Uncertainty factors for chemical risk assessment: human variability in thepharmacokinetics of CYP1A2 probe substrates

A 100-fold uncertainty factor is used to derive acceptable daily intakes fo r compounds causing thresholded toxicity. The 10-fold factor for human vari ability can be further subdivided into two factors of 10(0.5) (3.16) to all ow for toxicokinetics and toxicodynamics. The validity of the human kinetic subfactor has been analysed in relation to CYP1A2 metabolism using publish ed in vivo pharmacokinetic parameters selected to reflect chronic exposure (metabolic and total clearances and area under the plasma concentration-tim e curve: CLm, CL and AUG) and acute exposure (the peak plasma concentration , C-max). The variability in CYP1A2 activity in healthy adults, based on da ta after oral and intravenous dosage (CLm, CL and AUG), ranged from 34 to 4 2%. The variability in C-max was 21%. The default kinetic factor of 3.16 wo uld cover at least 99% of the healthy adult population, assuming that the d ata were log-normally distributed, but would give lower protection for some subgroups (pregnant women at term, healthy elderly, patients with liver di sease), and was inadequate for neonates. This analysis of in vivo kinetic d ata for CYP1A2 substrates illustrates the importance of quantifying human v ariability in specific metabolic pathways, and of identifying potentially s usceptible subgroups of the human population, in order to determine the sci entific validity of uncertainty factors. (C) 2001 Elsevier Science Ltd. All rights reserved.