Evaluation of the Xpa-deficient transgenic mouse model for short-term carcinogenicity testing: 9-month studies with haloperidol, reserpine, phenacetin, and D-mannitol.
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.
Lina
Ben A R
BA
TNO Nutrition and Food Research, Zeist, The Netherlands. lina@voeding.tno.ul
Woutersen
Ruud A
RA
Bruijntjes
Joost P
JP
van Benthem
Jan
J
van den Berg
Jolanda A H
JA
Monbaliu
Johan
J
Thoolen
Bob J J M
BJ
Beems
Rudolf B
RB
van Kreijl
Coen F
CF
D000284:Administration, Oral; D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004032:Diet; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000008:administration & dosage / Q000633:toxicity*; D008353:Mannitol / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D010615:Phenacetin / Q000008:administration & dosage / Q000633:toxicity*; D015203:Reproducibility of Results; D012110:Reserpine / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors; D051760:Xeroderma Pigmentosum Group A Protein
D004268:DNA-Binding Proteins; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D008353:Mannitol; D012110:Reserpine; D010615:Phenacetin; D006220:Haloperidol