Response of the rat to saccharin with particular reference to the urinary bladder

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Summary.-Experiments were conducted to determine the dose response of rat bladder urothelium to a range of different single and fractionated intravesicular doses of the carcinogen, N-methyl-N-nitrosourea (MNU). A dose-related response of bladder-tumour incidence to single graded doses of MNU was found, and a threshold dose suitable for use in multistage carcinogenesis experiments was derived from these data. For any given total dose of MNU, the tumour incidence was greater if the MNU had been administered in several small fractions than if it had been administered in fewer larger ones. Extending the interval between doses did not reduce the tumour incidence. It is argued that these results support the multistage theory of carcinogenesis. The histopathology and cell-surface alterations which characterize the development of MNU-induced bladder cancer are described and the contribution of hyperplasia and calculi are discussed.

“…A few hyperplasias in control Wistar males (but not females) were recorded in previous experiments from this laboratory (Chowaniec & Hicks, 1979).…”

Section: Electron Microscopymentioning

confidence: 51%

Section: Electron Microscopymentioning

confidence: 98%

Induction of bladder cancer in rats by fractionated intravesicular doses of N-methyl-N-nitrosourea

Severs¹,

Barnes²,

Wright³

et al. 1982

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“…Relatively more (47%) of the free N-hydroxy derivative is found if the urine of the treated rats is made acidic (pH 5 7 + 0.3) than if it is made alkaline (pH 7 7 + 0.2), when only 29% is in the form of the free N-hydroxy compound (Kadlubar et al, 1978). These authors suggested that urinary pH is the controlling factor in 2-naphthylamine- (Chowaniec & Hicks, 1979) is slightly lower than that found by Kadlubar and his colleagues. By comparison with the relatively low doses of MNU, BBN and FANFT required to produce bladder cancer in the rat, a very high dose of 2-naphthylamine was used here to produce less than a 100% incidence.…”

Section: Discussionmentioning

confidence: 79%

The induction of rat bladder cancer by 2-naphthylamine

Hicks¹,

Wright²,

Wakefield³

1982

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Summary.-The widely held belief that 2 -naphthylamine is not carcinogenic for the rat has been re-examined. Twenty female Wistar rats were dosed by gastric intubation weekly for 57 weeks with 2 -naphthylamine, 300 mg/kg body wt, in arachis oil and 20 controls were given arachis oil alone. Animals which became moribund were killed during the course of the experiment and the remainder after 100 weeks. A 2-naphthylamine -treated animal died at 21 weeks; all others survived 57 weeks or longer. The urinary tracts of all but two 2-naphthylamine-treated animals, which were found dead and cannibalized, were examined histologically.No neoplastic disease of the urinary tract was present in control animals. In 10 of the 2-naphthylamine -treated rats there was neither neoplasia nor hyperplasia of the urothelium, but 4 of the 18 examined histologically had large, macroscopically visible bladder cancers; one of these also had bilateral transitional cell tumours of the kidney calyces and multiple tumours in both ureters. Another animal had bilateral urothelial cancers in the ureters. The histology and ultrastructure of these urothelial cancers were comparable to those of rat transitional-cell carcinomas experimentally induced with other chemical carcinogens.These results, considered in the context both of early and more recently published biochemical studies of 2-naphthylamine metabolism in the rat, support the possibility that production of the active carcinogenic metabolite in this species may be influenced by a pH-dependent, non-enzymic mechanism in the urine, which could account for individual, strain-and diet-related variations in response in the rat.

“…Saccharin is not mutagenic but, like MMS, does cause sister chromatid exchange (Albe and Sakaki, 1977;Wolff and Rodin, 1978). If a genetic event of this sort which is not a new mutation can result in tumour formation, this is evidence per se either that the rat urothelium carries a latent oncogene, or as we have suggested elsewhere (Chowaniec and Hicks, 1979), that most animal populations are exposed to low levels of undetected environmental initiating carcinogens.…”

Section: Discussionmentioning

confidence: 97%

The induction of urothelial hyperplasia by methyl methanesulphonate and ethyl methanesulphonate

Tudor¹,

Severs²,

Hicks³

1983

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Summary The early and late morphological changes induced in rat bladder urothelium by intravesicular administration of the alkylating agents methyl methanesulphonate (MMS) and ethyl methanesulphonate (EMS) are described. In the short-term, both compounds produced dose-related toxic damage followed by a regenerative hyperplasia of the urothelium. At any given dose-level, the effects of MMS were more severe than those of EMS. Previous experiments in this laboratory established that the alkylating agent N-methyl-N-nitrosourea (MNU) is both a powerful hyperplastic agent and a bladder carcinogen when administered by intravesicular instillation (Hicks and Wakefield, 1972). This finding has provided a useful model system in which the mechanisms of carcinogenesis and the effects of modulators can be explored (Hicks, 1980;Hicks et al.,1975Hicks et al., , 1978Severs et al., 1982). Intravesicular instillation of two other alkylating agents, viz. methyl methanesulphonate (MMS) and ethyl methanesulphonate (EMS) in the short-term produced toxic damage followed by urothelial hyperplasia (Wakefield & Hicks, 1974