TY - JOUR
T1 - Proposed Key Characteristics of Female Reproductive Toxicants as an Approach for Organizing and Evaluating Mechanistic Data in Hazard Assessment
AU - Luderer, Ulrike
AU - Eskenazi, Brenda
AU - Hauser, Russ
AU - Korach, Kenneth S
AU - McHale, Cliona M
AU - Moran, Francisco
AU - Rieswijk, Linda
AU - Solomon, Gina
AU - Udagawa, Osamu
AU - Zhang, Luoping
AU - Zlatnik, Marya
AU - Zeise, Lauren
AU - Smith, Martyn T
N1 - Funding Information:
Here we argue that predicting the potential for human hazard from in vitro assays would be aided by an understanding of the key characteristics of chemicals that induce female reproductive toxicity. Previously, Smith et al. (2016) identified 10 key characteristics of human carcinogens. This framework has been utilized by the International Agency for Research on Cancer (IARC) in their Monographs Program as described by Guyton et al. (2018). The key characteristics of carcinogens create a uniform approach for searching, organizing, and evaluating mechanistic evidence to support carcinogenic hazard identification. A 2017 National Academy of Sciences report recommended that the key characteristics approach be expanded to other end points, including reproductive effects, endocrine disruption, and cardiovascular disease (National Academies of Science, Engineering, and Medicine 2017).
Funding Information:
Address correspondence to Ulrike Luderer, Center for Occupational and Environmental Health, 100 Theory Dr., Suite 100, Irvine, CA 92617 USA. Telephone: (949) 824-8641. Email: [email protected] This article represents the views of the authors and does not constitute or imply endorsement, recommendation, or favoring of these views by the State of California Environmental Protection Agency, Office of Environmental Health Hazard Assessment; the Agency for Toxic Substances and Disease Registry, U.S. Environmental Protection Agency or the National Institute of Environmental Health Sciences.
Funding Information:
This project was supported by contract 17-E0023 from the California EPA and by the Research Translation Core of the NIEHS Superfund Research Center at University of California, Berkeley under National Institutes of Health (NIH) grant P42ES004705. The authors acknowledge funding from the NIH/NIEHS (R01ES020454 to U.L.; P42ES004705 to M.T.S.; P30ES000002 to R.H.; P01ES022841 to M.Z.); California OEHHA (17-E0023 to M.T.S. and L.Z.); U.S. EPA (RD83543301 to M.Z.). In addition, U.L. and M.Z. acknowledge support from the Region 9 Pediatric Environmental Health Specialty Unit funded by Agency for Toxic Substances and Disease Registry (ATSDR) cooperative agreement award 1 U61TS000237-01 and U.S. EPA inter-agency agreement DW-75-95877701 to ATSDR.
Publisher Copyright:
© 2019, Public Health Services, US Dept of Health and Human Services. All rights reserved.
PY - 2019/7
Y1 - 2019/7
N2 - BACKGROUND: Identification of female reproductive toxicants is currently based largely on integrated epidemiological and in vivo toxicology data and, to a lesser degree, on mechanistic data. A uniform approach to systematically search, organize, integrate, and evaluate mechanistic evidence of female reproductive toxicity from various data types is lacking.OBJECTIVE: We sought to apply a key characteristics approach similar to that pioneered for carcinogen hazard identification to female reproductive toxicant hazard identification.METHODS: A working group of international experts was convened to discuss mechanisms associated with chemical-induced female reproductive toxicity and identified 10 key characteristics of chemicals that cause female reproductive toxicity: 1) alters hormone receptor signaling; alters reproductive hormone production, secretion, or metabolism; 2) chemical or metabolite is genotoxic; 3) induces epigenetic alterations; 4) causes mitochondrial dysfunction; 5) induces oxidative stress; 6) alters immune function; 7) alters cell signal transduction; 8) alters direct cell-cell interactions; 9) alters survival, proliferation, cell death, or metabolic pathways: and 10) alters microtubules and associated structures. As proof of principle, cyclophosphamide and diethylstilbestrol (DES), for which both human and animal studies have demonstrated female reproductive toxicity, display at least 5 and 3 key characteristics, respectively. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), for which the epidemiological evidence is mixed, exhibits 5 key characteristics.DISCUSSION: Future efforts should focus on evaluating the proposed key characteristics against additional known and suspected female reproductive toxicants. Chemicals that exhibit one or more of the key characteristics could be prioritized for additional evaluation and testing. A key characteristics approach has the potential to integrate with pathway-based toxicity testing to improve prediction of female reproductive toxicity in chemicals and potentially prevent some toxicants from entering common use.
AB - BACKGROUND: Identification of female reproductive toxicants is currently based largely on integrated epidemiological and in vivo toxicology data and, to a lesser degree, on mechanistic data. A uniform approach to systematically search, organize, integrate, and evaluate mechanistic evidence of female reproductive toxicity from various data types is lacking.OBJECTIVE: We sought to apply a key characteristics approach similar to that pioneered for carcinogen hazard identification to female reproductive toxicant hazard identification.METHODS: A working group of international experts was convened to discuss mechanisms associated with chemical-induced female reproductive toxicity and identified 10 key characteristics of chemicals that cause female reproductive toxicity: 1) alters hormone receptor signaling; alters reproductive hormone production, secretion, or metabolism; 2) chemical or metabolite is genotoxic; 3) induces epigenetic alterations; 4) causes mitochondrial dysfunction; 5) induces oxidative stress; 6) alters immune function; 7) alters cell signal transduction; 8) alters direct cell-cell interactions; 9) alters survival, proliferation, cell death, or metabolic pathways: and 10) alters microtubules and associated structures. As proof of principle, cyclophosphamide and diethylstilbestrol (DES), for which both human and animal studies have demonstrated female reproductive toxicity, display at least 5 and 3 key characteristics, respectively. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), for which the epidemiological evidence is mixed, exhibits 5 key characteristics.DISCUSSION: Future efforts should focus on evaluating the proposed key characteristics against additional known and suspected female reproductive toxicants. Chemicals that exhibit one or more of the key characteristics could be prioritized for additional evaluation and testing. A key characteristics approach has the potential to integrate with pathway-based toxicity testing to improve prediction of female reproductive toxicity in chemicals and potentially prevent some toxicants from entering common use.
KW - 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN TCDD
KW - BISPHENOL-A EXPOSURE
KW - ENDOCRINE DISRUPTORS
KW - ESTROGEN-RECEPTOR-ALPHA
KW - GAP-JUNCTION PROTEINS
KW - GRANULOSA-CELLS
KW - IN-UTERO
KW - OOCYTE CUMULUS COMPLEX
KW - OXIDATIVE STRESS
KW - SERUM DIOXIN CONCENTRATIONS
U2 - 10.1289/EHP4971
DO - 10.1289/EHP4971
M3 - Article
C2 - 31322437
SN - 0091-6765
VL - 127
JO - Environmental Health Perspectives
JF - Environmental Health Perspectives
IS - 7
M1 - 075001
ER -