Lettert Hormesis controversy Regarding the debate over hormesis (Environ. Sci. Technol. 2006, 40, 6525–6526), my colleagues and I have published a series of research and review articles that address the mechanisms by which estrogenic endocrine-disrupting chemicals first stimulate and then inhibit responses as you move from very low doses, within a physiological range of hormonal activity, to very high doses, within a toxicological range of activity (Environ. Health Perspect. 2003, 111, 994–1006; Endocrinology 2006, 147, S56–S69). To an endocrinologist, the argument made by some toxicologists that dose–response curves are always monotonic (a central assumption in chemical risk assessments) is equivalent to arguing with an astronaut that the earth is flat. At high toxicological doses, hormones such as estradiol down-regulate their receptors and begin to bind to other members of the nuclear receptor superfamily. The consequence is that estradiol- and estrogen-mimicking chemicals stimulate and inhibit entirely different sets of genes (and thus cause qualitatively different effects) as doses increase from the physiological to toxicological range. When fetuses or babies are exposed to low doses of estrogenic chemicals that were previously thought to be below the no-effect dose during critical periods in cell differentiation, genetic imprinting occurs, which results in permanent changes in cell function and is implicated in adverse consequences,
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including cancer. These facts are taught to students in an introductory endocrinology course. For hormonemimicking chemicals, nonmonotonic dose–response relationships are thus expected for many responses. However, the undisputable fact that for hormones and hormonemimicking chemicals, nonmonotonic dose–response curves are common needs to be viewed as entirely separate from the hypothesis that disruption of development due to exposure to low doses of endocrine-disrupting chemicals is beneficial. The issue of the benefits associated with exposure to low doses of chemicals was addressed recently in a review (Hum. Exp. Toxicol. 2005, 24, 431–437) in which studies with endocrine-disrupting chemicals showed that disruption of normal development by exposure to very low doses of endocrine-disrupting chemicals resulted in adverse effects. The view expressed by Ed Calabrese concerning the potential for beneficial effects as a result of exposure to a low dose of chemicals such as dioxin (Nature 2003, 421, 691–692) is alarming and is contradicted by a large literature from the field of endocrine disruption. Unlike the field of endocrine disruption, hormesis is not a mechanistically driven field. This makes it easier to ignore than endocrinedisruption research where the molecular mechanisms mediating responses to very low doses of chemicals are identified. The hormesis issue was previously ignored by toxicologists conducting stud-
ies of chemicals for regulatory purposes, because they did not study low doses. The field of hormesis and the issue of nonmonotonic dose–response curves thus remained off of the radar screen until the chemical industry was spurred to action by studies showing adverse effects of endocrine-disrupting chemicals at very low doses (within the range of human exposure). Chemical corporations and trade associations became interested in this issue because in the endocrinedisrupter field, the great majority of studies now focus on the effects of environmentally relevant low doses of chemicals. This represents a radical paradigm shift and contrasts with the traditional approach in toxicology of examining only high doses to predict rather than directly test effects at lower doses within the range of human exposure; that approach allowed chemical corporations and regulatory agencies to assure the public that doses of chemicals that had never been directly tested were “safe”. The chemical industry is now joining Calabrese in promoting the idea that low doses of environmental chemicals are not only safe but, in fact, good for you. However, it is not logical to predict that disruption by chemicals of normal fetal development is desirable— not in my child, thank you! FREDERICK S. VOM SAAL Division of Biological Sciences University of Missouri
[email protected] JANUARY 1, 2007 / Environmental Science & Technology n
