Carcinogenicity of methylurea or morpholine in combination with sodium nitrite in rat multi-organ carcinogenesis bioassay.
For carcinogenic risk assessment of combinations of N-nitroso precursors in man, the effects of feeding methylurea (MU) or morpholine (Mor) plus sodium nitrite (NaNO2) were investigated using a multi-organ carcinogenesis model. In experiment 1, to initiate multiple organs, groups of 10 or 20 male F344 rats were treated with 6 carcinogens targeting different organs. Starting a week after completion of this initiation phase, animals were given 0.1% MU or 0.5% Mor in their food and/or 0.15% NaNO2 in their drinking water for 23 weeks. The induction of tumors and/or preneoplastic lesions in the forestomach and esophagus was significantly increased in the group receiving MU plus NaNO2. The numbers and areas of liver glutathione S-transferase placental form (GST-P)-positive foci were significantly elevated with MU or Mor plus NaNO2. Experiment 2 was conducted to assess formation of N-nitroso compounds in the stomach, and to detect DNA adduct generation in target organs by immunohistochemical staining. Groups of 5 or 14 animals were starved overnight, then given 0.4% MU or 2.0% Mor in the diet, or basal diet alone for 1 h. Then NaNO2 or distilled water was given intragastrically. The mean gastric N-methyl-N-nitrosourea yield in the MU plus NaNO2 group was 7700 micrograms at 2 h after combined administration. The mean N-nitrosomorpholine yield in the group given Mor plus NaNO2 was 6720 micrograms. Immunohistochemically, N7-methyldeoxyguanosine-positive nuclei were evident in the forestomach epithelium at 8 h after the combination treatment with MU plus NaNO2.
Kitano
M
M
First Department of Pathology, Osaka City University Medical School.
Takada
N
N
Chen
T
T
Ito
H
H
Nomura
T
T
Tsuda
H
H
Wild
C P
CP
Fukushima
S
S
D000284:Administration, Oral; D000821:Animal Feed; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D004347:Drug Interactions; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000473:pathology; D005982:Glutathione Transferase / Q000032:analysis; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000473:pathology; D008297:Male; D008782:Methylurea Compounds / Q000633:toxicity*; D009025:Morpholines / Q000633:toxicity*; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D009603:Nitroso Compounds / Q000032:analysis; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D012977:Sodium Nitrite / Q000633:toxicity*; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000473:pathology; D014881:Water Supply
D014408:Biomarkers, Tumor; D002273:Carcinogens; D008782:Methylurea Compounds; D009025:Morpholines; D009603:Nitroso Compounds; C037574:morpholine; D005982:Glutathione Transferase; D012977:Sodium Nitrite; C002352:methylurea