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. 1994 Jun;102(Suppl 2):63–78. doi: 10.1289/ehp.9410263

Summary of the National Toxicology Program benzidine dye initiative.

D L Morgan 1, J K Dunnick 1, T Goehl 1, M P Jokinen 1, H B Matthews 1, E Zeiger 1, J H Mennear 1
PMCID: PMC1567082  PMID: 7925189

Abstract

The benzidine dye initiative is a research program established by the National Toxicology Program to generate an integrated body of scientific information regarding the potential health risks associated with exposure to benzidine- and benzidine-congener-derived dyes. Because an in-depth evaluation of each of the hundreds of benzidine-congener-derived dyes was considered impractical, the research program was designed to study the metabolism and disposition, genetic toxicity, and in vivo toxicity and carcinogenicity of two primary benzidine congeners, 3,3'-dimethylbenzidine and 3,3'-dimethoxybenzidine, and a select group of prototypical dyes derived from those amines. It was anticipated that by applying the basic information generated in these extensive studies, it would be possible to make regulatory decisions about other dyes after conducting only a minimal number of experiments such as studies of disposition and metabolism, and in vitro mutagenicity. This paper summarizes the results of studies conducted to evaluate the metabolism, disposition, mutagenicity, toxicity, and carcinogenicity of representative benzidine congeners and derived dyes.

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Selected References

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

  1. Babu S. R., Lakshmi V. M., Hsu F. F., Zenser T. V., Davis B. B. Role of N-glucuronidation in benzidine-induced bladder cancer in dog. Carcinogenesis. 1992 Jul;13(7):1235–1240. doi: 10.1093/carcin/13.7.1235. [DOI] [PubMed] [Google Scholar]
  2. Beland F. A., Beranek D. T., Dooley K. L., Heflich R. H., Kadlubar F. F. Arylamine-DNA adducts in vitro and in vivo: their role in bacterial mutagenesis and urinary bladder carcinogenesis. Environ Health Perspect. 1983 Mar;49:125–134. doi: 10.1289/ehp.8349125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cerniglia C. E., Freeman J. P., Franklin W., Pack L. D. Metabolism of benzidine and benzidine-congener based dyes by human, monkey and rat intestinal bacteria. Biochem Biophys Res Commun. 1982 Aug 31;107(4):1224–1229. doi: 10.1016/s0006-291x(82)80128-9. [DOI] [PubMed] [Google Scholar]
  4. FOUTS J. R., KAMM J. J., BRODIE B. B. Enzymatic reduction of prontosil and other azo dyes. J Pharmacol Exp Ther. 1957 Jul;120(3):291–300. [PubMed] [Google Scholar]
  5. Flammang T. J., Yamazoe Y., Benson R. W., Roberts D. W., Potter D. W., Chu D. Z., Lang N. P., Kadlubar F. F. Arachidonic acid-dependent peroxidative activation of carcinogenic arylamines by extrahepatic human tissue microsomes. Cancer Res. 1989 Apr 15;49(8):1977–1982. [PubMed] [Google Scholar]
  6. Frederick C. B., Weis C. C., Flammang T. J., Martin C. N., Kadlubar F. F. Hepatic N-oxidation, acetyl-transfer and DNA-binding of the acetylated metabolites of the carcinogen, benzidine. Carcinogenesis. 1985 Jul;6(7):959–965. doi: 10.1093/carcin/6.7.959. [DOI] [PubMed] [Google Scholar]
  7. Fujita J., Srivastava S. K., Kraus M. H., Rhim J. S., Tronick S. R., Aaronson S. A. Frequency of molecular alterations affecting ras protooncogenes in human urinary tract tumors. Proc Natl Acad Sci U S A. 1985 Jun;82(11):3849–3853. doi: 10.1073/pnas.82.11.3849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fujita J., Yoshida O., Yuasa Y., Rhim J. S., Hatanaka M., Aaronson S. A. Ha-ras oncogenes are activated by somatic alterations in human urinary tract tumours. 1984 May 31-Jun 6Nature. 309(5967):464–466. doi: 10.1038/309464a0. [DOI] [PubMed] [Google Scholar]
  9. Goodman D. G., Ward J. M., Squire R. A., Chu K. C., Linhart M. S. Neoplastic and nonneoplastic lesions in aging F344 rats. Toxicol Appl Pharmacol. 1979 Apr;48(2):237–248. doi: 10.1016/0041-008x(79)90029-2. [DOI] [PubMed] [Google Scholar]
  10. Hadidian Z., Fredrickson T. N., Weisburger E. K., Weisburger J. H., Glass R. M., Mantel N. Tests for chemical carcinogens. Report on the activity of derivatives of aromatic amines, nitrosamines, quinolines, nitroalkanes, amides, epoxides, aziridines, and purine antimetabolites. J Natl Cancer Inst. 1968 Oct;41(4):985–1036. [PubMed] [Google Scholar]
  11. Haley T. J. Benzidine revisited: a review of the literature and problems associated with the use of benzidine and its congeners. Clin Toxicol. 1975;8(1):13–42. doi: 10.3109/15563657508988044. [DOI] [PubMed] [Google Scholar]
  12. Kadlubar F. F., Yamazoe Y., Lang N. P., Chu D. Z., Beland F. A. Carcinogen-DNA adduct formation as a predictor of metabolic activation pathways and reactive intermediates in benzidine carcinogenesis. Adv Exp Med Biol. 1986;197:537–549. doi: 10.1007/978-1-4684-5134-4_51. [DOI] [PubMed] [Google Scholar]
  13. Lower G. M., Jr, Bryan G. T. Enzymic deacetylation of carcinogenic arylacetamides by tissue microsomes of the dog and other species. J Toxicol Environ Health. 1976 Jan;1(3):421–432. doi: 10.1080/15287397609529341. [DOI] [PubMed] [Google Scholar]
  14. Lowry L. K., Tolos W. P., Boeniger M. F., Nony C. R., Bowman M. C. Chemical monitoring of urine from workers potentially exposed to benzidine-derived azo dyes. Toxicol Lett. 1980 Nov;7(1):29–36. doi: 10.1016/0378-4274(80)90081-8. [DOI] [PubMed] [Google Scholar]
  15. Lynn R. K., Donielson D. W., Ilias A. M., Kennish J. M., Wong K., Matthews H. B. Metabolism of bisazobiphenyl dyes derived from benzidine, 3,3'-dimethylbenzidine or 3,3'-dimethoxybenzidine to carcinogenic aromatic amines in the dog and rat. Toxicol Appl Pharmacol. 1980 Nov;56(2):248–258. doi: 10.1016/0041-008x(80)90296-3. [DOI] [PubMed] [Google Scholar]
  16. Lynn R. K., Garvie-Gould C. T., Milam D. F., Scott K. F., Eastman C. L., Ilias A. M., Rodgers R. M. Disposition of the aromatic amine, benzidine, in the rat: characterization of mutagenic urinary and biliary metabolites. Toxicol Appl Pharmacol. 1984 Jan;72(1):1–14. doi: 10.1016/0041-008x(84)90244-8. [DOI] [PubMed] [Google Scholar]
  17. Lynn R. K., Garvie-Gould C., Milam D. F., Scott K. F., Eastman C. L., Rodgers R. M. Metabolism of the human carcinogen, benzidine, in the isolated perfused rat liver. Drug Metab Dispos. 1983 Mar-Apr;11(2):109–114. [PubMed] [Google Scholar]
  18. Maronpot R. R., Ulland B., Mennear J. Transplantation characteristics, morphologic features, and interpretation of preputial gland neoplasia in the Fischer 344 rat. Environ Health Perspect. 1988 Apr;77:33–36. doi: 10.1289/ehp.887733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Martin C. N., Beland F. A., Kennelly J. C., Kadlubar F. F. Binding of benzidine, N-acetylbenzidine, N, N'-diacetylbenzidine and Direct Blue 6 to rat liver DNA. Environ Health Perspect. 1983 Mar;49:101–106. doi: 10.1289/ehp.8349101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Martin C. N., Beland F. A., Roth R. W., Kadlubar F. F. Covalent binding of benzidine and N-acetylbenzidine to DNA at the C-8 atom of deoxyguanosine in vivo and in vitro. Cancer Res. 1982 Jul;42(7):2678–2686. [PubMed] [Google Scholar]
  21. Morgan D. L., Jameson C. W., Mennear J. H., Ulland B. M., Lemen J. K. Thirteen-week toxicity studies of 3,3'-dimethoxybenzidene and C.I. Direct Blue 15 in the Fischer 344 rat. Toxicology. 1989 Dec 15;59(3):297–309. doi: 10.1016/0300-483x(89)90199-6. [DOI] [PubMed] [Google Scholar]
  22. Morton K. C., King C. M., Baetcke K. P. Metabolism of benzidine to N-hydroxy-N,N'-diacetylbenzidine and subsequent nucleic acid binding and mutagenicity. Cancer Res. 1979 Aug;39(8):3107–3113. [PubMed] [Google Scholar]
  23. PLISS G. B. ON SOME REGULAR RELATIONSHIPS BETWEEN CARCINOGENICITY OF AMINODIPHENYL DERIVATIVES AND THE STRUCTURE OF SUBSTANCE. Acta Unio Int Contra Cancrum. 1963;19:499–501. [PubMed] [Google Scholar]
  24. Portier C. J., Hoel D. G. Design of animal carcinogenicity studies for goodness-of-fit of multistage models. Fundam Appl Toxicol. 1984 Dec;4(6):949–959. doi: 10.1016/0272-0590(84)90233-1. [DOI] [PubMed] [Google Scholar]
  25. Prival M. J., Bell S. J., Mitchell V. D., Peiperl M. D., Vaughan V. L. Mutagenicity of benzidine and benzidine-congener dyes and selected monoazo dyes in a modified Salmonella assay. Mutat Res. 1984 Apr;136(1):33–47. doi: 10.1016/0165-1218(84)90132-0. [DOI] [PubMed] [Google Scholar]
  26. Prival M. J., Mitchell V. D. Analysis of a method for testing azo dyes for mutagenic activity in Salmonella typhimurium in the presence of flavin mononucleotide and hamster liver S9. Mutat Res. 1982 Apr;97(2):103–116. doi: 10.1016/0165-1161(82)90008-5. [DOI] [PubMed] [Google Scholar]
  27. Reid T. M., Morton K. C., Wang C. Y., King C. M. Mutagenicity of azo dyes following metabolism by different reductive/oxidative systems. Environ Mutagen. 1984;6(5):705–717. doi: 10.1002/em.2860060508. [DOI] [PubMed] [Google Scholar]
  28. Reid T. M., Wang C. Y., King C. M., Morton K. C. Mutagenicity of some benzidine congeners and their N-acetylated and N,N'-diacetylated derivatives in different strains of Salmonella typhimurium. Environ Mutagen. 1984;6(2):145–151. doi: 10.1002/em.2860060205. [DOI] [PubMed] [Google Scholar]
  29. Reynolds S. H., Patterson R. M., Mennear J. H., Maronpot R. R., Anderson M. W. ras gene activation in rat tumors induced by benzidine congeners and derived dyes. Cancer Res. 1990 Jan 15;50(2):266–272. [PubMed] [Google Scholar]
  30. Reznik G., Ward J. M. Morphology of hyperplastic and neoplastic lesions in the clitoral and preputial gland of the F344 rat. Vet Pathol. 1981 Mar;18(2):228–238. doi: 10.1177/030098588101800211. [DOI] [PubMed] [Google Scholar]
  31. Rinde E., Troll W. Metabolic reduction of benzidine azo dyes to benzidine in the rhesus monkey. J Natl Cancer Inst. 1975 Jul;55(1):181–182. doi: 10.1093/jnci/55.1.181. [DOI] [PubMed] [Google Scholar]
  32. Robens J. F., Dill G. S., Ward J. M., Joiner J. R., Griesemer R. A., Douglas J. F. Thirteen-week subchronic toxicity studies of Direct Blue 6, Direct Black 38, and Direct Brown 95 dyes. Toxicol Appl Pharmacol. 1980 Jul;54(3):431–442. doi: 10.1016/0041-008x(80)90170-2. [DOI] [PubMed] [Google Scholar]
  33. Rodgers R. M., Garvie-Gould C., Scott K. F., Milam D. F., Lynn R. K. Metabolism, distribution, and excretion of the carcinogenic aromatic amine, 3,3'-dimethoxybenzidine in the rat. Formation of mutagenic urinary and biliary metabolites. Drug Metab Dispos. 1983 Jul-Aug;11(4):293–300. [PubMed] [Google Scholar]
  34. SCIARINI L. J., MEIGS J. W. The biotransformation of benzidine. II. Studies in mouse and man. Arch Environ Health. 1961 Apr;2:423–428. doi: 10.1080/00039896.1961.10662876. [DOI] [PubMed] [Google Scholar]
  35. SPITZ S., MAGUIGAN W. H., DOBRINER K. The carcinogenic action of benzidine. Cancer. 1950 Sep;3(5):789–804. doi: 10.1002/1097-0142(1950)3:5<789::aid-cncr2820030505>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
  36. Schieferstein G. J., Shinohara Y., Allen R. R., Sheldon W., Greenman D. L., Allaben W. T. Carcinogenicity study of 3,3'-dimethylbenzidine dihydrochloride in BALB/c mice. Food Chem Toxicol. 1989 Dec;27(12):801–806. doi: 10.1016/0278-6915(89)90111-7. [DOI] [PubMed] [Google Scholar]
  37. Ulland B. M., Maronpot R. R., Lemen J. K., Mennear J. H. Transplantation studies of preputial gland and epithelial skin neoplasms derived from benzidine-based dye carcinogenicity assays in Fischer 344 male rats. Toxicol Pathol. 1989;17(1 Pt 1):50–56. doi: 10.1177/01926233890171P108. [DOI] [PubMed] [Google Scholar]
  38. Wise R. W., Zenser T. V., Kadlubar F. F., Davis B. B. Metabolic activation of carcinogenic aromatic amines by dog bladder and kidney prostaglandin H synthase. Cancer Res. 1984 May;44(5):1893–1897. [PubMed] [Google Scholar]
  39. Zeiger E., Anderson B., Haworth S., Lawlor T., Mortelmans K., Speck W. Salmonella mutagenicity tests: III. Results from the testing of 255 chemicals. Environ Mutagen. 1987;9 (Suppl 9):1–109. [PubMed] [Google Scholar]

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