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ToxSci Advance Access first published online on March 30, 2005
This version published online on May 27, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi160
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Published by Oxford University Press 2005.
Received January 26, 2005
Accepted March 18, 2005

Risk Assessment

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

J.L.C.M Dorne 1* and A.G. Renwick 1

1 Division of Developmental Origins of Health and Disease, Institute of Human Nutrition, Clinical Pharmacology Group, School of Medicine, University of Southampton, Biomedical Sciences Building, Bassett Crescent East, Southampton, SO16 7PX, UK

* To whom correspondence should be addressed.
J.L.C.M Dorne, E-mail: jeanloudorne{at}hotmail.com


  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.

Keywords: safety factors; human variability; interspecies differences; metabolism; phase I; phase II; toxicokinetics; uncertainty factors; risk assessment.
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