Uncertainty factors for chemical risk assessment: Interspecies differences in the in vivo pharmacokinetics and metabolism of human CYP1A2 substrates
Walton, K; Dorne, JL; Renwick, AG
HERO ID
629954
Reference Type
Journal Article
Year
2001
Language
English
PMID
| HERO ID | 629954 |
|---|---|
| In Press | No |
| Year | 2001 |
| Title | Uncertainty factors for chemical risk assessment: Interspecies differences in the in vivo pharmacokinetics and metabolism of human CYP1A2 substrates |
| Authors | Walton, K; Dorne, JL; Renwick, AG |
| Journal | Food and Chemical Toxicology |
| Volume | 39 |
| Issue | 7 |
| Page Numbers | 667-680 |
| Abstract | 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. |
| Pmid | 11397514 |
| Wosid | WOS:000169306000005 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |
| Keyword | Uncertainty factors; Toxicokinetics; Interspecies; CYP1A2; Metabolism |
| Is Qa | No |