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Identification of key characteristics of male reproductive toxicants as an approach for screening and sorting mechanistic evidence.
Citation:
Arzuaga, X., E. Yost, A. Hotchkiss, B. Beverly, AND C. Gibbons. Identification of key characteristics of male reproductive toxicants as an approach for screening and sorting mechanistic evidence. 4th International Symposium on Systematic Review and Meta-Analysis of Laboratory Animal Studies, Durham, North Carolina, August 23 - 25, 2017.
Impact/Purpose:
This abstract is for a platform presentation at the 2017 4th International Symposium on Systematic Review and Meta-Analysis of Laboratory Animal Studies. The meeting will be held August 24-25, 2017, in Durham, NC. Our objective in this analysis was to identify a set of key characteristics that could be applied for screening mechanistic evidence for male reproductive effects. Identification of seven key characteristics of male reproductive toxicants was based on a survey of established mechanisms/pathways of toxicity. As a proof of principle, we applied this set of key characteristics to organize experimental and mechanistic studies on a PCB mixture (Aroclor 1254). The proposed key characteristics provide a useful method for risk assessors in EPA regional and program offices to systematically and transparently organize and sort of mechanistic evidence as part of a mode of action analysis on non-cancer effects.
Description:
The application of systematic review practices in human health assessment includes integration of multi-disciplinary evidence from epidemiological, experimental, and mechanistic studies. Although mode of action analysis relies on the evaluation of mechanistic and toxicological outcomes, the process of organizing and analyzing studies and results can be challenging due to the diversity of research models, methods and endpoints, and the variety of known pathways for chemical-induced toxicity. The recently proposed Ten Key Characteristics of Carcinogens provide a useful approach for screening and sorting chemical-specific mechanistic data on carcinogenesis. Our objective was to identify a set of key characteristics that could be used for screening mechanistic evidence on chemical-induced adverse effects in the male reproductive system. Seven key characteristics were identified and include alterations in: 1) reproductive hormone levels/production, 2) hormone receptors, 3) germ/somatic cell functions, 4) cell signaling pathways, 5) epigenetic modifications, 6) DNA damage, and 7) reactive oxygen species production. These key characteristics are based on a survey and analysis of established mechanisms for recognized male reproductive toxicants. As a proof of principle, this set of key characteristics was used to organize mechanistic and experimental evidence on a PCB mixture (Aroclor 1254)-induced adverse outcomes in the male reproductive system. A database was developed to capture experimental design details and mechanistic outcomes identified in Aroclor 1254 studies. The resulting database can be used to organize and analyze the available mechanistic evidence. The proposed key characteristics of male reproductive toxicants provide a method that can facilitate the systematic screening and sorting of mechanistic evidence considered for mode of action analysis. Disclaimer: The views expressed are those of the authors and do not necessarily represent the views or policies of the US EPA.