Existence of a threshold for induction of aberrant crypt foci in the rat colon with low doses of 2-amino-1-methyl-6-phenolimidazo[4,5-b]pyridine.
Until recently it has been generally considered that genotoxic carcinogens have no threshold in exerting their potential for cancer induction. However, the nonthreshold theory can be challenged with regard to assessment of cancer risk to humans. In the present study we show that a food derived, genotoxic hepatocarcinogen, 2-amino-1-methyl-6-phenolimidazo[4,5-b]pyridine (PhIP), does not induce aberrant crypt foci (ACF) as preneoplastic lesions at low dose (below 50 ppm) or 8-hydroxy-2'-deoxyguanosine (below 400 ppm) in the rat colon. Moreover PhIP-DNA adducts were not formed at the lowest dose (below 0.01 ppm). Thus, the dose required to initiate ACF is approximately 5000 times higher than that needed for adduct formation. The results imply a no-observed effect level (existence of a threshold) for colon carcinogenesis by a genotoxic carcinogen.
Fukushima
S
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
H
H
Morimura
K
K
Iwai
S
S
Nakae
D
D
Kishida
H
H
Tsuda
H
H
Uehara
N
N
Imaida
K
K
Shirai
T
T
Tatematsu
M
M
Tsukamoto
T
T
Hirose
M
M
Furukawa
F
F
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000473:pathology; D018736:DNA Adducts / Q000096:biosynthesis / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000008:administration & dosage / Q000633:toxicity*; D019055:No-Observed-Adverse-Effect Level; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344
C502239:2-amino-1-methyl-6-phenolimidazo(4,5-b)pyridine-DNA adduct; D002273:Carcinogens; D018736:DNA Adducts; D007093:Imidazoles; D009153:Mutagens; D000080242:8-Hydroxy-2'-Deoxyguanosine; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D003849:Deoxyguanosine