Pesticides are a collective term for a wide array of chemicals intended to kill unwanted insects, plants, molds, and rodents. Food, water, and treatment in the home, yard, and school are all potential sources of children’s exposure. Exposures to pesticides may be overt or subacute, and effects range from acute to chronic toxicity. In 2008, pesticides were the ninth most common substance reported to poison control centers, and approximately 45% of all reports of pesticide poisoning were for children. Organophosphate and carbamate poisoning are perhaps the most widely known acute poisoning syndromes, can be diagnosed by depressed red blood cell cholinesterase levels, and have available antidotal therapy. However, numerous other pesticides that may cause acute toxicity, such as pyrethroid and neonicotinoid insecticides, herbicides, fungicides, and rodenticides, also have specific toxic effects; recognition of these effects may help identify acute exposures. Evidence is increasingly emerging about chronic health implications from both acute and chronic exposure. A growing body of epidemiological evidence demonstrates associations between parental use of pesticides, particularly insecticides, with acute lymphocytic leukemia and brain tumors. Prenatal, household, and occupational exposures (maternal and paternal) appear to be the largest risks. Prospective cohort studies link early-life exposure to organophosphates and organochlorine pesticides (primarily DDT) with adverse effects on neurodevelopment and behavior. Among the findings associated with increased pesticide levels are poorer mental development by using the Bayley index and increased scores on measures assessing pervasive developmental disorder, inattention, and attention-deficit/hyperactivity disorder. Related animal toxicology studies provide supportive biological plausibility for these findings. Additional data suggest that there may also be an association between parental pesticide use and adverse birth outcomes including physical birth defects, low birth weight, and fetal death, although the data are less robust than for cancer and neurodevelopmental effects. Children’s exposures to pesticides should be limited as much as possible.
Pesticides represent a broad classification of chemicals that are applied to kill or control insects, unwanted plants, molds, or unwanted animals (eg, rodents). “Pesticide” is a collective term for a wide array of products but is often inappropriately used in reference to only insecticides. The universe of pesticide types and products is broad, and a comprehensive review of all active ingredients is beyond the scope of this report. This review focuses on select insecticides, herbicides, and rodenticides and specific chemical classes within these groups that have the greatest acute and chronic toxicity for children on the basis of historical experience and/or emerging evidence (Table 1).
The Centers for Disease Control and Prevention (CDC) conducts a population-based biomonitoring program associated with the NHANES.19 The most recent report includes biomarker data for many organochlorine, OP, and carbamate insecticides; herbicides; pyrethroid insecticides; and some other pesticides. Testing of 44 pesticide metabolites revealed that 29 were detectable in most people from whom samples were analyzed (ages 6–59 years), with OP and organochlorine insecticides reported to be most prevalent in the US population.19 Although the health implications of these “snapshot” sampling data are largely unknown, they do provide a reference point on pesticide metabolite distributions. Periodic reassessment also allows for evaluations of population-level exposure trends.
As noted previously, children’s unique behaviors and metabolic rate often place them at risk for absorption of higher doses from contaminated environments in comparison with adults. One example evident from the biomonitoring data is chlorpyrifos, a nonpersistent OP insecticide. Although banned in 2000 for use inside the home, it continues to be used in agriculture, including orchard fruits, such as apples and pears, and other dietary staples of children. In the CDC biomonitoring data, chlorpyrifos-specific urinary metabolites were highest for the youngest age group assessed (6–11 years) compared with older children and adults.19 In contrast, biomonitoring of serum markers of organochlorine insecticides and their metabolites, such as DDT, dieldrin, and chlordane, many of which were banned from use in the United States in the 1970s and 1980s, revealed lower concentrations in the youngest age group monitored (12–19 years). Despite relatively lower concentrations, the ongoing detection and the higher levels with increasing age likely reflect the influence of the accumulation of these fat-soluble, persistent compounds over a lifetime.
Poisoning with OPs and carbamates can be detected on the basis of clinical findings and history of exposure. Laboratory confirmation can assist in the diagnosis by using red blood cell and plasma cholinesterase levels; both are typically depressed with acute poisoning, although there is some variation among active ingredients as well as variation in levels by severity of poisoning.35 Measurement techniques and resultant levels vary among laboratories; therefore, clinicians will need to check with their own laboratory for reference values. Red blood cell cholinesterase levels typically are more specific for acute poisoning and will be depressed longer than plasma cholinesterase levels (often 1–3 months) until enzyme is replaced.3 Interpretation of results can be discussed with a pediatric environmental health specialist or clinical toxicologist.
The parent active ingredient cannot typically be measured in biological specimens. These compounds undergo metabolic transformation in the liver and are excreted in the urine mostly in their metabolized form, most of which are nonspecific metabolites for all OPs.19 Exceptions include parathion, methyl-parathion, and chlorpyrifos, all of which have their own specific metabolite in addition to the nonspecific metabolites. Urinary metabolites can be measured, and human data are available from the CDC on a nationally representative sample.19 However, an evidence base to support clinical interpretation of urinary concentrations is lacking.
Pyrethrins and pyrethroids are a relatively more recent class of insecticides that have been largely replacing the use of cholinesterase-inhibiting insecticides, especially in the consumer market. These insecticides are used for structural pest control in urban areas, in gardening or agriculture for row crops and orchards, and in the home for pet sprays and shampoo.
Pyrethroids exert their toxic effect by blocking the sodium channel at the level of the cell membrane. Most clinical reports of poisoning occur either through excessive skin contact or through ingestion or inhalation. The result is continued hyperpolarization, effectively inhibiting cell function. Some types of pyrethroids also work at other sites, including voltage-dependent chloride channels and γ-aminobutyric acid–gated chloride channels. This appears to be one of the reasons for a variety of toxicity found among pyrethroid insecticides.42,43 Pyrethroids with a cyano group, also known as type II pyrethroids, constitute most cases of human poisoning.42,43 Pyrethroids are well absorbed across the GI tract, but limited penetration occurs across the skin barrier, which can limit acute toxicity.42,44 Some pyrethroids have a high acute toxicity, usually after ingestion.42,45 Pyrethroids are metabolized by the liver and excreted in their metabolic forms.
Pyrethroid toxicity is identified through clinical history and knowledge of exposure to the agent. There are no rapidly available diagnostic laboratory tests. Most pyrethroids are metabolized to 3-phenoxybenzoic acid, which can be recovered in the urine. CDC national surveys provide biomonitoring information on pyrethroid urinary metabolites and can act as comparison for background measures of exposure in the general population. However, in the clinical setting, results of metabolite levels are usually obtained from specialty laboratories and are not immediately available; therefore, these results not useful in acute clinical management.
Treatment of systemic pyrethroid poisoning is supportive, in general, and there are no specific antidotes. Because of the similar features of cholinesterase inhibitor poisoning, some patients have been treated erroneously with high atropine, sometimes with disastrous results.45 Efforts have been aimed at antagonizing the sodium current resulting from the pyrethroid blockade. Several medications have been tested in the animal model, but, to date, none have been considered effective antidotes for systemic pyrethroid poisoning in humans. For significant neurologic effects, patients should have standard decontamination, including GI tract decontamination, supportive respiratory care, seizure control with diazepam or lorazepam, and careful dosing of atropine for excessive salivation.42 Proper identification of the offending agent is imperative to distinguish these poisonings from OPs and often requires a high index of suspicion and a thorough exposure history.
The discussion of acute toxicity for organochlorines is focused on lindane, because most other organochlorine compounds have been banned for use in the United States. Other organochlorines, including DDT and some of the cyclodienes, including chlordane and dieldrin, are important compounds, because they can still persist in human and environmental samples. These chronic exposures are of continuing concern for developmental health effects, including immunotoxicity, endocrine disruption, and neurodevelopmental insults (see Chronic Health Effects of Pesticide Exposure).
Neonicotinoids are a new class of insecticides based on metabolic alterations of nicotine. They are used primarily in agriculture and are gaining widespread use for flea control on domestic animals. They act on the nicotinic N-acetylcholine receptors and selectively displace acetylcholine. They do have a relatively selective affinity for insects as opposed to mammals, although there have been a few reports of human poisoning.54–56 The most commonly used neonicotinoid in the United States is imidacloprid. Information about toxicity and signs and symptoms can be found in Tables 1 and 2.
Fipronil is the primary representative of this class and was developed in the mid-1990s. It is widely used in flea control on domestic pets. It is also used in ant and roach bait stations, agriculture crops, and lawn treatments. It acts by inhibiting γ-aminobutyric acid–gated chlorine channels. The inhibition will block chloride passage and result in hyperexcitability of the cell.57–59 Signs and symptoms are reported in Table 2.
Glyphosate is a commonly used herbicide and is commercially available in many products. Glyphosate acts on the cell wall of plants, so, theoretically, it should have no effect on human cells, at least by way of its primary mechanism of action. Despite this, there are numerous reports in the medical literature of adverse events after human exposure, particularly unintentional ingestions. Patients have presented with signs and symptoms consistent with an aspiration pneumonia–like syndrome, and the offending agent may be the hydrocarbon solvent with which the glyphosate is mixed. Treatment is primarily supportive, and providers should be vigilant for aspiration pneumonia.
The associated health effects of chronic pesticide exposure in children vary, reflecting the diversity of toxicological properties of this broad group of differing chemicals. Some of the important end points of concern include an increased risk of cancer, abnormal neurodevelopment, asthma, perturbation of gestational growth, and endocrine-mimicking effects. Health effects of pesticides and the current relative strength of the evidence base are reviewed in subsequent sections for each of these health outcomes.
All pesticides undergo in vitro and animal testing to determine their likelihood of causing cancer. The EPA maintains a list and classification of all active ingredients in pesticides and their potential for carcinogenicity. The method of identifying potential carcinogenicity has changed. Before 1996, pesticides were assigned a letter classification (eg, pesticides with the “C” classification were considered “possibly carcinogenic”). Subsequently, pesticides have been assigned a category such as “likely to be carcinogenic to humans,” “suggestive evidence of carcinogenic potential,” “inadequate evidence,” and “not likely.” These categories are not directly comparable, so both classifications (before 1996) and categories (after 1996) continue to exist.
The pesticides that are categorized as “possibly carcinogenic” or “likely to be carcinogenic to humans” are available from the EPA via an e-mailed report.77 Included in this report are some well-known and widely used OPs, carbamates, pyrethroids, and fungicides. Within classes of pesticides, variation in carcinogenicity potential exists. Note that a pesticide, such as cypermethrin, that has “replaced” use of cancer-causing OPs has cancer-causing potential.
In 1998, Zahm and Ward79 reviewed 18 studies assessing the relationship between pesticide exposure and leukemia; 13 studies found an elevated risk, and, for 6 of those studies, the association was statistically significant. The most frequently occurring associations among the studies were between pesticide exposure and acute lymphocytic leukemia.
Two case-control studies were performed to evaluate potential parental occupational exposures and the development of Ewing sarcoma (ES). One study of 196 cases and matched controls found an association between ES in boys age 15 years or younger and household pesticide extermination (OR, 3.0; 95% CI, 1.1–9.2). There was no association between parental occupational exposure to pesticides and ES.101 A study in Australia compared 106 cases of either ES or peripheral primitive neuroectodermal tumor with 344 population-based controls. Exposures included prenatal exposure from conception through pregnancy and also included parental exposures through the time of the child’s diagnosis. Notable elevated risks were observed for mothers who worked on farms (OR, 2.3; 95% CI, 0.5–12.0), mothers who handled pesticides (OR, 2.3; 95% CI, 0.6–8.5), patients who ever lived on a farm (OR, 2.0; 95% CI, 1.0–3.9), and farming fathers at the time of conception and/or pregnancy (OR, 3.5; 95% CI, 1.0–11.9).102 Of note in this study, all 95% CIs include 1.0, so they did not reach statistical significance, although some ORs approached it.
In summary, there is some evidence of increased risk of developing several childhood cancers after preconception and/or prenatal exposure to pesticides. The strongest evidence appears to be for leukemia, which is a relatively more common type of childhood cancer than brain tumors. Maternal exposure to insecticides and paternal occupational exposure appear to carry the greatest risk.
In one of the cohorts, postnatal exposure effects in the child have been investigated and reported. Interestingly, improved mental development based on Bayley’s Index at 12 and 24 months of age is associated with higher contemporary child excretion of OP urinary metabolites. Explanations for this are debated but include theories that children with higher cognitive abilities may explore their environments more thoroughly and, as such, experience higher exposure.
One study based in Ecuador has examined the relationship of OP exposure on neurodevelopment in school-aged children.119 Prenatal exposure (based on mother occupational history questionnaire) was associated with a decrease on the Stanford-Binet copying test among the study subjects at 7 years of age. Their concurrent exposure (on the basis of OP urinary metabolites) was associated with an increase in simple reaction time.
In summary, the existing and recently emerging evidence base suggests that organochlorine and OP exposure in early life, particularly prenatally, may have adverse consequences on child neurodevelopment.
Among studies that are able to address specific types of pesticide exposures, there are more data focused on the organochlorine and OP insecticides or phenoxy or triazine herbicides. These represent the currently or historically (eg, organochlorine) most heavily used pesticides. This review summarizes the highlights of the existing evidence base with a focus on studies that incorporate direct measures of exposure for individual study subjects.
A 1995 review article discussed the available evidence for associations between birth defects and potential pesticide exposure.132 Five studies were included that assessed various birth defects (central nervous system, oral cleft, limb defects) compared with maternal agricultural occupation. Four of those 5 reported an elevated RR or an OR ranging from 1.6 to 5.0; however, only 2 were statistically significant.133–137 Of note, in these studies, there was not an assessment to any single pesticide; rather, the “exposure” was maternal occupation.
Studies of birth defects often include all types within the analysis because of insufficient numbers of individual defects to allow adequate power of statistical analyses. A meta-analysis used 19 studies that had sufficient data to be included to estimate the effects of pesticides on orofacial clefting. Maternal occupational exposure to pesticides was associated with orofacial clefts (OR, 1.37; 95% CI, 1.04–1.81). There was a weaker association for paternal occupation (OR, 1.16; 95% CI, 0.94–1.44).146 Studies on 3 other birth defects—cryptorchidism, hypospadias, and polythelia—will be discussed in the section on endocrine effects.
In summary, a small risk elevation is noted for birth defects and pesticide exposure, but the findings are not robust, and the data specific to pesticide subtypes are not adequate.
In summary, the true extent and nature of pesticide exposure on adverse fetal growth and birth outcomes is unknown despite suggestive epidemiological studies that link some of the most widely used pesticides to reduced intrauterine growth, fetal death, preterm birth, and congenital anomalies. Very little is known about many pesticide types in current use, including synthetic pyrethroids and carbamate insecticides, rodenticides, and fungicides. Studies that examine the timing and extent of exposure to pesticides and exposure to pesticide mixtures with validated exposure assessment techniques including biological markers are needed. The potential for differential vulnerabilities because of genetic polymorphisms that influence the toxicological properties of these exposures must also be explored.
Given the widespread use of pesticides and the high morbidity of asthma in children, questions have been raised regarding pesticides as triggers as well as risk factors for incident disease. Concern is raised by a mounting adult occupational literature associating pesticides with asthma or other measures of respiratory health. In addition, preliminary toxicological data provide mechanisms that link pesticides and asthma. An important limitation of most epidemiological studies to date is the lack of exposure specificity regarding pesticide chemicals or chemical classes. In addition, studies regarding children are few.
There is indirect evidence that pesticides skew the immune response toward the T helper 2 (Th2) phenotype associated with atopic disease. The National Institutes of Health/EPA-sponsored rural birth cohort described above regarding evaluation of neurodevelopmental effects has also observed that maternal agricultural work was associated with a 26% increase in proportion of Th2 cells in their 24-month-old infants’ blood samples.173 The percentage of Th2 cells was associated with both physician-diagnosed asthma and maternal report of wheeze in these infants. This population of largely Mexican American farmworkers was selected for study on the basis of the relatively high use of OP pesticides in this agricultural area.
The few epidemiological data on pesticides and respiratory health in children have mixed results. In a cohort of rural Iowan children, any pesticide use indoors or any outdoor use in the previous year was not significantly associated with asthma symptoms and prevalence.178 Contrarily, a cross-sectional analysis of Lebanese children identified increased risk of chronic respiratory symptoms, including wheeze, among those with any pesticide exposure in the home, exposure related to parent’s occupation, and use outside the home. The highest risk was observed for children whose parents had occupational exposure to pesticides (OR, 4.61; 95% CI, 2.06–10.29).179 However, given this study’s cross-sectional design, it is not possible to discern whether the pesticide exposure preceded the diagnosis of asthma.
More published data are available regarding adult farmers and adult rural residents. These studies more consistently support a link between pesticides and respiratory symptoms or chronic respiratory disease, such as asthma.181,182 For example, use of multiple individual pesticides was evaluated in relation to self-reported episodes of wheeze in the previous year in a large cohort of commercial pesticide applicators (adults) and farmers enrolled in the Agricultural Health Study.182 Among the pesticides classes, several OPs showed associations with wheeze, including several that demonstrated a dose–response trend. Chlorpyrifos, malathion, and parathion were positively associated with wheeze among the farmers; for the commercial applicators, the OPs chlorpyrifos, dichlorvos, and phorate were positively associated with wheeze. Among commercial applicators, the strongest OR was for applying chlorpyrifos on more than 40 days per year (OR, 2.40; 95% CI, 1.24–4.65). Elevated risk for wheeze related to herbicide use was almost exclusively associated with chlorimuron-ethyl (urea-derivative class).
In summary, the available data regarding chronic exposure to pesticides and children’s respiratory health remain limited. Studies that incorporate pesticide-specific exposure assessment and markers of biological mechanisms and consider the influence of timing of exposure across the life span are needed.
The “directions for use” section on the label explains when, how, and where the pesticide may be applied. The label is considered the law; therefore, any use of the product in a manner inconsistent with the label is a violation of the Federal Insecticide, Fungicide, and Rodenticide Act (Pub L No. 80-104).187 Information on recommended storage of the product and disposal of the container is also printed on the label.
The label will contain a signal word and symbol to identify acute toxicity potential: “danger” along with the word poison and the skull and crossbones symbol signifies high acute toxicity; “warning” signifies moderate acute toxicity; and “caution” represents slight acute toxicity. There is a section for precautionary statements regarding the potential hazards to people or pets and the actions that can be taken to reduce these hazards, such as wearing gloves or other protective equipment. Basic first aid advice for responding to dermal, inhalational, and/or oral exposure is provided. Some labels contain a “note for physicians” that includes specific medical information. The label does not provide any information or warnings about the potential for chronic toxicity arising from normal use or misuse of the pesticide. An example of an interactive pesticide label can be found at the EPA Web site.188 It includes “pop-up” features that define each of the components on the pesticide label.
Self-reported medical education and self-efficacy suggests pediatricians are not well prepared to identify pesticide exposure and illness, including taking a relevant environmental history or discussing pesticide risks with their patients.189–191 Even in agricultural areas of the Pacific Northwest, where pesticide use is heavy, a survey of health care providers who serve high volumes of agricultural farmworkers and their families found that 61% did not feel comfortable responding to patient/client questions regarding pesticides on the basis of their training, background, and experience.75 Among academic pediatricians with an interest in pediatric environmental health, pesticides were among the topics they felt least prepared to teach to their trainees.192 Given the widespread use of pesticides and concerns for child health, opportunities to increase pesticide competency in pediatric medical education are likely to prevent missed diagnoses and reduce exposure because of improved anticipatory guidance.
Dietary modifications can help reduce pesticide exposure. As mentioned previously, consuming organic produce has shown a reduced amount of urinary pesticide levels in comparison with a conventional diet.22 Because many food-based pesticide residues occur on the surface of food crops, other practical approaches may be used to reduce exposures by washing produce, peeling off outer layers of leafy vegetables, and removing peels from fruits and vegetables. Trimming fat from meat and fat and skin from poultry and fish may reduce residues of persistent pesticides, such as the organochlorines, that concentrate in animal fat.
Efforts to address and reduce chronic pesticide exposure via the food supply in children have included regulatory approaches that consider the unique vulnerability of the developing child in policy decision-making. For example, the 1996 Food Quality Protection Act (Pub L No. 104-170, Section 405) required that the EPA use an additional 10-fold margin of safety regarding limits of pesticide residues on food (unless there are data that show a less stringent residue level is safe for prenatal and postnatal development; for description, see http://www.epa.gov/opp00001/factsheets/riskassess.htm).
In addition to food residues, use of pesticides in and around the home and other settings where children spend time (child care, school, and playgrounds and sports fields) is an important influence on the chronic and cumulative exposure to pesticides among US children. Most of the pest problems that occur indoors as well as control of lawn and garden pests can be addressed with least toxic approaches, including integrated pest management (IPM) techniques. IPM focuses on nontoxic and least toxic control methods to address pest problems have been promoted and adopted for residential, school, and agricultural settings (fact sheets available at http://www.epa.gov/opp00001/factsheets/ipm.htm).
“Integrated” refers to employment of complementary strategies of pest control, which may include mechanical devices; physical devices; genetic, biological, and cultural management; and chemical management. For example, to control cockroaches, a family could be counseled to keep garbage and trash in containers with well-fitted lids, eliminate plumbing leaks or other sources of moisture, store food in insect-proof containers, vacuum cracks and crevices, clean up spills immediately, and use the least-toxic insecticides, such as boric acid, in cracks and crevices or bait stations. The goal is to target the pest and limit the effect on other organisms and the environment. Although developed with a focus on agricultural insect pests, IPM programs and knowledge have extended to address weeds and pest control in residential settings and schools, commercial structures, lawn and turf, and community gardens.
Within agriculture, IPM has been recognized and promoted for decades; however, inadequate leadership, coordination, and management of US Department of Agriculture IPM programs were identified as impediments to adequate progress in a 2001 report.194 The report provided the basis for an ongoing national roadmap effort to improve ongoing development of increased IPM in agriculture.
To protect children, IPM in schools has been recommended by the US Department of Agriculture, EPA, American Public Health Association, and National Parent Teacher Association. Many states and local municipalities have adopted programs and resources to encourage IPM in public places, in addition to homes and schools (see Table 3). IPM strategies seek to minimize insecticide use by applying strategies such as cleaning up food and water, sealing cracks and crevices, and using pesticides that are contained in baits or traps, which are far less likely to pose a health concern compared with any type of broadcast spray application. Avoiding combination products with pesticides and fertilizers (ie, “weed and feed” preparations) is advised for lawn maintenance, because these tend to result in overapplication of pesticides. Hand weeding is always a reasonable alternative to herbicides. However, if an herbicide is to be used, some (such as glyphosate) have better acute human toxicity profiles than others (such as 2,4-D). Even so, glyphosate is not without its risks. Most cases of moderate to severe toxicity have occurred after intentional (suicidal) ingestion.195 Using safe storage practices (in a locked cabinet or building) and not reusing pesticide containers are important components toward the prevention of acute poisonings after unintentional ingestion by small children. Reliable resources for useful information on pest-control alternatives and safe use of pesticides are available from the EPA and University of California-Davis (Table 3).
Although there is no federal mandate for notification of pesticide use in communities, many states, locales, or schools have implemented requirements for posting warning signs or developing registries to alert individuals of planned pesticide application (see Table 3). These are designed to allow the public to make decisions to avoid exposures during application or soon after from residues. Other local policies that have been developed include restricting spray zones that create buffers from schools or other areas or restrict specific types of pesticide products in schools. Pediatricians can play a role in the promotion of development of model programs and practices in the communities and schools of their patients. For example, in some communities, pediatricians have participated in local organizations that have successfully advocated for no pesticide application in schools.
Pesticides are a complex group of chemicals with a wide range of acute and chronic toxicity. Poison control centers report lower rates of more severe poisonings but continue to report similar total numbers of acute exposures among children. There is a growing body of literature that suggests that pesticides may induce chronic health complications in children, including neurodevelopmental or behavioral problems, birth defects, asthma, and cancer. Pediatricians are a trusted source of information for families and communities, although current training focused on pesticide toxicity and environmental health, in general, is limited. Pediatricians should be familiar with the common pesticide types, signs and symptoms of acute toxicity, and chronic health implications. Efforts should be made to limit children’s exposure as much as possible and to ensure that products released to the marketplace have been appropriately tested for safety to protect fetuses, infants, and children from adverse effects.