A Case Study on the Application of an Expert-driven Read-across Approach in Support of Quantitative Risk Assessment of P,p'-dichlorodiphenyldichloroethane

Deriving human health risk estimates for environmental chemicals has traditionally relied on in vivo toxicity databases to characterize potential adverse health effects and associated dose-response relationships. In the absence of in vivo toxicity information, new approach methods (NAMs) such as read-across have the potential to fill the required data gaps. This case study applied an expert-driven read-across approach to identify and evaluate analogues to fill non-cancer oral toxicity data gaps for p,p'-dichlorodiphenyldichloroethane (p,p'-DDD), an organochlorine contaminant known to occur at contaminated sites in the U.S. The source analogue p,p'-dichlorodiphenyltrichloroethane (DDT) and its no-observed-adverse-effect level of 0.05 mg/kg-day were proposed for the derivation of screening-level health reference values for the target chemical, p,p'-DDD. Among the primary similarity contexts (structure, toxicokinetics, and toxicodynamics), toxicokinetic considerations were instrumental in separating p,p'-DDT as the best source analogue from other potential candidates (p,p'-DDE and methoxychlor). In vitro high-throughput screening (HTS) assays from ToxCast were used to evaluate similarity in bioactivity profiles and make inferences toward plausible mechanisms of toxicity to build confidence in the read-across approach. This work demonstrated the value of NAMs such as read-across and in vitro HTS in human health risk assessment of environmental contaminants with the potential to inform regulatory decision-making.