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Assessment of Carcinogenicity of Di(2-ethylhexyl phthalate in a Short-Term Assay Using Xpa-/- and Xpa-/ - /p53+/-Mice

Danish Veterinary and Food Administration, Institute of Food Safety and Toxicology, 19 Mørkhøj Bygade, Søborg, Denmark, alm{at}fdir.dk

Margareta Bertram

Danish Veterinary and Food Administration, Institute of Food Safety and Toxicology, 19 Mørkhøj Bygade, Søborg, Denmark

Vibeke Aarup

Danish Veterinary and Food Administration, Institute of Food Safety and Toxicology, 19 Mørkhøj Bygade, Søborg, Denmark

Ilona K. Sørensen

Danish Veterinary and Food Administration, Institute of Food Safety and Toxicology, 19 Mørkhøj Bygade, Søborg, Denmark

The potential of Xpa ^-/- and Xpa^-/-/p53^+/-mice for short-term carcinogenicity assays was evaluated with di(2-ethylhexyl)phthalate (DEHP). Groups of 15 male and female Xpa^-/- mice, received diets containing 0, 1,500, 3,000, or 6,000 ppm DEHP, and wild-type (WT) and X pa^-/-/p53^+/- mice 0 or 6,000 ppm DEHP for 39 weeks. Xpa^-/-, Xpa^-/-/p53 ^+/-, and WT males, fed 2,500 ppm p-cresidine, served as a positive control. In all models, the survival was not altered by DEHP. Increased incidences of nonneoplastic lesions were recorded in testes and kidneys with no apparent difference between the models. The only liver tumors in all models were adenomas in males with no statistically signifi cantly increased incidence. For p-cresidine, the survival was decreased (p < 0.05) only in transgenic models. Statistically signifi cantly increased incidences of nonneoplastic lesions were recorded in the liver, urinary bladder, and nasal cavity in all models, and in kidneys in transgenic models. The only tumors with statistically signifi cantly increased incidence were liver adenomas in transgenic models (XPA: 1 vs 7; `XPA/p53': 0 vs 12; WT: 0 vs 5, p = 0.053) and urinary bladder carcinomas in XPA/p53 model (0 vs 7). The negative carcinogenic response to DEHP and the positive response to p-cresidine support the expected sensitivity to genotoxic carcinogens in these transgenic models.

Key Words: XPA • xeroderma pigmentosum • p53 tumor suppressor gene • carcinogenicity testing • hepatocellular adenoma • testicular atrophy • p-cresidine.

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Toxicologic Pathology, Vol. 30, No. 2, 188-199 (2002)
DOI: 10.1080/019262302753559524


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