New NTP 5-day assay speeds toxicity screening of chemicals
NTP scientists evaluated a high-throughput transcriptomics approach using liver and kidney tissue from five-day assays in male rats to estimate the toxicological potency of chemicals. Toxicity and carcinogenicity are typically assessed by the resource intensive two-year cancer bioassay. In the five-day assays, the authors determined toxicological potency based on the most sensitive sets of genes active in liver and kidney. For most chemicals, the results approximated the toxicological potency derived from the most sensitive histopathological effects — independent of target tissue or organ — observed in male rats in long-term assays. Notably, these approximations were similar in female rats, as well as in male and female mice. The findings suggest that estimates of transcriptomics-based potency from short-term in vivo assays can, in the absence of other data, provide a rapid and effective estimate of toxicological potency.
Motivated by the need for alternative and more rapid and efficient assays, the authors used benchmark dose (BMD) analysis to compare toxicological potency between short- and long-term in vivo assays. Regulatory agencies such as the U.S. Environmental Protection Agency use the lower bound estimate of the BMD as the preferred metric for calculating chemical exposure levels that may pose minimal human risk. (AR)
Citation: Gwinn WM, Auerbach SS, Parham F, Stout MD, Waidyanatha S, Mutlu E, Collins B, Paules RS, Merrick BA, Ferguson S, Ramaiahgari S, Bucher JR, Sparrow B, Toy H, Gorospe J, Machesky N, Shah RR, Balik-Meisner MR, Mav D, Phadke DP, Roberts G, DeVito MJ. 2020. Evaluation of 5-day in vivo rat liver and kidney with high-throughput transcriptomics for estimating benchmark doses of apical outcomes. Toxicol Sci; doi: 10.1093/toxsci/kfaa081 [Online 3 June 2020].