Uncertainty factors for chemical risk assessment: interspecies differences in the in vivo pharmacokinetics and metabolism of human CYP1A2 substrates.
The 100-fold default uncertainty factor is used to convert a no-observed-adverse-effect level (NOAEL) from a animal toxicity study, to a "safe" value for human intake. The composite uncertainty factor (100) has to allow for interspecies (10-fold) and interindividual (10-fold) differences in toxicokinetics and toxicodynamics. The aim of the current study was to assess the validity of the interspecies default for toxicokinetics (4.0) for each of the test species (dog, rabbit, rat and mouse), using published data for compounds eliminated by CYP1A2 in humans (caffeine, theobromine, theophylline and paraxanthine). An analysis of the published literature showed that the absorption, bioavailability and route of excretion were generally similar between humans and the test species, for each probe substrate. However, interspecies differences in the route of metabolism, and the enzymes involved in this process, were identified. The magnitude of difference in the internal dose, between species, showed that values for the mouse (10.6) and rat (5.4) exceed the 4.0-fold default, whereas the rabbit (2.6) and dog (1.6) were below this value. This work supports the need to replace the generic default factors by a compound-related value derived from specific, relevant, quantitative data; this would result in more relevant and reliable non-cancer risk assessments.
Walton
K
K
Clinical Pharmacology Group, Biomedical Sciences Building, University of Southampton, Bassett Crescent East, SO16 7PX, Southampton, UK. kw3@soton.ac.uk
Dorne
J L
JL
Renwick
A G
AG
D000818:Animals; D002110:Caffeine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000652:urine; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010599:Pharmacokinetics; D011336:Probability; D011817:Rabbits; D051381:Rats; D015203:Reproducibility of Results; D018570:Risk Assessment; D013045:Species Specificity; D013379:Substrate Specificity; D013805:Theobromine / Q000008:administration & dosage / Q000493:pharmacokinetics; D013806:Theophylline / Q000008:administration & dosage / Q000493:pharmacokinetics
D002110:Caffeine; D013806:Theophylline; D019388:Cytochrome P-450 CYP1A2; D013805:Theobromine; C021183:1,7-dimethylxanthine