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.

Glyoxal and methylglyoxal were tested for tumor-promoting potential in a two-stage stomach carcinogenesis model. Male outbred Wistar rats were initially given N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the drinking water (100 mg/l) along with a 10% sodium chloride dietary supplement for 8 weeks. Thereafter, they were returned to basal diet and maintained on drinking water containing no addition or either 0.5% glyoxal or 0.25% methylglyoxal for 32 weeks and then killed for necropsy and histological examination at week 40. Glyoxal treatment significantly increased the incidence of adenocarcinomas in the pylorus of the glandular stomach of rats pretreated with MNNG and sodium chloride. Furthermore, although methylglyoxal did not enhance the development of adenocarcinomas, the incidence of hyperplasias in the pylorus was significantly increased. The results indicate that glyoxal exerts tumor promoting activity on rat glandular stomach carcinogenesis and that methylglyoxal might also have promoting potential.

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The effects of prostaglandin synthesis inhibitors on development of N-nitrosobis(2-oxopropyl)amine (BOP)-initiated pancreatic tumors were investigated. Female Syrian golden hamsters were given five weekly s.c. injections of BOP (10 mg/kg body weight) during the first 5 weeks and then given 20 p.p.m. indomethacin in the drinking water, 0.25% phenylbutazone in the diet, 1% aspirin in the diet, or no treatment (control group). The resultant incidence of pancreatic carcinoma at week 32 was significantly lower (P less than 0.05) in animals receiving phenylbutazone (36.8%) than in the controls (71.4%) and the numbers of carcinomas per hamster were significantly reduced by indomethacin (0.63) and phenylbutazone (0.58) treatment compared with the control group value (1.29). Aspirin also showed a tendency to decrease pancreatic tumor incidence, but this was not significant. Thus, prostaglandin synthesis inhibitors reduce the development of pancreatic cancer when administered during the post-initiation phase in this animal model.

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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.

Titanium dioxide (TiO(2)) is evaluated by World Health Organization/International Agency for Research on Cancer as a Group 2B carcinogen. The present study was conducted to detect carcinogenic activity of nanoscale TiO(2) administered by a novel intrapulmonary spraying (IPS)-initiation-promotion protocol in the rat lung. Female human c-Ha-ras proto-oncogene transgenic rat (Hras128) transgenic rats were treated first with N-nitrosobis(2-hydroxypropyl)amine (DHPN) in the drinking water and then with TiO(2) (rutile type, mean diameter 20 nm, without coating) by IPS. TiO(2) treatment significantly increased the multiplicity of DHPN-induced alveolar cell hyperplasias and adenomas in the lung, and the multiplicity of mammary adenocarcinomas, confirming the effectiveness of the IPS-initiation-promotion protocol. TiO(2) aggregates were localized exclusively in alveolar macrophages and had a mean diameter of 107.4 nm. To investigate the underlying mechanism of its carcinogenic effects, TiO(2) was administered to wild-type rats by IPS five times over 9 days. TiO(2) treatment significantly increased 8-hydroxydeoxy guanosine level, superoxide dismutase activity and macrophage inflammatory protein 1alpha (MIP1alpha) expression in the lung. MIP1alpha, detected in the cytoplasm of TiO(2)-laden alveolar macrophages in vivo and in the media of rat primary alveolar macrophages treated with TiO(2) in vitro, enhanced proliferation of human lung cancer cells. Furthermore, MIP1alpha, also detected in the sera and mammary adenocarcinomas of TiO(2)-treated Hras128 rats, enhanced proliferation of rat mammary carcinoma cells. These data indicate that secreted MIP1alpha from TiO(2)-laden alveolar macrophages can cause cell proliferation in the alveoli and mammary gland and suggest that TiO(2) tumor promotion is mediated by MIP1alpha acting locally in the alveoli and distantly in the mammary gland after transport via the circulation.