title: An assessment of the impact of physico-chemical and biochemical characteristics on the human kinetic adjustment factor for systemic toxicants.
abstract: The objective of this study was to evaluate the magnitude of the human kinetic adjustment factor (HKAF) as a function of physico- and bio-chemical characteristics impacting the systemic clearance of chemicals. This factor is intended to replace the default value of 3.16 in non-cancer risk assessments and aims at accounting for interindividual variability in toxicokinetics. A steady-state algorithm was used to compute the internal dose metrics (blood concentration (C(blood)) and rate of metabolite produced/L liver (RAM)) of hypothetical chemicals in neonates, adults, elderly, and pregnant women. After evaluating the algorithm with chemical-specific experimental data, C(blood) and RAM were calculated for hypothetical chemicals exhibiting blood:air partition coefficients (Pb) between 1 and 10,000 and hepatic extraction ratios in the average adult (E) between 0.01 and 0.99. Based on Monte Carlo simulation results, HKAF values were computed as the ratio of the 95th percentile value for each subpopulation to the 50th percentile value in adults. The highest HKAF among those obtained for each subpopulation was reported in route-, pathway-, and dose metric-specific HKAF matrices as a function of Pb and E. These matrices allowed the recognition of cases where the default HKAF could be exceeded, and these occurred in neonates based on C(blood) in two situations. First, when the average adult-to-neonate ratio of body weight-adjusted systemic clearance was at least equal to 2.2 for a given systemic exposure (i.e., for CYP1A2 substrates only). Second, when E=0.01-0.2 and Pb ≥ 300 or when E=0.3-0.7 and Pb ≥ 100 for inhalation exposures to CYP2E1 substrates, with comparable values for the other substrates (higher for CYP1A2). Overall, this study showed the dependency of the HKAF on the dose metrics, chemical characteristics, metabolic pathways, and subpopulations considered.
authors: Département de Santé Environnementale et Santé au Travail, Université de Montréal, CP 6128, Succursale Centre-Ville, Montréal, Québec, Canada H3C3J7. mathieu.valcke@inspq.qc.ca
authors: M
authors: M
authors: Valcke
authors: K
authors: K
authors: Krishnan