Kidney Tumors in Male Rats

Toxicokinetic behavior is normally assumed to be similar in animals and humans, at least from a qualitative perspective. On the other hand, certain tumor types in animals may be associated with toxicokinetics or toxicodynamics that are unique to the animal species tested and may not be predictive of carcinogenicity in humans. Very few such examples have been agreed internationally. However, one example is the lack of human relevance of kidney tumors in male rats associated with compounds causing o2u-globulin nephropathy (lARC, Scientific Publication N° 147). Even when a particular tumor type may be discounted, expert judgment must be used in assessing the total tumor profile in any animal experiment. 

The carcinogenic potential of hexachloroethane has not been evaluated following chronic inhalation or dermal exposure. Hexachloroethane increased the incidence of renal tumors in male rats (NTP 1989) following chronic oral exposure. However, these tumors were associated with renal hyaline droplets and, thus, are unique to male rats. Although kidney damage was present in female rats after lifetime exposures to 80 and 160 ppm hexachloroethane, there was no increase in renal tumors. Liver lesions and liver tumors were found in mice following long-term oral exposure (NTP 1977). 

Further analysis of the results of the NTP (1987) bioassay has raised certain questions as to the relevance of the observed renal tumors in male rats and hepatic tumors in mice to the potential carcinogenicity of 1,4-dichlorobenzene in humans. The observation that kidney tumors are induced in male but not female rats in response to exposure to chemicals in addition to 1,4-dichlorobenzene has been the focus of recent... 

Chronic exposure (12 months) of rats and mice to 1000 or 5000 mg/m JP-4 did not cause respiratory tract irritation or pulmonary lesions in rats at the end of the exposure or at 12 months after exposure. An increase of interstitial cell tumors was observed in the testis 12 months after exposure. No effect on the incidence of neoplastic tumors was seen in mice in the same study. A 1-year JP-7 exposure study to rats at 750mg/m produced no toxicologi-cally significant treatment-related neoplastic lesions in mice or rats except for a small increase in incidence of C-cell adenomas and kidney adenomas in male rats. However, these tumors are of the type that are considered to be specific to the male rat and not relevant to humans or other animals. The exposure period in these two studies was 1 year, rather than the typical 2-year lifetime period. This time period... 

Cancer. 2,3-Benzofuran is carcinogenic to rats and mice (NTP 1989). Chronic oral exposure increased the incidence of kidney tumors in female rats, and increased the incidence of lung, forestomach, and liver tumors in male and female mice (NTP 1989). These findings indicate that chronic exposure to... 

In the chronic gavage study by NTP (1986), dosed male rats had increased incidences of renal tubular cell hyperplasia, epithelial cell hyperplasia of the renal pelvis, and tubular mineralization. The male rats also had increased incidences of renal tubular cell tumors. The hyperplasia of the tubular cells, therefore, may represent a preneoplastic response (see discussion of cancer below). These proliferative kidney lesions were not observed in male or female mice or in female rats. The mechanism for the induction of proliferative kidney lesions may also be related to a2p-globulin-induced nephropathy (see discussion of cancer below), again raising the question of the relevance of the proliferative kidney lesions in male rats to humans. This issue is presently the subject of scientific investigation. 

In 2 year gavage studies, there was clear evidence of carcinogenic activity of D-limonene for male rats, as shown by increased incidences of tubular cell hyperplasia, adenomas, and adenocarcinomas of the kidney. There was no evidence of carcinogenic activity of D-limonene for female rats. There was no evidence of carcinogenic activity of D-limonene for male or female mice. The nephrotoxicity of D-limonene was studied in rats and mice. Kidney sections taken from male rats that had been part of a 91 day oral dosing study of limonene in rats and mice were examined by light microscopy. The study showed that renal alterations were induced only in male rats. As discussed above, the mechanism by which D-limonene caused the tumors in male rats is irrelevant to humans. 

There are inadequate human cancer data available for all forms of mercury. Mercuric chloride has caused increases in several types of tumors in rats and mice, and methylmercuiy has caused kidney tumors in male mice. The HPA has determined that mercuric chloride and methylmercury are possible human carcinogens. 

The National Institute of Environmental Health Sciences [39] studied myrcene for its cancerogenic activity, because it is heavily produced and shows structural connections to limonene, which induces tumors in male rat kidneys. The study was performed on male and female rats and mice by force-feeding with myrcene for either 3 months or 2 years. The results of the 2-year studies showed that myrcene possesses a carcinogenic effect based on increased incidence of renal tubule neoplasms in male rats and renal tubule adenomas in female rats. Increased incidence of hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma was seen in male mice and marginally increased incidences hepatocellular adenoma and carcinoma were observed in female mice. 

Male Sprague-Dawley rats were administered lead acetate equivalent to 37 mg lead/kg/day in their drinking water for 76 weeks as part of a study to determine interactions between sodium nitrite, ethyl urea, and lead. There were no kidney tumors in the 10 control rats. Renal tubular carcinomas were found in 13 (81%) of the 16 treated rats. Three of these tumors were detected at 72 weeks and the remaining were found at terminal necropsy (Roller et al. 1985). 

Based on a combination of available human case studies and experiments with laboratory animals, the major public health concerns associated with exposure to 1,4-dichlorobenzene are effects on the liver, kidneys, and blood. Some immunological, dermatological, and neurological effects have also been reported in exposed humans. There is information from animal studies which raises the question of whether 1,4-dichlorobenzene can cross the placenta and elicit structural effects on the developing fetus. Data from a study conducted in rats using the intraperitoneal route have demonstrated sperm abnormalities. Cancer of the liver as a result of lifetime exposure to 1,4-dichlorobenzene has been shown in mice, and renal cancer has been reported in male rats. However, recent studies related to the mechanism of renal carcinogenesis in rats suggest that these tumors may not be expected to occur in exposed humans. Issues relevant to children are explicitly discussed in Section 2.6, Children s Susceptibility, and Section 5.6, Exposures of Children. 

In studies conducted using animals, evidence of carcinogenicity from 1,4-dichlorobenzene exposure is based on 2-year oral studies in mice and rats. 1,4-Dichlorobenzene was administered by gavage to male rats at doses of 150 mg/kg/day and 300 mg/kg/day, and to female rats and mice of both sexes at doses of 300 mg/kg/day and 600 mg/kg/day. There was a dose-related increase in the incidence of tubular cell adenocarcinomas of the kidneys of male rats. There were no tubular cell tumors in dosed or vehicle-control female rats. There was a marginal increase in the incidence of mononuclear cell leukemia in dosed male rats compared with either vehicle controls or historical controls (NTP 1987). Based on the finding of renal tumors in this study, 1,4-dichlorobenzene was found to be carcinogenic in male rats. 

In a carcinogenicity inhalation study, rats and mice were exposed to 9 ppm 6 hours/day, 1 day/week for 12 months 2 ppm 6 hours/day, 1 day/week for 18 months or 2 ppm 6 hours/ day, 2 days/week for 18 months. There was a significant increase in cystic kidney tumors in all exposed animals. Male mice were the most susceptible, with kidney tumors in 90% of exposed animals. Female rats showed an excess of malignant lymphomas. 

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