title: Characterization of the human kinetic adjustment factor for the health risk assessment of environmental contaminants.
abstract: A default uncertainty factor of 3.16 (√10) is applied to account for interindividual variability in toxicokinetics when performing non-cancer risk assessments. Using relevant human data for specific chemicals, as WHO/IPCS suggests, it is possible to evaluate, and replace when appropriate, this default factor by quantifying chemical-specific adjustment factors for interindividual variability in toxicokinetics (also referred to as the human kinetic adjustment factor, HKAF). The HKAF has been determined based on the distributions of pharmacokinetic parameters (e.g., half-life, area under the curve, maximum blood concentration) in relevant populations. This article focuses on the current state of knowledge of the use of physiologically based algorithms and models in characterizing the HKAF for environmental contaminants. The recent modeling efforts on the computation of HKAF as a function of the characteristics of the population, chemical and its mode of action (dose metrics), as well as exposure scenario of relevance to the assessment are reviewed here. The results of these studies, taken together, suggest the HKAF varies as a function of the sensitive subpopulation and dose metrics of interest, exposure conditions considered (route, duration, and intensity), metabolic pathways involved and theoretical model underlying its computation. The HKAF seldom exceeded the default value of 3.16, except in very young children (i.e., <≈ 3 months) and when the parent compound is the toxic moiety. Overall, from a public health perspective, the current state of knowledge generally suggest that the default uncertainty factor is sufficient to account for human variability in non-cancer risk assessments of environmental contaminants.
authors.affiliation: Département de santé environnementale et santé au travail, Université de Montréal, CP 6128, Succursale Centre-Ville, Montréal, Québec, Canada, H3C 3 J7; Institut national de santé publique du Québec, 190 Boul. Crémazie Est, Montréal, QC, Canada, H2P 1E2.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Valcke
authors.forename: Kannan
authors.initials: K
authors.lastname: Krishnan
mesh_terms: D000367:Age Factors; D000818:Animals; D004781:Environmental Exposure / Q000032:analysis* / Q000706:statistics & numerical data; D004785:Environmental Pollutants / Q000493:pharmacokinetics* / Q000633:toxicity; D006801:Humans; D050216:Metabolic Detoxication, Phase I; D050217:Metabolic Detoxication, Phase II; D008954:Models, Biological; D011634:Public Health / Q000706:statistics & numerical data*; D018570:Risk Assessment; D035501:Uncertainty
chemical_list: D004785:Environmental Pollutants
keywords: environmental contaminants; exposure conditions; human kinetic adjustment factor (HKAF); interindividual variability; monte Carlo simulations; phase I metabolism; physiologically-based pharmacokinetic (PBPK) modeling; risk assessment; steady-state solutions; toxicokinetics