Use of high throughput screening data in IARC monograph evaluations

Weihsueh CHIU, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, United States
GUYTON K. 1 , MARTIN M. 2 , REIF D. 3 , RUSYN I. 4

1 Monographs Section, International Agency for Research on Cancer, Lyon, France
2 Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA
3 Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
4 Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA

Purpose: Evaluation of carcinogenic mechanisms serves a critical role in IARC monograph evaluations, and can lead to “upgrade” or “downgrade” of the carcinogenicity conclusions based on human and animal evidence alone.  Three recent IARC monograph Working Groups (110, 112, and 113) pioneered analysis of high throughput in vitro screening data from the U.S. Environmental Protection Agency’s ToxCast program in evaluations of carcinogenic mechanisms. 
Methods: For monograph 110, ToxCast assay data across multiple nuclear receptors were used to test the hypothesis that PFOA acts exclusively through the PPAR family of receptors, with activity profiles compared to several prototypical nuclear receptor-activating compounds.  For monographs 112 and 113, ToxCast assays were systematically evaluated and used as an additional data stream in the overall evaluation of the mechanistic evidence.  Specifically, ToxCast assays were mapped to 10 “key characteristics of carcinogens” recently identified by an IARC expert group, and chemicals' bioactivity profiles were evaluated both in absolute terms (number of relevant assays positive for bioactivity) and relative terms (ranking with respect to other compounds evaluated by IARC, using the ToxPi methodology). 
Results: PFOA activates multiple nuclear receptors in addition to the PPAR family in the ToxCast assays.  ToxCast assays offered substantial coverage for 5 of the 10 “key characteristics,” with the greatest coverage for modulation of receptor-mediated effects.  The patterns of bioactivity observed in ToxCast assays provided additional support to Working Group evaluations of the mechanistic evidence.
Conclusions: High throughput in vitro screening data such as those from ToxCast provide a useful resource for evaluating both specific mechanistic hypotheses as well as the overall strength of the mechanistic evidence.  However, ToxCast is limited or absent in its coverage of 5 of the 10 key characteristics of carcinogens that form the framework for current IARC mechanistic evaluations.
Funding source: None