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Six chemicals, known to induce kidney tumors in rats, were examined for their ability to induce DNA fragmentation and formation of micronuclei in primary cultures of rat and human kidney cells, and in the kidney of intact rats. Significant dose-dependent increases in the frequency of DNA single-strand breaks and alkali-labile sites, as measured by the Comet assay, and in micronuclei frequency, were obtained in primary kidney cells from both male rats and humans of both genders with the following subtoxic concentrations of five of the six test compounds: bromodichlorometane (BDCM) from 0.5 to 4 mM, captafol (CF) from 0.5 to 2 microM, nitrobenzene (NB) from 0.062 to 0.5 mM, ochratoxin A (OTA) from 0.015 to 1.215 microM, and trichloroethylene (TCE) from 1 to 4 mM. Benzofuran (BF), consistent with its carcinogenic activity for the kidney of female, but not of male rats, at concentrations from 0.125 to 0.5 mM gave positive responses in cells from females but did not induce DNA damage and increased the frequency of micronuclei in cells from males to a lower extent; in contrast, it was active in cells from humans of both genders. DNA-damaging and micronuclei-inducing potencies were similar in the two species. In agreement with these findings, statistically significant increases in the average frequency of both DNA breaks and micronucleated cells were obtained in the kidney of rats, given p.o. a single dose (1/2 LD50) of the six compounds, BF in this assay being more genotoxic in female than in male rats. Taken as a whole, these findings give further evidence that kidney carcinogens may be identified by short-term genotoxicity assays, using as target kidney cells, and show that the six chemicals tested produce, in primary cultures of kidney cells from human donors, effects similar to those observed in rats.

Possible modifying effects of pesticide mixtures on tumorigenesis were investigated with medium-term carcinogenesis protocols for rapid detection of carcinogenic agents using male F344 rats. In the 8-wk liver model, administration of 20 pesticides (19 organophosphorus compounds and one organochlorine), added to the diet each at acceptable daily intake (ADI) levels, did not enhance rat liver preneoplastic lesion development initiated by diethylnitrosamine. In contrast, a mixture of these 20 pesticides at 100 times the ADI significantly increased the number and area of liver lesions. In the second experiment using a multi-organ carcinogenicity protocol of 28 wk, mixtures of 40 pesticides (high production examples) or 20 pesticides (suspected carcinogens) added to the diet at their respective ADI levels did not modulate carcinogenesis in any organ initiated by five known potent carcinogens in combination. These results thus provide direct support for the safety factor (usually 100) approach using ADI values for the quantitative risk evaluation of pesticides.

Effects of quinoline and captafol, both of which are hemangiocarcinogenic agents, were investigated in spontaneously hypertensive rats (SHR). Male SHR and Wistar Kyoto rats (WKY), the parent strain of SHR, were administered quinoline (0.2%) or captafol (0.15%) supplemented in the diet for 32 weeks. Resultant incidences of hepatic hemangioendothelial sarcomas were in animals receiving quinoline 93% for WKY and only 7% for SHR. A few hepatocellular nodules were also induced in both strains. No histopathological lesions were observed in the other organs. Thus, the SHR proved unexpectedly less susceptible to vascular carcinogenicity than its WKY counterpart.

The potential carcinogenicity of captafol in B6C3F1 mice was examined. Captafol was given at levels of 0 (control), 0.075, 0.15 or 0.3% in the diet to a total of 203 males and 203 females for 96 weeks, after which time the animals were returned to basal diet for a further 8 weeks. Mice surviving 42 weeks or longer were included in the effective numbers. Males and females given 0.3% captafol showed increased cumulative mortalities in the final quarter period of the experiment. Significant increases in the development of neoplastic lesions were found in the heart, spleen, forestomach, small intestine and liver of mice of both sexes treated with captafol. Tumors induced by captafol were, histologically, hemangioendothelioma in the heart, hemangioma or hemangioendothelioma in the spleen, papilloma and squamous cell carcinoma in the forestomach, adenoma and adenocarcinoma in the small intestine, and hyperplastic nodule and hepatocellular carcinoma in the liver. These results demonstrate a broad-spectrum carcinogenicity of captafol in B6C3F1 mice.

Three groups of Fischer 344 rats were fed Merpafol (Makhteshim, Israel), an agricultural fungicide, in increasing concentrations for a period of 2 years. A control group was maintained under identical conditions, but without the addition of the fungicide in the diet. A range of nonneoplastic and neoplastic lesions were observed in the kidneys of rats fed Merpafol. The histogenesis of the renal tumors is discussed in relation to chemical-induced epithelial hyperplasia and cystic tubular dilation. Comparative aspects of renal cyst development and carcinoma in humans are also discussed.