In recent years, there’s been a lot of media coverage and scientific interest in environmental toxicants such as bisphenol A (BPA) – including campaigns to eliminate BPA from plastics and other consumer products. What about BPA is so concerning and why is it important to regulate it? The answer lies in two important characteristics of BPA (and chemicals like it): 1) BPA can disrupt normal hormone function in the body and 2) BPA doesn’t follow the rules in terms of the Environmental Protection Agency (EPA)’s “safe exposure”levels  .
Fig. 1 BPA and estrogen have some similarities in chemical structure. The ring structures with a hydroxyl group (OH) that are circled in red are important for both chemicals to bind to estrogen receptors in the body.
Normal hormone function. Hormones are molecules that influence cellular function through binding to their specific “hormone receptors” – other proteins than can specifically bind with a hormone based (largely) on how the hormone is shaped (Fig. 2A) .
Hormone mimicking. However, EDCs that mimic hormone shape can interact with the hormone receptor, even when the actual hormone is not present. In a normal setting, without the hormone present, there would be no consequential (downstream) effects of stimulating the hormone receptor because it was not interacting with the hormone. However, when the EDC binds the receptor in place of the hormone, it will stimulate an effect despite a lack of hormone (Fig. 2B) .
Hormone blocking. Alternatively, the EDC may bind the hormone receptor in a way that doesn’t cause a direct response, but rather blocks further binding of the hormone with its receptor and decreases the efficacy of the hormone on that cell (Fig. 2C) .
Fig. 2 Some ways in which endocrine disrupting chemicals that mimic hormones can alter normal hormone function in cells. Adapted from the NIEHS website . Green rectangle = naturally-produced hormones; purple hexagon = naturally-occurring hormone receptors; pink rectangles & red triangles = hormone mimicking EDCs.
As an example, BPA can interact with the estrogen receptor to stimulate a response even without the presence of estrogen (as depicted in Fig. 2B), and has been linked to early onset puberty, which itself has been linked to a higher risk for certain cancers .
So we know endocrine disruptors like BPA can change a cell’s function through altered hormone signaling. Our next concern should be “how much BPA can we be exposed to before we see those effects?” Hundreds of research studies have shown that the answer is “it’s complicated” . For many years, we have largely considered the effects of synthetic (and other) chemicals in light of the mantra “the dose makes the poison” – implying that a little of something isn’t nearly as harmful as a lot of that something. While this is sometimes true, we’re finding that it is not always the case.
In many studies, BPA behaves in a non-monotonic manner – meaning that a higher dose of BPA does not always prompt a stronger effect than lower doses . Figure 3 is a simplified comparison of monotonic and non-monotonic dose responses . In Fig. 3A, the response on the Y-axis (which is intentionally vague – it could be any cellular function) increases as dose increases (shown on the x-axis). This is an example of a monotonic response where the response increases or decreases in a consistent direction in relationship to the dose. However, Fig. 3B demonstrates an example of a non-monotonic dose response in which the median exposure level elicits a greater response than either the lowest or highest dose. Biological causes for non-monotonic dose responses can be incredibly complex – too little of a substance can cause particular biological pathways to activate or deactivate while too much of a substance can influence those same pathways differently, or completely different pathways (for more information, refer to ).
Fig. 3 Monotonic and non-monotonic dosage responses.
This is important because we are discovering that many endocrine disrupters demonstrate non-monotonic dose responses but are regulated by the EPA as if they have monotonic dose responses, wherein keeping exposure levels below a certain threshold would ensure safety. While having a single threshold is convenient and even appropriate for some synthetic chemicals, it’s probably not appropriate for EDCs  . For example, the EPA’s safety threshold for lead is 400 parts per million (ppm) of lead in soil in children’s play areas . However, if lead exhibited a non-monotonic dose response like BPA does, there could be little biological effect at both 100 ppm and 400 ppm but a significant effect at 250 ppm – and only very thorough research would determine the dynamics of exposure levels. Proper regulation of these chemicals will involve very particular dosage considerations for individual EDCs – not a “one size fits all” regulation for all EDCs.
Endocrine disruptors such as BPA are public health concerns due to their potential to interfere with hormone signaling in the body that may lead to abnormal development and/or disease. Many groups of scientists around the world are researching these chemicals, but the verdict is still out on precisely how to regulate safe exposure levels. Our goal is to learn more about the extent of EDCs’ biological effects in addition to developing proper exposure regulations to keep ourselves and the environment safe.
 “Endocrine-disrupting compounds: Chemicals that interfere with the body’s natural hormones.” 2013. Breast Cancer Fund. N.p.
 “Endocrine Disruptors.” 2016. National Institute of Environmental Health Sciences. N.p.
 Nah, W. H., M. J. Park, and M. C. Gye. 2011. “Effects of early prepubertal exposure to bisphenol A on the onset of puberty, ovarian weights, and estrous cycle in female mice.” Clinical and experimental reproductive medicine 38: 75-81.
 Vandenberg, L. N. 2014. “Non-monotonic dose responses in studies of endocrine disrupting chemicals: bisphenol a as a case study.” Dose-response 12: 250-276.
 Lagarde, F., C. Beausoleil, S. M. Belcher, L. P. Belzunces, C. Emond, M. Guerbet, and C. Rousselle. 2015. “Non-monotonic dose-response relationships and endocrine disruptors: a qualitative method of assessment.” Environ Health 14: 13.
 Environmental Protection Agency (US). 2001. “Lead; identification of dangerous levels of lead; final rule” [Internet]. Fed Regist 66: 1206-40.
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