Environmental and Molecular Mutagenesis - Legacy Tobacco ...

688
CYfOGENETIC EFFECTS OF PHORBOL ESTER TUMOR PROMOTERS : POSSIBLE ROLE IN IIULTISTEP TUKORI-
GENESIS. V . Kinzel . B. Farber, R .T. Petrusevska . N . E . Fusenle . Institute of Exp. Pathology,
Institute of Biochemistry', German Cancer Research Center . D-8900 Heldelber¢ . PRG
Tumoriyenesis in mouse skin can be effected in a number of steps : by initiation with DMBA, by
conversion with one or two applications of TPA (12-0-tetradecanoylphorbol-13-acetate) and by reprated
treatment with RPA (12-0-retinoylphorbol-13-acetate) . The conversion step effected by TPA
(but not by RPA) Is characterized by a half-life of 10-12 weeks (in NMRI aice) : it is Sndependent
from initiation (Fiirstenberger . G . et al ., 1985, Science, L3-0. 76) . '1'his specific effect of TPA
may be explained best by the clastogenic activity of TPA shown In mouse keratinocytes In culture
(Petrusevska, R.T. at al . 198fi, Carcirto¢enesis $, 1207) as well as in ex vivo studies (Fiirstenbereer,
G . et al ., 1988, Carcino¢eneals . In press). Details of the olastoYenic action of TPA were studied in
HeLa cells which exhibit a rodiuaimetic cell cycle response to TPA (Klnzel, V . at al ., 1980, Science
210 . 429) . Only TPA exerted a significant elastogenic activity at non-eytotoxic concentrations (10-8
to 10-6 M) measured after 24 and 48 hrs . Values obtained with RPA were close to those obtained in
the presence of solvent (acetone 0.2k). The response to TPA was only to some extent correlated with
the dose. Chromosome aberrations including gaps and breaks were predominantly of the chromatid type ;
they are earliest measurable after 6-8 hrs, I .e. as the cells recover from TPA-induced 02-inhibition
(Kinzel . V . et al., 1988. Cancer Res . 40 . 1759). A 30 ∎in exposure to TPA (10-7 N) is sufficient to
induce aberrations . The data point to an indirect, possibly receptor-mediated action of TPA . If it
is supposed that TPA-iuduced chromosome lesions represent a key event required for conversion it
might be further speculated that the absolute requirement for DNA replication In the conversion step
(Kinsel, V . et a1 ., 1984 . PNAS $1. 5858) is necessary to "fix" a certain degree of chromosome damaQe
(supported by the DFG) .
689
ASSESSMENT OF EXPOSURE AND POTENTIAL RISK FROM MUTAGENIC AIR POLLUTANTS . Joellen
Levtas, U .S . Environmental Protection Agency, Research Triangle Park, N .C . 27711
(U .S .A .) .
Genetic bioassays have been used to identify airborne mutagens and tlieir sources,
to measure human exposure and to provide comparative assessment of potential cancer
risk from air pollutants . Recent air pollution studies have integrated the use of
genetic bioassays into sampling and analysis strategies to seet these goals . Complex
mixtures of urban air pollutants from vehicles andaresidential heating sources have
been studied in field investigations in both Western and Eastern cities in the U .S .
as part of EPA's Integrated Air Cancer Project . Genetic bioassays were applied to
source emissions and ambient outdoor and indoor air to characterize the exposure and
potential risk from the gaseous, semi-volatile and particle-bound organic species .
Source apportionment of the mutagens in these airsheds has been accomplished through
receptor-modeling of mutagens using multiple linear regression analysis .
Mutagenesia, tumorigenesis and DNA adduct dosimetry studies of these air pollution
mixtures have been used in further developing a comparative potency method for
assessing cancer risk from complex mixtures . This is an abstract of a proposed
presentation and does not necessarily reflect EPA policy .
690
THE GENETIC TOXICITY OF THE HUMAN CARCINOGENS BENZIDINE AND BENZIDINE-
BASED DYES : CHROMOSOMAL ANALYSIS IN EXPOSED WORKERS
E .Mirkova and S .Lalchev,The Medical Academy,Sofia (Bulgaria)
The activities of the human carcinogens benzidine (BENZ) and BENZ-based
dye Direct Black 38 in the rodent bone marrow micronucleus assays ( BM
MNA) were established unequivocally (Ashby and Mirkova,1988 ;Beije 1987) .
The lack of data on their genetic effects in humans acted as the stimulus
for the present cytogenetic study .Chromosomal analysis was performed
in the lymphocytes of 23 BENZ-based dyes manufacturing workers and 30
matched control .individuals . The period of exposure was 7-31 yr . BENZ
was detecSed in the workplace air at concentration levels of 0 .42 -
0 .86 mg/m and in the urine of exposed workers respectively at mean level
of 1 .78 ± 1 .4 µg/1 . The total airborne particulate levels of BENZ -
based dyes (mainly Direct Black 38) ranged from 7 .8 to 32 .3 mg/m3 . i
significant increase in the X of aberrant cells (-gaps) was found in the
exposed group (7 .9 ± 5 .9) as compared with the control incidence of
0 .87 ± 0 .26X aberrant cells (-gaps) . Aberrations were mainly chromatid
breaks . The X frequency of polyploid cells in the exposed grou was
found to be 1 .1 ± 0 .1 and the control incidence was 0 .17 * 0 .5~ . The
present data "establish that the rodent BM MNA has predicted correctly
the mutagenicity to humans of the IARC carcinogens BENZ and BENZ-based
dyes .
http://legacy.library.ucsf.edu/tid/clb93d00/pdf
1989 EMS Abstracts 237
Notes