Cited by 3,209Effects and risks of endocrine disrupting chemicalsEstrogen and related hormone effectsToxic Organic Pollutants Impact

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

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Vandenberg, Laura N., Colborn, Theo, Hayes, Tyrone B., Heindel, Jerrold J., Jacobs, David R., Lee, Duk-Hee, Shioda, Toshi, Soto, Ana M., vom Saal, Frederick S., Welshons, Wade V., Zoeller, R. Thomas, Myers, John Peterson·2012·Endocrine Reviews

DOI 10.1210/er.2011-1050PMC PMC3365860

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Abstract

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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Authors: Vandenberg, L. N., Colborn, T., Hayes, T. B., Heindel, J. J., Jacobs, D. R., Lee, D.-H., Shioda, T., Soto, A. M., vom Saal, F. S., Welshons, W. V., Zoeller, R. T., & Myers, J. P.
Affiliations: Tufts University (US)
The Endocrine Disruption Exchange (T.C.), Paonia, Colorado 81428;
Museum of Vertebrate Zoology (US)
National Institutes of Health (US)
University of Minnesota (US)
Kyungpook National University (KR)
Massachusetts General Hospital (US)
Division of Biological Sciences (F.S.v.S.) University of Missouri-Columbia, Columbia, Missouri 65211;
University of Missouri (US)
University of Massachusetts Amherst (US)
Environmental Health Sciences (J.P.M.), Charlottesville, Virginia 22902
Corresponding author: Vandenberg, Laura N.
ORCID: Vandenberg, Laura N.
Heindel, Jerrold J.
Jacobs, David R.
Lee, Duk-Hee
Shioda, Toshi
Soto, Ana M.
Zoeller, R. Thomas
Myers, John Peterson
Venue: Endocrine Reviews
Publisher: The Endocrine Society
Published: 2012-03-14
Volume: 33
Issue: 3
Pages: 378-455
ISSN: 0163-769X (ISSN-L)
1945-7189
DOI: 10.1210/er.2011-1050
PMC: PMC3365860
OpenAlex: W2097327668
Cited by: 3,209
References: 858
Citations by year: 2026: 237 · 2025: 196 · 2024: 203 · 2023: 193 · 2022: 225 · 2021: 263 · 2020: 233 · 2019: 209 · 2018: 253 · 2017: 235 · 2016: 224 · 2015: 215 · 2014: 254 · 2013: 195 · 2012: 69
FWCI: 27.52
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Endocrine Reviews (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
ScholarWorks@UMassAmherst (University of Massachusetts Amherst) (submittedVersion)
Funders: National Heart, Lung, and Blood Institute (R56HL053560, HL 53560, R01HL053560)
National Institute of General Medical Sciences (F32GM087107, GM 087107)
National Institute of Environmental Health Sciences (ES08314, R01ES008314, ES010026, ES 018764, R56ES010026, R01ES010026, RC2ES018764)
Topics: Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
Keywords: endocrine disruptors, low-dose effects, non-monotonic dose-response, dose-response relationship, hormesis, chemical safety assessment, chemical testing
MeSH terms: Bisphenol A Compounds, Amphibians, Animals, Animals, Wild, Atrazine, Benzhydryl Compounds, Breast, Dioxins, Dose-Response Relationship, Drug, Environmental Exposure, Female, Herbicides, Humans, Male, Perchlorates, Phenols, Prostate, Spermatogenesis, Thyroid Gland, Twins, Sexual Development, Endocrine Disruptors

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