New approach methodologies (NAM) to characterize neurotoxic chemicals for use in risk assessment: case study of four neurotoxic pesticides

Abstract

Neurotoxic pesticides: Cyfluthrin (CYF), βCYF, endosulfan (ENDO) and chlorpyrifos-oxon (CPFO) were examined using new approach methodologies (NAM) to assess ToxCast in vitro neurotoxic assay activities (50% concentration–AC₅₀s), chemical-target specificity (Z-Scores) and in vitro to in vivo extrapolation with ToxCast assay AC₅₀s as inputs to calculate human Administered Equivalent Dose (AED_Human mg/kg) through Integrated Chemical Environment (ICE) models. Fold differences (FD) between AED_Human NAM predictions and adjusted (animal to human interspecies extrapolation) in vivo regulatory neurotoxicity points of departure (POD) were calculated to assess modeled predictions against measured in vivo data. Interspecies (animal to human) in vivo adjusted PODs were 0.147 mg/kg/d (CYF/βCYF), 0.180 mg/kg/d (ENDO) and 0.106 mg/kg/d (CPFO). ToxCast neurotoxicity assay results supported in vivo observations: CYF, βCYF and CPFO showed depressed neuroactivity, while ENDO showed increased neuroactivity. βCYF is known to have twice the toxicity of CYF in vivo but was less toxic in the in vitro assays. Percent assays with Z-Scores greater than 3 for CYF, βCYF, ENDO and CPFO were 100%, 100%, 67% and 71% respectively. Most AED_Human were less than 10-FD indicating good predictivity of the in vivo adjusted PODs with ICE models. The NAMs were useful for characterizing the main neurotoxic activities and the ICE models were highly predictive of in vivo PODs to support mechanisms in risk assessment.

Keywords:

• New approach methodologies
• ToxCast
• integrated chemical environment
• neurotoxic pesticides

Acknowledgments

I want to thank Dr. Eric Kwok Department of Pesticide Regulation, California Environmental Protection Agency for technical support for this project and Dr. Poorni Iyer, PhD, DABT Office of Environmental Health Hazard Assessment, California Environmental Protection Agency for help reviewing this work.

Authors’ contributions

I am the sole author of this work.

Disclosure statement

The author declares that he has no actual or potential competing conflict of interests.