Use of computational toxicology models to predict toxicological points of departure: A case study with triazine herbicides.

Abstract

Atrazine simazine and propazine, widely used triazine herbicides on food crops and in residential areas, disrupt the neuroendocrine system raising human health concerns. USEPA developed a PBPK model based on triazine common Mode of Action (MOA)-suppression of luteinizing hormone surge in female rats-to generate human regulatory points of departure (POD: mg/kg/day). We compared triazine Human Administered Equivalent Dose (AEDHuman mg/kg/day) predictions from open access computational tools to the PBPK PODs to assess concordance. Computational tools were the following: ToxCast/Tox21 in vitro assays; Toxicogenomic databases to assess concordance with ToxCast/Tox21 targets; integrated chemical environment (ICE) models with ToxCast/Tox21 inputs to predict AEDHuman PODs and population-based age-refined high throughput toxicokinetics (HTTK-Pop) to compare to age-related PBPK PODs. ToxCast/Tox21 assays identified critical targets in the triazine common MOA and gene databases; ICE AEDHuman predictions were mainly concordant with the USEPA PBPK PODs quantitatively. Low fold-differences between PBPK POD and ICE AEDHuman predictions indicated that the ICE models are health-protective. HTTK-Pop age-refinements were within 10-fold of the USEPA PBPK PODs. CompTox tools were used to identify assay targets in the MOA and identify potential molecular initiating targets in the adverse outcome pathway for potential use in risk assessment.