A Pharmacokinetic Model of cis- and trans-Permethrin Disposition in Rats and Humans With Aggregate Exposure Application

Abstract

Permethrin is a broad-spectrum pyrethroid insecticide and among the most widely used insecticides in homes and crops. Managing the risks for pesticides such as permethrin depends on the ability to consider diverse exposure scenarios and their relative risks. Physiologically based pharmacokinetic models of delta methrin disposition were modified to describe permethrin kinetics in the rat and human. Unlike formulated deltamethrin which consists of a single stereoisomer, permethrin is formulated as a blend of cis- and trans-diastereomers. We assessed time courses for cis-permethrin and trans-permethrin in several tissues (brain, blood, liver, and fat) in the rat following oral administration of 1 and 10mg/kg permethrin (cis/trans: 40/60). Accurate simulation of permethrin in the rat suggests that a generic model structure is promising for modeling pyrethroids. Human in vitro data and appropriate anatomical information were used to develop a provisional model of permethrin disposition with structures for managing oral, dermal, and inhalation routes of exposure. The human permethrin model was used to evaluate dietary and residential exposures in the U.S. population as estimated by EPA's Stochastic Human Exposure and Dose Simulation model. Simulated cis- and trans-DCCA, metabolites of permethrin, were consistent with measured values in the National Health and Nutrition Examination Survey, indicating that the model holds promise for assessing population exposures and quantifying dose metrics.

Tissue time course and bioavailability of the pyrethroid insecticide bifenthrin in the Long-Evans rat

“…The mammalian disposition of several type-I and type-II pyrethroids such as permethrin (Anadón et al, 1991;Tornero-Velez et al, 2012) and deltamethrin (Anadón et al, 1996;Godin et al, 2010;Kim et al, 2008), respectively, have been studied. However, information regarding the disposition of many other pyrethroids that are also in use today, such as bifenthrin, are not well characterized.…”

“…Bifenthrin kinetics in the rat have many similarities with pyrethroids such as deltamethrin (Anadón et al, 1996;Godin et al, 2010;Kim et al, 2008), permethrin (Anadón et al, 1991;Tornero-Velez et al, 2012) and l-cyhalothrin (Anadón et al, 2006) after oral administration. The similarities are prompt absorption into the systemic circulation and clearance from it.…”

“…For both experiments, rats were administered bifenthrin at a dose of 0.3 or 3 mg/kg in corn oil (1 mL/kg) by oral (po) gavage. Our group has used corn oil as a vehicle for the oral administration of pyrethroids in several studies (Godin et al, 2010;Tornero-Velez et al, 2012;Wolansky et al, 2006Wolansky et al, , 2007. The high dose of bifenthrin is equivalent to an oral dose that decreases motor activity in a rat by 30% (Wolansky et al, 2006).…”

“…Pyrethroids studied in rats include deltamethrin (Anadón et al, 1996;Godin et al, 2010;Gray & Rickard, 1982a;Kim et al, 2008;Mirfazaelian et al, 2006;Ruzo et al, 1978), permethrin (Anadón et al, 1991;Gaughan et al, 1977;Tornero-Velez et al, 2012), l-cyhalothrin (Anadón et al, 2006) and more recently bifenthrin (Gammon et al, 2014). Oral bioavailability of pyrethroids ranges from 25% for deltamethrin (Godin et al, 2010) to 71% for l-cyhalothrin (Anadón et al, 2006).…”

“…Our laboratory and collaborators used this rat strain in several neurotoxicology and disposition studies (Crofton et al, 1995;Godin et al, 2010;Scollon et al, 2011;Tornero-Velez et al, 2012;Wolansky et al, 2006Wolansky et al, , 2007. We administered bifenthrin by oral gavage at two dose levels and studied the tissue disposition of parent compound out to 21 days.…”