RESUMEN
In a National Toxicology Program (NTP) bioassay, inhalation of tetrahydrofuran (THF) induced liver tumors in female B6C3F1 mice but not in male mice or rats of either sex. Since THF is not genotoxic, the NTP concluded this carcinogenic activity was likely mediated via non-genotoxic modes of action (MOA). Based on evidence that THF and phenobarbital share a similar MOA, female Car/Pxr knock-out mice were orally exposed to THF to evaluate the potential role of CAR activation in the MOA for THF-induced liver tumors. Because data from this oral study with Car/Pxr knock-out mice (C57Bl/6) and the inhalation studies with wild type mice (B6C3F1) reported by NTP and others were derived from different strains, oral studies with wild type B6C3F1 and C57Bl/6 mice were conducted to ensure THF responses in both strains were comparable. As seen in inhalation studies with THF, oral exposure of wild type female mice to a maximum tolerated dose of THF increased total P450 content, CAR-related P450 activities, and hepatocyte proliferation; these effects were not observed in Car/Pxr knock-out female mice. This finding supports the hypothesis THF-induced carcinogenicity is likely mediated via CAR activation that has limited, if any, relevance to humans.
Asunto(s)
Carcinógenos/toxicidad , Furanos/toxicidad , Neoplasias Hepáticas Experimentales/inducido químicamente , Hígado/efectos de los fármacos , Administración Oral , Animales , Carcinógenos/administración & dosificación , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Receptor de Androstano Constitutivo , Sistema Enzimático del Citocromo P-450/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Furanos/administración & dosificación , Genotipo , Humanos , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas Experimentales/genética , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Dosis Máxima Tolerada , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Receptor X de Pregnano , Receptores Citoplasmáticos y Nucleares/deficiencia , Receptores Citoplasmáticos y Nucleares/genética , Receptores de Esteroides/deficiencia , Receptores de Esteroides/genética , Medición de Riesgo , Especificidad de la EspecieRESUMEN
Polyurethanes (PU) are polymers made from diisocyanates and polyols for a variety of consumer products. It has been suggested that PU foam may contain trace amounts of residual toluene diisocyanate (TDI) monomers and present a health risk. To address this concern, the exposure scenario and health risks posed by sleeping on a PU foam mattress were evaluated. Toxicity benchmarks for key non-cancer endpoints (i.e., irritation, sensitization, respiratory tract effects) were determined by dividing points of departure by uncertainty factors. The cancer benchmark was derived using the USEPA Benchmark Dose Software. Results of previous migration and emission data of TDI from PU foam were combined with conservative exposure factors to calculate upper-bound dermal and inhalation exposures to TDI as well as a lifetime average daily dose to TDI from dermal exposure. For each non-cancer endpoint, the toxicity benchmark was divided by the calculated exposure to determine the margin of safety (MOS), which ranged from 200 (respiratory tract) to 3×10(6) (irritation). Although available data indicate TDI is not carcinogenic, a theoretical excess cancer risk (1×10(-7)) was calculated. We conclude from this assessment that sleeping on a PU foam mattress does not pose TDI-related health risks to consumers.
