Environmental and Molecular Mutagenesis - Legacy Tobacco ...

STRUCTURE ACTIVITY ANALYSIS OF AZO DYES AND RELATED CONPOUNDS . L .D . Claxtonl, D .B .
Walsh2, J . Esancy3, and H . Freeman3, lEnvironmental Protection Agency, Research
Triangle Park, NC (USA), 2Environmental Health Research and Testing, Inc ., Research
Triangle Park, NC (USA), and 3North Carolina State University, Raleigh, NC (USA) .
Azo dyes represent a significant group of industrial dyes . The carcinogenicity of
some azo dyes have been known for decades . However, debates persist as to the role of
metabolism and various substructural units in the genotoxicity of these azo dyes . For
example, although one of the most prevalent metabolic pathways implicated in the
activity of azo dyes is azo reduction, not all reductive cleavage products are
mutagenic . A computerized SAR system, ADAPT, was used to analyze two separate data
bases : a group of azo dyes and a group of reductive cleavage products . The data used
for both data bases was the response when tested in the Salmonella reversion bioassay .
A compound was considered mutagenic if there was a positive response in any of the
standard five tester strains either with or without metabolic activation . However, a
compound was considered nonmutagenic only if there was no response in any of the
strains with or without metabolic activation . The azo dye data base consists of 25
mutagens and 13 nonmutagens . A set of molecular descriptors, including substructural
descriptors, was selected that successfully classified the mutagens from the
nonmutagens . These molecular descriptors were used to predict the mutagenicity of a
group of azo dyes not included in the data base . The reductive cleavage data base
consists of 48 mutagens and 13 nonmutagens . Structure activity relationships of both
data bases, as well as their predictive capability, will be discussed . This is an
abstract of a proposed presentation and does not necessarily reflect EPA policy .
108
IN VIVO MICRONUCLEUS TESTS IN MOUSE . COPPARISON OF TFE SENSITIVITY OF THREE TARGET ORGANS
(BONE MARROW, LIVER AND TESTIS) TO SIX CARCINOGENS .
I .Cliet, E .Fournier, C .Melcion and A .Cordler . Dbpartement de Toxicologie, Centre de
Recherches de Vitry, RhBne-Poulenc SantB, 13 Qual Jules Guesde, 94400 Vitry sur Seine,
France .
In vivo somatic chromosome mutation is usually carried out using the bone marrow
micronucleus (BMM) test In mouse, which is considered of predictive value In the study of
clastogenicity In the germ cell line . However, it has been reported that the sensitivity
of the BMM test !s insufficient to detect unstable compounds or short-lived metabolites
and the use of target cells with metabolic activity (hepatocytes and spermatids) has been
questioned . In order to analyze In vivo micronucleus lnduction, particularly In celis with
metabolic enzyme activity, we compared the sensitivity of somatic and germ cell lines
towards six carcinogens In the bone marrow, liver and .spermatld micronucleus test In
mouse . Five procarcinogens, with a complex metabolic pattern : dlmethylnitrosamine (DMN),
diethyinitrosamine (DEN), 1-1-dimethyihydrazine (1-1-DMW), 4-aminophenol (4-APOL) and
4-aminobiphenyl (4-ABPYL) and one direct unstable mutagen, a-proplolactone (BPL) were
tested . DMN, DEN, 1-1DMH, BPL were not detected by the BMM test due to their lnstability,
whereas 4-APOL and 4-ABPYL were clearly positive . All six carcinogens were detected In the
mouse liver and spermatid micronucleus test and induced clear clastogenic effects . In
conclusion this study demonstrates the importance of organ-specificity studies . Moreover,
the results of the liver and spermatid micronucleus tests show that the BMM test cannot
replace clastogenicity evaluation in the germ cell line .
109
MAMMALIAN CELL MUTAGENESIS: A MAJOR ROLE FOR NON-DNA TARGETS . D . Clive,
Wellcome Research Laboratories, Research Triangle Park, NC 27709 USA
Evidence is accumulating for major non-DNA targets for specific locus mutageniclty In mammalian
cells involving heritable DNA alterations . Such a possibility (a) Is consistent with radial-loop models
of chromosome structure In mammalian cells (Marsden and Laemmll, Cell17 : 849, 1979) ; (b) is
based upon non-DNA structural components of the eukaryotic chromosome (e .g., topolsomerase is ; TP)
(Gaulden, Mutagenesis 2(1987) 357 ; Evans et al., Mutation Res. 217 : 53, 1989) ; (c) invokes
genetic alterations quantitatively larger than, and mechanistically different from, classical point
mutations as a major class of gene mutations (Yandell et al ., Som. Cell Mol. Gen . 12 : 255, 1987;
Applegate and Hozier, Banbury Report #28 : 213, 1987) which (d) are of the types seen In rodent and
human tumors (All et al ., Science 236 : 933, 1987) ; (e) attributes the relative Insensitivity of some
genotoxicity tests to the wrong chromosomal architecture (prokaryotes, including the Ames assay), the
wrong chemistry (DNA repair synthesis incapable of detecting TP redimerization) or the wrong
endpoint (dominant or X-linked loci fail to detect large scale recombination events) ; (f) explains the
higher sensitivities of other assays (SCE assays, chromosome aberration tests, L517gY/fk +/- mouse
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