Oral toxicokinetics of the indoor air pollutant, α-pinene, and its genotoxic metabolite, α-pinene oxide, in rodents and comparison to inhalation route of exposure

Abstract

α-Pinene is a monoterpene with potential human exposure via oral and inhalation routes and has been associated with bladder hyperplasia and decrease in sperm counts in rodents following inhalation exposure. The toxicokinetics of α-pinene and α-pinene oxide was investigated following 7-day oral administration of α-pinene in rats (10, 50, and 150 mg/kg) and mice (50 mg/kg). α-Pinene was absorbed following oral administration. In rats, α-pinene systemic exposure (maximum concentration (Cmax) and area the under the concentration versus time curve (AUC)) increased less than dose-proportionally, except for Cmax in females, which increased proportionally with dose. While no sex difference was apparent at 10 mg/kg, female rats exhibited 2- to 3-fold higher exposure than males at 150 mg/kg. Oral bioavailability in rats was moderate at 10 mg/kg and higher in females (49%) than in males (32.7%)-bioavailability decreased at 150 mg/kg (females, 22.4%; males 4.89%). In mice, bioavailability was lower and similar between sexes (female, 18.5%; male, 19.8%). In both species, α-pinene was metabolized to α-pinene oxide. In rats, α-pinene oxide systemic exposure was similar to α-pinene, in contrast to inhalation exposure where α-pinene oxide concentration was lower than α-pinene. In mice, α-pinene oxide exposure was lower than that of α-pinene following oral administration. No apparent sex difference in α-pinene oxide systemic exposure were observed in either species. Both α-pinene and α-pinene oxide were distributed to mammary tissues. These findings will allow extrapolation of inhalation toxicology data to oral exposures and subsequent assessment of potential adverse human health impact to α-pinene exposure.