A pharmacokinetic analysis of interspecies extrapolation in dioxin risk assessment

This study entails a pharmacoldnetic analysis of the relationship between the external dose of 2,3,7,8-tetrachlorodibenzo- p-dioxin (dioxin, TCDD) and resulting concentrations of TCDD in internal tissues and organs of humans and rodent species. The methodology is based on the development and testing of physiologically based pharmacokinetic models for several rodent species and humans. The results indicate that the relationship between the external dose of TCDD and resulting TCDD concentrations in liver and adipose tissue of humans and various species of rats and mice can vary by as much as 725 fold, illustrating that humans and experimental animals differ considerably in their ability to convert external dosages of dioxin to tissue concentrations. Interspecies scaling factors are reported to express the differences in tissue concentrations of dioxin between mice, rats and humans in response to an equivalent external dose. The significance of these findings for conducting human cancer and ecological risk assessments is discussed. It is recommended that pharmacokinetic differences be considered explicitly in risk estimation, while separately recognizing interspecies differences in pharmacodynamics (sensitivity).