Magnitude and mechanistic determinants of the interspecies toxicokinetic uncertainty factor for organic chemicals.
The interspecies uncertainty factor, UF(AH), of 10 was recently subdivided into two components to account separately for interspecies differences in toxicokinetics and toxicodynamics (UF(AH-TK)=3.16, UF(AH-TD)=3.16). Even though the UF(AH) in its composite or dissociated form is used during the health risk assessment of systemic toxicants, there is no convincing scientific basis to justify the use of the same UF for all chemicals. In this study, we use equations that describe the toxicokinetics of chemicals at steady-state to characterize the magnitude and mechanistic determinants of UF(AH-TK) for several volatile organic chemicals (VOCs). Further, algorithms have been developed to determine the magnitude of the components of UF(AH-TK), namely the UF(AH-TK-ABS) (accounting for interspecies differences in dose absorbed during identical inhalation exposure conditions), UF(AH-TK-MET) (referring to the factor by which the blood concentration of unchanged parent chemical differs from one species to another, due to metabolic clearance, when both species receive identical doses) and UF(AH-TK-DIS) (reflecting the magnitude of difference in chemical concentrations distributed in target tissues of two species when the arterial blood concentration in both species is identical). The results show that the body weight, the rate of alveolar ventilation, the fraction of cardiac output flowing to the liver, partition coefficients (blood:air and tissue:blood), and the hepatic extraction ratio are the only parameters that play a critical role in the extrapolation of tissue and blood concentrations across species. Further, the magnitude of the UF(AH-TK-ABS) (means+/-SD, 0.19+/-0.04), UF(AH-TK-MET) (means+/-SD, 0.24+/-0.05) and UF(AH-TK-DIS) (mean range: 1.76-0.93) obtained in this study for several VOCs compares well with that obtained previously using physiologically based toxicokinetic models.
Pelekis
Michael
M
Pelekis Group, P.O. Box 415, Nazareth, PA 18064, USA. pelikism@aol.com
Krishnan
Kannan
K
D000465:Algorithms; D000818:Animals; D001835:Body Weight / Q000502:physiology; D002302:Cardiac Output / Q000502:physiology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008099:Liver / Q000378:metabolism; D008102:Liver Circulation / Q000502:physiology; D009930:Organic Chemicals / Q000633:toxicity*; D010599:Pharmacokinetics; D011650:Pulmonary Alveoli / Q000502:physiology; D051381:Rats; D013045:Species Specificity
D009930:Organic Chemicals