Refinement of uncertainty/safety factors in risk assessment by the incorporation of data on toxicokinetic variability in humans

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 Interna-tional Programme on Chemical Safety has suggested the sub-division 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 avail-able. 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 data-base 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. Key Words: safety factors; human variability; interspecies differences; metabolism; phase I; phase II; toxicokinetics; un