSIONS: The evidence of lung cancer risk caused by cigarette smoke radioactivity is compelling enough to warrant its removal.

positive: Wet deposition of fission-product isotopes to North America from the Fukushima Dai-ichi incident, March 2011. Using the infrastructure of the National Atmospheric Deposition Program (NADP), numerous measurements of radionuclide wet deposition over North America were made for 167 NADP sites before and after the Fukushima Dai-ichi Nuclear Power Station incident of March 12, 2011. For the period from March 8 through April 5, 2011, wet-only precipitation samples were collected by NADP and analyzed for fission-product isotopes within whole-water and filterable solid samples by the United States Geological Survey using gamma spectrometry. Variable amounts of (131)I, (134)Cs, or (137)Cs were measured at approximately 21% of sampled NADP sites distributed widely across the contiguous United States and Alaska. Calculated 1- to 2-week individual radionuclide deposition fluxes ranged from 0.47 to 5100 Becquerels per square meter during the sampling period. Wet deposition activity was small compared to measured activity already present in U.S. soil. NADP networks responded to this complex disaster, and provided scientifically valid measurements that are comparable and complementary to other networks in North America and Europe.

positive: Death by polonium-210: lessons learned from the murder of former Soviet spy Alexander Litvinenko. The medical response to radiation--whether the result of radiological warfare, terrorist deployment of improvised radiation dispersal weapons, political assassination, occupational or industrial accidents or the medically radiated patient remains one of the least taught among all disciplines within medical education. In the aftermath of 9/11 among medical vulnerabilities to toxicant threats, of all the categories of weapons of mass destruction (WMD)--whether using the CBRNE (chemical, biological, radiological, nuclear, explosive) or NBC (nuclear, biological, chemical) acronym--radiation is the least taught in professional schools, responder cultures or civil preparedness organizations. To date, few health care professionals (HCP) possess the fundamental knowledge or skills to identify and diagnose, let alone treat a radiation victim; this vulnerability made even more obvious in the aftermath of the high profile assassination of former Russian agent Alexander Litvinenko. He was poisoned with Polonium210. Radioactive substances are ubiquitous with radiation sources being in or transported through virtually every region nationwide. It is essential to increase preparedness among community and rural health care facilities as well as urban and university hospitals. Managing radiation injuries effectively requires access to specialized equipment and expertise. Radiation sickness is progressive and may require acute, critical and long-term care throughout the course of illness. Regardless of the source, preparedness rests upon acknowledging a threat exists and dedicating the resources to address the risks including the enhancement of training and equipment. Mass or individual exposures to radiation present unique challenges to the entire response continuum from law enforcement, first responders and emergency medical care. Increased education about and practice in responding to radiological threats is essential to enhance preparedness.

positive: Carcinogenic potencies of polycyclic aromatic hydrocarbons for back-door neighbors of restaurants with cooking emissions. In the present study, 21 polycyclic aromatic hydrocarbon (PAH) congeners were measured in the exhaust stack of 3 types of restaurants: 9 Chinese, 7 Western, and 4 barbeque (BBQ). The total PAH concentration of BBQ restaurants (58.81 ± 23.89 μg m(-3)) was significantly higher than that of Chinese (20.99 ± 13.67 μg m(-3)) and Western (21.47 ± 11.44 μg m(-3)) restaurants. The total benzo[a]pyrene potency equivalent (B[a]P(eq)) concentrations, however, were highest in Chinese restaurants (1.82 ± 2.24 μg m(-3)), followed by Western (0.86 ± 1.43 μg m(-3), p<0.01) and BBQ-type restaurants (0.59 ± 0.55 μg m(-3), p<0.01). We further developed a probabilistic risk model to assess the incremental lifetime cancer risk (ILCR) for people exposed to carcinogenic PAHs. Because the exhaust stack directly affected the back-door neighbors of these restaurants, we were concerned with the real exposure of groups near the exhaust stack outlets of these restaurants. The ILCRs for total exposure of the neighbors (inhalation+dermal contact+ingestion) were 2.6-31.3, 1.5-14.8, and 1.3-12.2 × 10(-6) in Chinese, Western, and BBQ restaurants, respectively. We suggest that the maximum acceptable exposure time to the exhaust stack outlet area for Chinese, Western, and BBQ restaurants ranges between 5-19, 17-42, and 18-56 h month(-1), respectively, based on an ILCR of less than 10(-6). Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

positive: IMPACT OF BARBECUED MEAT CONSUMED IN PREGNANCY ON BIRTH OUTCOMES ACCOUNTING FOR PERSONAL PRENATAL EXPOSURE TO AIRBORNE POLYCYCLIC AROMATIC HYDROCARBONS. BIRTH COHORT STUDY IN POLAND We previously reported an association between prenatal exposure to airborne PAH and lower birth weight, birth length and head circumference. The main goal of the present analysis was to assess the possible impact of co-exposure to PAH-containing of barbecued meat consumed during pregnancy on birth outcomes. The birth cohort consisted of 432 pregnant women who gave birth at term (>36 weeks of gestation). Only non-smoking women with singleton pregnancies, 18-35 years of age, and who were free from chronic diseases such as diabetes and hypertension were included in the study. Detailed information on diet over pregnancy was collected through interviews and the measurement of exposure to airborne PAHs was carried out by personal air monitoring during the second trimester of pregnancy. The effect of barbecued meat consumption on birth outcomes (birthweight, length and head circumference at birth) was adjusted in multiple linear regression models for potential confounding factors such as prenatal exposure to airborne PAHs, child’s sex, gestational age, parity, size of mother (maternal prepregnancy weight, weight gain in pregnancy) and prenatal environmental tobacco smoke (ETS). The multivariable regression model showed a significant deficit in birthweight associated with barbecued meat consumption in pregnancy (coeff = −106.0 g; 95%CI: −293.3, −35.8); The effect of exposure to airborne PAHs was about the same magnitude order (coeff. = −164.6 g; 95%CI: −172.3, − 34.7). Combined effect of both sources of exposure amounted to birth weight deficit of 214.3 g (95%CI: −419.0, − 9.6). Regression models performed for birth length and head circumference showed similar trends but the estimated effects were of borderline significance level. As the intake of barbecued meat did not affect the duration of pregnancy, the reduced birthweight could not have been mediated by shortened gestation period. In conclusion, the study results provided epidemiologic evidence that prenatal PAH exposure from diet including grilled meat might be hazardous for fetal development.

positive: Airborne mutagens produced by frying beef, pork and a soy-based food. Airborne cooking by-products from frying beef (hamburgers), pork (bacon strips) and soybean-based food (tempeh burgers) were collected, extracted, tested for mutagenicity and chemically analysed. The fumes generated by frying pork and beef were mutagenic, with 4900 and 1300 revertants/g of food cooked, respectively. No mutagenicity was detected in fumes from frying tempeh burgers. Bacon fried to a well-done but non-charred state was eight times more mutagenic in a microsuspension Ames/Salmonella test (TA98 with S-9) than hamburgers and about 350 times more mutagenic than tempeh burgers. Among food samples cooked to a well-done, non-charred state, bacon strips had almost 15-fold more mass (109.5 ng/g) than that of the beef, whereas no heterocyclic amine (HCA) was detected in the fried tempeh burgers. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was the most abundant HCA, followed by 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx). No 2-amino-9H-pyrido[2,3-b]indole (A alpha C) was detected in the food samples fried at about 200 degrees C, although it was present in the collected airborne products. The total amounts of HCAs in the smoke condensates were 3 ng/g from fried bacon, 0.37 ng/g from fried beef and 0.177 ng/g from fried soy-based food. This study indicates that cooks are potentially exposed to relatively high levels of airborne mutagens and carcinogens and that long-term sampling inside restaurants and kitchens may be warranted in order to assess the potential risk of prolonged exposure.

positive: Effect of cruciferous vegetable consumption on heterocyclic aromatic amine metabolism in man. The consumption of cooked meat appears to predispose individuals to colonic cancer and heterocyclic aromatic amines (HA), formed during the cooking of meat, have been suggested as aetiological agents. Consumption of cruciferous vegetables is thought to protect against cancer. To study the effect of cruciferous vegetables on heterocyclic aromatic amine metabolism in man, a three-period, dietary intervention study has been carried out with 20 non-smoking Caucasian male subjects consuming cooked meat meals containing known amounts of these carcinogens. A high cruciferous vegetable diet (250 g each of Brussels sprouts and broccoli per day) was maintained during period 2 but such vegetables were excluded from periods 1 and 3. At the end of each period, subjects consumed a cooked meat meal and urinary excretion of the HA 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) was measured. Following a 12 day period of cruciferous vegetable consumption (period 2), induction of hepatic CYP1A2 activity was apparent from changes in the kinetics of caffeine metabolism. Excretion of MeIQx and PhIP in urine at the end of this period of the study was reduced by 23 and 21%, respectively, compared with period 1. This reduction in excretion is probably due to an increase in amine metabolism that might be expected given the observed increase in CYP1A2 activity, since this enzyme has been shown to be primarily responsible for the oxidative activation of MeIQx and PhIP in man. In period 2, urinary mutagenicity was increased relative to period 1 by 52 and 64% in the absence and presence, respectively, of a human liver microsomal activation system, yet no evidence was found of PhIP adduction to lymphocyte DNA, a potential biomarker of the activation process. After another 12 days without cruciferous vegetables (period 3 of the study), the kinetics of caffeine metabolism had returned to original values but excretion of MeIQx and PhIP was still reduced by 17 and 30%, respectively, and urinary mutagenicity (with metabolic activation) was still elevated compared with period 1. This prolonged response of amine metabolism to the cruciferous vegetable diet, shown especially with PhIP, suggests that enzyme systems other than CYP1A2 are involved and affected by a cruciferous vegetable diet.

positive: Cooked meat and risk of breast cancer--lifetime versus recent dietary intake. BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs) are carcinogens formed in or on the surface of well-done meat, cooked at high temperature. METHODS: We estimated breast cancer risk in relation to intake of cooked meat in a population-based, case-control study (1508 cases and 1556 controls) conducted in Long Island, NY from 1996 to 1997. Lifetime intakes of grilled or barbecued and smoked meats were derived from the interviewer-administered questionnaire data. Dietary intakes of PAH and HCA were derived from the self-administered modified Block food frequency questionnaire of intake 1 year before reference date. Unconditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Modest increased risk was observed among postmenopausal, but not premenopausal, women consuming the most grilled or barbecued and smoked meats over the life course (OR = 1.47; CI = 1.12-1.92 for highest vs. lowest tertile of intake). Postmenopausal women with low fruit and vegetable intake, but high lifetime intake of grilled or barbecued and smoked meats, had a higher OR of 1.74 (CI = 1.20-2.50). No associations were observed with the food frequency questionnaire-derived intake measures of PAHs and HCAs, with the possible exception of benzo(alpha)pyrene from meat among postmenopausal women whose tumors were positive for both estrogen receptors and progesterone receptors (OR = 1.47; CI = 0.99-2.19). CONCLUSIONS: These results support the accumulating evidence that consumption of meats cooked by methods that promote carcinogen formation may increase risk of postmenopausal breast cancer.

positive: Intervention of human breast cell carcinogenesis chronically induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine More than 85% of breast cancers are sporadic and attributable to long-term exposure to environmental carcinogens, such as those in the diet, through a multistep disease process progressing from non-cancerous to premalignant and malignant stages. The chemical carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is one of the most abundant heterocyclic amines found in high-temperature cooked meats and is recognized as a mammary carcinogen. However, the PhIP’s mechanism of action in breast cell carcinogenesis is not clear. Here, we demonstrated, for the first time, that cumulative exposures to PhIP at physiologically achievable, pico to nanomolar concentrations effectively induced progressive carcinogenesis of human breast epithelial MCF10A cells from a non-cancerous stage to premalignant and malignant stages in a dose- and exposure-dependent manner. Progressive carcinogenesis was measured by increasingly- acquired cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth, acinar-conformational disruption, proliferation, migration, invasion, tumorigenicity with metastasis and increased stem-like cell populations. These biological changes were accompanied by biochemical and molecular changes, including upregulated H-Ras gene expression, extracellular signal-regulated kinase (ERK) pathway activation, Nox-1 expression, reactive oxygen species (ROS) elevation, increased HIF-1α, Sp1, tumor necrosis factor-α, matrix metalloproteinase (MMP)-2, MMP-9, aldehyde dehydrogenase activity and reduced E-cadherin. The Ras-ERK-Nox-ROS pathway played an important role in not only initiation but also maintenance of cellular carcinogenesis induced by PhIP. Using biological, biochemical and molecular changes as targeted endpoints, we identified that the green tea catechin components epicatechin-3-gallate and epigallocatechin-3-gallate, at non-cytotoxic doses, were capable of suppressing PhIP-induced cellular carcinogenesis and tumorigenicity.

positive: Occurrence of heterocyclic amines in cooked meat products. Heterocyclic amines (HCAs), potent mutagens and a risk factor for human cancers, are produced in meats cooked at high temperature. The aim of this study was to determine the HCA content in cooked meat products (beef, chicken, pork, fish) prepared by various cooking methods (pan frying, oven broiling, and oven baking at 170 to 230°C) that are preferred by U.S. meat consumers. The primary HCAs in these samples were PhIP (2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine) (1.49-10.89ng/g), MeIQx (2-amino-3,8-dimethylimidazo [4,5-f]quinoxaline) (not detected-4.0ng/g), and DiMeIQx (2-amino-3,4,8-trimethyl-imidazo [4,5-f]quinoxaline) (not detected-3.57ng/g). Type and content of HCAs in cooked meat samples were highly dependent on cooking conditions. The total HCA content in well-done meat was 3.5 times higher than that of medium-rare meat. Fried pork (13.91ng/g) had higher levels of total HCAs than fried beef (8.92ng/g) and fried chicken (7.00ng/g). Among the samples, fried bacon contained the highest total HCA content (17.59ng/g). Copyright © 2011 Elsevier Ltd. All rights reserved.

positive: The protective effect of the flavonoids on food-mutagen-induced DNA damage in peripheral blood lymphocytes from colon cancer patients. The food mutagens IQ (2-amino-3-methylimidazo[4,5-f]quinoline) and PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) are heterocyclic amines (HCA), generated when heating proteinaceous food. This study investigates the protective potential of the flavonoids quercetin (Q) and rutin (R) against oxidative stress induced in vitro by IQ and PhIP in lymphocytes from healthy individuals and untreated, newly diagnosed colon cancer patients using the Comet assay. In the presence of up to 500μM Q and R, the DNA damage resulting from a high dose of PhIP (75μM) or IQ (150μM) was significantly reduced (P<0.001) to levels comparable to six times lower IQ or 7.5 times lower PhIP doses. Lymphocytes from colon cancer patients had greater baseline DNA damage than those from healthy individuals (P<0.01) and this higher level of damage was also observed throughout in vitro treatment. Except for the >50years of age group and male gender, confounding factors such as smoking, drinking and/or dietary habits were not found to be significant. In conclusion, flavonoids reduced oxidative stress caused by food mutagens in vitro in lymphocytes of healthy individuals and colon cancer patients. Thus, dietary supplementation with flavonoid-rich vegetables and fruits may prove very effective in protecting against oxidative stress. Copyright © 2011 Elsevier Ltd. All rights reserved.

positive: Dietary flavonoid intake and breast cancer survival among women on Long Island. BACKGROUND: Laboratory research and a growing number of epidemiologic studies have provided evidence for a reduced risk of breast cancer associated with dietary intake of certain classes of flavonoids. However, the effects of flavonoids on survival are not known. In a population-based cohort of breast cancer patients, we investigated whether dietary flavonoid intake before diagnosis is associated with subsequent survival. METHODS: Women ages 25 to 98 years who were newly diagnosed with a first primary invasive breast cancer between August 1, 1996, and July 31, 1997, and participated in a population-based, case-control study (n=1,210) were followed for vital status through December 31, 2002. At the case-control interview conducted shortly after diagnosis, respondents completed a FFQ that assessed dietary intake in the previous 12 months. All-cause mortality (n=173 deaths) and breast cancer-specific mortality (n=113 deaths) were determined through the National Death Index. RESULTS: Reduced hazard ratios [age- and energy-adjusted hazard ratio (95% confidence interval)] for all-cause mortality were observed among premenopausal and postmenopausal women for the highest quintile of intake, compared with the lowest, for flavones [0.63 (0.41-0.96)], isoflavones [0.52 (0.33-0.82)], and anthocyanidins [0.64 (0.42-0.98)]. No significant trends in risk were observed. Results were similar for breast cancer-specific mortality only. CONCLUSION: Mortality may be reduced in association with high levels of dietary flavones and isoflavones among postmenopausal U.S. breast cancer patients. Larger studies are needed to confirm our findings.

positive: Determination of total phenolic content and antioxidant activity of garlic (Allium sativum) and elephant garlic (Allium ampeloprasum) by attenuated... The total phenolic contents and antioxidant activities of garlics from California, Oregon, Washington, and New York were determined by Fourier transform infrared (FT-IR) spectroscopy (400-4000 cm(-1)). The total phenolic content was quantified [Folin-Ciocalteu assay (FC)] and three antioxidant activity assays, 2,2-diphenyl-picrylhydrazyl (DPPH) assay, Trolox equivalent antioxidant capacity (TEAC) assay, and ferric reducing antioxidant power (FRAP), were employed for reference measurements. Four independent partial least-squares regression (PLSR) models were constructed with spectra from 25 extracts and their corresponding FC, DPPH, TEAC, and FRAP with values for 20 additional extracts predicted (R > 0.95). The standard errors of calibration and standard error of cross-validation were <1.45 (TEAC), 0.36 (FRAP), and 0.33 μmol Trolox/g FW (DPPH) and 0.55 mg gallic acid/g FW (FC). Cluster and dendrogram analyses could segregate garlic grown at different locations. Hydroxyl and phenolic functional groups most closely correlated with garlic antioxidant activity.

positive: Diallyl sulfide inhibits PhIP-induced DNA strand breaks in normal human breast epithelial cells. Heterocyclic amines (HCAs) are formed when meat products such as beef, chicken, pork and fish are cooked at high temperatures. The most abundant HCA found in the human diet is 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP). PhIP causes mammary carcinomas in female rats and mice, and is associated with an increased risk of developing colon, breast, and prostate cancer in humans. PhIP is metabolized by cytochrome P-450s producing N-OH-PhIP. The N-OH-PhIP can be esterified by phase II enzymes forming an arylnitrenium ion that binds to DNA causing adducts. Furthermore, N-OH-PhIP may be reduced by cytochrome b5 reductase producing superoxide anions and hydroxyl radicals causing DNA strand breaks. Diallyl sulfide (DAS) has been shown to prevent cancer in several animal models, presumably by metabolic modulation. We hypothesize that PhIP produces reactive oxygen species causing DNA strand breaks and that DAS will inhibit the formation of PhIP induced DNA strand breaks. To test this hypothesis we treated normal breast epithelial (MCF-10A) cells with PhIP, DAS and a combination of PhIP and DAS. The detection of lipid peroxides was used as a surrogate for ROS. Lipid peroxides were detected using a PeroxiDetect kit (Sigma). PhIP increased the production of lipid peroxides and DAS decreased the PhIP-induced peroxidation by 47%. To determine if PhIP causes DNA strand breaks in MCF-10A cells, cells were treated for 3, 6, 9, and 24 h with PhIP (100 microM), DAS (100 microM) and a combination of PhIP (100 microM) and DAS (100 microM). DNA strand breaks were evaluated using the Comet assay. PhIP produced DNA strand breaks in a dose- and time-dependent fashion. We have shown that DAS inhibits PhIP-induced DNA strand breaks by inhibiting the production of reactive oxygen species. Therefore, we propose that DAS can prevent PhIP-induced breast cancer.

positive: Green tea consumption and breast cancer risk or recurrence: a meta-analysis. Green tea is a commonly consumed beverage in Asia and has been suggested to have anti-inflammatory and possible anti-carcinogenic properties in laboratory studies. We sought to examine the association between green tea consumption and risk of breast cancer incidence or recurrence, using all available epidemiologic evidence to date. We conducted a systematic search of five databases and performed a meta-analysis of studies of breast cancer risk and recurrence published between 1998 and 2009, encompassing 5,617 cases of breast cancer. Summary relative risks (RR) were calculated using a fixed effects model, and tests of heterogeneity across combined studies were conducted. We identified two studies of breast cancer recurrence and seven studies of breast cancer incidence. Increased green tea consumption (more than three cups a day) was inversely associated with breast cancer recurrence (Pooled RR = 0.73, 95% CI: 0.56-0.96). An analysis of case-control studies of breast cancer incidence suggested an inverse association with a pooled RR of 0.81 (95% CI: 0.75, 0.88) while no association was found among cohort studies of breast cancer incidence. Combining all studies of breast cancer incidence resulted in significant heterogeneity. Available epidemiologic evidence supports the hypothesis that increased green tea consumption may be inversely associated with risk of breast cancer recurrence. The association between green tea consumption and breast cancer incidence remains unclear based on the current evidence.

positive: Biomonitoring of Carcinogenic Heterocyclic Aromatic Amines in Hair: A Validation Study A facile method was established to measure heterocyclic aromatic amines (HAAs) accumulated in human hair and rodent fur. The samples were digested by base hydrolysis, and the liberated HAAs were isolated by tandem solvent/solid-phase extraction. Quantification was done by liquid chromatography/tandem mass spectrometry, using a triple stage quadrupole mass spectrometer in the selected reaction monitoring mode. In a pilot study of 12 human volunteers, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was detected in hair of six meat-eaters at levels ranging from 290 to 890 pg/g hair. 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-9H-pyrido[2,3-b]indole (AαC) were below the limit of quantification (LOQ) (50 pg/g hair) in hair from meat-eaters and six vegetarians. PhIP was detected in the hair from one vegetarian, and at level just above the LOQ (65 pg/g hair), indicating PhIP exposure occurs primarily through meat consumption. The levels of PhIP in hair samples from two meat-eaters varied by less than 24% over a 6-month interval, signifying that the exposure to PhIP and its accumulation in hair are relatively constant over time. In a controlled feeding study, female C57BL/6 mice were given these HAAs in their drinking water for 1 month, at six daily dose concentrations ranging from 0, 0.080 to 800 µg/kg body weight. PhIP was detected in fur of mice at all doses, whereas AαC and MeIQx were detected in fur at dosages ≥0.8 µg AαC/kg body weight and ≥8 µg MeIQx/kg body weight. There was a strong positive relationship between dosage and each of the HAAs accumulated in fur and their DNA adducts formed in liver and colon (p-values <0.0001); however, the levels of HAA in fur did not correlate to the levels of DNA adducts after adjustment of dose. Thus, hair appears to be a promising long-lived biomarker with by which we can assess the exposure to PhIP, a potential human carcinogen.

positive: Formation and biochemistry of carcinogenic heterocyclic aromatic amines in cooked meats. Heteroyclic aromatic amines (HAAs) are a class of hazardous chemicals that are receiving heightened attention as a risk factor for human cancer. HAAs arise during the cooking of meats, fish, and poultry, and several HAAs also occur in tobacco smoke condensate and diesel exhaust. Many HAAs are carcinogenic and induce tumors at multiple sites in rodents. A number of epidemiologic studies have reported that frequent consumption of well-done cooked meats containing HAAs can result in elevated risks for colon, prostate, and mammary cancers. Moreover, DNA adducts of HAAs have been detected in human tissues, demonstrating that HAAs induce genetic damage even though the concentrations of these compounds in cooked meats are generally in the low parts-per-billion (ppb) range. With recent improvements in sensitivity of mass spectrometry instrumentation, HAAs, their metabolites, and DNA adducts can be detected at trace amounts in biological fluids and tissues of humans. The incorporation of HAA biomarkers in epidemologic studies will help to clarify the role of these dietary genotoxicants in the etiology of human cancer.

positive: Well-done meat intake and the risk of breast cancer. BACKGROUND: Heterocyclic amines, mutagens formed in meats cooked at high temperatures, have been demonstrated as mammary carcinogens in animals. We conducted a nested, case-control study among 41836 cohort members of the Iowa Women's Health Study to evaluate the potential role of heterocyclic amines and intake of well-done meat in the risk for human breast cancer. METHODS: A questionnaire was mailed to individuals in the cohort who had breast cancer diagnosed during the period from 1992 through 1994 and a random sample of cancer-free cohort members to obtain information on usual intake of meats and on meat preparation practices. Color photographs showing various doneness levels of hamburger, beefsteak, and bacon were included. Multivariate analysis was performed on data from 273 case subjects and 657 control subjects who completed the survey. RESULTS: A dose-response relationship was found between doneness levels of meat consumed and breast cancer risk. The adjusted odds ratios (ORs) for very well-done meat versus rare or medium-done meat were 1.54 (95% confidence interval [CI]=0.96-2.47) for hamburger, 2.21 (95% CI=1.30-3.77) for beef steak, and 1.64 (95% CI=0.92-2.93) for bacon. Women who consumed these three meats consistently very well done had a 4.62 times higher risk (95% CI=1.36-15.70) than that of women who consumed the meats rare or medium done. Risk of breast cancer was also elevated with increasing intake of well-done to very well-done meat. CONCLUSIONS: Consumption of well-done meats and, thus, exposures to heterocyclic amines (or other compounds) formed during high-temperature cooking may play an important role in the risk of breast cancer.

positive: Effect of diet on serum albumin and hemoglobin adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in humans. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine formed in meat and fish during cooking and can be used as a model compound for this class of chemicals possibly involved in human carcinogenesis. Knowing the exposure to heterocyclic amines is important for establishing their role in human diseases. Serum albumin (SA) and globin (Gb) adducts were first tested as biomarkers of exposure to PhIP in male Fischer 344 rats given oral doses of 0.1, 0.5, 1 and 10 mg/kg. Blood samples were collected 24 hr after treatment and PhIP released from SA and Gb after acidic hydrolysis was analyzed by gas chromatography-mass spectrometry or liquid chromatography-tandem mass spectrometry. PhIP-SA and Gb adducts increased linearly with the dose. Studies on 35 volunteers with different dietary habits exhibited that diet was a major determinant in the formation of both adducts. PhIP-SA adducts were significantly higher in meat consumers than in vegetarians (6.7 +/- 1.6 and 0.7 +/- 0.3 fmol/mg SA; respectively, mean +/- SE; p = 0.04, Mann-Whitney U test). The Gb adduct pattern was quantitatively lower but paralleled SA (3 +/- 0.8 in meat consumers and 0.3 +/- 0.1 in vegetarians). PhIP-SA adducts were no different in smokers and in non-smokers. The results show for the first time that PhIP-blood protein adducts are present in humans not given the synthetic compound. Both biomarkers appear to be suitable for assessing dietary exposure and internal PhIP dose and may be promising tools for studying the role of heterocyclic amines in the etiology of colon cancer and other diseases. Copyright 2000 Wiley-Liss, Inc.

positive: Formation of a mutagenic heterocyclic aromatic amine from creatinine in urine of meat eaters and vegetarians. Liquid chromatography electrospray ionization mass spectrometry (MS) with a triple quadrupole MS was used to identify known and novel heterocyclic aromatic amines (HAAs) in human urine. The identities of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) were confirmed by their product ion spectra. The constant neutral loss scan mode was employed to probe for other analytes in urine that display the transition [M+H]+-->[M+H-CH3*]+*, which is common to HAAs containing an N-methylimidazo moiety, and led to the detection of a previously unreported isomer of 8-MeIQx [Holland, R., et al. (2004) Chem. Res. Toxicol. 17, 1121-1136]. We now report the identification of another novel HAA, 2-amino-1-methylimidazo[4,5-b]quinoline (IQ[4,5-b]), an isomer of the powerful animal carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). The amounts of IQ[4,5-b] measured in the urine of human volunteers who consumed grilled beef ranged from 15 to 135% of the ingested dose, while the amounts of 8-MeIQx and PhIP excreted in urine were on average <2% of the ingested dose. Base treatment of urine at 70 degrees C increased the concentrations of 8-MeIQx and PhIP by as much as 6-fold, indicating the presence of phase II conjugates; however, the amount of IQ[4,5-b] increased by more than 100-fold. IQ[4,5-b] was also detected in the urine of vegetarians following base hydrolysis. The formation of IQ[4,5-b], but not IQ, 8-MeIQx, or PhIP, also occurred in urine incubated at 37 degrees C. Creatinine and 2-aminobenzaldehyde are likely precursors of IQ[4,5-b]. The detection of IQ[4,5-b] in the urine of both meat eaters and vegetarians suggests that this HAA may be present in nonmeat staples or that IQ[4,5-b] formation may occur endogenously within the urinary bladder or other biological fluids.

positive: The cooked meat-derived mammary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine promotes invasive behaviour of breast cancer cells. The cooked meat derived genotoxic carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces cancer of the colon, prostate and mammary gland when fed to rats. Epidemiology studies link these tumours to a Western diet and exposure to heterocyclic amines such as PhIP. We have shown that PhIP is also potently estrogenic and have proposed that this hormonal activity contributes to its target site carcinogenicity. We now postulate that the estrogenic properties of PhIP influence metastatic potential. We have used an in vitro assay for cell invasion based upon digestion and migration through a reconstituted basement membrane model. Zymography and immunoblotting were used to confirm PhIP-mediated changes associated with induction of the invasive phenotype. Treatment of the mammary cancer cell lines MCF-7 and T47D with PhIP induces cells to digest and migrate through a reconstituted basement membrane. The response was dose dependent, observed at sub-nanomolar concentrations of PhIP and was inhibited by the antiestrogen ICI 182,780. The PhIP-induced invasive phenotype was associated with expression of cathepsin D, cyclooxygenase-2 and matrix metalloproteinase activity. These findings emphasise the range and potency of the biological activities associated with this cooked meat product and mechanistically support the tissue-specific carcinogenicity of the chemical. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

positive: Meat, fat and risk of breast cancer: a case-control study from Uruguay. To examine whether meat intake modifies breast-cancer risk, a case-control study was conducted in Uruguay. Dietary patterns were assessed in detail (for cases, before diagnosis or symptoms occurred) using a food frequency questionnaire involving 64 food items, which allowed total energy intake to be calculated. Nutrient residuals were calculated through regression analysis. After adjustment for potential confounders (which included family history of breast cancer, menopausal status, body-mass index, total energy and total alcohol intake), an increased risk associated with consumption of total meat intake, red meat intake, total fat and saturated fat intake was observed. The strongest effect was observed for red meat intake (OR 4.2, 95% CL 2.3-7.7) for consumption in the upper quartile, after controlling for protein and fat intake. This suggests an independent effect for meat. Since experimental studies have shown a strong effect of heterocyclic amines in rat mammary carcinogenesis, further studies should be performed in human epidemiology, perhaps using biomarkers of heterocyclic amine exposure.

positive: Dietary intake of meat and meat-derived heterocyclic aromatic amines and their correlation with DNA adducts in female breast tissue. It was the aim of this study to examine the association of the consumption of meat in general, meat prepared by different cooking methods and the dietary intake of heterocyclic aromatic amines (HCA) with the level of DNA adducts in the breast tissue of women undergoing reduction mammoplasty. Dietary intake of meat and HCA were assessed via questionnaire in 44 women undergoing reduction mammoplasty. DNA adduct analysis in breast tissue was performed by (32)P-postlabelling analysis. Spearman rank correlation coefficients (r) were calculated to examine the association of meat consumption and dietary HCA intake with tissue DNA adduct levels. A median DNA adduct level of 18.45 (interquartile range 12.81-25.65) per 10(9) nucleotides in breast tissue was observed; median HCA intake was 40.43 ng/day (interquartile range 19.55-102.33 ng/day). Total HCA intake (r = 0.33, P = 0.03), consumption of fried meat (r = 0.39, P = 0.01), beef (r = 0.32, P = 0.03) and processed meat (r = 0.51, P = 0.0004) were statistically significantly correlated with the level of DNA adducts in breast tissue. The detected DNA adducts could not be confirmed to be specific HCA-derived DNA adducts by comparison with external standards, using the (32)P-postlabelling assay. We observed strong correlations of dietary HCA intake and consumption of fried and processed meat with DNA adduct levels in breast tissue of 44 women. Since the detected DNA adducts were not necessarily specific only for HCA, it is possible that HCA intake is a surrogate of other genotoxic substances, such as polycyclic aromatic hydrocarbons, in meat prepared at high temperatures.

positive: Detection of PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) in the milk of healthy women. An increased risk of breast cancer has been observed in women who consume "very well-done" meats. Heterocyclic amines are mutagenic and carcinogenic pyrolysis products formed during high temperature cooking of meats. In the present study, human milk samples were analyzed for PhIP, one of the most abundant dietary heterocyclic amine. A protocol was developed with a mixed-mode cation exchange sorbent for the extraction of heterocyclic amines from milk. Milk samples were acquired from healthy Canadian women. With LC/MS analysis and the method of isotope dilution for quantification, levels of PhIP were determined in human milk samples. PhIP was detected in 9 of the 11 milk samples, at levels as high as 59 pg/mL (ppt). No PhIP was detected in the milk of the vegetarian donor. Detection of PhIP in milk indicates that ductal mammary epithelial cells are directly exposed to this carcinogen, suggesting that heterocyclic amines are possible human mammary carcinogens.

positive: The cooked food derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine is a potent oestrogen: a mechanistic basis for its tissue-speci... The cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces tumours of the breast, colon and prostate in rats. Here we show that in addition to its well-established genotoxicity, which can be detected at concentrations >10(-6) M, PhIP is also oestrogenic. In COS-1 cells transiently transfected with an oestrogen-responsive reporter gene, PhIP (10(-10)-10(-6) M) mediated transcription through oestrogen receptor (ER) alpha, but not ER-beta, and inhibition by the pure ER antagonist ICI 182 780 demonstrated a requirement for a functional ER. In contrast, the structurally related food-derived carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) failed to induce reporter gene transcription. Additionally, we show that in a hormonally responsive breast cancer cell line (MCF-7 cells), PhIP induced transcriptional activation using endogenously expressed ER. Examination of the genotoxic potential of PhIP using a model mammalian cell mutation assay (hprt(-) locus) demonstrated that the genetic toxicology of PhIP was readily detectable, but separate, in terms of effective concentration, from its oestrogenic activity. To determine whether the oestrogenicity of PhIP could mediate oestrogen-dependent responses such as cell growth, we examined the growth of hormonally responsive cells (MCF-7 cells). We show that PhIP can stimulate cell proliferation and, again, this was dependent upon a functional ER. Using ligand blotting, we further show that PhIP can stimulate the expression of progesterone receptor (PR-A and PR-B) and c-MYC and activate the MAPK signal transduction pathway. These responses were similar to that produced by oestradiol, in terms of temporal aspects, potency and a requirement for a functional ER. Each of these dose-dependent mitogenic responses occurred at concentrations of PhIP ( approximately 10(-9)-10(-11)M) that are likely to be equivalent to systemic human exposure via consumption of cooked meat. Thus PhIP can induce cellular responses that encompass altered gene expression and mitogenesis. We suggest that the combination of genetic toxicology and oestrogen-like promotion of genomic and cellular events provide a mechanism for the tissue-specific tumorigenicity of this compound.

positive: Uric acid: A marker of increased cardiovascular risk. The relationship between uric acid and cardiovascular disease has been known since the 19th century, after that many authors reported the classical association of gout, hypertension, obesity and cardiovascular disease. With the exception of specific genetic defects in purine metabolism, increased uric acid is generally associated with important risk factors for atherosclerosis like hypertension, abdominal obesity, insulin resistance, the metabolic syndrome and renal failure. Studies have clearly shown an association between increased uric acid concentrations with oxidative stress, endothelial dysfunction, inflammation, subclinical atherosclerosis and an increased risk of cardiovascular events. Increased uric acid levels are independent markers of cardiovascular disease risk. Prospective studies are necessary to show that reduction of uric acid levels prevent cardiovascular events.

positive: Serum uric acid level as an independent risk factor for all-cause, cardiovascular, and ischemic stroke mortality: a Chinese cohort study. OBJECTIVE: The association between hyperuricemia and cardiovascular events has been documented in high-risk groups, but is still undetermined in general populations, especially Chinese. This study assessed the temporal association between serum uric acid level, hyperuricemia, and cardiovascular mortality. METHODS: A prospective cohort study of 41,879 men and 48,514 women ages > or = 35 years was conducted using data from the MJ Health Screening Centers in Taiwan. Mortality from all causes, total cardiovascular disease (CVD), ischemic stroke, congestive heart failure, hypertensive disease, and coronary heart disease were compared according to increasing serum uric acid levels. RESULTS: A total of 1,151 (21.2%) events of 5,427 total deaths were ascribed to CVD (mean followup 8.2 years). Hazard ratios (HRs) for hyperuricemia (serum uric acid level >7 mg/dl) were estimated with Cox regression model after adjusting for age, sex, body mass index, cholesterol, triglycerides, diabetes, hypertension, heavy cigarette smoking, and frequent alcohol consumption. In all patients, HRs were 1.16 (P < 0.001) for all-cause mortality, 1.39 (P < 0.001) for total CVD, and 1.35 (P = 0.02) for ischemic stroke. In subgroup analysis, the HRs for cardiovascular risk remained significant in patients with hypertension (1.44, P < 0.001) and in patients with diabetes (1.64, P < 0.001). In addition, in a low metabolic risk subgroup, the HRs for all-cause mortality and total cardiovascular morbidity were 1.24 (P = 0.02) and 1.48 (P = 0.16), respectively. CONCLUSION: Hyperuricemia was an independent risk factor of mortality from all causes, total CVD, and ischemic stroke in the Taiwanese general population, in high-risk groups, and potentially in low-risk groups.

positive: Antimutagens and anticarcinogens: a survey of putative interceptor molecules. In this review recent publications are cited for a number of antimutagens. The molecules surveyed are potential or proven "desmutagens" or "interceptors." These are biologically prevalent or synthetic molecules that are most often small metabolites proficient in binding to, or reacting with, mutagenic chemicals and free radicals. Many of this class of "blocking agents" are "soft" and "hard" nucleophiles with consequently varying abilities to react with particular classes of electrophiles, the major classes of direct-acting mutagens. Although they serve as a first line of defense against mutagens and carcinogens, many interceptor molecules are under-investigated with regard to their spectra of activity and their possible relevance to prophylaxis or treatment of human disease states.

positive: Effects of chlorophyll and chlorophyllin on low-dose aflatoxin B(1) pharmacokinetics in human volunteers. Chlorophyll (Chla) and chlorophyllin (CHL) were shown previously to reduce carcinogen bioavailability, biomarker damage, and tumorigenicity in trout and rats. These findings were partially extended to humans, where CHL reduced excretion of aflatoxin B(1) (AFB(1))-DNA repair products in Chinese unavoidably exposed to dietary AFB(1). However, neither AFB(1) pharmacokinetics nor Chla effects were examined. We conducted an unblinded crossover study to establish AFB(1) pharmacokinetic parameters among four human volunteers, and to explore possible effects of CHL or Chla cotreatment in three of those volunteers. For protocol 1, fasted subjects received an Institutional Review Board-approved dose of 14C-AFB(1) (30 ng, 5 nCi) by capsule with 100 mL water, followed by normal eating and drinking after 2 hours. Blood and cumulative urine samples were collected over 72 hours, and 14C- AFB(1) equivalents were determined by accelerator mass spectrometry. Protocols 2 and 3 were similar except capsules also contained 150 mg of purified Chla or CHL, respectively. Protocols were repeated thrice for each volunteer. The study revealed rapid human AFB(1) uptake (plasma k(a), 5.05 + or - 1.10 h(-1); T(max), 1.0 hour) and urinary elimination (95% complete by 24 hours) kinetics. Chla and CHL treatment each significantly impeded AFB(1) absorption and reduced Cmax and AUCs (plasma and urine) in one or more subjects. These initial results provide AFB(1) pharmacokinetic parameters previously unavailable for humans, and suggest that Chla or CHL co-consumption may limit the bioavailability of ingested aflatoxin in humans, as they do in animal models.

positive: Molecular pathways for cancer chemoprevention by dietary phytochemicals. Interest in dietary phytochemicals for potential cancer chemoprevention has increased substantially. Screening dietary compounds for chemopreventive activity however, requires a systematic and wide-ranging approach to encompass the complexity of carcinogenesis. We present some of the molecular pathways that underpin the broad biological processes involved in carcinogenesis. Oxidative stress, inflammation, and the evasion of apoptosis are important biological mechanisms by which carcinogenesis occurs. Subsequently, antioxidant, anti-inflammatory, and pro-apoptotic activity represent important activities for preventing, suppressing, or reversing the development of carcinogenesis. Ultimately, these mechanisms of action may provide a useful basis for screening novel phytochemicals for chemopreventive activity. In this review, we identify the important molecular processes that may be targeted in routine screenings of dietary phytochemicals to ultimately select the most effective potential candidates for cancer chemoprevention.

positive: Natural compounds in the human diet and their ability to bind mutagens prevents DNA-mutagen intercalation. Human diet may contain many mutagenic or carcinogenic aromatic compounds as well as some beneficial physiologically active dietary components, especially plant food phytochemicals, which act as mutagenesis or carcinogenesis inhibitors. This study compared the binding properties of natural compounds in the human diet (caffeine, theophylline, theobromine, and resveratrol) with a water-soluble derivative of chlorophyll to bind to acridine orange, a known mutagen. An analysis was conducted to determine which substances were effective binding agents and may thus be useful in prevention of chemical-induced mutagenesis and carcinogenesis. Data indicated that in order to bind 50% of the mutagen in a complex, less than twice the concentration of chlorophyllin was needed, the resveratrol concentration was 20-fold higher, while a 1000-fold or even 10,000-fold excess of xanthines were required to bind acridine orange.

positive: Potent antimutagenic activity of white tea in comparison with green tea in the Salmonella assay. There is growing interest in the potential health benefits of tea, including the antimutagenic properties. Four varieties of white tea, which represent the least processed form of tea, were shown to have marked antimutagenic activity in the Salmonella assay, particularly in the presence of S9. The most active of these teas, Exotica China white tea, was significantly more effective than Premium green tea (Dragonwell special grade) against 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and four other heterocyclic amine mutagens, namely 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethyl-3H-imidazo[4,5-f]quinoxaline (4,8-DiMeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). Mechanism studies were performed using rat liver S9 in assays for methoxyresorufin O-demethylase (MROD), a marker for the enzyme cytochrome P4501A2 that activates heterocyclic amines, as well as Salmonella assays with the direct-acting mutagen 2-hydroxyamino-3-methylimidazo[4,5-f]quinoline (N-hydroxy-IQ). White tea at low concentrations in the assay inhibited MROD activity, and attenuated the mutagenic activity of N-hydroxy-IQ in the absence of S9. Nine of the major constituents found in green tea also were detected in white tea, including high levels of epigallocatechin-3-gallate (EGCG) and several other polyphenols. When these major constituents were mixed to produce "artificial" teas, according to their relative levels in white and green teas, the complete tea exhibited higher antimutagenic potency compared with the corresponding artificial tea. The results suggest that the greater inhibitory potency of white versus green tea in the Salmonella assay might be related to the relative levels of the nine major constituents, perhaps acting synergistically with other (minor) constituents, to inhibit mutagen activation as well as "scavenging" the reactive intermediate(s).

positive: Consumption of meat and dairy and lymphoma risk in the European Prospective Investigation into Cancer and Nutrition. The consumption of meat and other foods of animal origin is a risk factor for several types of cancer, but the results for lymphomas are inconclusive. Therefore, we examined these associations among 411,097 participants of the European Prospective Investigation into Cancer and Nutrition. During a median follow-up of 8.5 years, 1,334 lymphomas (1,267 non-Hodgkin lymphoma (NHL) and 67 Hodgkin lymphomas) were identified. Consumption of red and processed meat, poultry, milk and dairy products was assessed by dietary questionnaires. Cox proportional hazard regression was used to evaluate the association of the consumption of these food groups with lymphoma risk. Overall, the consumption of foods of animal origin was not associated with an increased risk of NHLS or HL, but the associations with specific subgroups of NHL entities were noted. A high intake of processed meat was associated with an increased risk of B-cell chronic lymphocytic leukemia (BCLL) [relative risk (RR) per 50 g intake = 1.31, 95% confidence interval (CI) 1.06-1.63], but a decreased risk of follicular lymphomas (FL) (RR = 0.58; CI 0.38-0.89). A high intake of poultry was related to an increased risk of B-cell lymphomas (RR = 1.22; CI 1.05-1.42 per 10 g intake), FL (RR = 1.65; CI 1.18-2.32) and BCLL (RR = 1.54; CI 1.18-2.01) in the continuous models. In conclusion, no consistent associations between red and processed meat consumption and lymphoma risk were observed, but we found that the consumption of poultry was related to an increased risk of B-cell lymphomas. Chance is a plausible explanation of the observed associations, which need to be confirmed in further studies.

positive: Post-diagnosis dietary factors and survival after invasive breast cancer Little is known about the effects of diet after breast cancer diagnosis on survival. We prospectively examined the relation between post-diagnosis dietary factors and breast cancer and all-cause survival in women with a history of invasive breast cancer diagnosed between 1987 and 1999 (at ages 20–79 years). Diet after breast cancer diagnosis was measured using a 126-item food frequency questionnaire. Among 4,441 women without a history of breast cancer recurrence prior to completing the questionnaire, 137 subsequently died from breast cancer within 7 years of enrollment. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated for intake of macronutrients as well as selected micronutrients and food groups from Cox proportional hazards regression models. After adjustment for factors at diagnosis (age, state of residence, menopausal status, smoking, breast cancer stage, alcohol, history of hormone replacement therapy), interval between diagnosis and diet assessment, and at follow-up (energy intake, breast cancer treatment, body mass index, and physical activity), women in the highest compared to lowest quintile of intake of saturated fat and trans fat had a significantly higher risk of dying from any cause (HR = 1.41, 95% CI = 1.06 to 1.87, P-trend = 0.03) for saturated fat; (HR = 1.78, 95% CI = 1.35 to 2.32, P-trend = 0.01) for trans fat intake. Associations were similar, though did not achieve statistical significance, for breast cancer survival. This study suggests that lower intake of saturated and trans fat in the post-diagnosis diet is associated with improved survival after breast cancer diagnosis.

positive: Effect of ascorbic acid and green tea on endogenous formation of N-nitrosodimethylamine and N-nitrosopiperidine in humans. Many constituents present in the human diet may inhibit endogenous formation of N-nitroso compounds (NOC). Studies with human volunteers showed inhibiting effects of intake of ascorbic acid and green tea consumption on nitrosation using the N-nitrosoproline test. The aim of the present study was to evaluate the effects of ascorbic acid and green tea on urinary excretion of carcinogenic N-nitrosodimethylamine (NDMA) and N-nitrosopiperidine (NPIP) in humans. Twenty-five healthy female volunteers consumed a fish meal rich in amines as nitrosatable precursors in combination with intake of nitrate-containing drinking water at the Acceptable Daily Intake level during 7 consecutive days. During 1 week before and after nitrate intake a diet low in nitrate was consumed. Using the same protocol, the effect of two different doses of ascorbic acid (250 mg and 1 g/day) and two different doses of green tea (2 g and 4 g/day) on formation of NDMA and NPIP was studied. Mean nitrate excretion in urine significantly increased from control (76+/-24) to 167+/-25 mg/24 h. Intake of nitrate and fish resulted in a significant increase in mean urinary excretion of NDMA compared with the control weeks: 871+/-430 and 640+/-277 ng/24 h during days 1-3 and 4-7, respectively, compared with 385+/-196 ng/24 h (p<0.0002). Excretion of NPIP in urine was not related to nitrate intake and composition of the diet. Intake of 250 mg and 1 g of ascorbic acid per day resulted in a significant decrease in urinary NDMA excretion during days 4-7 (p=0.0001), but not during days 1-3. Also, consumption of four cups of green tea per day (2 g) significantly decreased excretion of NDMA during days 4-7 (p=0.0035), but not during days 1-3. Surprisingly, consumption of eight cups of green tea per day (4 g) significantly increased NDMA excretion during days 4-7 (p=0.0001), again not during days 1-3. This increase is probably a result of catalytic effects of tea polyphenols on nitrosation, or of another, yet unknown, mechanism. These results suggest that intake of ascorbic acid and moderate consumption of green tea can reduce endogenous NDMA formation.

positive: Paleolithic vs. modern diets--selected pathophysiological implications. The nutritional patterns of Paleolithic humans influenced genetic evolution during the time segment within which defining characteristics of contemporary humans were selected. Our genome can have changed little since the beginnings of agriculture, so, genetically, humans remain Stone Agers--adapted for a Paleolithic dietary regimen. Such diets were based chiefly on wild game, fish and uncultivated plant foods. They provided abundant protein; a fat profile much different from that of affluent Western nations; high fibre; carbohydrate from fruits and vegetables (and some honey) but not from cereals, refined sugars and dairy products; high levels of micronutrients and probably of phytochemicals as well. Differences between contemporary and ancestral diets have many pathophysiological implications. This review addresses phytochemicals and cancer; calcium, physical exertion, bone mineral density and bone structural geometry; dietary protein, potassium, renal acid secretion and urinary calcium loss; and finally sarcopenia, adiposity, insulin receptors and insulin resistance. While not, yet, a basis for formal recommendations, awareness of Paleolithic nutritional patterns should generate novel, testable hypotheses grounded in evolutionary theory and it should dispel complacency regarding currently accepted nutritional tenets.

positive: Effects of vitamins C and E on N-nitroso compound formation, carcinogenesis, and cancer. The properties of N-nitroso compounds (NNC) and of vitamins C and E are briefly described. The author reviews the ability of vitamins C and E to inhibit NNC formation in chemical systems, in nitrite-preserved meat, in experimental animals and in humans. Dietary vitamins C and E both produced 30% to 60% inhibitions in most carcinogenesis experiments employing preformed carcinogens. Vitamin C reversed transformation in an in vitro system. Carcinogenicity tests of the vitamins are reviewed (vitamin C can promote bladder carcinogenesis). Intake of fresh fruits and vegetables (which contain vitamin C) is negatively correlated with cancer of the stomach, esophagus, larynx, mouth and cervix. For gastric and esophageal cancer, there is evidence that this association is due to an inhibition of in vivo NNC formation. Vitamin C is apparently not a useful treatment for cancer. The author supports the recommendation that fresh fruit and vegetable intake be increased to lower the risk of cancer.

positive: Lung deposition of fine and ultrafine particles outdoors and indoors during a cooking event and a no activity period. Some indoor activities increase the number concentration of small particles and, hence, enhance the dose delivered to the lungs. The received particle dose indoors may exceed noticeably the dose from ambient air under routine in-house activities like cooking. In the present work, the internal dose by inhalation of ultrafine and fine particles is assessed, using an appropriate mechanistic model of lung deposition, accommodating aerosol, and inhalation dynamics. The analysis is based on size distribution measurements (10-350 nm) of indoor and outdoor aerosol number concentrations in a typical residence in Athens, Greece. Four different cases are examined, namely, a cooking event, a no activity period indoors and the equivalent time periods outdoors. When the cooking event (frying of bacon-eggs with a gas fire) occurred, the amount of deposited particles deep into the lung of an individual indoors exceeded by up to 10 times the amount received by an individual at the same time period outdoors. The fine particle deposition depends on the level of physical exertion and the hygroscopic properties of the inhaled aerosol. The dose is not found linearly dependant on the indoor/outdoor concentrations during the cooking event, whereas it is during the no activity period. PRACTICAL IMPLICATIONS: The necessity for determining the dose in specific regions of the human lung, as well as the non-linear relationship between aerosol concentration and internal dose makes the application of dosimetry models important. Lung dose of fine and ultrafine particles, during a cooking event, is compared with the dose at no indoor activity and the dose received under outdoor exposure conditions. The dose is expressed in terms of number or surface of deposited particles. This permits to address the dosimetry of very small particles, which are released by many indoor sources but represent a slight fraction of the particulate matter mass. The enhancement of the internal dose resulting from fine and ultrafine particles generated during the cooking event vs. the dose when no indoor source is active is assessed. The results for those cases are also compared with the dose calculated for the measured aerosol outdoors.

positive: N-Nitroso compounds in the diet. N-Nitroso compounds were known almost 40 years ago to be present in food treated with sodium nitrite, which made fish meal hepatotoxic to animals through formation of nitrosodimethylamine (NDMA). Since that time, N-nitroso compounds have been shown in animal experiments to be the most broadly acting and the most potent group of carcinogens. The key role of nitrite and nitrogen oxides in forming N-nitroso compounds by interaction with secondary and tertiary amino compounds has led to the examination worldwide of foods for the presence of N-nitroso compounds, which have been found almost exclusively in those foods containing nitrite or which have become exposed to nitrogen oxides. Among these are cured meats, especially bacon-and especially when cooked; concentrations of 100 micrograms kg(-1) have been found or, more usually, near 10 micrograms kg(-1). This would correspond to consumption of 1 microgram of NDMA in a 100-g portion. Much higher concentrations of NDMA (but lower ones of other nitrosamines) have been found in Japanese smoked and cured fish (more than 100 micrograms kg(-1)). Beer is one source of NDMA, in which as much as 70 micrograms l(-1) has been reported in some types of German beer, although usual levels are much lower (10 or 5 micrograms l(-1)); this could mean a considerable intake for a heavy beer drinker of several liters per day. Levels of nitrosamines have been declining during the past three decades, concurrent with a lowering of the nitrite used in food and greater control of exposure of malt to nitrogen oxides in beer making. There have been declines of N-nitroso compound concentrations in many foods during the past two decades. The small amounts of nitrosamines in food are nonetheless significant because of the possibility-even likelihood-that humans are more sensitive to these carcinogens than are laboratory rodents. Although it is probable that alkylnitrosamides (which induce brain tumors in rodents) are present in cured meats and other potentially nitrosated products in spite of much searching, there has been only limited indirect evidence of their presence. Copyright 1999 Elsevier Science B.V.

positive: The effect of dietary factors on nitrosoproline levels in human urine. The effect of dietary components on the levels of nitrosoproline ( NPRO ) excreted over a 24 h period in the urine was examined in volunteers ingesting known amounts of various food products. The ingestion of nitrite-preserved meats (85-170 g per meal), including canned, rolled or Yunnan ham, cured pork, luncheon meat, and various Chinese and European-style sausages, led to urinary NPRO excretion levels ranging from 2.5 to 78.5 micrograms/24 h, whereas the consumption of non-preserved meat and fish products, including chicken, herring, salmon, shrimp, ground beef (hamburger), pork chops and beef liver, led to relatively low NPRO excretion levels, ranging from 0.0 to 0.8 micrograms/24 h. The urinary NPRO levels of 22 vegetarians and 14 lacto-vegetarians averaged 0.8 and 1.4 micrograms/24 h, respectively. A change from a nitrite-preserved meat diet to a vegetarian diet was accompanied by an approximately six-fold reduction in urinary NPRO levels; however, these remained above control levels for at least 3 days following the dietary change. The relatively high NPRO levels following the ingestion of nitrite-preserved meats could not be reduced by nitrite-trapping chemicals, including ascorbic acid, ferulic acid, caffeic acid, or phenolic-containing mixtures such as coffee and tea, which were effective in suppressing endogenous NPRO formation following the intake of nitrate and proline. The high urinary NPRO levels after ingestion of preserved meat products appear to be due to the consumption of preformed NPRO . An understanding of the relative contribution of preformed and endogenously formed nitrosamines appears to be essential when designing dietary intervention programmes.

positive: Understanding tobacco smoke carcinogen NNK and lung tumorigenesis. The deleterious effects of tumor-promoting tobacco carcinogen, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, nicotine-derived nitrosamine ketone) have undoubtedly been stipulated. Though many tobacco agents play a part in the development of lung tumors, the potent effects of NNK remain unmatched. It is therefore critical to distinguish the variety of cofactors involved in NNK-mediated pathogenesis, and the unique pathways necessary for successful cellular biotransformation. Current reviews have consistently identified the strengths of NNK and prospective tumor capabilities. Others have delineated specific cellular factors mediating NNK and lung tumors, and have identified metabolic and signaling pathways largely responsible for NNK activation and tumorigenic initiation. Unique to this review is that it summarizes the extensive network of cofactors and cellular mechanisms that promote NNK-specific lung tumorigenesis. As such, it displays a fuller, more comprehensive overview, bringing us one step closer to understanding the fatal consequences of NNK, thus, discovering new avenues that successfully break the cycle of NNK-mediated lung carcinogenesis.

positive: Determination of volatile nitrosamines in meat products by microwave-assisted extraction and dispersive liquid-liquid microextraction coupled to ga... Microwave-assisted extraction (MAE) and dispersive liquid-liquid microextraction (DLLME) coupled with gas chromatography-mass spectrometry (GC-MS) were evaluated for use in the extraction and preconcentration of volatile nitrosamines in meat products. Parameters affecting MAE, such as the extraction solvent used, and DLLME, including the nature and volume of the extracting and disperser solvents, extraction time, salt addition and centrifugation time, were optimized. In the MAE method, 0.25g of sample mass was extracted in 10mL NaOH (0.05M) in a closed-vessel system. For DLLME, 1.5mL of methanol (disperser solvent) containing 20μL of carbon tetrachloride (extraction solvent) was rapidly injected by syringe into 5mL of the sample extract solution (previously adjusted to pH 6), thereby forming a cloudy solution. Phase separation was performed by centrifugation, and a volume of 3μL of the sedimented phase was analyzed by GC-MS. The enrichment factors provided by DLLME varied from 220 to 342 for N-nitrosodiethylamine and N-nitrosopiperidine, respectively. The matrix effect was evaluated for different samples, and it was concluded that sample quantification can be carried out by aqueous calibration. Under the optimized conditions, detection limits ranged from 0.003 to 0.014ngmL(-1) for NPIP and NMEA, respectively (0.12-0.56ngg(-1) in the meat products). Copyright © 2011 Elsevier B.V. All rights reserved.

positive: Epidemilogical trends strongly suggest exposures as etiologic agents in the pathogenesis of sporadic Alzheimer's disease, diabetes mellitus, and no... Nitrosamines mediate their mutagenic effects by causing DNA damage, oxidative stress, lipid peroxidation, and pro-inflammatory cytokine activation, which lead to increased cellular degeneration and death. However, the very same pathophysiological processes comprise the "unbuilding" blocks of aging and insulin-resistance diseases including, neurodegeneration, diabetes mellitus (DM), and non-alcoholic steatohepatitis (NASH). Previous studies demonstrated that experimental exposure to streptozotocin, a nitrosamine-related compound, causes NASH, and diabetes mellitus Types 1, 2 and 3 (Alzheimer (AD)-type neurodegeneration). Herein, we review evidence that the upwardly spiraling trends in mortality rates due to DM, AD, and Parkinson's disease typify exposure rather than genetic-based disease models, and parallel the progressive increases in human exposure to nitrates, nitrites, and nitrosamines via processed/preserved foods. We propose that such chronic exposures have critical roles in the pathogenesis of our insulin resistance disease pandemic. Potential solutions include: 1) eliminating the use of nitrites in food; 2) reducing nitrate levels in fertilizer and water used to irrigate crops; and 3) employing safe and effective measures to detoxify food and water prior to human consumption. Future research efforts should focus on refining our ability to detect and monitor human exposures to nitrosamines and assess early evidence of nitrosamine-mediated tissue injury and insulin resistance.

positive: Long-term exposure to sodium nitrite and risk of esophageal carcinoma: a cohort study for 30 years. The objective of this study is to investigate the risk of esophageal carcinoma in a cohort with long-term occupational exposure to sodium nitrite. The method used was a retrospective cohort study. A small wood screw manufacturer was founded in 1977 and closed down in 2000. In their production process, the sodium nitrite solution was used to serve as anticorrosive and coolant fluid. One hundred sixty workers in turning and milling shops had direct exposure to sodium nitrite through skin, mouth, and airway because of lack of occupational protective knowledge (study group), whereas 255 workers from other workshops without direct contact with sodium nitrite served as control group. The incidence, diagnosis, and treatment of esophageal carcinoma as well as other malignant tumors in these two groups were followed until the end of 2007. The sodium nitrite exposure time in the study group ranged from 16 to 23 years, with an average of 22.1 years. During 30 years of follow-up, there were 11 esophageal carcinomas and 10 other malignant tumors (4 hepatic cell carcinomas, 3 lung cancers, 2 breast cancers, and 1 leukemia) documented in the study group, while no cancer developed in the control group. The risk for esophageal carcinoma was significantly increased in the study group compared with the control group (relative risk = 1.26, 95% confidence interval = 1.08-1.46, chi-square = 116.83, P < 0.001). Long-term exposure to sodium nitrite markedly increases the risk of esophageal carcinoma in human body. © 2010 Copyright the Authors. Journal compilation © 2010, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.

positive: Principal component analysis of dietary and lifestyle patterns in relation to risk of subtypes of esophageal and gastric cancer Purpose To perform pattern analyses of dietary and lifestyle factors in relation to risk of esophageal and gastric cancers. Methods We evaluated risk factors for esophageal adenocarcinoma (EA), esophageal squamous cell carcinoma (ESCC), gastric cardia adenocarcinoma (GCA), and other gastric cancers (OGA) using data from a population-based case-control study conducted in Connecticut, New Jersey, and western Washington state. Dietary/lifestyle patterns were created using principal component analysis (PCA). Impact of the resultant scores on cancer risk was estimated through logistic regression. Results PCA identified six patterns: meat/nitrite, fruit/vegetable, smoking/alcohol, legume/meat alternate, GERD/BMI, and fish/vitamin C. Risk of each cancer under study increased with rising meat/nitrite score. Risk of EA increased with increasing GERD/BMI score, and risk of ESCC rose with increasing smoking/alcohol score and decreasing GERD/BMI score. Fruit/vegetable scores were inversely associated with EA, ESCC, and GCA. Conclusions PCA may provide a useful approach for summarizing extensive dietary/lifestyle data into fewer interpretable combinations that discriminate between cancer cases and controls. The analyses suggest that meat/nitrite intake is associated with elevated risk of each cancer under study, while fruit/vegetable intake reduces risk of EA, ESCC, and GCA. GERD/obesity were confirmed as risk factors for EA and smoking/alcohol as risk factors for ESCC.

positive: Dietary fat and meat intakes and risk of reflux esophagitis, Barrett’s esophagus and esophageal adenocarcinoma The aim of this study was to investigate whether dietary fat and meat intakes are associated with reflux esophagitis (RE), Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). In this all-Ireland case-control study, dietary intake data was collected using a food frequency questionnaire in 219 RE patients, 220 BE patients, 224 EAC patients, and 256 frequency-matched controls between 2002 and 2005. Unconditional multiple logistic regression analysis was used to examine the association between dietary variables and disease risk using quartiles of intake, to attain odds ratios (OR) and 95% confidence intervals (95%CI), while adjusting for potential confounders. Patients in the highest quartile of total fat intake had a higher risk of RE (OR=3.54; 95%CI=1.32–9.46) and EAC (OR=5.44; 95%CI=2.08–14.27). A higher risk of RE and EAC was also reported for patients in the highest quartile of saturated fat intake (OR=2.79; 95%CI=1.11–7.04; OR=2.41; 95%CI=1.14–5.08, respectively) and monounsaturated fat intake (OR=2.63; 95%CI=1.01–6.86; OR=5.35; 95%CI=2.14–13.34, respectively). Patients in the highest quartile of fresh red meat intake had a higher risk of EAC (OR=3.15; 95%CI=1.38–7.20). Patients in the highest category of processed meat intake had a higher risk of RE (OR=4.67; 95%CI=1.71–12.74). No consistent associations were seen for BE with either fat or meat intakes. Further studies, investigating the association between dietary fat and food sources of fat are needed to confirm these results.

positive: Meat consumption, Cooking Practices, Meat Mutagens and Risk of Prostate Cancer Consumption of red meat, particularly well done meat, has been associated with increased prostate cancer risk. High temperature cooking methods such as grilling and barbequeing may produce heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) which are known carcinogens. We assessed the association with meat consumption and estimated HCA and PAH exposure in a population-based case-control study of prostate cancer. Newly diagnosed cases aged 40–79 years (531 advanced cases, 195 localized cases) and 527 controls were asked about dietary intake, including usual meat cooking methods and doneness levels. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariate logistic regression. For advanced prostate cancer, but not localized disease, increased risks were associated with higher consumption of hamburgers (OR=1.79. CI=1.10–2.92), processed meat (OR=1.57, CI=1.04, 2.36), grilled red meat (OR=1.63, CI=0.99–2.68), and well done red meat (OR=1.52, CI=0.93–2.46), and intermediate intake of 2-amino-1-methyl1-6-phenylimidazo[4,5-b]pyridine (PhIP) (quartile 2 vs. 1: OR=1.41, CI=0.98–2.01; quartile 3 vs. 1: OR=1.42, CI=0.98–2.04), but not for higher intake. White meat consumption was not associated with prostate cancer. These findings provide further evidence that consumption of processed meat and red meat cooked at high temperature is associated with increased risk of advanced, but not localized prostate cancer.

positive: N-Nitroso compounds and cancer incidence: the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Study. BACKGROUND: Humans are exposed to preformed N-nitroso compounds (NOCs) and endogenous NOCs. Several NOCs are potential human carcinogens, including N-nitrosodimethylamine (NDMA), but evidence from population studies is inconsistent. OBJECTIVE: We examined the relation between dietary NOCs (NDMA), the endogenous NOC index, and dietary nitrite and cancer incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk, United Kingdom, study. DESIGN: This was a prospective study of 23,363 men and women, aged 40-79 y, who were recruited in 1993-1997 and followed up to 2008. The baseline diet was assessed with food-frequency questionnaires. RESULTS: There were 3268 incident cancers after a mean follow-up of 11.4 y. Dietary NDMA intake was significantly associated with increased cancer risk in men and women [hazard ratio (HR): 1.14; 95% CI: 1.03, 1.27; P for trend = 0.03] and in men (HR: 1.24; 95% CI: 1.07, 1.44; P for trend = 0.005) when the highest quartile was compared with the lowest quartile in age- and sex-adjusted analyses but not in multivariate analyses (HR: 1.10; 95% CI: 0.97, 1.24; HR for men: 1.18; 95% CI: 1.00, 1.40; P for trend ≥ 0.05). When continuously analyzed, NDMA was associated with increased risk of gastrointestinal cancers (HR: 1.13; 95% CI: 1.00, 1.28), specifically of rectal cancer (HR: 1.46; 95% CI: 1.16, 1.84) per 1-SD increase after adjustment for age, sex, body mass index, cigarette smoking status, alcohol intake, energy intake, physical activity, education, and menopausal status (in women). The endogenous NOC index and dietary nitrite were not significantly associated with cancer risk. There was a significant interaction between plasma vitamin C concentrations and dietary NDMA intake on cancer incidence (P for interaction < 0.00001). CONCLUSIONS: Dietary NOC (NDMA) was associated with a higher gastrointestinal cancer incidence, specifically of rectal cancer. Plasma vitamin C may modify the relation between NDMA exposure and cancer risk.

positive: Salt, processed meat and the risk of cancer. This study assesses the association between salt added at the table, processed meat and the risk of various cancers. Mailed questionnaires were completed by 19 732 patients with histologically confirmed incident cancer of the stomach, colon, rectum, pancreas, lung, breast, ovary, prostate, testis, kidney, bladder, brain, non-Hodgkin's lymphoma or leukaemia, and 5039 population controls,between 1994 and 1997. Measurement included information on socioeconomic status, lifestyle habits and diet. A 69-item food frequency questionnaire provided data on eating habits 2 years before the study. Odds ratios and 95% confidence intervals were derived through unconditional logistic regression. Compared with never adding salt at the table, always or often adding salt at the table was associated with an increased risk of stomach, lung, testicular and bladder cancer. Processed meat was significantly related to the risk of the stomach, colon, rectum, pancreas, lung, prostate, testis, kidney and bladder cancer and leukaemia; the odds ratios for the highest quartile ranged from 1.3 to 1.7. The findings add to the evidence that high consumption of salt and processed meat may play a role in the aetiology of several cancers.

positive: Meat and components of meat and the risk of bladder cancer in the NIH-AARP Diet and Health Study Background Meat could be involved in bladder carcinogenesis via multiple potentially carcinogenic meat-related compounds related to cooking and processing, including nitrate, nitrite, heterocyclic amines (HCAs), and polycyclic aromatic hydrocarbons. We comprehensively investigated the association between meat and meat components and bladder cancer. Methods During 7 years of follow-up, 854 transitional cell bladder cancer cases were identified among 300,933 men and women who completed a validated food frequency questionnaire in the large prospective NIH-AARP Diet and Health Study. We estimated intake of nitrate and nitrite from processed meat and HCAs and PAHs from cooked meat using quantitative databases of measured values. We calculated total dietary nitrate and nitrite based on literature values. Results The hazard ratios (HR) and 95% confidence intervals (CI) for red meat (HR for fifth compared to first quintile=1.22, 95% CI=0.96–1.54, p-trend=0.07) and the HCA 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) (HR=1.19, 95% CI=0.95–1.48, p-trend=0.06) conferred a borderline statistically significant increased risk of bladder cancer. We observed positive associations in the top quintile for total dietary nitrite (HR=1.28, 95% CI=1.02–1.61, p-trend= 0.06) and nitrate plus nitrite intake from processed meat (HR=1.29 95% CI=1.00–1.67, p-trend= 0.11). Conclusions These findings provide modest support for a role for total dietary nitrite and nitrate plus nitrite from processed meat in bladder cancer. Our results also suggest a positive association between red meat and PhIP and bladder carcinogenesis.

positive: Endometrial cancer and meat consumption: a case-cohort study. Diet plays an important role in the etiology of certain cancers, but there is limited evidence with regard to the association between diet and risk of endometrial cancer. Few prospective studies have investigated meat intake as a potential determinant of endometrial cancer risk. The objective of this study was to examine the association between endometrial cancer risk and total meat, red meat, processed meat, fish, and poultry intake. We conducted a case-cohort analysis within the Canadian Study of Diet, Lifestyle, and Health, a prospective cohort of 73 909 adults (39 614 women). Participants were recruited from 1992 to 1999, predominantly from three Canadian universities. We conducted a linkage with the Ontario Cancer Registry for the years 1992-2007 for the female cohort members, who resided in Ontario at the time of enrollment (n=26 024), to yield data on cancer incidence. The analytic sample was comprised of 107 incident cases and 1830 subcohort members, the latter being an age-stratified sample of the full cohort. A nonsignificant increase in the risk of endometrial cancer was associated with increased consumption of red meat [hazard ratio (HR)=1.62, 95% confidence intervals (CI)=0.86-3.08, for high vs. low intake; P trend=0.13)], processed meat (HR=1.45, 95% CI=0.80-2.61, for high vs. low intake; P trend=0.058), and all meat combined (HR=1.50, 95% CI=0.78-2.89, for high vs. low intake; P trend=0.14). No clear patterns were noted for poultry or fish. The results of this study, although based on a limited number of cases, suggest that relatively high meat intake may be associated with increased risk of endometrial cancer.

positive: Red and Processed Meat and Colorectal Cancer Incidence: Meta-Analysis of Prospective Studies Background The evidence that red and processed meat influences colorectal carcinogenesis was judged convincing in the 2007 World Cancer Research Fund/American Institute of Cancer Research report. Since then, ten prospective studies have published new results. Here we update the evidence from prospective studies and explore whether there is a non-linear association of red and processed meats with colorectal cancer risk. Methods and Findings Relevant prospective studies were identified in PubMed until March 2011. For each study, relative risks and 95% confidence intervals (CI) were extracted and pooled with a random-effects model, weighting for the inverse of the variance, in highest versus lowest intake comparison, and dose-response meta-analyses. Red and processed meats intake was associated with increased colorectal cancer risk. The summary relative risk (RR) of colorectal cancer for the highest versus the lowest intake was 1.22 (95% CI  = 1.11−1.34) and the RR for every 100 g/day increase was 1.14 (95% CI  = 1.04−1.24). Non-linear dose-response meta-analyses revealed that colorectal cancer risk increases approximately linearly with increasing intake of red and processed meats up to approximately 140 g/day, where the curve approaches its plateau. The associations were similar for colon and rectal cancer risk. When analyzed separately, colorectal cancer risk was related to intake of fresh red meat (RR for 100 g/day increase  = 1.17, 95% CI  = 1.05−1.31) and processed meat (RR for 50 g/day increase  = 1.18, 95% CI  = 1.10−1.28). Similar results were observed for colon cancer, but for rectal cancer, no significant associations were observed. Conclusions High intake of red and processed meat is associated with significant increased risk of colorectal, colon and rectal cancers. The overall evidence of prospective studies supports limiting red and processed meat consumption as one of the dietary recommendations for the prevention of colorectal cancer.

positive: The nitrate story--no end in sight. It has been demonstrated that nitrates are reduced to nitrites in humans, possibly through bacterial activity. Nitrites, together with ubiquitous amines, can lead to an in-vivo synthesis of carcinogenic nitrosamines. The average daily intake of nitrates depends upon the amount of vegetables consumed and on the nitrate concentration in drinking water. Agricultural practices play an important part in the concentration of nitrate in both water and vegetables. If nitrate is taken up by the plant and not metabolised to amino acids, proteins or nucleic acids, it is stored in cell vacuoles as a reserve. However, with an over-supply of nitrate relative to possible photosynthesis, this stored nitrate is still present at harvest and leads to high concentrations in plant tissue. The nitrate content in plants also depends upon other factors, such as plant variety (cultivar), kind and amount of fertiliser, time of harvest and environmental factors such as light intensity, temperature, etc. It is suggested that we should try to meet the recommendations of toxicologists who believe a dramatic reduction nitrate intake for humans is necessary. It has been demonstrated that modern biological-organic farming methods clearly lead both to lower leaching of nitrates and to lower nitrate content in vegetables. Since no synthetic fungicides are used in this farming method, problems with the reaction of metabolites of such products and nitrites e.g. to highly cancerogenic and multigenic nitroso-ethylenethiourea do not exist.

positive: A survey of feeding N-nitrosodimethylamine (NDMA) to domestic animals over an 18 year period. Sodium nitrite and formalin have been used as preservatives in the fish meal industry in Norway since 1953. In 1957, fur farms suffered losses of mink due to a new, malignant liver disease. Experimental feeding of herring meal to cows and sheep resulted in the death of some of the animals. Further studies showed that amines (TMAO) normally present in fish, can react with sodium nitrite used as preservative, or nitrogen oxides from the combustion of fuel oils used during processing, to produce the toxic agent, NDMA. Mink and fox may consume considerable amounts of fish meal in their diets. If the fish meal contains sufficient NDMA, the incidence of liver failure or tumours can be quite high. Long-term exposure to as little as 0.1 mg NDMA/kg b.w./day in the diet of mink, cows and sheep can produce fibro-occlusive changes in the hepatic vessels. These lesions can later cause capillary ectasies-like changes in cows, which are similar in appearance to hemangiomas seen in mink. The mink liver hemangiomas develop into hemangiosarcomas. We currently consider capillary ectasies-like changes in cows exposed to NDMA to represent pre-cancerous lesions.

positive: Nutritional composition of dry-cured ham and its role in a healthy diet. Dry-cured ham is a traditional product with a strong presence in markets in the Mediterranean area. It is very popular with European consumers and is of enormous economic importance for the meat industry in the Mediterranean area. Although the great palatability of ham largely outweighs other considerations, aspects relating to health and wellbeing are increasingly important factors in consumer decisions. The potential role of ham in a context of healthy nutrition has not been clearly elucidated, especially considering that origins and production methods of dry-cured hams can induce differences in composition. The object of this review was on the one hand to provide an analysis of the components of dry-cured ham and their role in a healthy diet, and on the other hand to suggest possible strategies for improving its nutritional composition. 2009 Elsevier Ltd. All rights reserved.

positive: A meta-analysis of maternal cured meat consumption during pregnancy and the risk of childhood brain tumors. OBJECTIVE: N-Nitroso compounds (NOCs) are recognized neural carcinogens in animal models and are suspected human carcinogens. A meta-analysis was performed examining the possible association of maternal intake of cured meat (an important source of dietary NOCs) during pregnancy and the risk of pediatric brain tumors. METHODS: Data from epidemiological studies were pooled using a general variance-based meta-analytic method employing confidence intervals described by Greenland in 1986. The outcome of interest was a summary relative risk (RR) reflecting the risk of childhood brain tumor (CBT) development associated with maternal intake of cured meats during pregnancy. Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity. RESULTS: Seven observational studies were found that met the protocol-specified inclusion criteria. Analysis for heterogeneity demonstrated a lack of statistical heterogeneity (p = 0.59), indicating that the data could be statistically combined. Pooling data from the 6 reports containing data on maternal cured meat intake of all types yielded an RR of 1.68 (1.30- 2.17), being a statistically significant result. Analyzing CBT risk by type of cured meat ingested showed that hot dog consumption increased CBT risk by 33% (1.08-1.66), with a similar increase shown by frequent ingestion of sausage, i.e. 44%. CONCLUSION: The data provide support for the suspected causal association between ingestion of NOCs from cured meats during pregnancy and subsequent CBT in offspring. Limitations in study design preclude definitive conclusions, but the relationship warrants exploration via additional observational and laboratory-based studies. Copyright 2004 S. Karger AG, Basel

positive: Acute and subacute toxicity of tyramine, spermidine, spermine, putrescine and cadaverine in rats. The acute and subacute toxicity of five biogenic amines-tyramine, spermidine, spermine, putrescine and cadaverine-were examined in Wistar rats. Tyramine and cadaverine had a low acute oral toxicity of more than 2000 mg/kg body weight. Putrescine had an acute oral toxicity of 2000 mg/kg body weight and spermidine and spermine each of 600 mg/kg body weight. All amines investigated caused a dose-related decrease in blood pressure after intravenous administration, except for tyramine, where an increase was found. In 6-wk studies the biogenic amines were administered in the diet to groups of 10 male and 10 female rats. Tyramine and cadaverine were given at levels of 0, 200, 2000 or 10,000 ppm, spermine and putrescine at levels of 0, 200, 2000 or 5000 ppm and spermidine at levels of 0, 20, 200 or 500/1000 ppm in the first study and at levels of 0 or 10,000 ppm in a second study. Spermine was the most toxic. The high dose level showed a great number of changes, such as emaciation, aggressiveness, convulsions and paralysis of the hind legs. Growth, food intake and water intake were considerably decreased. Slight anaemia (males) and changes in plasma clinical chemistry occurred. The relative weights of the thyroid, adrenals, spleen and heart were increased and that of the liver decreased. Impaired kidney function, together with renal histopathological changes and changes in plasma electrolytes and urea, occurred with spermine. Histopathological examinations also revealed decreased glycogen content in the liver, reduction of spermatogenesis, severe depletion of splenic white pulp, acute involution of the thymus and moderate myocardial degeneration in the heart. Myocardial degeneration was also seen in one mid-dose male. Adverse effects were also observed in the top dose groups of all other amines. Decreased body weights associated with diminished food intake were generally seen. Slight increases in packed cell volume, haemoglobin concentration and thrombocytes occurred with cadaverine. With spermidine, decreased plasma creatinine, calcium and inorganic phosphate were observed and decreased potassium levels with cadaverine. The no-observed-adverse-effect level was 2000 ppm (180 mg/kg body weight/day) for tyramine, cadaverine and putrescine, 1000 ppm (83 mg/kg body weight/day) for spermidine and 200 ppm (19 mg/kg body weight/day) for spermine.

positive: Determination of biogenic amines in Korean traditional fermented soybean paste (Doenjang). Biogenic amines, produced by bacterial decarboxylation of amino acids, have been associated with toxicological symptoms in food products. Twenty-three samples of traditionally available Korean fermented soybean paste samples (Doenjang) were analyzed in order to determine the content of biogenic amines. Amines were extracted with 0.4M perchloric acid and derivatized with dansyl chloride. Nine biogenic amines were separated from Doenjang samples by high performance liquid chromatography using gradient elution (acetonitrile and ammonium acetate), and detected with spectrophotometric UV-vis detection at 254 nm. The pH value of all the samples was ranged from 4.8 to 6.0, and the strong amino acid decarboxylase activity was found to be in an acidic environment. The mean values of biogenic amines (tryptamine, 2-phenyl-ethylamine, putrescine, cadaverine, agmatine, histamine, tyramine, spermidine and spermine) determined in 23 Doenjang samples were found to be 18.37, 82.03, 70.84, 34.24, 47.32, 26.79, 126.66, 74.41 and 244.36 mg%, respectively. The findings of this study enhance the safety of not only Doenjang but other salted and/or fermented food products. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

positive: Common Household Chemicals and the Allergy Risks in Pre-School Age Children Background The risk of indoor exposure to volatile organic compounds (VOCs) on allergic airway diseases in children remains unknown. Objective We examined the residential concentrations of VOCs, emitted from building materials, paints, furniture, and other lifestyle practices and the risks of multiple allergic diseases as well as the IgE-sensitization in pre-school age children in Sweden. Methods In a case-control investigation (198 case children with asthma and allergy and 202 healthy controls), air samples were collected in the room where the child slept. The air samples were analyzed for the levels of eight classes of VOCs. Results A natural-log unit of summed propylene glycol and glycol ethers (PGEs) in bedroom air (equal to interquartile range, or 3.43 – 15.65 µg/m3) was associated with 1.5-fold greater likelihood of being a case (95% CI, 1.1 – 2.1), 1.5-fold greater likelihood of asthma (95% CI, 1.0 – 2.3), 2.8-fold greater likelihood of rhinitis (95% CI, 1.6 – 4.7), and 1.6-fold greater likelihood of eczema (95% CI, 1.1 – 2.3), accounting for gender, secondhand smoke, allergies in both parents, wet cleaning with chemical agents, construction period of the building, limonene, cat and dog allergens, butyl benzyl phthalate (BBzP), and di(2-ethylhexyl)phthalate (DEHP). When the analysis was restricted to the cases, the same unit concentration was associated with 1.8-fold greater likelihood of IgE-sensitization (95% CI, 1.1 – 2.8) compared to the non-IgE sensitized cases. No similar associations were found for the other classes of VOCs. Conclusion We propose a novel hypothesis that PGEs in indoor air exacerbate and/or induce the multiple allergic symptoms, asthma, rhinitis and eczema, as well as IgE sensitization respectively.

positive: In vitro evaluation of genotoxicity of avocado (Persea americana) fruit and leaf extracts in human peripheral lymphocytes. Persea americana is much sought after both for the nutritional value of its fruit and the medicinal values of its various plant parts. A chromosomal aberration assay was undertaken to evaluate the potential genotoxicity of crude extracts from avocado fruits and leaves. Chromosomal aberrations were observed in cultured human peripheral lymphocytes exposed to separately increasing concentrations of 50% methanolic extracts of Persea americana fruit and leaves. The groups exposed to leaf and fruit extracts, respectively, showed a concentration-dependent increase in chromosomal aberrations as compared to that in a control group. The mean percentage total aberrant metaphases at 100 mg/kg, 200 mg/kg, and 300 mg/kg concentrations of leaf extract were found respectively to be 58 ± 7.05, 72 ± 6.41, and 78 ± 5.98, which were significantly higher (p < 0.0001 each) than that in the control group (6 ± 3.39). The mean percentage total aberrant metaphases at 100 mg/kg, 200 mg/kg, and 300 mg/kg concentrations of fruit extract were found to be 18 ± 5.49, 40 ± 10.00, and 52 ± 10.20, respectively, which were significantly higher (p = 0.033, p < 0.0001, and p < 0.0001, respectively) than that for control (6 ± 3.39). Acrocentric associations and premature centromeric separation were the two most common abnormalities observed in both the exposed groups. The group exposed to leaf extracts also showed a significant number of a variety of other structural aberrations, including breaks, fragments, dicentrics, terminal deletion, minutes, and Robertsonian translocations. The group exposed to leaf extract showed higher frequency of all types of aberrations at equal concentrations as compared to the group exposed to fruit extract.

positive: Impact of adopting a vegan diet or an olestra supplementation on plasma organochlorine concentrations: results from two pilot studies. The aim of these studies was to evaluate the potential of some nutritional approaches to prevent or reduce the body load of organochlorines (OC) in humans. Study 1 compared plasma OC concentrations between vegans and omnivores while study 2 verified if the dietary fat substitute olestra could prevent the increase in OC concentrations that is generally observed in response to a weight-reducing programme. In study 1, nine vegans and fifteen omnivores were recruited and the concentrations of twenty-six OC (beta-hexachlorocyclohexane (beta-HCH), p, p'-dichlorodiphenyldichloroethane (p, p'-DDE), p, p'-dichlorodiphenyltrichloroethane (p, p'-DDT), hexachlorobenzene, mirex, aldrin, alpha-chlordane, gamma-chlordane, oxychlordane, cis-nonachlor, trans-nonachlor, polychlorinated biphenyl (PCB) nos. 28, 52, 99, 101, 105, 118, 128, 138, 153, 156, 170, 180, 183 and 187, and aroclor 1260) were determined. In study 2, the concentrations of these twenty-six OC were measured before and after weight loss over 3 months in thirty-seven obese men assigned to one of the following treatments: standard group (33 % fat diet; n 13), fat-reduced group (25 % fat diet; n 14) or fat-substituted group (1/3 of dietary lipids substituted by olestra; n 10). In study 1, plasma concentrations of five OC compounds (aroclor 1260 and PCB 99, PCB 138, PCB 153 and PCB 180) were significantly lower in vegans compared with omnivores. In study 2, beta-HCH was the only OC which decreased in the fat-substituted group while increasing in the other two groups (P = 0.045). In conclusion, there was a trend toward lesser contamination in vegans than in omnivores, and olestra had a favourable influence on beta-HCH but did not prevent plasma hyperconcentration of the other OC during ongoing weight loss.

positive: Pork intake and human papillomavirus-related disease. Clinical and ecological evidence supporting an association between human papillomavirus (HPV)-related tumors and dietary factors are presented. Abstinence from high intake of fried pork (600-1,000 g/day) was associated with regression of an urethral condyloma in a healthy 19-year-old man treated with interferon gamma. International correlations suggest that pork intake is positively associated with incidence of cervical cancer, a disease also related to HPV. Pork meat or dietary factors associated with pork meat consumption may be involved in the development of HPV-related diseases.

positive: Mortality from malignant diseases-update of the Baltimore union poultry cohort. We previously studied mortality up to 1989 in 2,639 members of a local union who had ever worked in poultry slaughtering and processing plants, because they were exposed to oncogenic viruses present in poultry. In this report, cancer mortality was updated to the year 2003 for 2,580 of the 2,639 subjects who worked exclusively in poultry plants. Mortality in poultry workers was compared with that in the US general population through the estimation of proportional mortality and standardized mortality ratios separately for each race/sex group and for the whole cohort. Compared to the US general population, an excess of cancers of the buccal and nasal cavities and pharynx (base of the tongue, palate and other unspecified mouth, tonsil and oropharynx, nasal cavity/middle ear/accessory sinus), esophagus, recto-sigmoid/rectum/anus, liver and intrabiliary system, myelofibrosis, lymphoid leukemia and multiple myeloma was observed in particular subgroups or in the entire poultry cohort. We hypothesize that oncogenic viruses present in poultry, and exposure to fumes, are candidates for an etiologic role to explain the excess occurrence of at least some of these cancers in the poultry workers. Larger studies which can control for confounding factors are urgently needed to determine the significance of these findings.

positive: Cancer incidence in British vegetarians Background: Few prospective studies have examined cancer incidence among vegetarians. Methods: We studied 61 566 British men and women, comprising 32 403 meat eaters, 8562 non-meat eaters who did eat fish (‘fish eaters') and 20 601 vegetarians. After an average follow-up of 12.2 years, there were 3350 incident cancers of which 2204 were among meat eaters, 317 among fish eaters and 829 among vegetarians. Relative risks (RRs) were estimated by Cox regression, stratified by sex and recruitment protocol and adjusted for age, smoking, alcohol, body mass index, physical activity level and, for women only, parity and oral contraceptive use. Results: There was significant heterogeneity in cancer risk between groups for the following four cancer sites: stomach cancer, RRs (compared with meat eaters) of 0.29 (95% CI: 0.07–1.20) in fish eaters and 0.36 (0.16–0.78) in vegetarians, P for heterogeneity=0.007; ovarian cancer, RRs of 0.37 (0.18–0.77) in fish eaters and 0.69 (0.45–1.07) in vegetarians, P for heterogeneity=0.007; bladder cancer, RRs of 0.81 (0.36–1.81) in fish eaters and 0.47 (0.25–0.89) in vegetarians, P for heterogeneity=0.05; and cancers of the lymphatic and haematopoietic tissues, RRs of 0.85 (0.56–1.29) in fish eaters and 0.55 (0.39–0.78) in vegetarians, P for heterogeneity=0.002. The RRs for all malignant neoplasms were 0.82 (0.73–0.93) in fish eaters and 0.88 (0.81–0.96) in vegetarians (P for heterogeneity=0.001). Conclusion: The incidence of some cancers may be lower in fish eaters and vegetarians than in meat eaters.

positive: Diet, Lifestyle, and Acute Myeloid Leukemia in the NIH–AARP Cohort The relation between diet, lifestyle, and acute myeloid leukemia was assessed in a US cohort of 491,163 persons from the NIH–AARP Diet and Health Study (1995–2003). A total of 338 incident cases of acute myeloid leukemia were ascertained. Multivariate Cox models were utilized to estimate hazard ratios and 95% confidence intervals. Compared with those for never smokers, hazard ratios were 1.29 (95% confidence interval: 0.95, 1.75), 1.79 (95% confidence interval: 1.32, 2.42), 2.42 (95% confidence interval: 1.63, 3.57), and 2.29 (85% confidence interval: 1.38, 3.79) for former smokers who smoked ≤1 or >1 pack/day and for current smokers who smoked ≤1 or >1 pack/day, respectively. Higher meat intake was associated with an increased risk of acute myeloid leukemia (hazard ratio = 1.45, 95% confidence interval: 1.02, 2.07 for the fifth vs. first quintile; P for trend = 0.06); however, there were no clear effects of meat-cooking method or doneness level. Individuals who did not drink coffee appeared to have a higher risk of acute myeloid leukemia than those who drank various quantities of coffee. Neither fruit nor vegetable intake was associated with acute myeloid leukemia. This large prospective study identified smoking and meat intake as risk factors for acute myeloid leukemia.

positive: Evaluation of the cyto- and genotoxic activity of yerba mate (Ilex paraguariensis) in human lymphocytes in vitro. Despite its antioxidant capacity and well-known health benefits, yerba mate tea (Ilex paraguariensis) has been shown to possess some genotoxic and mutagenic activities and to increase incidence of some types of cancer. The aim of this study was to estimate the cyto- and genotoxicity of mate tea in human peripheral lymphocytes in vitro. We found that yerba mate extract induced a concentration-dependent, statistically significant increase in the level of apoptotic and necrotic cells and a decrease in the nuclear division index (NDI). Mate-exposed lymphocytes had a reduced transcriptional rDNA activity, which may be due to the stress conditions, and showed an elevated production of micronuclei. The FISH technique revealed the appearance of an acrocentric signal in mate-induced micronuclei, which suggests that under these conditions yerba mate extract may display aneugenic activity. Since caffeine is one of the most abundant compounds found in the dry mass of mate, we conducted additional experiments with caffeine alone. We showed that caffeine used at the same concentrations manifests a more potent cyto- and genotoxic effect that may account, at least in part, for the disadvantageous effects observed for yerba mate extract.

positive: MULTIVITAMIN USE AND RISK OF CANCER AND CARDIOVASCULAR DISEASE IN THE WOMEN’S HEALTH INITIATIVE COHORTS Context Millions of postmenopausal women use multivitamins, often believing that supplements prevent chronic diseases such as cancer and cardiovascular disease. Objective To examine associations between multivitamin use and risk of cancer, cardiovascular disease and mortality in postmenopausal women. Design, Setting and Participants 161,808 participants from the Women’s Health Initiative Clinical Trials (n=68,132 in three overlapping trials of hormone therapy, dietary modification and calcium-vitamin D) or Observational Study (n=93,676). Detailed data were collected on multivitamin use at baseline and follow-up time points. Study enrollment occurred between 1993–1998; women were followed for a median of 8.0 years in the clinical trials and 7.9 years in the observational study. Disease endpoints were collected through 2005. Outcome Measures Cancers of the breast (invasive), colon/rectum, endometrium, kidney, bladder, stomach, ovary and lung; cardiovascular disease (myocardial infarction, stroke, venous thrombosis); and total mortality. Results 41.5% of participants used multivitamins. After a median of 8.0 years of follow-up in the CT and 7.9 years in the OS, 9,619 cases of breast, colorectal, endometrium, kidney, bladder, stomach lung or ovary cancer; 8,751 CVD events and 9,865 deaths were reported. Multivariate-adjusted analyses revealed no association of multivitamins with risk of cancer (breast HR=0.98, 95%CI 0.91–1.05; colorectal HR = 0.99, 95% CI 0.88–1.11; endometrial HR = 1.05, 95%CI= 0.90–1.21; lung HR = 1.0, 95% CI=0.88–1.13; ovary HR = 1.07, 95%CI =0.88–1.29); CVD (MI HR= 0.96, 95%CI= 0.89–1.03; stroke HR = 0.99, 95%CI =0.91–1.07; VT HR = 1.05, 95%CI =0.85–1.29); or mortality (HR = 1.02, 95% CI=0.97–1.07). Conclusion After a median follow-up of 8.0 and 7.9 years in the CT and OS, respectively, the WHI cohorts provide convincing evidence that multivitamin use has little or no influence on the risk of common cancers, cardiovascular disease or total mortality in postmenopausal women. Clinical Trial Registration clinicaltrials.gov identifier: NCT00000611

positive: Long-term Use of β-Carotene, Retinol, Lycopene, and Lutein Supplements and Lung Cancer Risk: Results From the VITamins And Lifestyle (VITAL) Study High-dose β-carotene supplementation in high-risk persons has been linked to increased lung cancer risk in clinical trials; whether effects are similar in the general population is unclear. The authors examined associations of supplemental β-carotene, retinol, vitamin A, lutein, and lycopene with lung cancer risk among participants, aged 50–76 years, in the VITamins And Lifestyle (VITAL) cohort Study in Washington State. In 2000–2002, eligible persons (n = 77,126) completed a 24-page baseline questionnaire, including detailed questions about supplement use (duration, frequency, dose) during the previous 10 years from multivitamins and individual supplements/mixtures. Incident lung cancers (n = 521) through December 2005 were identified by linkage to the Surveillance, Epidemiology, and End Results cancer registry. Longer duration of use of individual β-carotene, retinol, and lutein supplements (but not total 10-year average dose) was associated with statistically significantly elevated risk of total lung cancer and histologic cell types; for example, hazard ratio = 2.02, 95% confidence interval: 1.28, 3.17 for individual supplemental lutein with total lung cancer and hazard ratio = 3.22, 95% confidence interval: 1.29, 8.07 for individual β-carotene with small-cell lung cancer for >4 years versus no use. There was little evidence for effect modification by gender or smoking status. Long-term use of individual β-carotene, retinol, and lutein supplements should not be recommended for lung cancer prevention, particularly among smokers.

positive: Detection of PhIP in grilled chicken entrées at popular chain restaurants throughout California. Heterocyclic amines (HCAs), compounds formed when meat is cooked at high temperatures particularly through pan frying, grilling, or barbequing, pose a potential carcinogenic risk to the public. It is unclear whether there is any level at which consumption of HCAs can be considered safe. Efforts to measure these compounds mainly include cooking studies under laboratory conditions and some measurement of home-cooked foods, but analysis of commercially cooked foods has been minimal. Attempts to estimate exposure of the public to these compounds must take into consideration dining outside the home, which could result in significant exposure for some individuals. We surveyed at least 9 locations each of 7 popular chain restaurants (McDonald's, Burger King, Chick-fil-A, Chili's, TGI Friday's, Outback Steakhouse, and Applebee's) in California, collecting one or two entrees from each location. Entrees were analyzed for 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) using high-performance liquid chromatography tandem mass spectrometry. All 100 samples contained PhIP. Concentrations were variable within and between entrees and ranged from 0.08 to 43.2 ng/g. When factoring in the weight of the entrees, absolute levels of PhIP reached over 1,000 ng for some entrees. Potential strategies for reducing exposure include the avoidance of meats cooked using methods that are known to form PhIP.

positive: Concentration and profile of 22 urinary polycyclic aromatic hydrocarbon metabolites in the US population. Urinary monohydroxy polycyclic aromatic hydrocarbons (OH-PAHs) are a class of PAH metabolites used as biomarkers for assessing human exposure to PAHs. The Centers for Disease Control and Prevention's National Health and Nutrition Examination Survey (NHANES) uses OH-PAHs to establish reference range concentrations for the US population, and to set benchmarks for future epidemiologic and biomonitoring studies. For the years 2001 and 2002, 22 OH-PAH metabolites were measured in urine specimens from 2748 NHANES participants. Percentages of samples with detectable levels ranged from nearly 100% for metabolites of naphthalene, fluorene, phenanthrene, and pyrene, to less than 5% for metabolites from parent compounds with higher molecular weight such as chrysene, benzo[c]phenanthrene, and benz[a]anthracene. The geometric mean for 1-hydroxypyrene (1-PYR)--the most commonly used biomarker for PAH exposure--was 49.6 ng/L urine, or 46.4 ng/g creatinine. Children (ages 6-11) generally had higher levels than did adolescents (ages 12-19) or adults (ages 20 and older). Model-adjusted, least-square geometric means for 1-PYR were 87, 53 and 43 ng/L for children, adolescents (ages 12-19) and adults (ages 20 years and older), respectively. Log-transformed concentrations for major detectable OH-PAHs were significantly correlated with each other. The correlation coefficients between 1-PYR and other metabolites ranging from 0.17 to 0.63 support the use of 1-PYR as a useful surrogate representing PAH exposure.

positive: Polycyclic aromatic hydrocarbons (PAHs) in coffee brew samples: analytical method by GC-MS, profile, levels and sources. Roasting is a crucial step for the production of coffee, as it enables the development of color, aroma, and flavor, which are essential for the characterization of the coffee quality. At the same time, roasting may lead to the formation of not desirable compounds, such as polycyclic aromatic hydrocarbons (PAHs). In this paper, we report a method for PAHs determination in coffee brew, based on saponification and liquid-liquid extraction with small volumes of hexane, with exclusion of further processes of purification since we analyze the extract by gas chromatography with mass spectrometric detectors in the single ion monitoring mode (SIM). The total concentration of the 28 compounds investigated, expressed as the sum of concentrations (SigmaPAH), in coffee brew varies from 0.52 to 1.8 microg/l. Carcinogenic PAHs, expressed as B[a]Peq ranged from 0.008 to 0.060 microg/l. The results indicate that coffee contributes with very insignificant quantities to the daily human intake of carcinogenic PAHs. The values of calculated isomeric ratios confirm that the PAHs identified in most of the coffee samples originate from high temperature processes.

positive: Serum polycyclic aromatic hydrocarbons among children with and without asthma: correlation to environmental and dietary factors. BACKGROUND: Children from low-income families may be subject to high exposures to polycyclic aromatic hydrocarbons (PAH) which can lead to respiratory disorders. This study aims to establish methods for assessing total PAH exposure of asthmatic and non-asthmatic children from low-income families; to estimate serum PAH concentrations of these children, and to estimate the relative importance of the environmental pathways for PAH exposure. MATERIALS AND METHODS: A total of 75 (61 asthmatic, 14 non-asthmatic) Saudi children 15 years old and below were included to participate in this cross-sectional study. Each participant answered a generalized questionnaire with dietary questions. Serum PAH were measured using HPLC with UV detection. RESULTS: Serum naphthalene and pyrene were significantly elevated among asthmatic children (p-values = 0.007 and 0.01, respectively). Serum acenaphthylene, fluorine and 1,2-benzanthracene, on the other hand, were significantly higher among non-asthmatics (p-values = 0.001, 0.04 and 0.03, respectively). There was a significant correlation between the presence of a smoker in the family and serum concentrations of carbazole, pyrene, 1,2-benzanthracene and benzacephenanthrylene (R = 0.37, 0.45, 0.43, 0.33; p-values = 0.01, 0.0002, 0.003 and 0.025, respectively). Significant correlations were elicited between daily meat intake and serum levels of acenaphthylene, benzopyrene and 1,2-benzanthracene (R = 0.27, 0.27, 0.33; p-values = 0.02 and < 0.001, respectively). CONCLUSION: Among the children, serum PAH were significantly correlated to meat intake as well as presence of smokers at home. Public health awareness should be enhanced by educating parents to take certain precautions at home, such as preventing indoor smoking and reducing the intake of grilled and smoked meat by children so as to decrease their exposure to carcinogenic PAH.

positive: Dietary Epidemiology of Essential Tremor: Meat Consumption and Meat Cooking Practices Background/Aim Harmane [1-methyl-9H-pyrido(3,4-b)indole] is a tremor-producing neurotoxin. Blood harmane concentrations are elevated in essential tremor (ET) patients for unclear reasons. Potential mechanisms include increased dietary harmane intake (especially through well-cooked meat) or genetic-metabolic factors. We tested the hypothesis that meat consumption and level of meat doneness are higher in ET cases than in controls. Methods Detailed data were collected using the Lawrence Livermore National Laboratory Meat Questionnaire. Results Total current meat consumption was greater in men with than without ET (135.3 ± 71.1 vs. 110.6 ± 80.4 g/day, p = 0.03) but not in women with versus without ET (80.6 ± 50.0 vs. 79.3 ± 51.0 g/day, p = 0.76). In an adjusted logistic regression analysis in males, higher total current meat consumption was associated with ET (OR = 1.006, p = 0.04, i.e., with 10 additional g/day of meat, odds of ET increased by 6%). Male cases had higher odds of being in the highest than lowest quartile of total current meat consumption (adjusted OR = 21.36, p = 0.001). Meat doneness level was similar in cases and controls. Conclusion This study provides evidence of a dietary difference between male ET cases and male controls. The etiological ramifications of these results warrant additional investigation. Copyright © 2008 S. Karger AG, Basel

positive: Biomonitoring of urinary metabolites of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) following human consumption of cooked chicken. Human risk assessment of exposure to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) through the diet may be improved by conducting biomonitoring studies comparing metabolism in humans and rodents. Eleven volunteers ingested a meal of cooked chicken containing 4 -OH-PhIP and PhIP in amounts of 0.6 and 0.8microg/kg, respectively and urine was collected for the next 16h. The large number of PhIP metabolites was by treatment of the urine samples with hydrazine hydrate and hydrolytic enzymes reduced to three substances, 4'-OH-PhIP, PhIP and 5-OH-PhIP of which the first is a biomarker for detoxification and the last a biomarker for activation. The eleven volunteers eliminated large amounts of 4'-OH-PhIP in the urine. The majority of which could be accounted for by the presence of 4'-OH-PhIP in the fried chicken, showing that PhIP only to a small extent (11%) was metabolised to 4'-OH-PhIP. A larger fraction of the PhIP exposure, 38%, was recovered as PhIP and the largest fraction (51%) was recovered as 5-OH-PhIP suggesting that PhIP in humans to a large extent is metabolised to reactive substances. In rats, less than 1% of the dose of PhIP was eliminated as 5-OH-PhIP, suggesting that human cancer risk from exposure to PhIP is considerable higher than risk estimations based on extrapolation from rodent bioassays.

positive: High tofu intake is associated with worse memory in elderly Indonesian men and women. BACKGROUND/AIMS: Cell culture studies suggest that phytoestrogens, abundant in soy products such as tempe and tofu, could protect against cognitive decline. Paradoxically, the Honolulu Asia Aging Study reported an increased risk for cognitive impairment and other dementia markers with high tofu (soybean curd) intake. METHODS: A cross-sectional study was carried out in 2 rural sites (Borobudur and Sumedang) and 1 urban site (Jakarta) among mainly Javanese and Sundanese elderly (n = 719, 52-98 years of age). Memory was measured using a word learning test sensitive to dementia and soy consumption was assessed using Food Frequency Questionnaire items. RESULTS: High tofu consumption was associated with worse memory (beta = -0.18, p < 0.01, 95% CI = -0.34 to -0.06), while high tempe consumption (a fermented whole soybean product) was independently related to better memory (beta = 0.12, p < 0.05, 95% CI = 0.00-0.28), particularly in participants over 68 years of age. Fruit consumption also had an independent positive association. The analyses were controlled for age, sex, education, site and intake of other foods. CONCLUSION: The results for tofu consumption as a risk factor for low memory function may tie in with the Honolulu Asia Aging Study data. It is unclear whether these negative associations could be attributed to potential toxins or to its phytoestrogen levels. Estrogen (through which receptors phytoestrogens can exert effects) was found to increase dementia risk in women over 65 years of age. Tempe contains high levels of phytoestrogens, but (due to fermentation) also exhibits high folate levels which may exert protective effects. Future studies should validate these findings and investigate potential mechanisms. Copyright 2008 S. Karger AG, Basel.

positive: Cancer chemopreventive potential of apples, apple juice, and apple components. Apples ( MALUS sp., Rosaceae) are a rich source of nutrient as well as non-nutrient components and contain high levels of polyphenols and other phytochemicals. Main structural classes of apple constituents include hydroxycinnamic acids, dihydrochalcones, flavonols (quercetin glycosides), catechins and oligomeric procyanidins, as well as triterpenoids in apple peel and anthocyanins in red apples. Several lines of evidence suggest that apples and apple products possess a wide range of biological activities which may contribute to health beneficial effects against cardiovascular disease, asthma and pulmonary dysfunction, diabetes, obesity, and cancer (reviewed by Boyer and Liu, Nutr J 2004). The present review will summarize the current knowledge on potential cancer preventive effects of apples, apple juice and apple extracts (jointly designated as apple products). In brief, apple extracts and components, especially oligomeric procyanidins, have been shown to influence multiple mechanisms relevant for cancer prevention in IN VITRO studies. These include antimutagenic activity, modulation of carcinogen metabolism, antioxidant activity, anti-inflammatory mechanisms, modulation of signal transduction pathways, antiproliferative and apoptosis-inducing activity, as well as novel mechanisms on epigenetic events and innate immunity. Apple products have been shown to prevent skin, mammary and colon carcinogenesis in animal models. Epidemiological observations indicate that regular consumption of one or more apples a day may reduce the risk for lung and colon cancer.

positive: Phytochemicals of apple peels: isolation, structure elucidation, and their antiproliferative and antioxidant activities. Bioactivity-guided fractionation of Red Delicious apple peels was used to determine the chemical identity of bioactive constituents, which showed potent antiproliferative and antioxidant activities. Twenty-nine compounds, including triterpenoids, flavonoids, organic acids and plant sterols, were isolated using gradient solvent fractionation, Diaion HP-20, silica gel, and ODS columns, and preparative HPLC. Their chemical structures were identified using HR-MS and 1D and 2D NMR. Antiproliferative activities of isolated pure compounds against HepG2 human liver cancer cells and MCF-7 human breast cancer cells were evaluated. On the basis of the yields of isolated flavonoids (compounds 18- 23), the major flavonoids in apple peels are quercetin-3-O-beta-D-glucopyranoside (compound 20, 82.6%), then quercetin-3-O-beta-D-galactopyranoside (compound 19, 17.1%), followed by trace amounts of quercetin (compound 18, 0.2%), (-)-catechin (compound 22), (-)-epicatechin (compound 23), and quercetin-3-O-alpha-L-arabinofuranoside (compound 21). Among the compounds isolated, quercetin (18) and quercetin-3-O-beta-D-glucopyranoside (20) showed potent antiproliferative activities against HepG2 and MCF-7 cells, with EC 50 values of 40.9 +/- 1.1 and 49.2 +/- 4.9 microM to HepG2 cells and 137.5 +/- 2.6 and 23.9 +/- 3.9 microM to MCF-7 cells, respectively. Six flavonoids (18-23) and three phenolic compounds (10, 11, and 14) showed potent antioxidant activities. Caffeic acid (10), quercetin (18), and quercetin-3-O-beta-D-arabinofuranoside (21) showed higher antioxidant activity, with EC 50 values of <10 microM. Most tested flavonoids and phenolic compounds had high antioxidant activity when compared to ascorbic acid and might be responsible for the antioxidant activities of apples. These results showed apple peel phytochemicals have potent antioxidant and antiproliferative activities.

positive: Meta-analysis of long-term mobile phone use and the association with brain tumours. We evaluated long-term use of mobile phones and the risk for brain tumours in case-control studies published so far on this issue. We identified ten studies on glioma and meta-analysis yielded OR = 0.9, 95% CI = 0.8-1.1. Latency period of > or =10-years gave OR = 1.2, 95% CI = 0.8-1.9 based on six studies, for ipsilateral use (same side as tumour) OR = 2.0, 95% CI = 1.2-3.4 (four studies), but contralateral use did not increase the risk significantly, OR = 1.1, 95% CI = 0.6-2.0. Meta-analysis of nine studies on acoustic neuroma gave OR = 0.9, 95% CI = 0.7-1.1 increasing to OR = 1.3, 95% CI = 0.6-2.8 using > or =10-years latency period (four studies). Ipsilateral use gave OR = 2.4, 95% CI = 1.1-5.3 and contra-lateral OR = 1.2, 95% CI = 0.7-2.2 in the > or =10-years latency period group (three studies). Seven studies gave results for meningioma yielding overall OR = 0.8, 95% CI = 0.7-0.99. Using > or =10-years latency period OR = 1.3, 95% CI = 0.9-1.8 was calculated (four studies) increasing to OR = 1.7, 95% CI = 0.99-3.1 for ipsilateral use and OR = 1.0, 95% CI = 0.3-3.1 for contralateral use (two studies). We conclude that this meta-analysis gave a consistent pattern of an association between mobile phone use and ipsilateral glioma and acoustic neuroma using > or =10-years latency period.

positive: Factors dominating adhesion of NaCl onto potato chips. In this study, the adhesion factors examined were time between frying and coating, surface oil content, chip temperature, oil composition, NaCl size, NaCl shape, and electrostatic coating. Three different surface oil content potato chips, high, low, and no, were produced. Oils used were soybean, olive, corn, peanut, and coconut. After frying, chips were coated immediately, after 1 d, and after 1 mo. NaCl crystals of 5 different particle sizes (24.7, 123, 259, 291, and 388 microm) were coated both electrostatically and nonelectrostatically. Adhesion of cubic, dendritic, and flake crystals was examined. Chips were coated at different temperatures. Chips with high surface oil had the highest adhesion of salt, making surface oil content the most important factor. Decreasing chip temperature decreased surface oil and adhesion. Increasing time between frying and coating reduced adhesion for low surface oil chips, but did not affect high and no surface oil chips. Changing oil composition did not affect adhesion. Increasing salt size decreased adhesion. Salt size had a greater effect on chips with lower surface oil content. When there were significant differences, cubic crystals gave the best adhesion followed by flake crystals then dendritic crystals. For high and low surface oil chips, electrostatic coating did not change adhesion of small size crystals but decreased adhesion of large salts. For no surface oil content chips, electrostatic coating improved adhesion for small salt sizes but did not affect adhesion of large crystals.

positive: A prospective study of dietary acrylamide intake and the risk of endometrial, ovarian, and breast cancer. BACKGROUND: Acrylamide, a probable human carcinogen, was detected in various heat-treated carbohydrate-rich foods in 2002. The few epidemiologic studies done thus far have not shown a relationship with cancer. Our aim was to investigate the association between acrylamide intake and endometrial, ovarian, and breast cancer risk. METHODS: The Netherlands Cohort Study on diet and cancer includes 62,573 women, aged 55-69 years. At baseline (1986), a random subcohort of 2,589 women was selected using a case cohort analysis approach for analysis. The acrylamide intake of subcohort members and cases was assessed with a food frequency questionnaire and was based on chemical analysis of all relevant Dutch foods. Subgroup analyses were done for never-smokers to eliminate the influence of smoking; an important source of acrylamide. RESULTS: After 11.3 years of follow-up, 327, 300, and 1,835 cases of endometrial, ovarian, and breast cancer, respectively, were documented. Compared with the lowest quintile of acrylamide intake (mean intake, 8.9 mug/day), multivariable-adjusted hazard rate ratios (HR) for endometrial, ovarian, and breast cancer in the highest quintile (mean intake, 40.2 mug/day) were 1.29 [95% confidence interval (95% CI), 0.81-2.07; P(trend)=0.18], 1.78 (95% CI, 1.10-2.88; P(trend)=0.02), and 0.93 (95% CI, 0.73-1.19; P(trend)=0.79), respectively. For never-smokers, the corresponding HRs were 1.99 (95% CI, 1.12-3.52; P(trend)=0.03), 2.22 (95% CI, 1.20-4.08; P(trend)=0.01), and 1.10 (95% CI, 0.80-1.52; P(trend)=0.55). CONCLUSIONS: We observed increased risks of postmenopausal endometrial and ovarian cancer with increasing dietary acrylamide intake, particularly among never-smokers. Risk of breast cancer was not associated with acrylamide intake.

positive: Acrylamide exposure and incidence of breast cancer among postmenopausal women in the Danish Diet, Cancer and Health Study. Acrylamide, a probable human carcinogen, is formed in several foods during high-temperature processing. So far, epidemiological studies have not shown any association between human cancer risk and dietary exposure to acrylamide. The purpose of this study was to conduct a nested case control study within a prospective cohort study on the association between breast cancer and exposure to acrylamide using biomarkers. N-terminal hemoglobin adduct levels of acrylamide and its genotoxic metabolite, glycidamide in red blood cells were analyzed (by LC/MS/MS) as biomarkers of exposure on 374 breast cancer cases and 374 controls from a cohort of postmenopausal women. The adduct levels of acrylamide and glycidamide were similar in cases and controls, with smokers having much higher levels (approximately 3 times) than nonsmokers. No association was seen between acrylamide-hemoglobin levels and breast cancer risk neither unadjusted nor adjusted for the potential confounders HRT duration, parity, BMI, alcohol intake and education. After adjustment for smoking behavior, however, a positive association was seen between acrylamide-hemoglobin levels and estrogen receptor positive breast cancer with an estimated incidence rate ratio (95% CI) of 2.7 (1.1-6.6) per 10-fold increase in acrylamide-hemoglobin level. A weak association between glycidamide hemoglobin levels and incidence of estrogen receptor positive breast cancer was also found, this association, however, entirely disappeared when acrylamide and glycidamide hemoglobin levels were mutually adjusted. (c) 2008 Wiley-Liss, Inc.

positive: Mitigation strategies to reduce acrylamide formation in fried potato products. Potato products contain high amounts of acrylamide, which sometimes exceeds the concentration of 1 mg/L. However, many strategies for acrylamide reduction in potato products are possible. In this work, the different approaches for reducing acrylamide formation have been reviewed, keeping in mind that in the application of strategies for acrylamide formation, the main criteria to be maintained are the overall organoleptic and nutritional qualities of the final product.

positive: Dietary acrylamide intake and the risk of renal cell, bladder, and prostate cancer. BACKGROUND: Acrylamide, a probable human carcinogen, was recently detected in various heat-treated carbohydrate-rich foods. Epidemiologic studies on the relation with cancer have been few and largely negative. OBJECTIVE: We aimed to prospectively examine the association between dietary acrylamide intake and renal cell, bladder, and prostate cancers. DESIGN: The Netherlands Cohort Study on diet and cancer includes 120,852 men and women aged 55-69 y. At baseline (1986), a random subcohort of 5000 participants was selected for a case-cohort analysis approach using Cox proportional hazards analysis. Acrylamide intake was assessed with a food-frequency questionnaire at baseline and was based on chemical analysis of all relevant Dutch foods. RESULTS: After 13.3 y of follow-up, 339, 1210, and 2246 cases of renal cell, bladder, and prostate cancer, respectively, were available for analysis. Compared with the lowest quintile of acrylamide intake (mean intake: 9.5 microg/d), multivariable-adjusted hazard rates for renal cell, bladder, and prostate cancer in the highest quintile (mean intake: 40.8 microg/d) were 1.59 (95% CI: 1.09, 2.30; P for trend = 0.04), 0.91 (95% CI: 0.73, 1.15; P for trend = 0.60), and 1.06 (95% CI: 0.87, 1.30; P for trend = 0.69), respectively. There was an inverse nonsignificant trend for advanced prostate cancer in never smokers. CONCLUSIONS: We found some indications for a positive association between dietary acrylamide and renal cell cancer risk. There were no positive associations with bladder and prostate cancer risk.

positive: High levels of carcinogenic polycyclic aromatic hydrocarbons in mate drinks. BACKGROUND: Drinking mate has been associated with cancers of the esophagus, oropharynx, larynx, lung, kidney, and bladder. We conducted this study to determine whether drinking mate could lead to substantial exposure to polycyclic aromatic hydrocarbons (PAH), including known carcinogens, such as benzo[a]pyrene. METHODS: The concentrations of 21 individual PAHs were measured in dry leaves of eight commercial brands of yerba mate and in infusions made with hot (80 degrees C) or cold (5 degrees C) water. Measurements were done using gas chromatography/mass spectrometry, with deuterated PAHs as the surrogates. Infusions were made by adding water to the leaves, removing the resulting infusion after 5 min, and then adding more water to the remaining leaves. This process was repeated 12 times for each infusion temperature. RESULTS: The total concentrations of the 21 PAHs in different brands of yerba mate ranged from 536 to 2,906 ng/g dry leaves. Benzo[a]pyrene concentrations ranged from 8.03 to 53.3 ng/g dry leaves. For the mate infusions prepared using hot water and brand 1, 37% (1,092 of 2,906 ng) of the total measured PAHs and 50% (25.1 of 50 ng) of the benzo[a]pyrene content were released into the 12 infusions. Similar results were obtained for other hot and cold infusions. CONCLUSION: Very high concentrations of carcinogenic PAHs were found in yerba mate leaves and in hot and cold mate infusions. Our results support the hypothesis that the carcinogenicity of mate may be related to its PAH content.

negative: Sulforaphane mobilizes cellular defenses that protect skin against damage by UV radiation UV radiation (UVR) is a complete carcinogen that elicits a constellation of pathological events, including direct DNA damage, generation of reactive oxidants that peroxidize lipids and damage other cellular components, initiation of inflammation, and suppression of the immune response. Recent dramatic increases in the incidence of nonmelanoma skin cancers are largely attributable to higher exposure of an aging population to UVR. Therefore, the development of cellular strategies for intrinsic protection of the skin against the deleterious effects of UVR is imperative. Here we show that erythema resulting from UVR is a comprehensive and noninvasive biomarker for assessing UVR damage and can be precisely and easily quantified in human skin. Topical application of sulforaphane-rich extracts of 3-day-old broccoli sprouts up-regulated phase 2 enzymes in the mouse and human skin, protected against UVR-induced inflammation and edema in mice, and reduced susceptibility to erythema arising from narrow-band 311-nm UVR in humans. In six human subjects (three males and three females, 28–53 years of age), the mean reduction in erythema across six doses of UVR (300–800 mJ/cm2 in 100 mJ/cm2 increments) was 37.7% (range 8.37–78.1%; P = 0.025). This protection against a carcinogen in humans is catalytic and long lasting.

negative: Cancer mortality in workers employed in cattle, pigs, and sheep slaughtering and processing plants. OBJECTIVES: We studied mortality in two separate cohorts of workers in abattoirs (N=4996) and meat processing plants (N=3642) belonging to a meatcutters' union, because they were exposed to viruses that cause cancer in food animals, and also to chemical carcinogens at work. METHODS: Standardized mortality ratios (SMRs) and proportional mortality ratios (PMRs) were estimated for each cohort as a whole and in subgroups defined by race and sex, using the US general population mortality rates for comparison. Study subjects were followed up from January 1950 to December 2006, during which time over 60% of them died. RESULTS: An excess of deaths from cancers of the base of the tongue, esophagus, lung, skin, bone and bladder, lymphoid leukemia, and benign tumors of the thyroid and other endocrine glands, and possibly Hodgkin's disease, was observed in abattoir and meat processing workers. Significantly lower SMRs were recorded for cancer of the thymus, mediastinum, pleura, etc., breast cancer, and non-Hodgkin's lymphoma. CONCLUSION: This study confirms the excess occurrence of cancer in workers in abattoirs and meat processing plants, butchers, and meatcutters, previously reported in this cohort and other similar cohorts worldwide. Large nested case-control studies are now needed to examine which specific occupational and non-occupational exposures are responsible for the excess. There is now sufficient evidence for steps to be taken to protect workers from carcinogenic exposures at the workplace. There are also serious implications for the general population which may also be exposed to some of these viruses. Copyright © 2011 Elsevier Ltd. All rights reserved.

negative: Epidemiologic studies of glyphosate and cancer: a review. The United States Environmental Protection Agency and other regulatory agencies around the world have registered glyphosate as a broad-spectrum herbicide for use on multiple food and non-food use crops. Glyphosate is widely considered by regulatory authorities and scientific bodies to have no carcinogenic potential, based primarily on results of carcinogenicity studies of rats and mice. To examine potential cancer risks in humans, we reviewed the epidemiologic literature to evaluate whether exposure to glyphosate is associated causally with cancer risk in humans. We also reviewed relevant methodological and biomonitoring studies of glyphosate. Seven cohort studies and fourteen case-control studies examined the association between glyphosate and one or more cancer outcomes. Our review found no consistent pattern of positive associations indicating a causal relationship between total cancer (in adults or children) or any site-specific cancer and exposure to glyphosate. Data from biomonitoring studies underscore the importance of exposure assessment in epidemiologic studies, and indicate that studies should incorporate not only duration and frequency of pesticide use, but also type of pesticide formulation. Because generic exposure assessments likely lead to exposure misclassification, it is recommended that exposure algorithms be validated with biomonitoring data. Copyright © 2012 Elsevier Inc. All rights reserved.

negative: Anthocyanin-rich grape extract blocks breast cell DNA damage. Anthocyanins, belonging to the flavonoid family of phytochemicals, have received attention as agents that may have potential in preventing chronic diseases such as cardiovascular diseases and certain cancers. In the present study, an anthocyanin-rich extract from Concord grapes [referred to as Concord grape extract (CGE)] and the anthocyanin delphinidin were evaluated for their capacity to inhibit DNA adduct formation due to the environmental carcinogen benzo[a]pyrene (BP) in MCF-10F cells, a noncancerous, immortalized human breast epithelial cell line. CGE at 10 and 20 microg/mL and delphinidin at 0.6 microM concentrations significantly inhibited BP-DNA adduct formation. This was associated with a significant increase in activities of the phase II detoxification enzymes glutathione S-transferase and NAD(P)H:quinone reductase 1. In addition, these grape components also suppressed reactive oxygen species (ROS) formation, but did not induce antioxidant response element-dependent transcription. Taken together, these data suggest that CGE and a component grape anthocyanin have breast cancer chemopreventive potential due in part to their capacity to block carcinogen-DNA adduct formation, modulate activities of carcinogen-metabolizing enzymes, and suppress ROS in these noncancerous human breast cells.

negative: Toxicology of food dyes. BACKGROUND: Food dyes, synthesized originally from coal tar and now petroleum, have long been controversial because of safety concerns. Many dyes have been banned because of their adverse effects on laboratory animals or inadequate testing. CONCLUSIONS: This review finds that all of the nine currently US-approved dyes raise health concerns of varying degrees. Red 3 causes cancer in animals, and there is evidence that several other dyes also are carcinogenic. Three dyes (Red 40, Yellow 5, and Yellow 6) have been found to be contaminated with benzidine or other carcinogens. At least four dyes (Blue 1, Red 40, Yellow 5, and Yellow 6) cause hypersensitivity reactions. Numerous microbiological and rodent studies of Yellow 5 were positive for genotoxicity. Toxicity tests on two dyes (Citrus Red 2 and Orange B) also suggest safety concerns, but Citrus Red 2 is used at low levels and only on some Florida oranges and Orange B has not been used for several years. The inadequacy of much of the testing and the evidence for carcinogenicity, genotoxicity, and hypersensitivity, coupled with the fact that dyes do not improve the safety or nutritional quality of foods, indicates that all of the currently used dyes should be removed from the food supply and replaced, if at all, by safer colorings. It is recommended that regulatory authorities require better and independent toxicity testing, exercise greater caution regarding continued approval of these dyes, and in the future approve only well-tested, safe dyes.

negative: Multi-targeted prevention of cancer by sulforaphane Isothiocyanates are found in cruciferous vegetables such as broccoli, Brussels sprouts, cauliflower, and cabbage. Epidemiologic studies suggest that cruciferous vegetable intake may lower overall cancer risk, including colon and prostate cancer. Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables and is especially high in broccoli and broccoli sprouts. SFN has proved to be an effective chemoprotective agent in cell culture, carcinogen-induced and genetic animal cancer models, as well as in xenograft models of cancer. Early research focused on the “blocking activity” of SFN via Phase 2 enzyme induction, as well as inhibition of enzymes involved in carcinogen activation, but there has been growing interest in other mechanisms of chemoprotection by SFN. Recent studies suggest that SFN offers protection against tumor development during the “post-initiation” phase and mechanisms for suppression effects of SFN, including cell cycle arrest and apoptosis induction are of particular interest. In humans, a key factor in determining the efficacy of SFN as a chemoprevention agent is gaining an understanding of the metabolism, distribution and bioavailability of SFN and the factors that alter these parameters. This review discusses the established anti-cancer properties of SFN, with an emphasis on the possible chemoprevention mechanisms. The current status of SFN in human clinical trials also is included, with consideration of the chemistry, metabolism, absorption and factors influencing SFN bioavailability.

negative: Review of harmful gastrointestinal effects of carrageenan in animal experiments. In this article I review the association between exposure to carrageenan and the occurrence of colonic ulcerations and gastrointestinal neoplasms in animal models. Although the International Agency for Research on Cancer in 1982 identified sufficient evidence for the carcinogenicity of degraded carrageenan in animals to regard it as posing a carcinogenic risk to humans, carrageenan is still used widely as a thickener, stabilizer, and texturizer in a variety of processed foods prevalent in the Western diet. I reviewed experimental data pertaining to carrageenan's effects with particular attention to the occurrence of ulcerations and neoplasms in association with exposure to carrageenan. In addition, I reviewed from established sources mechanisms for production of degraded carrageenan from undegraded or native carrageenan and data with regard to carrageenan intake. Review of these data demonstrated that exposure to undegraded as well as to degraded carrageenan was associated with the occurrence of intestinal ulcerations and neoplasms. This association may be attributed to contamination of undegraded carrageenan by components of low molecular weight, spontaneous metabolism of undegraded carrageenan by acid hydrolysis under conditions of normal digestion, or the interactions with intestinal bacteria. Although in 1972, the U.S. Food and Drug Administration considered restricting dietary carrageenan to an average molecular weight > 100,000, this resolution did not prevail, and no subsequent regulation has restricted use. Because of the acknowledged carcinogenic properties of degraded carrageenan in animal models and the cancer-promoting effects of undegraded carrageenan in experimental models, the widespread use of carrageenan in the Western diet should be reconsidered.

negative: Red meat consumption and cancer: reasons to suspect involvement of bovine infectious factors in colorectal cancer. An increased risk for colorectal cancer has been consistently reported for long-time consumption of cooked and processed red meat. This has frequently been attributed to chemical carcinogens arising during the cooking process of meat. Long-time fish or poultry consumption apparently does not increase the risk, although similar or higher concentrations of chemical carcinogens were recorded in their preparation for consumption. The geographic epidemiology of colorectal cancer seems to correspond to regions with a high rate of beef consumption. Countries with a virtual absence of beef in the diet (India) or where preferably lamb or goat meat is consumed (several Arabic countries) reveal low rates of colorectal cancer. In China, pork consumption has a long tradition, with an intermediate colorectal cancer rate. In Japan and Korea, large scale beef and pork imports started after World War II or after the Korean War. A steep rise in colorectal cancer incidence was noted after 1970 in Japan and 1990 in Korea. The consumption of undercooked beef (e.g., shabu-shabu, Korean yukhoe and Japanese yukke) became very popular in both countries. The available data are compatible with the interpretation that a specific beef factor, suspected to be one or more thermoresistant potentially oncogenic bovine viruses (e.g., polyoma-, papilloma- or possibly single-stranded DNA viruses) may contaminate beef preparations and lead to latent infections in the colorectal tract. Preceding, concomitant or subsequent exposure to chemical carcinogens arising during cooking procedures should result in increased risk for colorectal cancer synergistic with these infections. Copyright © 2011 UICC.

negative: Benzene in infant carrot juice: further insight into formation mechanism and risk assessment including consumption data from the DONALD study. Benzene was previously detected as a heat-induced contaminant in infant carrot juices. This study shows that carrot juice contains substances such as beta-carotene, phenylalanine or terpenes that may act as precursors for benzene formation during food processing. As benzene exposure has been associated with childhood leukaemia and other cancers, this study aimed to provide a quantitative risk assessment. To accomplish this, we used measured food consumption data from the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) study, along with survey data on benzene in different juice categories. The calculated exposures for infants between 3 and 12 months were low, with averages between 1 and 10 ng/kg bw/day, resulting in a margin of exposure above 100,000. The exposures were judged as unlikely to pose a health risk for infants. Nevertheless, carcinogenic contaminants should be reduced to levels as low as reasonably achievable. The focus should be set on improving the sterilization conditions. Copyright 2009 Elsevier Ltd. All rights reserved.

negative: Toxicology and risk assessment of coumarin: focus on human data. Coumarin is a secondary phytochemical with hepatotoxic and carcinogenic properties. For the carcinogenic effect, a genotoxic mechanism was considered possible, but was discounted by the European Food Safety Authority in 2004 based on new evidence. This allowed the derivation of a tolerable daily intake (TDI) for the first time, and a value of 0.1 mg/kg body weight was arrived at based on animal hepatotoxicity data. However, clinical data on hepatotoxicity from patients treated with coumarin as medicinal drug is also available. This data revealed a subgroup of the human population being more susceptible for the hepatotoxic effect than the animal species investigated. The cause of the high susceptibility is currently unknown; possible mechanisms are discussed. Using the human data, a TDI of 0.1 mg/kg body weight was derived, confirming that of the European Food Safety Authority. Nutritional exposure may be considerably, and is mainly due to use of cassia cinnamon, which is a popular spice especially, used for cookies and sweet dishes. To estimate exposure to coumarin during the Christmas season in Germany, a telephone survey was performed with more than 1000 randomly selected persons. Heavy consumers of cassia cinnamon may reach a daily coumarin intake corresponding to the TDI.

negative: Sulforaphane as a promising molecule for fighting cancer. A number of natural compounds with inhibitory effects on tumorigenesis have been identified from our diet. Several studies have documented the cancer-preventive activity of a significant number of isothiocyanates (ITCs), the majority of which occur in plants, especially in Cruciferous vegetables. The most characterized ITC is sulforaphane (SFN). SFN has received a great deal of attention because of its ability to simultaneously modulate multiple cellular targets involved in cancer development, including: (i) DNA protection by modulating carcinogen-metabolizing enzymes and blocking the action of mutagens; (ii) inhibition of cell proliferation and induction of apoptosis, thereby retarding or eliminating clonal expansion of initiated, transformed, and/or neoplastic cells; (iii) inhibition of neoangiogenesis, progression of benign tumors to malignant tumors, and metastasis formation. SFN is therefore able to prevent, delay, or reverse preneoplastic lesions, as well as to act on cancer cells as a therapeutic agent. Taking into account this evidence and its favorable toxicological profile, SFN can be viewed as a conceptually promising agent in cancer prevention and/or therapy.

negative: Fecal bacterial beta-glucuronidase: control by diet. The effect of a mixed Western, high meat diet or a nonmeat diet on the intestinal bacterial beta-glucuronidase activity was studied in human volunteers. This enzyme was significantly higher in stools of subjects on a high meat diet as compared to the nonmeat regimen. Thus, intestinal flora of subjects on a high meat diet was more able to hydrolyze glucuronide conjugates than that of individuals on a nonmeat diet. This, in turn, may raise the amount of substances, such as carcinogens, within the colonic lumen.

negative: Fresh aromatic herbs containing methylchavicol did not exhibit the pro-oxidative effects of pure methylchavicol on a human hepatoma cell line, HepG2. Methylchavicol (CH(3)-CV), an important aromatic constituent of different plants like tarragon and basils, has been shown to be carcinogenic by a mechanism yet unclear, although it has been reported that carcinogenicity of CH(3)-CV in rodent might be linked to its metabolic conversion into a genotoxic electrophilic metabolite generated through a two steps bioactivation pathway catalyzed by cytochrome P450 enzymes and sulfotransferases. The induction of carcinogenesis by certain agents has been associated with the generation of oxidative stress. The aim of the present study was to determine whether pure methylchavicol applied on a human hepatoma cell line, HepG2, could promote oxidative stress and might alter the expression of procarcinogenic biomarkers such as the drug-metabolizing enzyme (CYP2E1), the inducible form of nitric oxide synthase (iNOS) and might induce the expression of Cu/Zn-superoxide dismutase (Cu/Zn-SOD) and Mn-SOD that control the redox equilibrium of the cells. CH(3)-CV was shown to cause a significant induction of oxidative stress, as revealed by luminol-dependent chemiluminescence (LDCL) and to alter dramatically the expression of CYP2E1, iNOS and Mn-SOD, indicating that the toxic effect of CH(3)-CV could be mediated through a nitric oxide dependent mechanism. Under similar experimental conditions, the extracts from tarragon, chervil and basil did not induce such biological changes. These results provide evidence that the generation of an oxidative stress may be a significant event occurring during CH(3)-CV-induced toxicity. It also suggests that natural extracts containing different amounts of CH(3)-CV (tarragon, chervil and basil) did not elicit such toxicity and might contain compounds able to counteract this detrimental property. Copyright © 2012. Published by Elsevier Masson SAS.

negative: Mechanisms of primary cancer prevention by butyrate and other products formed during gut flora-mediated fermentation of dietary fibre. Dietary fibres are indigestible food ingredients that reach the colon and are then fermented by colonic bacteria, resulting mainly in the formation of short-chain fatty acids (SCFA) such as acetate, propionate, and butyrate. Those SCFA, especially butyrate, are recognised for their potential to act on secondary chemoprevention by slowing growth and activating apoptosis in colon cancer cells. Additionally, SCFA can also act on primary prevention by activation of different drug metabolising enzymes. This can reduce the burden of carcinogens and, therefore, decrease the number of mutations, reducing cancer risk. Activation of GSTs by butyrate has been studied on mRNA, protein, and enzyme activity level by real-time RT-PCR, cDNA microarrays, Western blotting, or photometrical approaches, respectively. Butyrate had differential effects in colon cells of different stages of cancer development. In HT29 tumour cells, e.g., mRNA GSTA4, GSTP1, GSTM2, and GSTT2 were induced. In LT97 adenoma cells, GSTM3, GSTT2, and MGST3 were induced, whereas GSTA2, GSTT2, and catalase (CAT) were elevated in primary colon cells. Colon cells of different stages of carcinogenesis differed in post-transcriptional regulatory mechanisms because butyrate increased protein levels of different GST isoforms and total GST enzyme activity in HT29 cells, whereas in LT97 cells, GST protein levels and activity were slightly reduced. Because butyrate increased histone acetylation and phosphorylation of ERK in HT29 cells, inhibition of histone deacetylases and the influence on MAPK signalling are possible mechanisms of GST activation by butyrate. Functional consequences of this activation include a reduction of DNA damage caused by carcinogens like hydrogen peroxide or 4-hydroxynonenal (HNE) in butyrate-treated colon cells. Treatment of colon cells with the supernatant from an in vitro fermentation of inulin increased GST activity and decreased HNE-induced DNA damage in HT29 cells. Additional animal and human studies are needed to define the exact role of dietary fibre and butyrate in inducing GST activity and reducing the risk of colon cancer.

negative: Cherries and health: a review. Cherries, and in particular sweet cherries, are a nutritionally dense food rich in anthocyanins, quercetin, hydroxycinnamates, potassium, fiber, vitamin C, carotenoids, and melatonin. UV concentration, degree of ripeness, postharvest storage conditions, and processing, each can significantly alter the amounts of nutrients and bioactive components. These constituent nutrients and bioactive food components support the potential preventive health benefits of cherry intake in relation to cancer, cardiovascular disease, diabetes, inflammatory diseases, and Alzheimer's disease. Mechanistically, cherries exhibit relatively high antioxidant activity, low glycemic response, COX 1 and 2 enzyme inhibition, and other anti-carcinogenic effects in vitro and in animal experiments. Well-designed cherry feeding studies are needed to further substantiate any health benefits in humans.

negative: Phytochemicals and cancer risk: a review of the epidemiological evidence. A number of epidemiological studies have investigated associations between various phytochemicals and cancer risk. Phytoestrogens and carotenoids are the two most commonly studied classes of phytochemicals; phytosterols, isothiocyanates, and chlorophyll also have been investigated, although to a much lesser extent. Because there have been no systematic reviews of the literature on all phytochemicals and cancer risk to date, this article systematically reviews 96 published epidemiological studies that examined associations between phytochemicals and cancer risk. Most studies found null associations between individual phytochemicals and cancer risk at various sites. In addition, results from past studies have been largely inconsistent, and observed associations have been of relatively modest magnitude. The most consistent protective effects were observed for higher levels--dietary intake, serum, plasma, or urinary metabolites--of β-carotene and renal cell cancer, β-cryptoxanthin and lung cancer, isothiocyanates and lung cancer, isothiocyanates and gastrointestinal cancer, lignans and postmenopausal breast cancer, and flavonoids and lung cancer. Although elevated risk of certain cancers with higher levels of certain phytochemicals was observed, an insufficient pool of studies examining the same associations or inconsistent findings across studies limit the ability to conclude that any one phytochemical increases cancer risk. Additional research is needed to support previously identified associations in cases where only one study has examined a particular relationship. Importantly, continued research efforts are needed to evaluate the cumulative and interactive effects of numerous phytochemicals and phytochemical-rich foods on cancer risk.

negative: Creatine: are the benefits worth the risk? Creatine monohydrate is a popular sports supplement used to maintain levels of high-energy phosphates during exercise. As a supplement, varying amounts are consumed per person corresponding to parameters such as body mass and level of training (i.e. maintenance versus loading doses). Numerous studies have reported beneficial effects including increased muscle mass during training and neural protection. However, negative reports have also been made of possible side effects, such as muscle cramping during exercise, and potential impurities. The present paper introduces the positive and negative aspects of creatine supplementation and focuses on the toxicological data of creatine, its metabolites and associated mutagenicity or carcinogenicity, genomeceutical effect(s), and any potential 'contaminants.' Additionally, the novel applications of creatine to the areas of neurology, cardiology, and diabetes are presented and discussed along with the representative data for sports nutrition.

negative: Integrative assessment of multiple pesticides as risk factors for non-Hodgkin's lymphoma among men Methods: During the 1980s, the National Cancer Institute conducted three case-control studies of NHL in the midwestern United States. These pooled data were used to examine pesticide exposures in farming as risk factors for NHL in men. The large sample size (n = 3417) allowed analysis of 47 pesticides simultaneously, controlling for potential confounding by other pesticides in the model, and adjusting the estimates based on a prespecified variance to make them more stable. Results: Reported use of several individual pesticides was associated with increased NHL incidence, including organophosphate insecticides coumaphos, diazinon, and fonofos, insecticides chlordane, dieldrin, and copper acetoarsenite, and herbicides atrazine, glyphosate, and sodium chlorate. A subanalysis of these "potentially carcinogenic" pesticides suggested a positive trend of risk with exposure to increasing numbers. Conclusion: Consideration of multiple exposures is important in accurately estimating specific effects and in evaluating realistic exposure scenarios.

negative: Anti-cancer properties of phenolics from apple waste on colon carcinogenesis in vitro. Colorectal cancer is one of the most common cancers in Western countries. The World Health Organisation identifies diet as a critical risk factor in the development and progression of this disease and the protective role of high levels of fruit and vegetable consumption. Several studies have shown that apples contain several phenolic compounds that are potent anti-oxidants in humans. However, little is known about other beneficial properties of apple phenolics in cancer. We have used the HT29, HT115 and CaCo-2 cell lines as in vitro models to examine the effect of apple phenolics (0.01-0.1% apple extract) on key stages of colorectal carcinogenesis, namely; DNA damage (Comet assay), colonic barrier function (TER assay), cell cycle progression (DNA content assay) and invasion (Matrigel assay). Our results indicate that a crude extract of apple phenolics can protect against DNA damage, improve barrier function and inhibit invasion (p<0.05). The anti-invasive effects of the extract were enhanced with twenty-four hour pretreatment of cells (p<0.05). We have shown that a crude apple extract from waste, rich in phenolic compounds, beneficially influences key stages of carcinogenesis in colon cells in vitro.

negative: Generation of gaseous sulfur-containing compounds in tumour tissue and suppression of gas diffusion as an antitumour treatment. BACKGROUND AND AIMS: The mechanisms of cancer cell growth and metastasis are still not entirely understood, especially from the viewpoint of chemical reactions in tumours. Glycolytic metabolism is markedly accelerated in cancer cells, causing the accumulation of glucose (a reducing sugar) and methionine (an amino acid), which can non-enzymatically react and form carcinogenic substances. There is speculation that this reaction produces gaseous sulfur-containing compounds in tumour tissue. The aims of this study were to clarify the products in tumour and to investigate their effect on tumour proliferation. METHODS: Products formed in the reaction between glucose and methionine or its metabolites were analysed in vitro using gas chromatography. Flatus samples from patients with colon cancer and exhaled air samples from patients with lung cancer were analysed using near-edge x-ray fine adsorption structure spectroscopy and compared with those from healthy individuals. The tumour proliferation rates of mice into which HT29 human colon cancer cells had been implanted were compared with those of mice in which the cancer cells were surrounded by sodium hyaluronate gel to prevent diffusion of gaseous material into the healthy cells. RESULTS: Gaseous sulfur-containing compounds such as methanethiol and hydrogen sulfide were produced when glucose was allowed to react with methionine or its metabolites homocysteine or cysteine. Near-edge x-ray fine adsorption structure spectroscopy showed that the concentrations of sulfur-containing compounds in the samples of flatus from patients with colon cancer and in the samples of exhaled air from patients with lung cancer were significantly higher than in those from healthy individuals. Animal experiments showed that preventing the diffusion of sulfur-containing compounds had a pronounced antitumour effect. CONCLUSIONS: Gaseous sulfur-containing compounds are the main products in tumours and preventing the diffusion of these compounds reduces the tumour proliferation rate, which suggests the possibility of a new approach to cancer treatment.

negative: Update on the biological effects of ionizing radiation, relative dose factors and radiation hygiene. Diagnostic imaging is an indispensable part of contemporary medical and dental practice. Over the last few decades there has been a dramatic increase in the use of ionizing radiation for diagnostic imaging. The carcinogenic effects of high-dose exposure are well known. Does diagnostic radiation rarely cause cancer? We don't know but we should act as if it does. Accordingly, dentists should select patients wisely - only make radiographs when there is patient-specific reason to believe there is a reasonable expectation the radiograph will offer unique information influencing diagnosis or treatment. Low-dose examinations should be made: intraoral imaging - use fast film or digital sensors, thyroid collars, rectangular collimation; panoramic and lateral cephalometric imaging - use digital systems or rare-earth film screen combinations; and cone beam computed tomography - use low-dose machines, restrict field size to region of interest, reduce mA and length of exposure arc as appropriate. © 2012 Australian Dental Association.

negative: Antigenotoxic activity of watercress extract in an in vitro mammalian system using comet assay. Watercress (Cruciferae), an integral part of Mediterranean diets, is a nutritive food which is used in the treatment of several diseases. Oxidative DNA damage seems to play a crucial role in chronic, aging-related diseases and it is considered an important and probably carcinogenic factor. The aim of this work was to determine the impact of watercress extract on cell viability and its potential antigenotoxic properties against induced oxidative damage, using a comet assay and peripheral blood cells as an in vitro model. An aqueous extract of the leaves was prepared using a juice processor, centrifuged, filtered and preserved at -20 °C. Two concentrations of the aqueous extract (13.2 and 26.4 mg/mL) were assayed. No differences were found in cell viability between the control and treated groups at any time. Significant antigenotoxic effects were observed for both concentrations, expressed as the damage index (p = 0.005 at 30 min; p < 0.001 at 60 and 90 min), the percentage reductions in damage being similar between them (67.1-75.2% respectively). These results suggest that the consumption watercress in the diet is a powerful tool for improving health and the quality of life. Copyright © 2011 John Wiley & Sons, Ltd.

negative: The concentration and distribution of 2,3,7,8-dibenzo-p-dioxins/-furans in chickens. The concentrations of the 2,3,7,8-Cl substituted dibenzo-p-dioxins/-furans (PCDDs/PCDFs) were determined in the edible tissues of whole chicken fryers and compared with the values found in their abdominal fat. The values are presented both on a whole weight basis and on a lipid adjusted basis for each tissue. While there is a marked difference in the concentration of the 2,3,7,8-dibenzo-p-dioxins in the edible tissues expressed on a whole weight basis, the lipid-adjusted concentrations of the individual dioxins were not statistically different in the various tissues. This validates the use of lipid adjusted concentrations of 2,3,7,8-PCDDs/PCDFs in abdominal fat for the determination of the presence of these compounds in different tissues.

negative: High concentrations of polybrominated diphenylethers (PBDEs) in breast adipose tissue of California women. We measured major PBDEs and PCBs in breast adipose tissues of California women participating in a breast cancer study in the late 1990s. Samples were analyzed using gas chromatography with electron impact ionization and tandem mass spectrometry detection. The congener profile observed was: BDE47>BDE99>BDE153>BDE100>BDE154 and PCB153>PCB180>PCB138>PCB118. Whereas high correlations were observed within each chemical class, very weak correlations appeared between classes, pointing to different exposure pathways. Weak negative associations were observed for PBDE congeners and age. Our PBDE data are among the highest reported, exceeding data from the National Health and Nutrition Examination Survey and consistent with the high use of PBDEs in California. These data may be helpful in establishing a baseline for PBDE body burdens to gauge changes over time as a result of restrictions in the use of PBDE formulations. Copyright © 2010 Elsevier Ltd. All rights reserved.

negative: Flavones and flavonols at dietary levels inhibit a transformation of aryl hydrocarbon receptor induced by dioxin. Dioxins invade the body mainly through the diet, and produce toxicity through the transformation of aryl hydrocarbon receptor (AhR). An inhibitor of the transformation should therefore protect against the toxicity and ideally be part of the diet. We examined flavonoids ubiquitously expressed in plant foods as one of the best candidates, and found that the subclasses flavones and flavonols suppressed antagonistically the transformation of AhR induced by 1 nM of 2,3,7,8-tetrachlorodibenzo-p-dioxin, without exhibiting agonistic effects that transform AhR. The antagonistic IC(50) values ranged from 0.14 to 10 microM, close to the physiological levels in human.

negative: Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans Background: Epidemiologic studies have suggested that most cases of sporadic colon cancer can be attributed to diet. The recognition that colonic microbiota have a major influence on colonic health suggests that they might mediate colonic carcinogenesis. Objective: To examine the hypothesis that the influence of diet on colon cancer risk is mediated by the microbiota through their metabolites, we measured differences in colonic microbes and their metabolites in African Americans with a high risk and in rural native Africans with a low risk of colon cancer. Design: Fresh fecal samples were collected from 12 healthy African Americans aged 50–65 y and from 12 age- and sex-matched native Africans. Microbiomes were analyzed with 16S ribosomal RNA gene pyrosequencing together with quantitative polymerase chain reaction of the major fermentative, butyrate-producing, and bile acid–deconjugating bacteria. Fecal short-chain fatty acids were measured by gas chromatography and bile acids by liquid chromatography–mass spectrometry. Results: Microbial composition was fundamentally different, with a predominance of Prevotella in native Africans (enterotype 2) and of Bacteroides in African Americans (enterotype 1). Total bacteria and major butyrate-producing groups were significantly more abundant in fecal samples from native Africans. Microbial genes encoding for secondary bile acid production were more abundant in African Americans, whereas those encoding for methanogenesis and hydrogen sulfide production were higher in native Africans. Fecal secondary bile acid concentrations were higher in African Americans, whereas short-chain fatty acids were higher in native Africans. Conclusion: Our results support the hypothesis that colon cancer risk is influenced by the balance between microbial production of health-promoting metabolites such as butyrate and potentially carcinogenic metabolites such as secondary bile acids.

negative: Anti-carcinogenic effects of sulforaphane in association with its apoptosis-inducing and anti-inflammatory properties in human cervical cancer cells. BACKGROUND: The multistep process of carcinogenesis is characterized by progressive disorganization and occurrence of initiation, promotion, and progression events. Several new strategies such as chemoprevention are being developed for treatment and prevention at various stages of carcinogenesis. Sulforaphane, a potential chemopreventive agent, possesses anti-proliferative, anti-inflammatory, anti-oxidant and anti-cancer activities and has attracted extensive interest for better cancer management. METHODS: We evaluated the effect of sulforaphane alone or in combination with gemcitabine on HeLa cells by cell viability assay and confirmed the results by apoptosis assay. Further we analyzed the effect of sulforaphane on the expression of Bcl-2, COX-2 and IL-1β by RT-PCR on HeLa cells. RESULTS: In the present study, sulforaphane was found to induce dose-dependent selective cytotoxicity in HeLa cells in comparison to normal cells pointing to its safe cytotoxicity profile. Additionally, a combination of sulforaphane and gemcitabine was found to increase the growth inhibition in a synergistic manner in HeLa cells compared to the individual drugs. Also, the expression analysis of genes involved in apoptosis and inflammation revealed significant downregulation of Bcl-2, COX-2 and IL-1β upon treatment with sulforaphane. CONCLUSION: Our results suggest that sulforaphane exerts its anticancer activities via apoptosis induction and anti-inflammatory properties and provides the first evidence demonstrating synergism between sulforaphane and gemcitabine which may enhance the therapeutic index of prevention and/or treatment of cervical cancer. Copyright © 2010 Elsevier Ltd. All rights reserved.

negative: Flaxseed: a potential source of food, feed and fiber. Flaxseed is one of the most important oilseed crops for industrial as well as food, feed, and fiber purposes. Almost every part of the flaxseed plant is utilized commercially, either directly or after processing. The stem yields good quality fiber having high strength and durability. The seed provides oil rich in omega-3, digestible proteins, and lignans. In addition to being one of the richest sources of α-linolenic acid oil and lignans, flaxseed is an essential source of high quality protein and soluble fiber and has considerable potential as a source of phenolic compounds. Flaxseed is emerging as an important functional food ingredient because of its rich contents of α-linolenic acid (ALA), lignans, and fiber. Lignans appear to be anti-carcinogenic compounds. The omega-3s and lignan phytoestrogens of flaxseed are in focus for their benefits for a wide range of health conditions and may possess chemo-protective properties in animals and humans. This paper presents a review of literature on the nutritional composition of flaxseed, its health benefits, and disease-prevention qualities, utilization of flaxseed for food, feed, and fiber, and processing of flaxseed.

negative: Non-occupational malignant pleural mesothelioma due to asbestos and non-asbestos fibres. BACKGROUND AND AIM: The occurrence of malignant pleural mesothelioma (MPM) has been reported among population groups with no documented professional exposure to asbestos fibres living in different geographic areas. This paper reviews existing data related to non occupational MPM including its occurrence in the province of Catania (Sicily, Italy). METHODS: An electronic search of literature related to non occupational MPM was performed including the year 2005. RESULTS: Non occupational MPM in subjects living in areas contaminated by a variety of asbestos and non asbestos fibres has been well documented through a number of epidemiologic studies including cases series, case-control studies, and a cohort study. In addition, the observation of familial clustering of MPM, suggests that genetic factors may play a role in the pathogenesis of this malignancy. The epidemiological evidence also suggests that MPM may occur as a result of the interaction between environmental carcinogens, genetic factors, and virus infection. CONCLUSION: It is likely that genetic predisposition and non-occupational exposure to low doses of asbestos and asbestos-like fibres may concur to the development of malignant mesothelioma. However, additional epidemiological and laboratory studies are needed to further understand the relationship between environmental exposure and individual susceptibility to this malignancy.

negative: Curcumin impairs tumor suppressor p53 function in colon cancer cells. Curcumin (diferuloylmethane) is being considered as a potential chemopreventive agent in humans. In vitro it inhibits transcription by NF-kappaB, and the activity of lipoxygenase or cyclooxygenase enzymes, which facilitate tumor progression. In vivo it is protective in rodent models of chemical carcinogenesis. Curcumin contains an alpha,beta-unsaturated ketone, a reactive chemical substituent that is responsible for its repression of NF-kappaB. In compounds other than curcumin this same electrophilic moiety is associated with inactivation of the tumor suppressor, p53. Here we report that curcumin behaves analogously to these compounds. It disrupts the conformation of the p53 protein required for its serine phosphorylation, its binding to DNA, its transactivation of p53-responsive genes and p53-mediated cell cycle arrest.

negative: Epidemiology and pathophysiology of alcohol and breast cancer: Update 2012. AIMS: To update epidemiological data on alcohol and breast cancer, with special emphasis on light alcohol consumption, and to review mechanisms of alcohol mediated mammary carcinogenesis. METHODS: For epidemiological data, in November 2011 we performed a literature search in various bibliographic databases, and we conducted a meta-analysis of data on light alcohol drinking. Relevant mechanistic studies were also reviewed to November 2011. RESULTS: A significant increase of the order of 4% in the risk of breast cancer is already present at intakes of up to one alcoholic drink/day. Heavy alcohol consumption, defined as three or more drinks/day, is associated with an increased risk by 40-50%. This translates into up to 5% of breast cancers attributable to alcohol in northern Europe and North America for a total of approximately 50,000 alcohol-attributable cases of breast cancer worldwide. Up to 1-2% of breast cancers in Europe and North America are attributable to light drinking alone, given its larger prevalence in most female populations when compared with heavy drinking. Alcohol increases estrogen levels, and estrogens may exert its carcinogenic effect on breast tissue either via the ER or directly. Other mechanisms may include acetaldehyde, oxidative stress, epigenetic changes due to a disturbed methyl transfer and decreased retinoic acid concentrations associated with an altered cell cycle. CONCLUSIONS: Women should not exceed one drink/day, and women at elevated risk for breast cancer should avoid alcohol or consume alcohol occasionally only.

negative: Sugar substitutes: Health controversy over perceived benefits Sugar is an inseparable part of the food we consume. But too much sugar is not ideal for our teeth and waistline. There have been some controversial suggestions that excessive sugar may play an important role in certain degenerative diseases. So artificial sweeteners or artificially sweetened products continue to attract consumers. A sugar substitute (artificial sweetener) is a food additive that duplicates the effect of sugar in taste, but usually has less food energy. Besides its benefits, animal studies have convincingly proven that artificial sweeteners cause weight gain, brain tumors, bladder cancer and many other health hazards. Some kind of health related side effects including carcinogenicity are also noted in humans. A large number of studies have been carried out on these substances with conclusions ranging from “safe under all conditions” to “unsafe at any dose”. Scientists are divided in their views on the issue of artificial sweetener safety. In scientific as well as in lay publications, supporting studies are often widely referenced while the opposing results are de-emphasized or dismissed. So this review aims to explore the health controversy over perceived benefits of sugar substitutes.