The objective of this study was to evaluate the impact of whole- and sub-population-related variabilities on the determination of the human kinetic adjustment factor (HKAF) used in risk assessment of inhaled volatile organic chemicals (VOCs). Monte Carlo simulations were applied to a steady-state algorithm to generate population distributions for blood concentrations (CAss) and rates of metabolism (RAMs) for inhalation exposures to benzene (BZ) and 1,4-dioxane (1,4-D). The simulated population consisted of various proportions of adults, elderly, children, neonates and pregnant women as per the Canadian demography. Subgroup-specific input parameters were obtained from the literature and P3M software. Under the “whole population” approach, the HKAF was computed as the ratio of the entire population’s upper percentile value (99th, 95th) of dose metrics to the median value in either the entire population or the adult population. Under the “distinct subpopulation” approach, the upper percentile values in each subpopulation were considered, and the greatest resulting HKAF was retained. CAss-based HKAFs that considered the Canadian demography varied between 1.2 (BZ) and 2.8 (1,4-D). The “distinct subpopulation” CAss-based HKAF varied between 1.6 (BZ) and 8.5 (1,4-D). RAM-based HKAFs always remained below 1.6. Overall, this study evaluated for the first time the impact of underlying assumptions with respect to the interindividual variability considered (whole population or each subpopulation taken separately) when determining the HKAF. 1. Introduction An interindividual variability (or uncertainty) factor (IVF) of a default value of 10 is usually applied to the point of departure (POD) for deriving reference doses (RfDs) or reference concentrations (RfCs) for use in noncancer risk assessment [1–3]. As reviewed by Price et al. [4], the IVF has historically been defined as a factor required to protect the sensitive members of the population since the POD is generally determined for average healthy individuals. Actually, two models have been proposed to describe the IVF. Under the “sensitive population” model, the IVF is applied to correct for the possible failure of a critical study to include a sufficient number of members pertaining to distinct subpopulation exhibiting an increased sensitivity. Conversely, under the “finite sample size” model, the application of the IVF relates to the possibility that the retained POD may fail to identify the toxicity threshold in the overall population simply because of the finite size of the sample in which it was determined
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