Environmental and Molecular Mutagenesis - Legacy Tobacco ...

32 1989 EMS Abstracts
Notes IN VIVO DETECTION OF UDS IN THE RAT GASTRIC NUCOSA 86
B . Burlinson, D .G . .Gatehouse and D .J . Tweats, Dept . Genetic and Reproductive Tox .,
Glaxo Group Res . Ltd ., Ware, Herts, England .
An assay is needed to detect genotoxicity in vivo in tissues other than the liver
or bone marrow . For the pharmaceutical industry the most obvious tissue to
investigate is the stomach and although there are UDS assays already described for
this organ they are relatively insensitive or require the use of hydroxyurea . An
assay has been developed in which account is taken of the morphology of the gastric
mucosa to enable the isolation of non-S-phase cells and the measurement of UDS by
scintillation counting without the need of hydroxyurea . The assay is sensitive and
has a stable control background, (209 * 83 dpa/ vg DNA (11 .34)) . The gastric
carcinogen ICPNG was detectable at doses down to 12 .6mg/kg (316 t 87 dpm/ vg DNA
(N :5)) . Indomethacin a non-genotoxic gastric lrritant, was inactive at doses known
to induce moderate cellular damage indicating that false positive responses due to
gastric irritancy should not occur . The value of this assay is clearly demonstrated
by the results obtained with epichlorhydrin . This compound is a direct acting,
forestomach carcinogen which is Ames positive but which is not detectable in the bone
marrow micronucleus test or the in vivo liver UDS assay . It was however, easily
detected in the stomach UDS assay at 50 mg/kg (LD50 .2S0 mg/kg) . From the data
obtained so far this assay appears to be a rapid and reliable method of measuring UDS
in gastric mucosa . It can be used in cases where, becacse of the pharmacokinetics or
lability of the compound, negative results obtained using the marrow or liver as the
indicator tissue offer little confidence . It is also of use for investigating drug
nitrosation in vivo, this aspect of a test is currently being investigated .
http://legacy.library.ucsf.edu/tid/clb93d00/pdf
COHPLFMENTATION GBOUP ASSIGl0KM1TS FOR W-SENSITIVB CH0 CELIS . D .B . BUSCH, L.H. -"
THCMON, AND G . ADAIR, Armed Forces Inatitute of Pathology, Washington, D .C. (USA),
Lawrence Livermore National laboratory, Livermore, CA (USA), and University of Texas
System Cancer Center, Smithville, TZ (USA)
These studies were performed in order to determine the number of oomplementation
groups of W-sensitive CH0 cells, and to investigate the effeot of mutagen treatment
of the parental lines on the distribution of CH0 W mutant groups . Parental cells
included E-rey sensitive (EM9), mitoaqoin-C (MM) sensitive (M05), and wild type
(AA8) CH0 cells . Using a rapid screening procedure, 166 of approximatel,y 284 W
mutant CH0 cells were assigned to a total of six groups . Over 90% of the assigned
mutants were in the first two groups, with group 1 predominating after frameshift
mutagen ICR-170 treatment, and class 2 predominating after use of miesense mutagena .
The relative scarcity of group 2 mutants following ICR-170 is consistent with the
hypothesis that the gene damaged in group 2 mutants, VX,2-, is an essential gene . The
effect of mutagen treatment on the yield of mutant groups demonstrates the potential
value of varying the mutagen treatment during mutant hunts . Our isolation of W
mutants of X-ray sensitive, MAiC sensitive, and (in one case) W-sensitive CH0 oells
shows that mammalian cells can yield viable double mutants in mutagen sensitivity .
Work supported by the National Institutes of Health (grant numbers GM22021 and
R1O0961) and performed under the auspices of the U.S . Department of Energy by
Iewrence Berkeley laboratory grant number 7134700 and by the Lawrence Livermore
National Isboratory under contract W-7405-11110-48 .
RIiR 71gsEgsMENT OF s00o 1WTJ10sNgt
by Lait Dusk
Toxicology Laboratory, National tood Administration, box 622, 8-75126 Uppsala, Sweden .
There is little doubt that pyrido-iaidasoles/indolss and imidasoasaarenes ferasd during
normal cooking are eapable of producing cancer in man, sinoe they induoa malignant
tumours at aultiple sites in both sexes of rats and mios . ginoa very few food autagens
have been tested in anwlti-dose experiments, the possibility to perform hi9h-to-lov doss
extrapolations is Ii .ited . Usinq the simieluantitativ. TDSO approach, sinql"ose
exparisents can be used to provide rough estisutes of the potency in animals . Such
calculations 4ive TDSO values in the 1-100 mg/kg dose range, indioatino a moderate carelnoqenio
potency in high-dose animal experiments . It is not known whether this is true
for low doses or if man and animals are equally sensitive . At present, the axposura of
humans to food autagens cannot be adequately detar .ined, since Quantitativs data are
∎canty . A very rough estimate from the available data suq0ests that humans might be
exposed to 1 Y9 of oooked food autaq .ns/kq bw . Combining thes* very rough exposure data
with the eQually rough cancer potency estiaates and assuming that aan and rodents are
equally sensitive, that the dose-rasponse relationship is linear, it saams unlikely
that the cooked food autaqens tssted so far represent a major threat to human health .
However, the carcinogenicity of the muta9ens present at the highest levels in food have
not yet been detersin.d and virtually nothing is known about aodifyiaq dietary factors
and differences in sensitivity between animals and man . The need for furthar resaaroh
in order to provide a data base for a swre meaningful human risk assessment will be
disoussad .
50869 3544
88