Impact/Purpose:

Pyrethroids are a family of pesticides that are neurotoxicants and are one of the most common pesticides used in indoor environments. Under the Food Quality Protection Act, EPA is required to consider cumulative risks from pesticides and other substances acting by a common mode of action. Cumulative risk assessments examine mixtures of chemicals and their exposure by multiple routes. Pyrethroids fall into this category because they induce toxicity through a common mode of action by interacting with sodium channels in the nervous system, they are commonly found as a mixture, and routes of exposure include oral (diet, hand-to-mouth),dermal, and inhalation. As part of a multi-disciplinary team members of NHEERL will be developing exposure dose response models to estimate the potential cumulative risk to pyrethroid pesticides.

Description:

This project is part of a multi-laboratory and center study whose goal is to develop a cumulative risk assessment for pyrethroid pesticides. NHEERL's role is to understand the relationship between exposure, dose and response for individual pyrethroids and mixtures of these chemicals in rats. This will be done by a combination of in vitro metabolism studies and PBPK modeling, followed by in vivo pharmacokinetic studies. This is an initial attempt to develop and test predictive pharmacokinetic methods in order to develop high throughput methods that would decrease the costs and the number of animals used in testing environmental chemicals. Initial attempts will examine the use of in vitro data to parameterize PBPK models for select pyrethroids and then test these models using limited in vivo studies. Extrapolation of these results to humans will be facilitated by comparing in vitro metabolism studies in animal and human tissues, cultured cells or subcellular fractions and incorporate metabolic parameters into the PBPK model. Development of the PBPK model will be done in collaboration with the National Exposure Research Laboratory (NERL). The pharmacokinetic and neurotoxicity data and PBPK models will then be used by researchers in the National Center for Exposure Assessment and Office of Pesticides Program to develop a cumulative risk assessment for the pyrethroids. The data and model developed in this collaborative effort will be used by the Office of Pesticide Program to make more informed decisions on managing the potential cumulative risks associated with exposures to pyrethroid pesticides.

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