An Algorithm for Calculating the Magnitude of Interindividual Uncertainty Factor. M. O. Fouchecourt and K. Krishnan, Toxhum, Dept de Medecine du Travail et Hygiene du Milieu, University de Montreal, Canada.
The inter-individual uncertainty factor (UFi-i) is used to account for variations in the pharmacokinetics (PK) and pharmacodynamics among human population, and has a default value of 10. With regard to the PK of volatile organic chemicals (VOCs), the UFi-i can be calculated with knowledge of variations in blood: air partition coefficient (Pb), hepatic extraction ratio (E), and fraction of blood flow to the liver (Qlc). Since the Qlc is about 26% of cardiac output in humans, the effect of variability of Pb and E on PK of VOCs needs to be considered for determining the magnitude of UFi-i. The objective of this study was to develop an algorithm to quantify the chemical-specific UFi-i for VOCs from knowledge of inter-individual variations in critical determinants of PK, namely, Pb and E. The approach involved: (i) calculating inter-individual variation in steady-state arterial blood concentration (Cass) according to variations in Pb and E, and (ii) dividing the maximal Cass value by the minimal Cass value to quantify the UFi-i. This was done for 26 VOCs (alkanes, chloroalkanes, chloroethylenes, aromatic hydrocarbons, alcohols, ketones and ether), for which the experimental human Pb values were compiled from the literature and the E was varied between 0.1 and 1. For these VOCs, when the inter-individual variations in both Pb and E were considered, the UFi-i had a maximal value of 10. The maximal value of UFi-i equals the ratio of E considered in this study (i.e., 0.1 vs 1), regardless of the numerical value of Pb. The results of this study suggest that a UFi-iof 10 used in non-cancer risk assessments may be defensible if it is considered to account for the theoretically-plausible variations in PK determinants in human population.
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