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

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.