Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification

Michele A La Merrill¹, Laura N Vandenberg², Martyn T Smith³, William Goodson⁴, Patience Browne⁵, Heather B Patisaul⁶, Kathryn Z Guyton⁷, Andreas Kortenkamp⁸, Vincent J Cogliano⁹, Tracey J Woodruff¹⁰, Linda Rieswijk^{3

11}, Hideko Sone¹², Kenneth S Korach¹³, Andrea C Gore¹⁴, Lauren Zeise¹⁵, R Thomas Zoeller¹⁶

Affiliations

¹ Department of Environmental Toxicology, University of California, Davis, CA, USA. mlamerrill@ucdavis.edu.
² Department of Environmental Health Science, School of Public Health and Health Sciences, University of Masschusetts, Amherst, MA, USA.
³ School of Public Health, University of California, Berkeley, CA, USA.
⁴ California Pacific Medical Center Research Institute, Sutter Hospital, San Francisco, CA, USA.
⁵ Environmental Directorate, Organisation for Economic Co-operation and Development, Paris, France.
⁶ Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
⁷ International Agency for Research on Cancer, World Health Organization, Lyon, France.
⁸ Department of Life Sciences, Brunel University, London, UK.
⁹ Office of the Science Advisor, United States Environmental Protection Agency, Washington, DC, USA.
¹⁰ Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA.
¹¹ Institute of Data Science, Maastricht University, Maastricht, Netherlands.
¹² Center for Health and Environmental Risk Research, National Institute for Environmental Studies, Ibaraki, Japan.
¹³ Receptor Biology, Section Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Science, Durham, NC, USA.
¹⁴ Division of Pharmacology and Toxicology, University of Texas at Austin, Austin, TX, USA.
¹⁵ Office of the Director, Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency, Sacramento, CA, USA.
¹⁶ Biology Department, University of Masschusetts, Amherst, MA, USA.

PMID: 31719706
PMCID: PMC6902641
DOI: 10.1038/s41574-019-0273-8

Review

Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification

Michele A La Merrill et al. Nat Rev Endocrinol. 2020 Jan.

. 2020 Jan;16(1):45-57.

doi: 10.1038/s41574-019-0273-8. Epub 2019 Nov 12.

Authors

Affiliations

¹ Department of Environmental Toxicology, University of California, Davis, CA, USA. mlamerrill@ucdavis.edu.
² Department of Environmental Health Science, School of Public Health and Health Sciences, University of Masschusetts, Amherst, MA, USA.
³ School of Public Health, University of California, Berkeley, CA, USA.
⁴ California Pacific Medical Center Research Institute, Sutter Hospital, San Francisco, CA, USA.
⁵ Environmental Directorate, Organisation for Economic Co-operation and Development, Paris, France.
⁶ Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
⁷ International Agency for Research on Cancer, World Health Organization, Lyon, France.
⁸ Department of Life Sciences, Brunel University, London, UK.
⁹ Office of the Science Advisor, United States Environmental Protection Agency, Washington, DC, USA.
¹⁰ Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA.
¹¹ Institute of Data Science, Maastricht University, Maastricht, Netherlands.
¹² Center for Health and Environmental Risk Research, National Institute for Environmental Studies, Ibaraki, Japan.
¹³ Receptor Biology, Section Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Science, Durham, NC, USA.
¹⁴ Division of Pharmacology and Toxicology, University of Texas at Austin, Austin, TX, USA.
¹⁵ Office of the Director, Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency, Sacramento, CA, USA.
¹⁶ Biology Department, University of Masschusetts, Amherst, MA, USA.

PMID: 31719706
PMCID: PMC6902641
DOI: 10.1038/s41574-019-0273-8

Abstract

Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that interfere with hormone action, thereby increasing the risk of adverse health outcomes, including cancer, reproductive impairment, cognitive deficits and obesity. A complex literature of mechanistic studies provides evidence on the hazards of EDC exposure, yet there is no widely accepted systematic method to integrate these data to help identify EDC hazards. Inspired by work to improve hazard identification of carcinogens using key characteristics (KCs), we have developed ten KCs of EDCs based on our knowledge of hormone actions and EDC effects. In this Expert Consensus Statement, we describe the logic by which these KCs are identified and the assays that could be used to assess several of these KCs. We reflect on how these ten KCs can be used to identify, organize and utilize mechanistic data when evaluating chemicals as EDCs, and we use diethylstilbestrol, bisphenol A and perchlorate as examples to illustrate this approach.

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Conflict of interest statement

M.T.S. has served as a consultant and expert witness in US litigation involving chemical and pharmaceutical exposures and various disease outcomes, including neuropathies and cancer. All other authors declare no competing interests.

Figures

**Fig. 1. The key characteristics of endocrine-disrupting chemicals.**
Arrows identify the ten specific key characteristics (KCs) of endocrine-disrupting chemicals (EDCs). The ± symbol indicates that an EDC can increase or decrease processes and effects. KC1 states that an EDC can interact with or activate hormone receptors. KC2 states that an EDC can antagonize hormone receptors. KC3 states that an EDC can alter hormone receptor expression. KC4 states that an EDC can alter signal transduction (including changes in protein or RNA expression, post-translational modifications and/or ion flux) in hormone-responsive cells. KC5 states that an EDC can induce epigenetic modifications in hormone-producing or hormone-responsive cells. KC6 states that an EDC can alter hormone synthesis. KC7 states that an EDC can alter hormone transport across cell membranes. KC8 states that an EDC can alter hormone distribution or circulating hormone levels. KC9 states that an EDC can alter hormone metabolism or clearance. KC10 states that an EDC can alter the fate of hormone-producing or hormone-responsive cells. Depicted EDC actions include amplification and attenuation of effects. Ac, acetyl group; Me, methyl group.

See this image and copyright information in PMC

References

1. Jameson, J. L. Endocrinology: Adult & Pediatric 7th edn (Elsevier Saunders, 2016).
1. Axelstad M, et al. EDC IMPACT: reduced sperm counts in rats exposed to human relevant mixtures of endocrine disrupters. Endocr. Connect. 2018;7:139–148. - PMC - PubMed
1. Johansson HKL, Svingen T, Fowler PA, Vinggaard AM, Boberg J. Environmental influences on ovarian dysgenesis — developmental windows sensitive to chemical exposures. Nat. Rev. Endocrinol. 2017;13:400–414. - PubMed
1. Skakkebaek NE. A brief review of the link between environment and male reproductive health: lessons from studies of testicular germ cell cancer. Horm. Res. Paediatr. 2016;86:240–246. - PubMed
1. Amano I, et al. Effects of mild perinatal hypothyroidism on cognitive function of adult male offspring. Endocrinology. 2018;159:1910–1921. - PubMed

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Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification

Affiliations

Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

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