Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses

Endocrine Reviews - Tập 33 Số 3 - Trang 378-455 - 2012
Laura N. Vandenberg1, Theo Colborn2, Thomas R. Hayes3, Jerrold J. Heindel4, David R. Jacobs5, Duk‐Hee Lee6, Toshi Shioda7, Ana M. Soto8, Frederick S. vom Saal9, Wade V. Welshons10, R. Thomas Zoeller11, John Peterson Myers12
1Center for Regenerative and Developmental Biology and Department of Biology (L.N.V.), Tufts University, Medford, Massachusetts 02155;
2The Endocrine Disruption Exchange (T.C.), Paonia, Colorado 81428;
3Laboratory for Integrative Studies in Amphibian Biology (T.B.H.), Molecular Toxicology, Group in Endocrinology, Energy and Resources Group, Museum of Vertebrate Zoology, and Department of Integrative Biology, University of California, Berkeley, California 94720;
4Division of Extramural Research and Training (J.J.H.), National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services, Research Triangle Park, North Carolina 27709;
5Division of Epidemiology and Community Health (D.R.J.), School of Public Health, University of Minnesota, Minneapolis, Minnesota 55455;
6Department of Preventive Medicine (D.-H.L.), School of Medicine, Kyungpook National University, Daegu 702-701, Korea;
7Molecular Profiling Laboratory (T.S.), Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts 02129;
8Department of Anatomy and Cellular Biology (A.M.S.), Tufts University School of Medicine, Boston, Massachusetts 02111;
9Division of Biological Sciences (F.S.v.S.) University of Missouri-Columbia, Columbia, Missouri 65211;
10Department of Biomedical Sciences (W.V.W.), University of Missouri-Columbia, Columbia, Missouri 65211;
11Biology Department (T.Z.), University of Massachusetts-Amherst, Amherst, Massachusetts 01003
12Environmental Health Sciences (J.P.M.), Charlottesville, Virginia 22902

Tóm tắt

For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from the cell culture, animal, and epidemiology literature. We illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health.

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