Toxicity profile of benzo[a]pyrene in the male LacZ transgenic mouse (MutaMouse) following oral administration for 5 consecutive days.
The toxicity profile of benzo[a]pyrene (BP) was examined in the MutaMouse. The transgenic mouse integrated with lambda gt10 lacZ vectors is used worldwide as an experimental animal in in vivo mutagenesis testing systems. There are few toxicity studies including carcinogenicity in the MutaMouse, and so far only a few carcinogenicity studies of BP accompanied with hematological and plasma biochemical examinations have been conducted even in generic mice. Accordingly, male mice were orally administered BP at doses of 75 and 125 mg/kg/day for 5 consecutive days, and complete autopsy was conducted together with pathological, hematological, and plasma biochemical examinations and measurement of organ weights 41 weeks after the last treatment. Squamous cell papilloma and hyperplasia in the forestomach were induced at incidences of 25 and 50%, respectively and were induced 26 weeks after the final treatment without any significant alterations in t he hematological and plasma biochemical parameters in mice of the 125 mg/kg/day BP-treated satellite group. Fourty-one weeks after the final treatments, 75 and 125 mg/kg/day BP induced squamous cell carcinoma, papilloma, and hyperplasia in the forestomach at incidences of 18 and 18%, 36 and 45%, and 91 and 91%, respectively, and anemia possibly due to continuous hemorrhage from tumors in the forestomach. BP (125 mg/kg/day) also produced malignant lymphoma with an incidence of 18%, accompanied by a marked increase in leukocyte count and decrease in erythrocyte count and by a remarkable decrease in body weights 26 and 39 weeks after the last treatment. Moreover, administration of 75 and 125 mg/kg/day BP induced bronchiolar-alveolar hyperplasia in the lung at incidences of 18 and 9%, respectively. Slight increases were also observed in the weight of the liver and in the levels of urea nitrogen, creatinine, and potassium ion in the plasma biochemical examinations, although no significant pathological alterations were found in the liver and kidney. This study provides new information about BP toxicity including carcinogenicity in the MutaMouse developed for in vivo mutational analysis.
Hakura
A
A
Drug Safety Laboratories, Eisai Co., Ltd., Ibaraki, Japan. al-hakura@eisai.co.jp
Sonoda
J
J
Tsutsui
Y
Y
Mikami
T
T
Imade
T
T
Shimada
M
M
Yaguchi
S
S
Yamanaka
M
M
Tomimatsu
M
M
Tsukidate
K
K
D000284:Administration, Oral; D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006470:Hemorrhage / Q000139:chemically induced; D006965:Hyperplasia / Q000139:chemically induced; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010212:Papilloma / Q000139:chemically induced* / Q000473:pathology; D013274:Stomach Neoplasms / Q000139:chemically induced* / Q000473:pathology
D002273:Carcinogens; D001564:Benzo(a)pyrene