Biomedical subjects
Publications and source records attributed to C Ramel.
Treatment of Drosophila males with 1--20% vinyl chloride in air gave an increased frequency of complete and mosaic recessive lethals. Pretreatment with phenobarbiturate for 24 h caused an increase in the mutagenic effect of vinyl chloride. This indicates that the mixed-function oxygenase system can be induced in Drosophila in the same way as in mammals.
Thioacetamide, which is carcinogenic in mice and rats, has been reported as negative in Ames's test on Salmonella his- with and without liver microsomal fraction (S 9 mix). Tests on Drosophila reported here showed a significant increase in sex-linked recessive lethals after treatment with thioacetamide, both after injection and after feeding of males.
In erythrocytes from mouse bone marrow the time schedule of micronucleus formation in relation to the last DNA synthesis was investigate by [3H]thymidine labelling in the autoradiographic technique. The results suggest that micronuclei can be produced both in the G 2 and S periods by X-irradiation. Furthermore, X-rays had a delaying effect on the cell cycle leading to a pronounced under-estimation of the dose-effect curve at higher dosages. Even when the cells were harvested as late as 30 h after irradiation, the full effect had most likely not yet appeared at dosages over 100 rad. Combined treatment with caffeine did not influence the dose-effect curve of X-rays, indicating no influence of a caffeine-sensitive repair mechanism. The induction of micronuclei by MMS, in contrast with the effect of X-rays, seems to have been restricted, at least predominantly, to the period of DNA synthesis. The dose-effect relation of MMS was characterized by a threshold giving a weaker effect than expected at low doses. Pretreatment with caffeine enhanced the effect of MMS at high but not at low doses, suggesting an error-free repair process operating at low doses and an error-prone and caffeine-sensitive repair at higher doses. The extent of alkylation in the bone-marrow cells was linear with respect to injected dose of MMS both in the presence and absence of caffeine. Pretreatment with phenobarbital reduced the effect of MMS sixfold, which can be explained by a reduction of alkylation found in the bone marrow. This result is in agreement with the enhanced excretion of MMS or its metabolites into urine and bile after pretreatment of the mice with phenobarbital. DMN had no measurable effect on the frequency of micronuclei. However, in the presence of caffeine a significant effect was observed, which was roughly of the same magnitude for the two dosages used. Pretreatment with phenobarbital also indicated a synergistic effect between DMN and phenobarbital. The treatment with DMN, phenobarbital and caffeine together gave a frequency of micronuclei not different from the control level, suggesting some antagonistic action between phenobarbital and caffeine. The indication that DMN is caffeine-sensitive at low dosages, whereas MMS is not, might be related to the difference in the alkylating properties of these chemicals.
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The stray light effect on the visual field was quantitatively studied in normal subjects under experimental conditions. Stray light comparable to that caused by lens opacities was produced by means of selective occluders or diascleral illumination. The results derived from this model were compared with the statistical evaluation of the visual fields of 123 eyes with glaucoma followed for a minimum of 10 years. As expected lens opacities resulted in a concentric constriction of the peripheral fields and a loss of the inner isopters. The light difference sensitivity as determined by static perimetry was generally reduced preferentially in the central fields. These calculations provide a measure to anticipate the degree of lens opacifications from a depressed visual without knowledge of the visual acuity.
The by-product from vinyl chloride production, EDC-tar, is a complex mixture of mainly short-chained chlorinated aliphatic hydrocarbons. This mixture has been tested for mutagenicity by means of Ames' Salmonella/mammalian microsome method. Since most of the components in the tar are poorly soluble in water, three agents were used as solvents or emulsifier: ethanol, DMSO, and Tween 80. The results with all these agents showed that EDC-tar contains direct as well as indirect mutagenic constitutents. It could be concluded that the mutagenic effect observed in the test could not be due to any significant extent to one of the main components, ethylene dichloride (1,2-dichloroethane). This substance showed a weak mutagenic effect, but only at higher concentrations than could be available in the highest concentration tested of the tar. Although the microsomal system enhanced the mutagenicity both of the EDC-tar and of 1,2-dichloroethane, this enhancement was dependent on NADPH in the case of EDC-tar but independent of NADPH with 1,2-dichloroethane. The Salmonella/mammalian microsome method seems to be a suitable tool for both mutagenicity screening of complex chemical mixtures and identification of mutagenic constituents in such mixtures.
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Welding fume particles collected from different welding procedures were tested for mutagenicity in Escherichia coli, with the inhibition zone in pol A- as compared to pol A+, and in Salmonella typhimurium, TA 100 strain. While no mutagenicity was found with mild steel welding, a mutagenic effect was established with samples from stainless steel welding. This mutagenicity was particularly associated with manual metal arc (MMA) welding, and less so with metal inert-gas welding. A decrease in or an elimination of the effect occurred with a liver microsomal metabolizing system (S-9 mix). The MMA samples produced the strongest mutagenic effect. More-detailed investigations on these samples showed that the mutagenic agent(s) is water soluble. An increased mutagenicity, which also revealed the induction of frame shift mutations, was found with TA 98. The same welding fume sample was used for a mutagenicity test (resistance to 6-thioguanine) with V 79 hamster cells. Because of the high toxicity of these welding fume particles on the cells, only very low concentrations could be tested, but the increase of mutations, when compared to the negative control, was significant. It is suggested that hexavalent chromium may be involved in the mutagenic effect of the welding fumes.
The test of induced micronuclei in erythrocytes of mammalian bone marrow constitutes, because of its high experimental resolution power, a suitable method for the screening of induced chromosomal lesions at very low dosages of chemicals or irradiations. This test was used for a comparative investigation of the effect of low dose levels of X-irradiation and of the alkylating agent methyl methanesulphonate (MMS). The dose-effect curve of X-irradiation indicated a deviation from linearity at 10 rad, showing a significantly stronger effect than expected on extrapolation from the control to 100 rad. This deviation from linarity, however, only appeared at a low dose rate (18 R/min), whereas a linear dose-effect relation was indicated with a high dose rate (95 R/min). Experiments at 10 rad with different dose rates at two different current potentials suggested that this effect of the dose rate is more pronounced with soft than with hard X-irradiation. The induction of micronuclei with MMS follows a drastically different dose-effect curve as compared with X-irradiation. The relative efficiency of the treatment is lowest at low concentrations, presumably as a result of the efficient repair process at such dose levels. Simultaneous treatment with X-rays and MMS at low dose levels only resulted in an additive effect. This suggests that X-irradiation does not interfere with the repair process operating with MMS. The difference in the dose-effect relations of X-irradiation as compared with MMS may be brought back to the fact that X-rays, in contrast with MMS, produce double-strand breaks.
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A survey is given of Swedish legislation for control of chemicals in the environment. Although no direct legal requirements for mutagenicity testing of chemicals exist at present in Sweden, such requirements can be enforced within the existing laws. Testing and research in chemical mutagenicity are especially performed at the Environmental Toxicology Unit of the Wallenberg laboratory, University of Stockholm. An outline is given of the organization of the unit, which is based on an interdisciplinary cooperation, among divisions of organic and analytical chemistry, cellular toxicology, and genetics. As examples of projects under joint investigation results on polychlorinated biphenyl (PCB) and on vinyl chloride are briefly described.
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