Environmental and Molecular Mutagenesis - Legacy Tobacco ...

genicity of well known cytotoxic metals like lead, cadmium, tin,
cobalt, nickel, aluminum, barium and cesium could be modified by
the extract . Oral gavage of the mice with the extract for 7 days
prior to intraperitoneal injection of the metal salts, significantly
reduced the frequencies of chromosomal aberrations, gaps and
rearrangements induced by the metals when compared with control
mice given the metal alone and not previously fed the extract .
substitution of the fruit extract with an equivalent amount of
ascorbic acid as that presebt in the extract, also reduced the
frequency of chromosomal aberrations induced by the metals, but
to a lesser extent than the fruit extract . On the other hand,
following treatment with some of the higher doses of the metals
used, ascorbic acid increased the clastogenic'effects . The greater
efficacy of the •fr1dt, .Axtrdct can .be ii:LL'.lbuted to_ .the combined action .
136
REVISED GUIDELINES OF UK COMMITTEE ON MUTAGENICITY (COM) 1989
DR DIGGLE AND DR FIELDER (DEPT HEALTH LONDON)
The COM is an expert advisory Committee, chaired by Professor B Bridges, set up
to advise UK Government Departments on the mutagenic risk of substances . Their first
guidelines on testing (1982) have now been updated, a revised strategy being
recommended . Initial studies (Stage I) consist of in vitro screening designed to
ensure a high probability of detecting mutagenic poten-fia-T .7-7ests should be done to
the best available protocols, and results confirmed 1n an lndependent experiment . Two
tests are routinely required, a bacterial assay for gene mutation and a test for
clastogenicity tn mammalian cells, except where human exposure is expected to be
extensive or sustained and difficult to avoid, when a test for gene mutation in
mammalian cells is also necessary . This may be followed by 1n vivo studies (Stage
II) . It is not felt justifiable to use in vivo studies for gene-screening and 1f
the in vitro tests are negative no further lesting would normally be required . The
excep-tTon--Ts substances where relatively high exposure, or moderate but prolonged
exposure, is anticipated . An assay for chromosome damage in bone marrow would then be
recommended . This may also be required for substances mutagenic tn vitro, to see
whether the activity may be expressed In vivo . If negative one or more further
in vivo assays tn a different tissue Teg Ztver, gut) may give the necessary
reassurance (in the light of other toxicological data)•that the substance Is unlikely
to be genotoxic to man . The most appropriate test(s) need to be determined on a
case-by-case basis . Stage III consists of in vivo tests for germ cell effect, and is
only necessary when a risk assessment of herTl :abTe effects ts justified .
137
CHEMISTRY OF DNA ALKYLATION AND ARAIXYIATION . Anthony Dipple, BRI-Basic Research
Program, NCI-Frederick Cancer Research Facility, Frederick, MD 21701 .
Since the mutagenic properties of many carcinogens depend upon their metabolic
conversion to chemically reactive metabolites, chemical reactivity can be considered
to be the 'essence' of mutagenic/carcinogenic activity for these compounds . Agents
with different chemical reactivities modify different sites on DNA bases . For
example, simple alkylating agents preferentially modify the ring nitrogen at the 7position
of guanine residues whereas alkylnitrosoureas modify both the 0s- and the 7position,
and polycyclic aralkylating agents modify the exocyclic N=-site on guanine
residues almost exclusively . In order to understand the basis for these changes in
site selectivity with changes in reactivity of the agent, extensive studies of site
specificity in guanosine modification by benzylating agents, which attack the 7-, 0'and
N2-positions of guanosine, have been undertaken . More recently, an optically
active benzylating agent, styrene oxide, has been examined so that the
stereochemistry of various guanosine alkylation products gives insight into the
differences in mechanism through which alkylation at different sites occurs . These
investigations indicate that both the degree of ionic character in the reagent (i .e .
the Ssl or Ss2 character] and the nature of the ionic intermediate (i .e . whether the
charge on the reaction center is localized (hard) or dalocalized (soft)) determine
the sites of alkylation on guanine residues . Research sponsored by the NCI, DHHS,
under contract No . NO1-CO-74101 with Bionetics Research, Inc .
138
ANALYSIS OF MUTATION INDUCTION IN VIVO AND IN VITRO WITH AN SV40-BASED SHUTTLE
VECTOR. K . Dixon, J . Hauser, M . Carty, N . Zernik, E . Roilides, J . Carr, and A . S .
Levine, Section on Viruses and Cellular Biology, NICHD, NIH, Bethesda MD 20892
We have used the SV40-basad shuttle vector, p2189, to study mechanisms of
mutagenesis in mammalian cells . When the vector DNA is treated with either UV
http://legacy.library.ucsf.edu/tid/clb93d00/pdf
1989 EMS Abstracts 49
Notes