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. 1979 Apr;39(4):355–375. doi: 10.1038/bjc.1979.68

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

J Chowaniec, R M Hicks
PMCID: PMC2009921  PMID: 36123

Abstract

Male and female Wistar rats were administered sodium saccharin for life (2 yr) either in the drinking water or diet. The maximum palatable dose of saccharin in the drinking water was found to be 2 g/kg/day and, even then, there was some voluntary restriction of fluid intake in the males. By contrast, double this dose--namely 4 g/kg/day, was palatable in the diet. A control group of rats of both sexes received saccharin-free diet and drinking water. Mild urothelial hyperplasias developed from 85 weeks in rats of both sexes receiving saccharin either in the drinking water or diet; the incidence was statistically significant in both the bladders and kidneys of rats receiving the higher dose of saccharin in the diet, but in the kidneys only of rats receiving the lower dose of saccharin in the drinking water. Telangiectasia of the vasa recta was significant in saccharin-treated rats of both sexes at both doses. A very low incidence of bladder tumours, exclusively in males receiving the higher saccharin dose in the diet was seen from 95 weeks. No consistent relationship between bladder epithelial hyperplasias and crystalluria could be demonstrated, although all 3 bladder tumours were associated with some form of mineralisation. Results suggest a particular susceptibility of males to saccharin treatment. The possibility that saccharin may promote, or enhance, the development of latent tumour cells already present in the experimental population, rather than initiate carcinogenesis per se is considered.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ALLEN M. J., BOYLAND E., DUKES C. E., HORNING E. S., WATSON J. G. Cancer of the urinary bladder induced in mice with metabolites of aromatic amines and tryptophan. Br J Cancer. 1957 Jun;11(2):212–228. doi: 10.1038/bjc.1957.29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. ANDERSEN D. A. The nutritional significance of primary bladder stones. Br J Urol. 1962 Jun;34:160–177. doi: 10.1111/j.1464-410x.1962.tb06506.x. [DOI] [PubMed] [Google Scholar]
  3. Althoff J., Cardesa A., Pour P., Shubik P. A chronic study of artificial sweeteners in Syrian golden hamsters. Cancer Lett. 1975 Sep;1(1):21–24. doi: 10.1016/s0304-3835(75)94692-3. [DOI] [PubMed] [Google Scholar]
  4. Batzinger R. P., Ou S. Y., Bueding E. Saccharin and other sweeteners: mutagenic properties. Science. 1977 Dec 2;198(4320):944–946. doi: 10.1126/science.337489. [DOI] [PubMed] [Google Scholar]
  5. Boiron M., Levy J. P., Lasneret J., Oppenheim S., Bernard J. Pathogenesis of Rauscher leukemia. J Natl Cancer Inst. 1965 Nov;35(5):865–884. [PubMed] [Google Scholar]
  6. Bryan G. T., Ertürk E., Yoshida O. Production of urinary bladder carcinomas in mice by sodium saccharin. Science. 1970 Jun 5;168(3936):1238–1240. doi: 10.1126/science.168.3936.1238. [DOI] [PubMed] [Google Scholar]
  7. Byard J. L., McChesney E. W., Golberg L., Coulston F. Excretion and metabolism of saccharin in man. II. Studies with 14-C-labelled and unlabelled saccharin. Food Cosmet Toxicol. 1974 Apr;12(2):175–184. doi: 10.1016/0015-6264(74)90362-9. [DOI] [PubMed] [Google Scholar]
  8. CIZEK L. J., NOCENTI M. R. RELATIONSHIP BETWEEN WATER AND FOOD INGESTION IN THE RAT. Am J Physiol. 1965 Apr;208:615–620. doi: 10.1152/ajplegacy.1965.208.4.615. [DOI] [PubMed] [Google Scholar]
  9. Chapman W. H., Kirchheim D., McRoberts J. W. Effect of the urine and calculus formation on the incidence of bladder tumors in rats implanted with paraffin wax pellets. Cancer Res. 1973 Jun;33(6):1225–1229. [PubMed] [Google Scholar]
  10. Coleman G. L., Barthold W., Osbaldiston G. W., Foster S. J., Jonas A. M. Pathological changes during aging in barrier-reared Fischer 344 male rats. J Gerontol. 1977 May;32(3):258–278. doi: 10.1093/geronj/32.3.258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Coulston F., McCheaney E. W., Goldberg L. Long-term administration of artificial sweeteners to the rhesus monkey (M. mulatta). Food Cosmet Toxicol. 1975 Apr;13(2):297–300. doi: 10.1016/s0015-6264(75)80030-7. [DOI] [PubMed] [Google Scholar]
  12. Egeberg R. O., Steinfeld J. L., Frantz I., Griffith G. C., Knowles H., Jr, Rosenow E., Sebrell H., Van Itallie T. Report to the secretary of HEW from the medical advisory group on cyclamates. JAMA. 1970 Feb 23;211(8):1358–1361. [PubMed] [Google Scholar]
  13. FITZHUGH O. G., NELSON A. A., FRAWLEY J. P. A comparison of the chronic toxicities of synthetic sweetening agents. J Am Pharm Assoc Am Pharm Assoc. 1951 Nov;40(11):583–586. doi: 10.1002/jps.3030401117. [DOI] [PubMed] [Google Scholar]
  14. Flaks A., Clayson D. B. The influence of ammonium chloride on the induction of bladder tumours by 4-ethylsulphonylnaphthalene-1-sulphonamide. Br J Cancer. 1975 May;31(5):585–587. doi: 10.1038/bjc.1975.100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gaunt I. F., Hardy J., Grasso P., Gangolli S. D., Butterworth K. R. Long-term toxicity of cyclohexylamine hydrochloride in the rat. Food Cosmet Toxicol. 1976 Aug;14(4):255–267. doi: 10.1016/s0015-6264(76)80287-8. [DOI] [PubMed] [Google Scholar]
  16. Goldstein R. S., Hook J. B., Bond J. T. Renal tubular transport of saccharin. J Pharmacol Exp Ther. 1978 Mar;204(3):690–695. [PubMed] [Google Scholar]
  17. Hicks R. M., Chowaniec J. Experimental induction, histology, and ultrastructure of hyperplasia and neoplasia of the urinary bladder epithelium. Int Rev Exp Pathol. 1978;18:199–280. [PubMed] [Google Scholar]
  18. Hicks R. M., Chowaniec J. The importance of synergy between weak carcinogens in the induction of bladder cancer in experimental animals and humans. Cancer Res. 1977 Aug;37(8 Pt 2):2943–2949. [PubMed] [Google Scholar]
  19. Hicks R. M., Wakefield J. S., Chowaniec J. Impurities in saccharin and bladder cancer. Nature. 1973 Jun 15;243(5407):424–424. doi: 10.1038/243424a0. [DOI] [PubMed] [Google Scholar]
  20. Johansson S., Angervall L. Urothelial changes of the renal papillae in Sprague-Dawley rats induced by long term feeding of phenacetin. Acta Pathol Microbiol Scand A. 1976 Sep;84(5):375–383. doi: 10.1111/j.1699-0463.1976.tb00130.x. [DOI] [PubMed] [Google Scholar]
  21. Kennedy G. L., Jr, Fancher O. E., Calandra J. C. Subacute toxicity studies with sodium saccharin and two hydrolytic derivatives. Toxicology. 1976 Aug-Sep;6(2):133–138. doi: 10.1016/0300-483x(76)90015-9. [DOI] [PubMed] [Google Scholar]
  22. Kennedy G., Fancher O. E., Calandra J. C. Metabolic fate of saccharin in the albino rat. Food Cosmet Toxicol. 1972 Apr;10(2):143–149. doi: 10.1016/s0015-6264(72)80192-5. [DOI] [PubMed] [Google Scholar]
  23. Kramers P. G. The mutagenicity of saccharin. Mutat Res. 1975;32(1):81–92. doi: 10.1016/0165-1110(75)90012-3. [DOI] [PubMed] [Google Scholar]
  24. Krebs H. A. Inhibition of carbonic anhydrase by sulphonamides. Biochem J. 1948;43(4):525–528. doi: 10.1042/bj0430525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kroes R., Peters P. W., Berkvens J. M., Verschuuren H. G., de Vries T., van Esch G. J. Long term toxicity and reproduction study (including a teratogenicity study) with cyclamate, saccharin and cyclohexylamine. Toxicology. 1977 Dec;8(3):285–300. doi: 10.1016/0300-483x(77)90100-7. [DOI] [PubMed] [Google Scholar]
  26. Leegwater D. C., de Groot A. P., van Kalmthout-Kuyper M. The aetiology of caecal enlargement in the rat. Food Cosmet Toxicol. 1974 Oct;12(5-6):687–697. doi: 10.1016/0015-6264(74)90240-5. [DOI] [PubMed] [Google Scholar]
  27. Lethco E. J., Wallace W. C. The metabolism of saccharin in animals. Toxicology. 1975;3(3):287–300. doi: 10.1016/0300-483x(75)90030-x. [DOI] [PubMed] [Google Scholar]
  28. Levi P. E., Knowles J. C., Cowen D. M., Wood M., Cooper E. H. Disorganization of mouse bladder epithelium induced by 2-acetylaminofluorene and 4-ethylsulfonylnaphthalene-1-sulfonamide. J Natl Cancer Inst. 1971 Feb;46(2):337–352. [PubMed] [Google Scholar]
  29. Lutz W. K., Schlatter C. Saccharin does not bind to DNA of liver or bladder in the rat. Chem Biol Interact. 1977 Nov;19(2):253–257. doi: 10.1016/0009-2797(77)90036-9. [DOI] [PubMed] [Google Scholar]
  30. Lygre D. G. The inhibition by saccharin and cyclamate of phosphotransferase and phosphohydrolase activities of glucose-6-phosphatase. Biochim Biophys Acta. 1974 Mar 21;341(1):291–297. doi: 10.1016/0005-2744(74)90090-4. [DOI] [PubMed] [Google Scholar]
  31. Lyon E. S., Borden T. A., Ellis J. E., Vermeulen C. W. Calcium oxalate lithiasis produced by pyridoxine deficiency and inhibition with high magnesium diets. Invest Urol. 1966 Sep;4(2):133–142. [PubMed] [Google Scholar]
  32. Massry S. G., Coburn J. W. The hormonal and non-hormonal control of renal excretion of calcium and magnesium. Nephron. 1973;10(2):66–112. doi: 10.1159/000180181. [DOI] [PubMed] [Google Scholar]
  33. Matthews H. B., Fields M., Fishbein L. Saccharin: distribution and excretion of a limited dose in the rat. J Agric Food Chem. 1973 Sep-Oct;21(5):916–919. doi: 10.1021/jf60189a025. [DOI] [PubMed] [Google Scholar]
  34. Mondal S., Brankow D. W., Heidelberger C. Enhancement of oncogenesis in C3H/10T1/2 mouse embryo cell cultures by saccharin. Science. 1978 Sep 22;201(4361):1141–1142. doi: 10.1126/science.684434. [DOI] [PubMed] [Google Scholar]
  35. Munro I. C., Moodie C. A., Krewski D., Grice H. C. A carcinogenicity study of commercial saccharin in the rat. Toxicol Appl Pharmacol. 1975 Jun;32(3):513–526. doi: 10.1016/0041-008x(75)90116-7. [DOI] [PubMed] [Google Scholar]
  36. PERRY S. W. PROTEINURIA IN WISTAR RAT. J Pathol Bacteriol. 1965 Apr;89:729–733. [PubMed] [Google Scholar]
  37. Pitkin R. M., Andersen D. W., Reynolds W. A., Filer L. J., Jr Saccharin metabolism in Macaca mulatta. Proc Soc Exp Biol Med. 1971 Jul;137(3):803–806. doi: 10.3181/00379727-137-35671. [DOI] [PubMed] [Google Scholar]
  38. Pollard M., Kajima M. Leukemia in germfree rats. Proc Soc Exp Biol Med. 1966 Feb;121(2):585–589. doi: 10.3181/00379727-121-30837. [DOI] [PubMed] [Google Scholar]
  39. Price J. M., Biava C. G., Oser B. L., Vogin E. E., Steinfeld J., Ley H. L. Bladder tumors in rats fed cyclohexylamine or high doses of a mixture of cyclamate and saccharin. Science. 1970 Feb 20;167(3921):1131–1132. doi: 10.1126/science.167.3921.1131. [DOI] [PubMed] [Google Scholar]
  40. Pugh R. C. Proceedings: The pathology of cancer of the bladder. Cancer. 1973 Nov;32(5):1267–1274. doi: 10.1002/1097-0142(197311)32:5<1267::aid-cncr2820320536>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  41. Roe F. J., Levy L. S., Carter R. L. Feeding studies on sodium cyclamate, saccharin and sucrose for carcinogenic and tumour-promoting activity. Food Cosmet Toxicol. 1970 Apr;8(2):135–145. doi: 10.1016/s0015-6264(70)80332-7. [DOI] [PubMed] [Google Scholar]
  42. Ross M. H., Bras G. Influence of protein under- and overnutrition on spontaneous tumor prevalence in the rat. J Nutr. 1973 Jul;103(7):944–963. doi: 10.1093/jn/103.7.944. [DOI] [PubMed] [Google Scholar]
  43. Ross M. H., Bras G. Lasting influence of early caloric restriction on prevalence of neoplasms in the rat. J Natl Cancer Inst. 1971 Nov;47(5):1095–1113. [PubMed] [Google Scholar]
  44. SIEGLER R., RICH M. A. COMPARATIVE PATHOGENESIS OF MURINE VIRAL LYMPHOMA. Cancer Res. 1964 Sep;24:1406–1417. [PubMed] [Google Scholar]
  45. SILBERBERG M., SILBERBERG R. Diet and life span. Physiol Rev. 1955 Apr;35(2):347–362. doi: 10.1152/physrev.1955.35.2.347. [DOI] [PubMed] [Google Scholar]
  46. Schmähl D. Fehlen einer kanzerogenen Wirkung von Cyclamat, Cyclohexylamin und Saccharin bei Ratten. Arzneimittelforschung. 1973 Oct;23(10):1466–1470. [PubMed] [Google Scholar]
  47. Stoltz D. R., Stavric B., Klassen R., Bendall R. D., Craig J. The mutagenicity of saccharin impurities. I. Detection of mutagenic activity. J Environ Pathol Toxicol. 1978 Sep-Oct;1(1):139–146. [PubMed] [Google Scholar]
  48. Taylor J. D., Richards R. K., Wiegand R. G. Toxicological studies with sodium cyclamate and saccharin. Food Cosmet Toxicol. 1968 Oct;6(3):313–327. doi: 10.1016/s0015-6264(68)80002-1. [DOI] [PubMed] [Google Scholar]
  49. Tiltman A. J., Friedell G. H. The histogenesis of experimental bladder cancer. Invest Urol. 1971 Nov;9(3):218–226. [PubMed] [Google Scholar]
  50. VERMEULEN C. W., RAGINS H. D., GROVE W. J., GOETZ R. Experimental urolithiasis. III. Prevention and dissolution of calculi by alteration of urinary pH. J Urol. 1951 Jul;66(1):1–5. doi: 10.1016/S0022-5347(17)74306-6. [DOI] [PubMed] [Google Scholar]
  51. Vesely D. L., Levey G. S. Saccharin inhibits guanylate cyclase activity: possible relationship to carcinogenesis. Biochem Biophys Res Commun. 1978 Apr 28;81(4):1384–1389. doi: 10.1016/0006-291x(78)91289-5. [DOI] [PubMed] [Google Scholar]
  52. Weil C. S., Carpenter C. P., Smyth H. F., Jr Urinary bladder response to diethylene glycol. Calculi and tumors following repeated feeding and implants. Arch Environ Health. 1965 Oct;11(4):569–581. doi: 10.1080/00039896.1965.10664259. [DOI] [PubMed] [Google Scholar]
  53. Wolff S., Rodin B. Saccharin-induced sister chromatid exchanges in Chinese hamster and human cells. Science. 1978 May 5;200(4341):543–545. doi: 10.1126/science.644315. [DOI] [PubMed] [Google Scholar]
  54. Woodard J. C. Relationship between the ingredients of semipurified diets and nutritional nephrocalcinosis of rats. Am J Pathol. 1971 Oct;65(1):269–278. [PMC free article] [PubMed] [Google Scholar]
  55. de Groot A. P., Til H. P., Feron V. J., Dreef-van der Meulen H. C., Willems M. I. Two-year feeding amd multigeneration studies in rats on five chemically modified starches. Food Cosmet Toxicol. 1974 Oct;12(5-6):651–663. doi: 10.1016/0015-6264(74)90236-3. [DOI] [PubMed] [Google Scholar]

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