Human variability in xenobiotic metabolism and pathway-related uncertainty factors for chemical risk assessment: a review
- 作者：Dorne ; J.L.C.M. ; Walton ; K. ; Renwick ; A.G.
- 关键词：ADI ; acceptable daily intake ; BMD ; benchmark dose ; CSAF ; chemical-specific adjustment factor ; LOAEL ; low observed adverse effect level ; NOAEL ; no observed adverse effect level ; RfD ; reference dose ; TDI ; tolerable daily intake ; AUC ; area under the plasma-c
- 刊名：Food and Chemical Toxicology
- 出版年：2005
- 期刊代码：20_02786915
- 类别：pha
- 出版时间：February, 2005
- 卷：43
- 期：2
- 页码：203-216
- 文件大小：225 K
摘要
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芒芒芒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芒芒芒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.