Human variability in xenobiotic metabolism and pathway-related uncertainty factors for chemical risk assessment: a review.
This review provides an account of recent developments arising from a database that defined human variability in phase I metabolism (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, hydrolysis, alcohol dehydrogenase), phase II metabolism (N-acetyltransferases, glucuronidation, glycine conjugation, sulphation) and renal excretion. This database was used to derive pathway-related uncertainty factors for chemical risk assessment that allow for human variability in toxicokinetics. Probe substrates for each pathway of elimination were selected on the basis that oral absorption was >95% and that the metabolic route was the primary route of elimination of the compound (60-100% of a dose). Intravenous data were used for compounds for which absorption was variable. Human variability in kinetics was quantified for each compound from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups of the population using parameters relating to chronic exposure (metabolic and total clearances, area under the plasma concentration-time curve (AUC)) and acute exposure (Cmax) (data not presented here). The pathway-related uncertainty factors were calculated to cover 95%, 97.5% and 99% of the population of healthy adults and of each subgroup. Pathway-related uncertainty factors allow metabolism data to be incorporated into the derivation of health-based guidance values. They constitute an intermediate approach between the general kinetic default factors (3.16) and a chemical-specific adjustment factor. Applications of pathway-related uncertainty factors for chemical risk assessment and future refinements of the approach are discussed. A knowledge-based framework to predict human variability in kinetics for xenobiotics showing a threshold dose below which toxic effects are not observed, is proposed to move away from default assumptions.
Dorne
J L C M
JL
Clinical Pharmacology Group, School of Medicine, University of Southampton, Biomedical Sciences Building, Bassett Crescent East, Southampton SO16 7PX, UK. jeanloudorne@hotmail.com
Walton
K
K
Renwick
A G
AG
D000367:Age Factors; D019540:Area Under Curve; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004333:Drug Administration Routes; D006801:Humans; D007527:Isoenzymes; D008657:Metabolic Clearance Rate; D011110:Polymorphism, Genetic; D018570:Risk Assessment; D015262:Xenobiotics / Q000009:adverse effects* / Q000378:metabolism* / Q000493:pharmacokinetics
D007527:Isoenzymes; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System