Selenium effects on the carcinogenicity and metabolism of 2-acetylaminofluorene

Addition of 4 ppm Se to the drinking water of male albino rats fed diets containing 0.03% 2-acetylaminofluorene (AAF) provided protection against hepatic damage and also resulted in at least 50% reduction in liver tumor incidence. An in vitro assay system utilizing microsomes from Se supplemented or non-supplemented 3-methylcholanthrene (MC) induced rats was used to determine the effect of oral Se intake on the metabolism of AAF. Oral Se administration led to an increase in ring hydroxylation and a decrease in N-hydroxylation. Addition of Se to the microsomal assay system increased 3-OH AAF formation and decreased N-OH AAF formation, thus shifting the balance of metabolism toward detoxification pathways.     

A 2 year oral carcinogenicity study with cadmium on rats

A longterm 2-year feeding study on cadmium using CdCl₂ · 1H₂O has been performed on Wistar-rats. The tested Cd²⁺-dietary levels were 1, 3, 10 and 50 ppm, respectively. Fifty male and 50 female rats were used for each of the levels. Hundred rats of each sex served as controls. No effects occurred on food intake and survival rate at any dietary level. Growth was unchanged up to 10 ppm whereas 50 ppm resulted in lower weight gain in males only. Histopathological evaluation of a large variety of tissues revealed a number of tumours. Cadmium administered orally was not associated with an increased incidence of total numbers of tumours or of any specific type of neoplasia, although the highest level tested resulted in adverse effects.     

Lifetime carcinogenicity study of 1- and 2-naphthylamine in dogs.

Groups of male and female beagle dogs were given daily doses of 400 mg of various mixtures of naphthylamines for up to 109 months. Survivors were killed at 128 months. A variety of pathological conditions was diagnosed, but the only effect related to treatment was the induction of bladder neoplasms. All dogs which received pure 2-naphthylamine developed transitional-cell carcinomas of the bladder within 34 months. Two of 8 dogs receiving 6% 2-naphthylamine in 1-naphthylamine developed early carcinoma and 2/8 dogs receiving 0.5% 2-naphthylamine in 1-naphthylamine developed haemangioma of the bladder. Some of the dogs receiving 1-naphthylamine (total dose 950 g) and the controls had focal cystitis or hyperplasia, but no neoplasia of the bladder. These results confirm the carcinogenicity of 2-naphthylamine to dogs. No carcinogenic effect of 1-naphthylamine was observed, indicating that it is at least 200 times less potent as a carcinogen than 2-naphthylamine. The incidence of bladder cancer in dogs fed mixtures of both naphthylamines explains why previous experimental and epidemiological studies of impure 1-naphthylamine have revealed carcinogenicity.     

In-vivo activation of N-nitrosodiethanolamine and other n-nitroso-2-hydroxyalkylamines by alcohol dehydrogenase and sulfotransferase

Alcohol dehydrogenase (ADH) activates N-nitrosodiethanolamine (NDELA) to a potent mutagen in the Ames mammalian microsome mutagenicity assay. In vivo, NDELA, its metabolite N-nitroso-2-hydroxymorpholine (NHMOR) and other 2-hydroxylated N-nitrosoalkylamines induce single-strand breaks in rat liver after a single oral application. After competitive inhibition of ADH by pretreatment with ethanol, induction of single-strand breaks by NDELA and N-nitroso(2-hydroxyethyl)ethylamine (NHEEA) was completely suppressed, whereas breaks induced by NHMOR were only partially reduced. Ethanol also influences cytochrome P450-dependent monooxygenases. To investigate whether the observed effect depends on inhibition of ADH and/or of monooxygenases, rats were pretreated with the ADH inhibitor 3-butylthiolane-1-oxide; a considerable reduction in the single-strand-break-inducing potential of NDELA was seen. Moreover, DNA damage induced by NDELA, NHMOR and other hydroxylated N-nitroso compounds is strongly reduced by pretreatment with the sulfotransferase inhibitor, 2,6-dichloro-4-nitrophenol (DCNP). DCNP pretreatment completely suppressed the induction of single-strand breaks by NDELA, whereas the number induced by NHEEA was only partially reduced. Our data suggest that ADH and sulfotransferase are enzymes responsible for the in-vivo activation of N-nitroso-2-hydroxyalkylamines.     

The carcinogenicity of two diazadibenzopyrenes

1,12-Diazadibenzo(a,i)pyrene (I), an isostere of the extremely potent carcinogen dibenzo(a,i)pyrene, also displays carcinogenicity although to a considerably lesser degree than the latter compound. While dibenzo(a,h)pyrene is known to be distinctly less active than dibenzo(a,i)pyrene, surprisingly 4,11-diazadibenzo(a,h)pyrene (II) shows a greater activity than I. Another hexacyclic diaza-hydrocarbon, 4,12-diazadibenzo(g,p)chrysene (III), which is devoid of a meso-phenanthrenic region, proved totally inactive.     

Experimental study of ortho-toluidine carcinogenicity

Ortho-toluidine carcinogenicity has been tested in chronic experiments using mice, rats and dogs. Tumors were induced in 19% of mice (lung and kidney adenomas, leukemia), rats--40% (subcutaneous fat tumors, mammary fibroadenomas, leukemia, renal tumors and hepatic sarcoma). Bladder tumors developed in two dogs after 9 and 10 years of experiment. Both literature and experimental evidence point to o-toluidine as a hazard to humans.     

Inter-species comparisons of carcinogenicity.

The carcinogenicity of 250 chemicals in 2 species, usually the rat and the mouse, was obtained from the published literature through 3 independent sources. Of the 250 compounds listed, 38% were non-carcinogenic in both rats and mice, and 44% were carcinogenic in both species. A total of 43 compounds had different results in the two species, 21 (8%) being carcinogenic in mice only, 17 (7%) in rats only and 5 (2%) having differing results from other species. A comparison of the major target organs affected by chemicals carcinogenic in both species revealed that 64% of the chemicals studied produced cancer at the same site. This comparison of carcinogenic activity in 2 species suggests that extrapolation from results in a single-animal study to man may be subject to substantial errors.     

In-vivo experimental demonstration that hyperhistaminism counteracts tumor-growth

Induction of hyperhistaminism in peritoneum of rats by daily intraperitoneal supply of 0.005 mu g of histamine, counteracts the growth of 10(3) Yoshida ascite sarcoma cells only if administration precedes inoculation of tumor cells and has a long duration. Treating animals for two weeks before tumor cell inoculation we observed significant 70% survival, that was increased to 80% continuing the supply for 20-days after the inoculation; treatment for 3 days before or 20 days after the inoculation did not show significant results. The condition created in rat peritoneum is similar to that in allergic people, and our data in animals confirm statistical data observed in allergic people showing decreased incidence of neoplastic disease due to histamine, that appears to be integrated in a highly potent immunoregulatory circuit.     

The carcinogenicity of metals in humans

Epidemiologic evidence on the relation between exposure to metals and cancer is reviewed. Human exposure to metals is common, with wide use in industry and long-term environmental persistence. Historically, the heaviest metal exposures occurred in the workplace or in environmental settings in close proximity to industrial sources. Among the general population, exposure to a number of metals is widespread but generally at substantially lower levels than have been found in industry. The carcinogenicity of arsenic, chromium, and nickel has been established. Occupational and environmental arsenic exposure is linked to increased lung cancer risk in humans, although experimental studies remain inconclusive. Experimental studies clearly demonstrate the malignant potential of hexavalent (VI) chromium compounds, with solubility being an important determining factor. Epidemiologic studies of workers in chromium chemical production and use link exposure to lung and nasal cancer. Experimental and epidemiologic data show that sparingly-soluble nickel compounds and possibly also the soluble compounds are carcinogens linked to lung and nasal cancer in humans. Some experimental and epidemiologic studies suggest that lead may be a human carcinogen, but the evidence is inconclusive. Although epidemiologic data are less extensive for beryllium and cadmium, the findings in humans of excess cancer risk are supported by the clear demonstration of carcinogenicity in experimental studies. Other metals, including antimony and cobalt, maybe human carcinogens, but the experimental and epidemiologic data are limited.     

The carcinogenicity of environmental tobacco smoke

Male strain A/J mice were exposed for 6 h a day, 5 days a week to environmental tobacco smoke (ETS) generated from Kentucky 1R4F reference cigarettes. Chamber concentrations were 87 mg/m3 of total suspended particulate matter (TSP), 246 p.p.m. of CO and 16 mg/m3 of nicotine. After 5 months, 33% of the ETS exposed and 11% of the control animals had one or several lung tumors; the difference was statistically not significant. A second group of animals exposed for 5 months to ETS was allowed to recover for another 4 months in filtered air. When they were killed, 85% of the ETS animals had lung tumors (average number per lung: 1.4 +/- 0.2), whereas in the control group 38% had lung tumors (average number of lung tumors in all animals 0.5 +/- 0.2). The differences in tumor incidence and multiplicity were statistically significant. More than 80% of all tumors were adenomas, the rest adenocarcinomas. When animals were pretreated with a carcinogen, lung tumor multiplicity was lower in the ETS exposed animals after 5 months compared with controls injected with a carcinogen and kept in air. However, after an additional 4 month recovery period in air, lung tumor multiplicities were the same in ETS plus carcinogen exposed mice as in carcinogen-treated air-exposed controls. Histopathologic and morphometric analysis of the lung tissue failed to reveal any differences between ETS exposed and control animals. However, immediately after ETS exposure, immunohistochemistry revealed increased staining for CYP1A1 in airway epithelia and lung parenchyma; following recovery in air, the staining disappeared again. Analysis of cell kinetics showed an initial burst of increased DNA synthesis in the epithelial cells of the airways and a smaller early positive response in the parenchyma. Feeding of butylated hydroxytoluene during ETS exposure did not modulate lung tumor development. It was concluded that ETS is a pulmonary carcinogen in strain A/J mice.