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Proposed key characteristics of male reproductive toxicants as a method for organizing and screening mechanistic evidence for non-cancer outcomes.
Arzuaga, X., E. Yost, A. Hotchkiss, B. Beverly, AND C. Gibbons. Proposed key characteristics of male reproductive toxicants as a method for organizing and screening mechanistic evidence for non-cancer outcomes. Society for Risk Analysis, Arlington, VA, December 10 - 14, 2017.
Systematic review of animal toxicology literature will often reveal a wide range of health outcomes associated with exposure to a given chemical. This is particularly true for chemicals that are widely studied and have an exceptionally large number of studies available, such as polychlorinated biphenyls (PCBs). Risk assessors charged with evaluating such data-rich chemicals generally do not have the time and resources available to evaluate every potential health effect and related mechanisms/pathways. In such cases, it may be helpful to focus the systematic review on the outcomes identified as most relevant for protecting public health. Objectives: Develop sets of categories that can be used to organize and evaluate toxicological and mechanistic outcomes. - Toxicological categories and mechanistic key characteristics proposed here are aimed to facilitate the systematic organization and analysis of toxicological and mechanistic evidence relevant to adverse male reproductive outcomes. - A case study was performed by applying these key characteristics to the available evidence on Polychlorinated Biphenyls (PCBs)-induced male reproductive effects.
The adoption of systematic review practices for risk assessment includes integration of evidence obtained from experimental, epidemiological, and mechanistic studies. Although mechanistic evidence plays an important role in mode of action analysis, the process of sorting and analyzing mechanistic studies and outcomes is a challenging exercise due to the diversity of research models and methods, and the variety of known and proposed pathways for chemical-induced toxicity.The recently identified Ten Key Characteristics of Carcinogens provide a valuable tool for organizing chemical-specific data on potential mechanisms of carcinogenesis. However, such an approach has not yet been developed for non-cancer adverse outcomes. Our objective in this study was to identify a set of key characteristics that could be applied for screening mechanistic evidence formale reproductive effects. Identification of sevenkey characteristics of male reproductive toxicantswas 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 that evaluate the effects of the PCB mixture Aroclor 1254 on the male reproductive system. A database was developed to capture the available informationand experimental design details on Aroclor 1254 for each of the key characteristics of male reproductive toxicants. The proposed key characteristics provide a useful method that can facilitate the systematic and transparent organization of mechanistic evidence relevant to chemical-induced effects in the male reproductive system.