A. Léonard

Carcinogenicity, mutagenicity and teratogenicity of manganese compounds

Manganese, an essential trace element, is one of the most used metals in the industry. Recently, several new manganese compounds have been introduced as fungicide, as antiknock agent in petrol and as contrasting agent in nuclear magnetic resonance tomography. Manganese displays a somewhat unique behaviour with regard to its toxicity. It is relatively non-toxic to the adult organism except to the brain where it causes Parkinson-like symptoms when inhaled even at moderate amounts over longer periods of time. Relatively high doses of manganese affect DNA replication and repair in bacteria and causes mutations in microorganism and mammalian cells although the Ames test does not appear to be particularly responsive to manganese. In mammalian cells, manganese causes DNA damage and chromosome aberrations. Information on organic manganese derivatives is still insufficient. Large amounts of manganese affect fertility in mammals and are toxic to the embryo and foetus. The fungicide MANEB and the contrasting agent MnDPDP also can be embryotoxic, but the latter only at doses much higher than those clinically employed. Information on the anti-knock agent MMT is inadequate. On the other hand, manganese deficiency can also affect fertility and be teratogenic. Information on cancer due to manganese is scanty but the results available do not indicate that inorganic manganese is carcinogenic. More information is desirable with regard to the organic manganese derivatives. It may surprise that an agent that causes mutations is not also carcinogenic. The experience with manganese shows that conclusions with regard to carcinogenicity of an agent based on the observation of mutations are subject to uncertainties. Altogether, it appears that, because of the very high doses at which positive effects have been found, manganese would not represent a significant carcinogenic risk to the population and workers. Care must, however, be exercised with respect to central-nervous symptoms after chronic exposure and with respect to effects on the embryo. Pregnant women should not be exposed to manganese at the work place.

Development and validation of alternative metabolic systems for mutagenicity testing in short-term assays

We present here the results obtained within the framework of an EU funded project aimed to develop and validate alternative metabolic activating systems to be used in short-term mutagenicity assays, in order to reduce the use of laboratory animals for toxicology testing. The activating systems studied were established cell lines (Hep G2, CHEL), genetically engineered V79 cell lines expressing specific rat cytochromes P450, erythrocyte-derived systems, CYP-mimetic chemical systems and plant homogenates. The metabolically competent cell lines were used as indicator cells for genotoxic effects as well as for the preparation of external activating systems using other indicator cells. The following endpoints were used: micronuclei, chromosomal aberrations and sister chromatid exchanges, mutations at the hprt locus, gene mutations in bacteria (Ames test), unscheduled DNA synthesis and DNA breaks detected in the comet assay. All metabolic systems employed activated some promutagens. With some of them, promutagens belonging to many different classes of chemicals were activated to genotoxicants, including carcinogens negative in liver S9-mediated assays. In other cases, the use of the new activating systems allowed the detection of mutagens at much lower substrate concentrations than in liver S9-mediated assays. Therefore, the alternative metabolizing systems, which do not require the use of laboratory animals, have a substantial potential in in vitro toxicology, in the basic genotoxicity testing as well as in the elucidation of activation mechanisms. However, since the data basis is much smaller for the new systems than for the activating systems produced from subcellular liver preparations, the overlapping use of both systems is recommended for the present and near future. For example, liver S9 preparations may be used with some indicator systems (e.g., bacterial mutagenicity), and metabolically competent mammalian cell lines may be used with other indicator systems (e.g., a cytogenetic endpoint) in a battery of basic tests.

A Comparative-study, With 40 Chemicals, of the Efficiency of the Salmonella Assay and the Sos Chromotest (kit Procedure)

A comparison was made, for 40 compounds belonging to different chemical classes, of the mutagenicity as measured by the Salmonella assay and of the SOS-inducing potency as measured by the SOS chromotest kit procedure. It was found that most (78%) of the chemicals described as mutagens/carcinogens (14 compounds) were detected with a simplified Ames test procedure, using 3 strains (TA 97, TA 98, TA 100) and 3 concentrations of the tested material. The SOS chromotest, carried out following the recommendations of the commercially available kits, revealed that only 4 Ames test-positive compounds were mutagenic towards E. coli strain PQ 37.

Relation between the x-ray dose and the rate of chromosome rearrangements in spermatogonia of mice.

Male mice from the BALB/c strain were irradiated with increasing doses of X-irradiation. Ten weeks after the treatment, meiotic preparations from the testes were made by an air-drying technique. The reciprocal translocation was the most frequent chromosome rearrangement seen. No relation was found between the nature of the rearrangements and the X-ray dose. The relationship between the X-ray dose and the rate of abnormal cells appears to be linear with a regression coefficient b = 0.017121 ± 0.001048.

Mutagenicity, Carcinogenicity and Teratogenicity of Zinc

Zinc is a common element in the human environment and constitutes an important trace element intervening in many biological processes. Toxicity of zinc is low; zinc deficiency represents, however, a hazard for human health. Zinc is not mutagenic and has little, if any, clastogenic properties. Zinc can induce tumours but only following local application, and does not represent a carcinogenic risk to man. It is still uncertain whether zinc can cause malignant transformation but zinc is needed for cellular proliferation of existing tumours and tumour growth is retarded by zinc deficiency. Zinc is not teratogenic; it can, in fact, avert teratogenicity of other agents. Conversely, zinc deficiency may be harmful to the developing organism.

An Evaluation of the Mutagenic, Carcinogenic and Teratogenic Potential of Microwaves

A notable proportion of the population is exposed to an increasing number of devices emitting microwaves, a form of non-ionizing electromagnetic radiation in the range 300-30000 mHz. The activation energy of microwave radiations is too small to directly modify any chemical bonds in the irradiated matter. At microwave frequencies the macroscopic dielectric properties of tissues are strongly determined by their water content. Tissues like muscle, brain, skin, with a high water content, have higher permittivity and conductivity values than bone or fat with low water contents. Owing to the energy transfer, to living tissues, by a dipolar relaxation mechanism of water molecules, the penetration of microwaves is limited and one observes a fast and very efficient heat-loss production. A review of the available literature shows that most results on the mutagenicity of microwaves are negative or can often be explained by a temperature enhancement. If microwaves are apparently unable to damage DNA at sub-thermal exposure levels, some results indicate, however, that they might easily potentiate the damaging action of other DNA antagonist agents such as UV or chemicals.

Dose-response relationship for translocations induced by x-irradiation in spermatogonia of mice.

Male BALB/c mice received local irradiation to the testes with exposures of 250, 500, 750, 1000, or 1250 R of x-rays. Thirty weeks after treatment, the mice were killed, the testes were removed and...

A new marker for chromosome studies in the mouse.

THE mouse is one of the best mammals for genetic and cytogenetic investigations. Unfortunately, its value for cytogenetic research is restricted because all forty chromosomes are acrocentric. Their sizes range in the ratio of 5 : 2 (longest to shortest) with relatively little difference other than length to help in identification. At the first metaphase stage of meiosis, twenty bivalents are normally formed and this pairing is commonly used to correlate abnormal configurations with specific chromosome changes. It is obvious, however, that cellular markers (cells with a visible different karyotype from the normal) would be useful for transplantation experiments and work on carcinogenesis or radiation chimeras. Some translocations induced in mice by X-irradiation have been used as such cellular markers1,2.

Chromosome aberrations after treatment with radioactive iodine for thyroid cancer

The study aimed to investigate whether the determination of chromosome aberrations in circulating blood lymphocytes could be useful to assess whole-body exposure from radioactive iodine released accidentally. Ten patients treated with two doses of 1850 MBq of 131I given 24 h apart for thyroid cancer were studied for chromosome aberrations (dicentrics) in blood samples taken before and at various times after exposure. The increase in the yield of aberrations caused by the exposure to iodine was small but statistically significant. Compared to published values for whole-body doses after such treatment, this increase appears to be somewhat smaller than expected from dose-effect relationships obtained for an acute exposure of lymphocytes in vitro or in vivo, a fact which could be explained by the low dose rate of the 131I exposure. Thus, in situations where a population was exposed as a result of the release of radioactive iodine, a determination of chromosome aberrations in blood lymphocytes would not appear to be very useful to determine exposure from iodine.

Chromosome aberrations in employees from fossil-fueled and nuclear-power plants.

Chromosome aberrations were scored in 59 persons from fossil-fueled plants, in 89 persons from nuclear-power plants and in 23 controls. A significant increase in acentric chromosome fragments and dicentric chromosomes compared to the control group was observed in both types of workers. Moreover, the number of abnormal cells was significantly greater in workers of conventional plants than in those of nuclear-power plants. When adjusted for loss of lymphocytes according to a half-life of 3 years, this difference was also significant for the number of dicentric chromosomes observed. A significant effect of length of exposure or of frequency of radiological examinations could be discerned only in the group of workers from conventional plants.