title: The refinement of uncertainty/safety factors in risk assessment by the incorporation of data on toxicokinetic variability in humans.
abstract: The derivation of safe levels of exposure in humans for compounds that are assumed to cause threshold toxicity has relied on the application of a 100-fold uncertainty factor to a measure for the threshold, such as the no observed adverse effect level (NOAEL) or the benchmark dose (BMD). This 100-fold safety factor consists of the product of two 10-fold factors allowing for human variability and interspecies differences. The International Programme on Chemical Safety has suggested the subdivision of these 10-fold factors to allow for variability in toxicokinetics and toxicodynamics. This subdivision allows the replacement of the default uncertainty factors with a chemical-specific adjustment factor (CSAF) when suitable data are available. This short review describes potential options to refine safety factors used in risk assessment, with particular emphasis on pathway-related uncertainty factors associated with variability in kinetics. These pathway-related factors were derived from a database that quantified interspecies differences and human variability in phase I metabolism, phase II metabolism, and renal excretion. This approach allows metabolism and pharmacokinetic data in healthy adults and subgroups of the population to be incorporated in the risk-assessment process and constitutes an intermediate approach between simple default factors and chemical-specific adjustment factors.
authors.affiliation: Division of Developmental Origins of Health and Disease, Institute of Human Nutrition, Clinical Pharmacology Group, School of Medicine, University of Southampton, Bassett Crescent East, Southampton, UK. jeanloudorne@hotmail.com
authors.forename: J L C M
authors.initials: JL
authors.lastname: Dorne
authors.forename: A G
authors.initials: AG
authors.lastname: Renwick
mesh_terms: D000368:Aged; D015415:Biomarkers; D002648:Child; D003627:Data Interpretation, Statistical; D003628:Database Management Systems; D006801:Humans; D007231:Infant, Newborn; D010599:Pharmacokinetics; D018570:Risk Assessment; D013045:Species Specificity; D014116:Toxicology; D035501:Uncertainty
chemical_list: D015415:Biomarkers