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Toxicologic Pathology
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Evaluation of the Xpa-Deficient Transgenic Mouse Model for Short-Term Carcinogenicity Testing: 9-Month Studies with Haloperidol, Reserpine, Phenacetin, and D-Mannitol

Ben A.R. Lina

TNO Nutrition and Food Research, Zeist, The Netherlands, lina{at}voeding.tno.ul

Ruud A. Woutersen

TNO Nutrition and Food Research, Zeist, The Netherlands

Joost P. Bruijntjes

TNO Nutrition and Food Research, Zeist, The Netherlands

Jan Van Benthem

National Institute of Public Health and the Environment, Bilthoven, The Netherlands

Jolanda A.H. Van Den Berg

National Institute of Public Health and the Environment, Bilthoven, The Netherlands

Johan Monbaliu

Janssen Pharmaceutica N.V., Beerse, Belgium

Bob J.J.M. Thoolen

Solvay Pharmaceuticals B.V., Weesp, The Netherlands

Rudolf B. Beems

National Institute of Public Health and the Environment, Bilthoven, The Netherlands

Coen F. Van Kreijl

National Institute of Public Health and the Environment, Bilthoven, The Netherlands

As part of the international evaluation program coordinated by ILSI/HESI, the potential of DNA repair deficient Xpa-/- mice and the double knockout Xpa-/-.p53+/- mice for short term carcinogenicity assays was evaluated. For comparison also wild-type C57BL/6 mice (WT) were included in these studies. Four test compounds were administered to groups of 15 male and 15 female Xpa-/- mice, Xpa-/-.p53+/- mice and WT mice for 39 weeks. The model compounds investigated were haloperidol, reserpine (nongenotoxic rodent carcinogens, putative human noncarcinogens), phenacetin (genotoxic rodent carcinogen, suspected human carcinogen), and D-mannitol (noncarcinogen in rodents and humans). The test compounds were administered as admixture to rodent diet at levels up to 25 mg/kg diet for haloperidol, 7.5 mg/kg diet for reserpine, 0.75% for phenacetin, and 10% for D-mannitol. These levels included the maximum tolerable dose (MTD). Survival was not affected with any of the test compounds. Haloperidol, reserpine and D-mannitol were negative in the carcinogenicity assay with Xpa-/- and Xpa-/- .p53+/- mice, showing low and comparable tumor incidences in controls and high-dose animals. The results obtained with phenacetin may be designated equivocal in Xpa-/- .p53+/- mice, based on the occurrence of a single rare tumor in the target organ (kidney) accompanied by a low incidence of hyperplastic renal lesions and a high incidence of karyomegaly. These results are in agreement with the currently known carcinogenic potential of the 4 test compounds in humans.

Key Words: Xpa • Xpa/p53 • knockout mice • carcinogens • carcinogenicity testing • DNA repair deficient.

Toxicologic Pathology, Vol. 32, No. 2, 192-201 (2004)
DOI: 10.1080/01926230490274344
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