A Novel Method for the Development of Environmental Public Health Indicators and Benchmark Dose Estimation Using a Health-Based End Point for Chlorpyrifos

BACKGROUND: Organophosphorus (OP) compounds are the most widely used group of insecticides in the world. Risk assessments for these chemicals have focused primarily on 10% inhibition of acetylcholinesterase in the brain as the critical metric of effect. Aside from cholinergic effects resulting from acute exposure, many studies suggest a linkage between cognitive deficits and long-term OP exposure. OBJECTIVE: In this proof-of-concept study, we focused on one of the most widely used OP insecticides in the world, chlorpyrifos (CPF), and utilized an existing physiologically based pharmacokinetic (PBPK) model and a novel pharmacodynamic (PD) dose–response model to develop a point of departure benchmark dose estimate for cognitive deficits following long-term, low-dose exposure to this chemical in rodents. METHODS: Utilizing a validated PBPK/PD model for CPF, we generated a database of predicted biomarkers of exposure and internal dose metrics in both rat and human. Using simulated peak brain CPF concentrations, we developed a dose–response model to predict CPF-induced spatial memory deficits and correlated these changes to relevant biomarkers of exposure to derive a benchmark dose specific to neurobehavioral changes. We extended these cognitive deficit predictions to humans and simulated corresponding exposures using a model parameterized for humans. RESULTS: Results from this study indicate that the human-equivalent benchmark dose (BMD) based on a 15% cognitive deficit as an end point is lower than that using the present threshold for 10% brain AChE inhibition. This predicted human-equivalent subchronic BMD threshold compares to occupational exposure levels determined from biomarkers of exposure and corresponds to similar exposure conditions where deficits in cognition are observed. CONCLUSIONS: Quantitative PD models based on neurobehavioral testing in animals offer an important addition to the methodologies used for establishing useful environmental public health indicators and BMDs, and predictions from such models could help inform the human health risk assessment for chlorpyrifos. https://doi.org/10.1289/EHP1743