Utilizing High-Throughput Screening Data, Integrative Toxicological Prioritization Index Score, and Exposure-Activity Ratios for Chemical Prioritization: A Case Study of Endocrine-Active Pesticides in Food Crops.

Abstract

Endocrine-active chemicals can directly act on nuclear receptors and trigger the disturbances of metabolism and a homeostatic system, which are important risk factors for complicating chronic diseases in humans. The endocrine-active potentials of pesticides acting on estrogen, androgen, and thyroid hormone receptors have been extensively evaluated for pesticides; however, the effects on other receptors are less understood. This study aims to comprehensively characterize and prioritize the endocrine-active pesticides using an exposure-activity ratio (EAR) method and toxicological prioritization index (ToxPi). The aggregate exposure assessment of pesticides was performed using a computational exposure model [stochastic human exposure and dose simulation high-throughput model (SHEDS-HT)]. Minimum in vitro point of departure values were converted to human oral equivalent doses via in vitro-to-in vivo extrapolation. The overall endocrine-disrupting potentials of pesticides were evaluated via 76 assays, representing 11 nuclear receptors. EARs and ToxPi scores were then derived to prioritize 79 pesticides in food. This case study demonstrates that EAR profiling can inform the regulatory agencies for a relevant chemical prioritization, which would direct in-depth health risk assessments in the future.