Relative susceptibility of animals and humans to the cancer hazard posed by 2,3,7,8-tetrachlorodibenzo-p-dioxin using internal measures of dose.
An analysis of the cancer dose-response relationship for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in humans and animals was performed based on measured tissue and serum lipid TCDD concentrations and dosimetrics other than administered dose.
Basic pharmacologic principles indicate that measures of internal dose such as AUC should be used to describe the dose-response relationship in cancer risk assessments of TCDD and other highly persistent compounds.
The TCDD-related liver tumor response in female rats (1,2) was compared to that in humans (respiratory tract cancer rates in Fingerhut et al. ; 3).
Three measures of lifetime dose were used : serum lipid TCDD area-under-the-curve (AUC), peak serum lipid concentration (Cpeak), and average serum lipid concentration (Cavg).
Serum lipid TCDD concentration vs time profiles for the rat were constructed assuming first-order elimination and a half-life of 25 days.
Concentration vs time profiles for humans were estimated based on measured serum lipid TCDD concentrations and known dates of first and last exposure, assuming a 7.5-year half-life and first-order elimination.
A comparison of rat and human responses indicated that, using all three of these dosimetrics, humans are much less sensitive than rats to the carcinogenic effects of TCDD.
For example, at the peak concentration measured in rats exposed to 0.1 mug kg-1 day-1 for 2 years, the human cancer response was more than 9-fold lower than that observed in rats. (...)
Mots-clés Pascal : Toxicité, Comparaison interspécifique, Animal, Rat, Rodentia, Mammalia, Vertebrata, Foie, Appareil digestif pathologie, Homme, Appareil respiratoire pathologie, Carcinogène, Dibenzo-p-dioxine(2,3,7,8-tétrachloro), Relation dose réponse, Aire sous la courbe, Toxicocinétique, Cinétique, Tissu, Elimination, Epidémiologie, Dose répétée, Tumeur maligne
Mots-clés Pascal anglais : Toxicity, Interspecific comparison, Animal, Rat, Rodentia, Mammalia, Vertebrata, Liver, Digestive diseases, Human, Respiratory disease, Carcinogen, Dose activity relation, Area under the curve, Toxicokinetics, Kinetics, Tissue, Elimination, Epidemiology, Multiple dose, Malignant tumor
Notice produite par :
Inist-CNRS - Institut de l'Information Scientifique et Technique
Cote : 97-0055610
Code Inist : 002B04E02. Création : 21/05/1997.