Pii: S0045-6535(97)00108-2

This study entails a pharnutcokinetic analysis of the relationship between the external dose of 2,3,7,8tetrachlorodibenzo-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 pharmaeokinetic models for several rodent species and humans. The results indicate that the relationship between the external dose of TCDD and resulting TCDD concmltnttions in 5vef 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). © 1997 Elsevier Science Ltd In human health and ecological risk assessments of environmental contaminants it is common practice to extrapolate toxicological responses observed in animal bioassays to those in humans (Albert, 1989; Fishbein, 1986; Gaylor et al,, 1993). In most cases concerned with contaminants at environmental concentrations, this extrapolation involves (i) an interspeeies extrapolation, where the effects observed in test organisms are extrapolated to humans or other organisms, and (ii) a high-to-low-dose extrapolation, where the effects observed at high "experimental" doses are extrapolated to the low "environmentad" doses to which humans and organisms are typically exposed. The interspecies extrapolation is often performed by scaling the dose administered to the test organism to body weight, resulting in what we will refer to as an "external dose", typically expressed in units of milligrams of chemical per kilogram of organism body weight per day. If the chemical is recognized as a