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Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses
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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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“Our data show that, as is often the case for hormonal diseases, most observed effects in this study were not proportional to the dose of the treatment (GM maize with and without R application; R alone), non-monotonic and with a threshold effect (Vandenberg et al., 2012).”
From RETRACTED: Long term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize (2012) · cites this paper as Vandenberg et al., 2012
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“Similar degrees of pathological symptoms occurred from the lowest to the highest doses, suggesting a threshold effect [36].”
From Republished study: long-term toxicity of a Roundup herbicide and a Roundup-tolerantgenetically modified maize (2014) · cites this paper as [36]
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Metadata
- 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
- 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
- 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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