Environmental and Molecular Mutagenesis - Legacy Tobacco ...

159 1989 EMS Abstracts
Notes
VALUE-OF-INFORMATION ANALYSIS OF TESTING STRATEGIES . F .K . Ennever, H .S . Rosenkranz,
L .B . Lave, and G .S . Omenn, Case Western Reserve University . Cleveland . OH (USA),
Carnegie-Mellon University . Pittsburgh . PA (USA), and University of Washington .
Seattle . WA (USA) .
The goal of reducing the incidence of cancers caused by environmental exposures
requires strategies for identifying hazards among >50.000 chemicals in commerce and
industry . Our value-of-information framework analyzes strategies for classifying
chemicals as human carcinogens or non-carcinogens . Any classification will have false
negatives (FN) : falsely exonerating a human carcinogen ; false positives (FP) ; falsely
indicting a human non-carcinogen ; true negatives ; and true positives . One extreme
strategy treats all chemicals as non-carcinogena, as existing chemicals generally are
treated ; FP = 0 and FN = c, where c is the proportion of carcinogens among those
chemicals . A second extreme strategy treats all chemicals as carcinogens ; PN - 0 and
FP = 1 - c . A third strategy classifies chemicals on the basis of results of
structure-activity analyses, short-term tests, and/or rodent cancer bioassays ; PN -
(1 - p)c, where p is the weighted sensitivity of the tests, and PP =(1 - q)(l - c),
where q is the weighted specificity of the tests . Using reasonable estimates of c, p,
q, the cost of testing, and the societal costs of PN (needless cancers) and FP (loss
of the use of a chemical), our model has shown that in many cases the lifetime rodent
bioassay is not the most cost-effective way to classify chemicals as human carcinogens
or non-carcinogens . Our most recent work has focused on the influence of uncertainty
in parameter estimation and on deriving a sequential testing strategy with decision
rules for when to classify a chemical without further testing .
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COVALENT BINDING TO MICROTUBULAR PROTEINS AS A POSSIBLE CAUSE OF THE ANEUPLOIDY AND
MICRONUCLEUS FORMATION INDUCED BY CARCINOGENIC ESTROGENS AND OTHER CARCINOGENS .
B . Epe, U .H . Harttig, D . Schiffmann, and M. Metzler, Institute of Toxicology, University
of Wiirzburg, Versbacher Strasse 9, D-8700 Wurzburg, Fad . Rep . Germany .
Certain estrogens, e .g . diethylstilbestrol (DES), transform Syrian hamster embryo
fibroblasts neoplastically in vitro without producing detectable DNA damage or structural
chromosomal abnormalities . Instead, induction of aneuploidy and micronucleus formation
was observed and was associated with cell transformation . In order to elucidate
the biochemical mechanisms of aneuploidy induction, we have studied the interaction of
several radioactively labeled estrogens and their metabolites with tubulin in a cellfree
system . We observed highly specific covalent bindiijg to the carboxy terminal
domain of /1-tubulin of those estrogens which undergo peroxidase-mediated quinone formation
(DES, indenestrol A and the catechol estrogens 2-hydroxyestradiol and 2-hydroxy-
17a-ethinylestradiol) . Estrogens which do not form peroxidative quinone metabolites
(hexestrol, estradiol, 17K-ethinylestradiol) did not bind covalently . Covalent binding
was not inhibited by sulfhydryl reagents nor by colchicine, podophyllotoxin, taxol or
vinblastine . Specific covalent binding to tubulin was also obtained with hydroquinone,
a major metabolite of the non-mutagenic carcinogen benzene, upon peroxidase-mediated
oxidation . Electron microscopy of the microtubulee formed from tubulin coupled to DES
or hydroquinone shoved clear abnormalities indicating that covalent tubulin binding
has functional consequences . Therefore, we propose covalent binding to tubulin as an
early biochemical lesion in the mechanism of aneuploidy induction and neoplastlc cell
transformation by non-DNA-damaging carcinogens .
Supported by Deutsche Forschungsgemeinschaft and BMJFFG .
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SELECTION OF AN EAPERIMENTAI. PROTOCOL FOR SCREENING TEST AGENTS IN THE MOUSE BONE
MARROW MICRONUCLEUS TEST . G .L . Erexsonl, J .L . Hustonl*, R .M . Boehml*, D . Gulati2,
and M .D . Shelby3 . lEnvironmental Health Rea . 6 Testing, Inc ., P .O . Box 12199, RTP, NC
27709 and 22514 Regency Road, Lexington, KY 40503 ; 3NIERS . NTP, Box 12874, RTP, NC .
Due to methodological variations in the mouse bone marrow micronucleus (!D1) test ;
one universal treatment protocol for in vivo chemical exposure is desirable . A common
protocol among laboratories would simplify comparison of MN data . Mitomycin C(14/C)
and 7 .12-dimethylbenzanthracena (DMBA) were tested i .p . at doses of 0, 0 .5 . 1, and 1 .3
mg MMC/kg and 0, 25 . 50, and 100 mg DMBA/kg using three different protocols . Male
B6C3F1 mice (9 to 14 weeks of age, 5 mice/dose) were treated with either (1) one
exposure with harvests for bone marrow polychromatic erythrocytes (PCEs) at 24, 48, or
72 h post-treatment ; (2) two exposures separated by 24 h with harvests at 24 or 48 h
after the second treatment ; or (3) three exposures separated by 24 h with one harvest
time at 24 h after the third treatment . For comparison, DMBA was administered also by
gavage but only for the three-treatment protocol at the same doses used for the 1 .p .
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