Since recognition of benzidine as a human carcinogen and with the restrictions placed on its manufacture and use, there has been an economical incentive to produce benzidine analogues for use in the dye and polymer industries. However, there is only limited basic structure- toxicity data available to develop safer benzidine substitutes and to assist public health professionals to reach risk-assessment judgements of the hazards of industrial, environmental and consumer-product exposure to such analogues. It is the long-term goal of the project to study structure-genotoxicity relationships for benzidine analogues and to evaluate the application of short-term testing in the prediction of such toxicity. A specific objective is to continue to develop structure- mutagenicity relationships, using both the liquid-preincubation and plate- incorporation versions of the Ames Salmonella procedure, for commercially available benzidine analogues and for model compounds that will be synthesized. The selection of such compounds will serve to test the literature and the findings of this laboratory that the mutagenicity of the analogues can be related to substitution ortho to the amino groups, the planarity of the molecule or to the degree of conjugated unsaturation of the analogue. Model benzidine compounds will be compared to bridged diphenyl and stilbene compounds with the same substituent groups. Quantitative structure-toxicity relationships will be examined for the effects of changes in van der Waal volumes, partition coefficients, pKa values, chemical reactivity, planarity, and conformation in series of related compounds. Based upon the Ames tests' results, representative compounds with a range of mutagenicity will be tested for their possible correlation to the site and rate of alkylation of DNA. 32P-postlabeling analysis will be used to monitor adduct formation. In vitro mutagenicity and adduct formation results will be compared to in vivo genotoxicity where the end points will be adduct formation and bone marrow genotoxicity, as measured by chromosome aberrations and sister chromatid exchange.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Toxicology Subcommittee 2 (TOX)
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University of Michigan Ann Arbor
Schools of Pharmacy
Ann Arbor
United States
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Hooberman, B H; Brezzell, M D; Das, S K et al. (1994) Substituent effects on the genotoxicity of 4-nitrostilbene derivatives. Mutat Res 341:57-69
Das, L; Das, S K; Hooberman, B H et al. (1994) Chromosomal aberrations in mouse lymphocytes exposed in vitro and in vivo to benzidine and 5 related aromatic amines. Mutat Res 320:69-74
You, Z; Brezzell, M D; Das, S K et al. (1993) ortho-Substituent effects on the in vitro and in vivo genotoxicity of benzidine derivatives. Mutat Res 319:19-30
Sinsheimer, J E; Hooberman, B H; Das, S K et al. (1992) The in vivo and in vitro genotoxicity of aromatic amines in relationship to the genotoxicity of benzidine. Mutat Res 268:255-64