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Cytogenetic monitoring of nuclear power plant workers in Finland
217
A mixture of benzene metabolites produces a synergistic increase in aneuploidy in cultured human lymphocytes
zene may therefore be responsible for benzene-induced leukemia.
Structural and numerical aberrations (clastogenicity and aneuploidy) have been observed in the lymphocytes of workers exposed to benzene, a known human leukemogen. Recent studies implicate a relationship between chromosomal aberrations and cancer. Using the cytokinesis-blocked micronucleus assay in peripheral human lymphocytes, we have investigated the relative genotoxicity of benzene's phenolic and quinonoid metabolites. An antikinetochore antibody was used to distinguish micronuclei containing whole chromosomes (kinetochore-positive) from those containing acentric fragments (kinetochore-negative) thereby permitting aneuploidy-inducing events to be distinguished from clastogenic events. We recently showed that all tested metabolites of benzene were capable of inducing micronucleated cells. Relative potencies based on the slopes of the linear portion of the dose-response curves were as follows: 1,4-benzoquinone hydroquinone (HQ), catechol (CAT), phenol (PH). Here we report resuits from testing the genotoxicity of various mixtures of phenolic metabolites. Combinations of PH + HQ and PH + CAT exhibited only minor increases (additive or less than additive) in micronucleated cells over those exhibited by HQ or CAT alone. In contrast, a striking synergistic effect was observed when lymphocytes were exposed to equimolar concentrations of HQ and CAT. With background incidence removed, this combination produced 140 micronucleated cells per 1000 binucleate cells, a 6-fold increase over that expected from simple additivity. Further analysis revealed that the majority of these micronucleated cells (90%) were kinetochore-positive. Thus, HQ and CAT appear to cause a synergistic increase in potential aneuploidy in human lymphocytes. These results suggest that multiple metabolites may be involved in producing the patterns of genotoxicity observed in benzene-exposed workers and that HQ and CAT are potentially responsible for the majority of aneuploidy observed. Synergistic interactions between the phenolic metabolites of ben-
102
Salomaa, S., Finnish Centre for Radiation and Nuclear Safety, Laboratory of Radiobiology, Helsinki (Finland) Cytogenetic monitoring of nuclear power plant workers in Finland
Cytogenetic monitoring of Finnish nuclear power plant workers was initiated in 1988, Altogether 20 workers from 2 different plants are scored annually for chromosomal aberrations, The workers subject to chromosome analysis represent the most exposed personnel at the plants, with ,the highest cumulative a n d / o r annual radiation doses. The aberration frequencies are compared to an unexposed control population of the same size, matched for age, sex, smoking habits and X-ray examinations. - At the first surveillance, the mean lifetime radiation doses were 34 mSv for the group working at a boiling water reactor (BWR) plant in Olkiluoto and 71 mSv for the group working at a pressurized water reactor (PWR) plant in Loviisa. The mean employment time was about 10 years in both groups. The chromosome aberration frequencies of the BWR plant workers did not differ significantly from the controls, In the PWR group, however, there was a statistically significant (P < 0.025, Mann-Whitney U-test) increase in chromosome-type aberrations, which suggests that the observed elevation is caused by ionizing radiation. The possible role of radon exposure will be discussed.
103
Autio, K., H. Norppa, M. Hayashi 1, j. MakiPaakkanen and M. Sorsa, Institute of Occupational Health, Helsinki (Finland) and 1 National
A mixture of benzene metabolites produces a synergistic increase in aneuploidy in cultured human lymphocytes
zene may therefore be responsible for benzene-induced leukemia.
Structural and numerical aberrations (clastogenicity and aneuploidy) have been observed in the lymphocytes of workers exposed to benzene, a known human leukemogen. Recent studies implicate a relationship between chromosomal aberrations and cancer. Using the cytokinesis-blocked micronucleus assay in peripheral human lymphocytes, we have investigated the relative genotoxicity of benzene's phenolic and quinonoid metabolites. An antikinetochore antibody was used to distinguish micronuclei containing whole chromosomes (kinetochore-positive) from those containing acentric fragments (kinetochore-negative) thereby permitting aneuploidy-inducing events to be distinguished from clastogenic events. We recently showed that all tested metabolites of benzene were capable of inducing micronucleated cells. Relative potencies based on the slopes of the linear portion of the dose-response curves were as follows: 1,4-benzoquinone hydroquinone (HQ), catechol (CAT), phenol (PH). Here we report resuits from testing the genotoxicity of various mixtures of phenolic metabolites. Combinations of PH + HQ and PH + CAT exhibited only minor increases (additive or less than additive) in micronucleated cells over those exhibited by HQ or CAT alone. In contrast, a striking synergistic effect was observed when lymphocytes were exposed to equimolar concentrations of HQ and CAT. With background incidence removed, this combination produced 140 micronucleated cells per 1000 binucleate cells, a 6-fold increase over that expected from simple additivity. Further analysis revealed that the majority of these micronucleated cells (90%) were kinetochore-positive. Thus, HQ and CAT appear to cause a synergistic increase in potential aneuploidy in human lymphocytes. These results suggest that multiple metabolites may be involved in producing the patterns of genotoxicity observed in benzene-exposed workers and that HQ and CAT are potentially responsible for the majority of aneuploidy observed. Synergistic interactions between the phenolic metabolites of ben-
102
Salomaa, S., Finnish Centre for Radiation and Nuclear Safety, Laboratory of Radiobiology, Helsinki (Finland) Cytogenetic monitoring of nuclear power plant workers in Finland
Cytogenetic monitoring of Finnish nuclear power plant workers was initiated in 1988, Altogether 20 workers from 2 different plants are scored annually for chromosomal aberrations, The workers subject to chromosome analysis represent the most exposed personnel at the plants, with ,the highest cumulative a n d / o r annual radiation doses. The aberration frequencies are compared to an unexposed control population of the same size, matched for age, sex, smoking habits and X-ray examinations. - At the first surveillance, the mean lifetime radiation doses were 34 mSv for the group working at a boiling water reactor (BWR) plant in Olkiluoto and 71 mSv for the group working at a pressurized water reactor (PWR) plant in Loviisa. The mean employment time was about 10 years in both groups. The chromosome aberration frequencies of the BWR plant workers did not differ significantly from the controls, In the PWR group, however, there was a statistically significant (P < 0.025, Mann-Whitney U-test) increase in chromosome-type aberrations, which suggests that the observed elevation is caused by ionizing radiation. The possible role of radon exposure will be discussed.
103
Autio, K., H. Norppa, M. Hayashi 1, j. MakiPaakkanen and M. Sorsa, Institute of Occupational Health, Helsinki (Finland) and 1 National