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Titolo:
Default factors for interspecies differences in the major routes of xenobiotic elimination
Autore:
Walton, K; Dorne, JLCM; Renwick, AG;
Indirizzi:
Univ Southampton, Clin Pharmacol Grp, Southampton SO16 7PX, Hants, EnglandUniv Southampton Southampton Hants England SO16 7PX 6 7PX, Hants, England
Titolo Testata:
HUMAN AND ECOLOGICAL RISK ASSESSMENT
fascicolo: 1, volume: 7, anno: 2001,
pagine: 181 - 201
SICI:
1080-7039(200102)7:1<181:DFFIDI>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
NONCANCER RISK ASSESSMENT; RECTAL BIOAVAILABILITY; 1ST-PASS ELIMINATION; ACETYLSALICYLIC-ACID; LIDOCAINE KINETICS; UNCERTAINTY FACTOR; FOOD-ADDITIVES; SAFETY FACTORS; ASPIRIN; PHARMACOKINETICS;
Keywords:
uncertainty factors; interspecies; toxicokinetics; metabolism;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Agriculture,Biology & Environmental Sciences
Citazioni:
77
Recensione:
Indirizzi per estratti:
Indirizzo: Walton, K Univ Southampton, Clin Pharmacol Grp, Biomed Sci Bldg,Bassett Crescent E, Southampton SO16 7PX, Hants, England Univ Southampton Biomed Sci Bldg,Bassett Crescent E Southampton Hants England SO16 7PX
Citazione:
K. Walton et al., "Default factors for interspecies differences in the major routes of xenobiotic elimination", HUM ECOL R, 7(1), 2001, pp. 181-201

Abstract

For the risk to human health posed by chemicals that show threshold toxicity there is an increasing need to move away from using the default approaches, which inherently incorporate uncertainty, towards more biologically defensible risk assessments. However, most chemical databases do not contain data of sufficient quantity or quality that can be used to replace either the interspecies or interindividual aspects of toxicokinetic and toxicodynamic uncertainty. The purpose of the current analysis was to evaluate the use of alternative, species-specific, pathway-related, "categorical" default values to replace the current interspecies toxicokinetic default uncertainty factor of 4.0. The extent of the difference in the internal dose of a compound, for each test species, could then be related to the specific route of metabolism in humans. This refinement would allow for different categories of defaults to be used, providing that the metabolic fate of a toxicant wasknown in humans. Interspecies differences in metabolism, excretion, and bioavailability have been compared for probe substrates for four different human xenobiotic-metabolizing enzymes: CYP1A2 (caffeine, paraxanthine, theobromine, and theophylline), CYP3A4 (lidocaine), UDP-glucuronyltransferase (AZT), and esterases(aspirin). The results of this analysis showed that there are significant differencesbetween humans and the four test species in the metabolic fate of the probe compounds, the enzymes involved, the route of excretion and oral bioavailability - all of which are factors that can influence the extent of the difference between humans and a test species in the internal dose of a toxicant. The wide variability between both compounds and the individual species suggests that the categorical approach for species differences may be of limited use in refining the current default approach. However, future work to incorporate a wider database of compounds that are metabolized extensively by any pathway in humans to provide more information on the extent to whichthe different test species are not covered by the default of 4.0. Ultimately this work supports the necessity to remove the uncertainty from the riskassessment process by the generation and use of compound-specific data.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/03/20 alle ore 09:33:31