Uncertainty factors for chemical risk assessment: interspecies differences in glucuronidation.
For the risk assessment of effects other than cancer, a safe daily intake in humans is generally derived from a surrogate threshold dose (e.g. NOAEL) in an animal species to which an uncertainty factor of 100 is usually applied. This 100-fold is to allow for possible interspecies (10-fold) and interindividual (10-fold) differences in response to a toxicant, and incorporates toxicodynamic and toxicokinetic aspects of variability. The current study determined the magnitude of the interspecies differences in the internal dose of compounds for which glucuronidation is the major pathway of metabolism in either humans or in the test species. The results showed that there are major interspecies differences in the nature of the biological processes which influence the internal dose, including the route of metabolism, the extent of presystemic metabolism and enterohepatic recirculation. The work presented does not support the refinement of the interspecies toxicokinetic default to species- and pathway-specific values, but demonstrates the necessity for risk assessments to be carried out using quantitative chemical-specific data which define the fundamental processes which will influence the internal dose of a chemical (toxicokinetics), or the interaction of toxicant with its target site (toxicodynamics).
Walton
K
K
Clinical Pharmacology Group, Biomedical Sciences Building, University of Southampton, Bassett Crescent East, SO16 7PX, Southampton, United Kingdom. kw3@soton.ac.uk
Dorne
J L
JL
Renwick
A G
AG
D000818:Animals; D020719:Glucuronides / Q000009:adverse effects / Q000378:metabolism* / Q000652:urine; D006801:Humans; D016239:MEDLINE; D008954:Models, Biological; D019055:No-Observed-Adverse-Effect Level; D010599:Pharmacokinetics; D018570:Risk Assessment; D013045:Species Specificity
D020719:Glucuronides