Uncertainty factors for chemical risk assessment: interspecies differencesin the in vivo pharmacokinetics and metabolism of human CYP1A2 substrates

The 100-fold default uncertainty factor is used to convert a no-observed-ad verse-effect level (NOAEL) from a animal toxicity study, to a "safe" value for human intake. The composite uncertainty Factor (100) has to allow for i nterspecies (10-fold) and interindividual (10-fold) differences in toxicoki netics and toxicodynamics. The aim of the current study was to assess the v alidity of the interspecies default for toxicokinetics (4.0) for each of th e tear species (dog, rabbit, rat and mouse), using published data for compo unds eliminated by CYP1A2 in humans (caffeine, theobromine, theophylline an d paraxanthine). An analysis of the published literature showed that the ab sorption, bioavailability and route of excretion were generally similar bet ween humans and the test species, for each probe substrate. However, inters pecies 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 defaul t factors by a compound-related value derived from specific, relevant, quan titative data; this would result in mon relevant and reliable non-cancer ri sk assessments. (C) 2001 Elsevier Science Ltd. All rights reserved.