Lack of a dose-response relationship for carcinogenicity in the rat liver with low doses of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline or N-nitrosodiethylamine.
For a long period, it has been generally considered that carcinogens, particularly genotoxic ones, have no threshold in exerting their potential for cancer induction. However, the non-threshold theory can be challenged with regard to assessment of cancer risk to humans. Here we show that a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, forms DNA adducts at low doses, but does not induce glutathione S-transferase placental form (GST-P)-positive foci (considered to be preneoplastic lesions) or 8-hydroxy-2'-deoxyguanosine in rat liver. Moreover a N-nitroso compound, N-nitrosodiethylamine, at low doses was also found not to induce GST-P-positive foci in rat liver. These results imply that there is a no-observed effect level for hepatocarcinogenesis by these genotoxic carcinogens.
Fukushima
Shoji
S
Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. fukuchan@med.osaka-cu.ac.jp
Wanibuchi
Hideki
H
Morimura
Keiichirou
K
Wei
Min
M
Nakae
Dai
D
Konishi
Yoichi
Y
Tsuda
Hiroyuki
H
Uehara
Nobuaki
N
Imaida
Katsumi
K
Shirai
Tomoyuki
T
Tatematsu
Masae
M
Tsukamoto
Tetsuya
T
Hirose
Masao
M
Furukawa
Fumio
F
Wakabayashi
Keiji
K
Totsuka
Yukari
Y
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D018736:DNA Adducts / Q000032:analysis; D004052:Diethylnitrosamine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005982:Glutathione Transferase / Q000032:analysis; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced; D011810:Quinoxalines / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D018736:DNA Adducts; D011810:Quinoxalines; D004052:Diethylnitrosamine; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D005982:Glutathione Transferase