Application of mutagenicity tests in assessing occupational genotoxic risks.
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Biomedical subjects
Publications and source records attributed to M Sorsa.
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An overview on the metabolism and genotoxicity of styrene is given in this article. The mutagenic potency of styrene has been confirmed in a number of test systems providing the metabolic activation of styrene. Styrene is converted to styrene-7,8-oxide as catalyzed by cytochrome P-450 cored enzyme complex. Styrene-7,8-oxide is mutagenic in prokaryotic and eukaryotic test systems without metabolic activation. It reacts with nucleic acid bases, especially with deoxyguanosine producing 7-alkylguanine and deoxycytidine producing N-3 alkylcytosine. Quite recently, styrene-7,8-oxide has been found to be a potent carcinogen in rats. In human whole blood cultures, styrene is metabolized into styrene-7,8-oxide. Styrene is able to induce both SCEs and chromosomal aberrations in cultured lymphocytes. The clastogenic action of styrene can be explained by the metabolism of styrene into styrene-7,8-oxide in cultured human blood cells. Although also an arene oxide, styrene-3,4-oxide, has been suggested in the biotransformation of styrene, the evidence so far supports the view that the vinyl group oxidation and oxirane formation plays a predominant role in the genotoxicity of styrene.
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Scoring for structural chromosome abnormalities is one of the only practical methods available for detecting visual damage in human genetic material. Cytogenetic tests in vivo and in vitro have shown the clastogenic potential of a number of metals and metal compounds. The difficulties in in vivo studies lie in identifying a specific clastogen in an occupational setting, where simultaneous exposure to a number of organic and inorganic chemicals is a common phenomenon. Metals known to be carcinogens in animals also tend to possess chromosome-damaging properties, even though more extensive studies are needed before any conclusive evidence can be reached. The visible chromosomal damage produced by exposure to metal compounds should be considered as a warning indication of potentially adverse genetic and somatic effects in humans.
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New methods need to be developed for the biological monitoring and health surveillance of workers occupationally exposed to mutagenic and carcinogenic chemicals. Two potential approaches, the assay of urine for mutagenicity and the analysis of chromosomal changes in lymphocytes of workers, are discussed in this report with respect to experience in two occupational environments, the rubber industry and a hospital oncology unit. The urine of workers in the rubber industry has shown significantly increased mutagenic activity after the workweek in comparison to postvacation values. Handling cancer chemotherapeutic drugs in oncology units may cause exposure to the cytostatics, many of which are known mutagens and carcinogens. This exposure can be detected as an increased sister chromatid exchange frequency in cultured lymphocytes.
Epidemiological studies have shown that those who work in rubber industry have an increased risk of cancer. In the working environment they are exposed, probably, to several hundred different chemicals some of them being known or suspected carcinogens and mutagens. The bacterial fluctuation test was used to detect the mutagenicity in the urines of exposed workers. A group of unexposed office clerks served as controls. Both groups consisted of smokers and non-smokers, and that was taken into consideration in the results. Rubber workers, either smokers or non-smokers, exhibited significantly higher mutagenic activity in their urine than the occupationally unexposed controls when the base-pair substitution strain E. coli WP2 uvrA was used as indicator organism. Use of the frameshift strain S. typhimurium TA98 revealed increased mutagenicity in the urine of occupationally exposed smokers, nonsmokers and unexposed smokers. The extent of mutagenicity in the urine of workers who smoked suggested a synergistic effect of smoking and occupational exposure. The bacterial fluctuation test with urine samples as sources of mutagenicity is able to detect chemical exposure if the excreted compounds are still in active form or can be activated. The method can be used to identify hazardous working conditions long before the manifestation of possible pathological changes in exposed individuals.
No significant increase was detected in the number of chromosomally damaged cells in bone marrow of Chinese hamsters after either inhalation exposure to 300 ppm styrene or oral intake of 15% ethanol in drinking water (exposure time 4 days or 3 weeks). In combined exposure, a slight increase of chromosomal aberrations was observed in the group exposed for 4 days (2.0% aberrant cells vs. 0.0% in controls). The group exposed for 3 weeks to combined treatment showed no response (0.3% aberrant cells vs. 0.7% in controls).
Styrene produced no effect on induction of sex-chromosome nondisjunction in Drosophila melanogaster fed on 500 ppm styrene for 24 h. No increase in the frequency of micronuclei from chromosome fragments or from nondisjunction of whole chromosomes was seen in the bone marrow of Chinese hamsters (Cricetulus griseus) injected (i.p.) with a single dose of 1.0 g/kg b.wt. styrene or with 250 mg/kg b.wt. of the primary metabolite, styrene oxide.
Peripheral blood lymphocytes from 32 male rotogravure workers with daily exposure to toluene were studied for chromosome aberrations and sister chromatid exchange. Neither of these two cytogenetic parameters differed significantly from the correspondong frequencies in 15 unexposed control subjects. However, a significant increase in sister chromatid exchange was observed among smokers, both exposed and occupationally unexposed, compared to nonsmoking referents.
Both styrene and its presumed active metabolite styrene oxide show dose response as potent inducers of sister chromatid exchanges (SCEs) in human lymphocyte cultures. The SCE inducing and clastogenic capacity of styrene in lymphocytes in vitro can be explained by gas chromatographically measurable increase of styrene oxide in styrene treated cultures.
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