Environmental and Molecular Mutagenesis - Legacy Tobacco ...

1989 EMS Abstracts
aberrations/cell, respectively . Alpha-particles and X-rays given alone resulted in a Notes
linear increase in micronuclei/binucleated cell with respective slopes of 0 .77 1 0 .08
and 0 .20 t 0 .05 micronuclei/binucleated cell/Gy . When 1 .0 Gy of a-dose was given
simultaneously with 0 .0, 0 .75, 1 .5, or 3 .0 Gy of X-rays, the slope of the combined
exposure dose-response curve for the X-ray induced nicronuclei had a slope similar to
that observed after exposure to a-particles alone (0 .74 2 0 .05 micronuclei/binucleated
cell/Gy) . These data sets both suggest a synergistic interaction between a- and Xray-induced
damage . Regardless of exposure sequence, when alpha and X-ray exposures
were separated in time by 1/2, 2, or 6 hrs, synergistic interactions between the
damage induced by both exposures was no longer evident . These data demonstrate that
X-rays and a-particles can interact and that repair of the chromosome damage involved
in the interaction is very rapid . (Research sponsored by the U .S . Department of
Energy's Office of Health and Environmental Research under Contract DE-AC04-76EV01013 .)
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ORGAN-SPECIFIC GENOTOXIC EFFECTS OF CHEMICALS : THE USE OF ALKALINE ELUTION TO
DETECT DNA DAMAGE IN VARIOUS ORGANS OF IN VIVO-EXPOSED ANIMALS
G . Brunborg, ] .A . Holme, EJ Sederlund and E . Dybing, Department of Toxicology, National Institute of
Public Health, Oslo, Norway
The existence of genotoxic chemicals with marked organ specificity indicates that chemicals should be
tested in more than one organ or cell type . We have developed techniques for detecting aad comparing
DNA damage in different organs of experimental animals after in vivo administration of chemicals .
Exposed anim als are anesthetized, organs are re moved, cooled rapidly in cold buffer, and processed as
follows: The liver, kidney, testis, lung or spleen is minced with scissors aad forced through a stainless
steel screen + one layer of cotton gauze . The stomach, small or large intestines or the urine bladder is
rinsed, opened, the epithelial cells scraped off with a glass slide, and homogenized in a glass homogenizer .
The brain is homogenized directly . The femur is opened, and bone marrow cells are rinsed out and
homogenized . All samples are then centrifuged and counted . The procedure takes about 1 hour for 16
samples. Two million cells or nuclei are loaded on an automated alkaline elution system (Brunborg et al .,
Anal . Biochem . 1Z, 522-536, 1988) .
Experiments with 1,2-dibromo-3-chloropropane (DBCP) (10 mg/kg i .p ., 1 br) demonstrate highly
variable effects in the various organs : Maximum DNA damage was observed in the liver, kidney and
duodenum, with intermediate damage in the lung, spleen, brain, testis and stomach . Higher doses (40
mg/kg) were required to produce significant damage in bone marrow and colon . DBCP has been shown
to induce tumors in rat liver, kidney and stomach .
T he data indicate that an evaluation of the genotoxic properties of a chemical by means of short-term
tests should involve several organs . We are currently utilizing the methods described to study the
genotoxicity of various dietary mutagens .
79
THE EFFECTS OP MBTBAPYRILBNB oN IN VIVO SCE AND IN VITRO CBROMOSOME ABERRATION
INDUCTION. J . Brunny, D . Kindig, an-d f.Garriott, LThy tesaarch Laboratories, 8li
Lilly and Company, Greenfield, IN 46140
The antihistamine methapyrilene hydrochloride (MP) has been shovn to be a rat
liver carcinogen ; however, ∎ixed positive and negative results exist in short term
genetic toxicology assays . To date, the only in vivo data available on MP are
negative results from two unscheduled DNA synthe®Ts studies using rat (Mirsalis et
al ., Environ . Mutagen . 7, Suppl . 3 :73, 1985 ; Steinmetz et al ., Carcinogenesis 9t95§,
1988) and souse (Steinmetz et al ., op . cit .) hepatocytes and from an SCE assay in
Fischer 344 rats (Iype et al ., Cancer Res . 42t4614, 1982) . Results are presented
here from an in vivo SCS assay in male CD-1 Uce . Intravenous doses of 2 .5, 5, 10,
and 20 mg/kg oT IffP vere administered and bone marrow harvested 21 hr later . The
incidence of SCE was recorded and ranged from 3 .2 to 4 .3 SCE/metaphase, which was not
significantly different from solvent controls . Because of positive findings in the
L5178Y mouse lymphoma assay in which an increase in small colony mutants was observed
and chromosome damage confirmed (Blazak et al ., Environ . Mutagen .• Bt229, 1986), MP
vas also tested for its ability to induce cTiromosome aberrations in v1tro in cultured
Chinese hamster ovary cells . Doses of 375, 450, and 550 yg/al of MP were tested both
vith and without an S-9 activation system . The percent aberrations ranged from 0 to
2 percent in the activated assay and from 0 to 3 percent in the nonactivated assay .
These results were not significantly different from solvent controls . The negative
results from these two assays lend further support to the theory that NP is carcinogenic
through a nongenotoxic mechanism .
80
FffiFRE HAVE WE BFEN? 74fE IAST 20 YFJtRS OF FNVtRMlOWPAL 1'1t1DWMMIS
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Dnvid Brvsiak. Hazleton Laboratories, U .S .A .
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It is wr#Miile to assess the peaks an! valleys of the road travelled by
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the discipline of envirormental autagenesis daa'ing the past 20 years . /'
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