In 2010, the United States Environmental Protection Agency (US EPA) issued a request for proposals to evaluate the potential differential sensitivity between juvenile and adult rats exposed to pyrethroid insecticides.  A consortium of industry registrants organized with the objective of not only addressing the observations in rats, but also to determine the relevance of those findings to humans (i.e., are children more sensitive to pyrethroid toxicity than adults?). This consortium (i.e., the Council for the Advancement of Pyrethroid Human Risk Assessment; CAPHRA), working closely with experts across regulatory, industry, academic and contract research organizations, undertook a multi-year, multi-million dollar effort to design a research program to provide to the US EPA (and other regulatory agencies) the knowledge to reduce these uncertainties and suggest innovative methods for risk assessment for the entire class of pyrethroid insecticides. Novel toxicokinetic, toxicodynamic and metabolic ontogeny data were developed using in vivo, in vitro and in silico approaches.  Finally, a fully parameterized, life-stage PBPK model was developed for rats and humans that enabled the generation of human-relevant regulatory endpoints, which can be used to assess risk without the need for between-species uncertainty factors. The results of this work confirmed that the observed age-related sensitivity of rats to pyrethroids at high doses is due to differences in kinetics and that those differences are not manifest in humans. Based on these findings, the US EPA reduced the age-related uncertainty factor for pharmacokinetics for pyrethroids as a chemical class by 3-fold, representing a significant advancement in human health risk assessment methodology.  It also remains a definitive example of industry consortia working collaboratively to strengthen the scientific basis for animal to human extrapolation  thereby reducing the uncertainty associated with risk-based regulatory decisions. <br/>

Council for the Advancement of Pyrethroid Human Risk Assessment (CAPHRA): Broad collaboration and scientific innovation to reduce uncertainty in pyrethroid human risk assessment

ACS Fall 2020 Virtual Meeting

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