Environmental Chemicals: Large Effects from Low Doses June 11, 2012 Public Health, San Francisco Medicine EDCs, endocrine-disrupting chemicals, J.P. Myers, Lisa Vandenberg, Thomas Zoeller, EDC 0 By Laura N. Vandenberg, PhD; R. Thomas Zoeller, PhD; J.P. Myers, PhD Virtually all safety standards for chemical exposures are determined through a process that assumes that high-dose testing will reveal relevant risks because “the dose makes the poison.” For many well-studied contaminants this is a reasonable assumption, but for compounds that behave like hormones, it is demonstrably false. The public health implications of this conclusion are enormous, because it means that many—likely dozens, plausibly hundreds, possibly thousands—of today’s chemical safety standards are too weak by orders of magnitude. The basis for this conclusion derives from endocrinology. In endocrinology, it is well established that the impacts of hormones (such as estrogen) at high doses can differ from those in the "physiological range" of normal circulating levels of hormones in serum; it is at these concentrations that hormones interact with their receptors to cause physiological and developmental changes by altering gene expression. Indeed, hormones at abnormally high doses are often overtly toxic, through mechanisms that have nothing to do with receptor action. As research has expanded into the effects of endocrine-disrupting chemicals (EDCs), it has been shown that they follow the same rules that hormones follow. Unfortunately, this runs counter to the core assumption that forms the basis for all toxicological testing done to establish regulatory standards: High-dose testing will be informative about low-dose impacts. The EPA defines an EDC as “an exogenous agent that interferes with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for the maintenance of homeostasis, reproduction, development, and/or behavior.” Although Rachel Carson examined the effects of many environmental chemicals on health and reproduction in her landmark book Silent Spring, work on EDCs really took shape in 1991, when a group of scientists met at the Wingspread Conference Center in Racine, Wisconsin, to discuss research on the effects of environmental chemicals on sexual development. The Wingspread attendees produced a consensus statement stating, “We are certain of the following: A large number of man-made chemicals that have been released into the environment, as well as a few natural ones, have the potential to disrupt the endocrine system of animals, including humans.” EDCs are now understood to be any chemicals that interact with the endocrine system, including chemicals that act as agonists and antagonists of hormone receptors, including estrogen, androgen, thyroid, glucocorticoid, retinoid, and others. To determine the mode of action of these chemicals, both in vivo (animal) and in vitro (cell culture) assays have been developed. While most chemicals on the market today have never been tested for safety, much less for endocrine disruption, these assays could be used to test new chemicals for hormonal activity prior to their entry into the environment through the food supply, packaging materials, or as waste; they are also widely used to test for their hormonal activity many chemicals that are already in use. Chemicals with a wide range of uses, including detergents, plastics, cosmetics, pesticides, pharmaceuticals, and flame retardants, among others, have been shown to have endocrine-disruptor activities. In 2002, the National Toxicology Program (NTP) examined evidence for what has been termed “the low-dose hypothesis,” i.e., the theory that EDCs could have actions at low doses. What is meant by “low doses”? Typically, these are doses in the range of what humans experience in their everyday lives—residues on food, in the air, in dust, and in drinking water. Low doses are often within the range that traditional toxicological testing has determined to be “safe.” The question is whether EDCs are safe at the doses the typical person experiences. To determine what doses are safe, regulatory toxicology usually starts by administering large doses of a chemical to animals, identifying the highest dose at which no effect is found, and then extrapolating downward to calculate a safe dose. Those “safe” doses are rarely tested. Yet EDCs, like hormones, defy the toxicological dogma: Low doses can have effects that are not expected from high-dose exposures. In fact, these effects can be observed at doses orders of magnitude beneath the highest dose that produces no effect using traditional approaches. The mechanisms by which chemicals cause high-dose effects usually are completely unrelated to mechanisms that EDCs employ at low doses, and the effects of high and low doses can be on completely different endpoints. In our review of the EDC literature, we found hundreds of examples of these types of responses, termed nonmonotonic responses, in cultured cells, animals, and even human populations. Many of these chemicals have effects at low doses, providing strong evidence that calculated “safe” doses of these chemicals are not, in fact, safe. Are these chemicals adversely affecting human health? Many of the earliest epidemiology studies examining the effects of EDCs studied occupationally or accidentally exposed individuals, i.e., people who were exposed to relatively high doses, either acutely or over longer periods of time. Now a large number of epidemiology studies have focused on environmentally exposed individuals, i.e., people who are exposed to EDCs from everyday life. These studies show that many of the effects observed in cultured cells and controlled animal experiments accurately predict what epidemiologists are observing in human populations: Associations between human exposures and disease endpoints consistent with the “low-dose hypothesis.” So where do we go from here? As scientists, these findings suggest for us that EDCs, as a chemical class, act very similarly to the hormones they mimic or block: They act at low doses, with effects that are more pronounced when exposures occur during critical periods of development. Just as hormones have nonmonotonic relationships between dose and effect, nonmonotonic effects of EDCs are expected. This means that high-dose testing is insufficient to establish the safety of low doses. In our review, we propose some changes to the way risk assessors determine safety of EDCs: “Safe” doses of chemicals, and chemicals in the range of human exposures, should be tested; Regulators should assume that EDCs produce nonmonotonic dose responses; More sensitive endpoints should be included in chemical testing. What can the average person, or patient, do to reduce EDC exposures? This is, of course, an important issue for health care practitioners and others invested in improving public health. Several studies suggest that making small lifestyle changes can have dramatic effects on exposure levels. Patients should be encouraged to make lifestyle choices that reduce known EDC exposures. However, the lessons learned from the published literature seem to be clear: Even low doses, including reduced exposures from changes in consumer behavior, cannot be considered safe. Thus, widespread changes to chemical safety regulations are likely to have the widest effects on human health. We encourage physicians, nurses, public health administrators, and others working in the medical field to read our recent review and to get involved with the many scientific societies that support new approaches to chemical regulation that better reflect current scientific understanding than do standard toxicological procedures. Your expertise provides an important voice to help the risk assessment community develop new approaches to chemical risk assessment, especially as it pertains to EDCs. Hormones are important signaling molecules that dictate the health of individuals throughout the life course, and therefore the effects of EDCs simply cannot be ignored. Laura N. Vandenberg, PhD, is with the Center for Regenerative and Developmental Biology and Department of Biology at Tufts University. R. Thomas Zoeller, PhD, is with the Department of Biology at the University of Massachusetts in Amherst. J.P. Myers, PhD, works for Environmental Health Sciences in Charlottesville, Virginia. 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