Mutagenicity, carcinogenicity and teratogenicity of cobalt metal and cobalt compounds

Cobalt is a technically important metal, used mainly as a binder in the hard-metal industry and as a constituent of many alloys. Cobalt compounds are used as drying agents in paints and laquers. Since ancient times, cobalt compounds have been used as coloring agents for pottery, ceramics, and glass. Soluble cobalt salts interfere adversely with cell division, bind irreversibly to nucleic acids in the cell nucleus, induce chromosome aberrations in plants, and are weakly mutagenic in some in vitro tests with cultured animal cells, bacteria, and yeast. Injections or implantation of cobalt metal, cobalt alloys, and cobalt compounds induced local and sometimes metastasizing sarcomas in rats, rabbits, and mice. Mouse is the least susceptible animal. The only published inhalation study with hamsters exposed to CoO aerosols remained non-positive. Indication of possible carcinogenic effects of cobalt alloys or compounds in human populations has arisen from medical use, in hard-metal industries, and at cobalt production. Unfortunately, confounding by nickel and arsenic is a major problem, and the size of most of the investigated populations has been rather small, so none of the investigations alone gives sufficient evidence of a carcinogenic effect in humans, but taken together there is an indication of a carcinogenic potential that should be explored further.

The genetic mechanisms responsible for {alpha}-radiation-induced lung cancer in rats following inhalation of {sup 239}Pu is an ongoing area of research in our laboratory. Previous studies have examined the status of the p53 gene by immunohistochemistry. Only two tumors (2/26 squamous cell carcinomas) exhibited detectable levels of p53 products. Both were the result of mutations in codons 280 and 283. More recent studies of X-ray-induced lung tumors in rats showed a similar lack of involvement of p53. In conclusion, we found that {alpha}-radiation-induced rat lung tumors have a high incidence (31 of 39) of cyclin D{sub 1} overexpression.

Inhalation cancer risk assessment of cobalt metal

Cobalt is a natural metallic element with extensive applications across multiple industries, and a critical metal for lithium-ion battery production. Cobalt's only known biological function is its role as a metal component of vitamin B12. Other cobalt compounds have been described as toxic to the environment and the human body following excessive exposure. The International Agency for Research on Cancer (IARC) has classified cobalt, including cobalt metal and soluble cobalt(II) salts, as Group 2A, meaning it is probably carcinogenic to humans. This review aims to present a comprehensive overview of historical and current sources of cobalt in diverse exposure settings, along with its various intake routes. An extensive literature search was conducted between September 2021 and January 2022, analysing over 300 publications. The primary goal of these studies was to identify cobalt sources, intake routes, and exposure pathways. Workers may be exposed to various cobalt compounds and metal powders primarily through inhalation, but exposure can also occur via skin contact or ingestion. For the general population, food typically arises as the predominant source of cobalt exposure. Furthermore, exposure may occur through ambient air, tobacco smoke, and medical implants.

International Symposium on the Health Hazard Evaluation of Fibrous Particles Associated with Taconite and the Adjacent Duluth Complex

Relevance of the rat lung tumor response to particle overload for human risk assessment-Update and interpretation of new data since ILSI 2000.

The current ecological situation sharply raises the question of checking water sources for mutagenic,genotoxic, and phytotoxic activity. An increase in human activity around water sources increases therisk of surface water pollution by various emissions and wastes, an increase in the concentration ofvarious pollutants in the aquatic environment can lead to mutagenic activity of this source. Since therivers Esik, Turgen, and Lake Esik, located in the Enbekshikazakh district of the Almaty region, are closeto highways, various enterprises and proximity to human activities, the risk of pollution is continuallyincreasing. As a result of physicochemical analysis of the composition of water samples, an excessof the maximum permissible concentration for manganese, lead, zinc, and cadmium was found. TheAllium-test revealed toxicity and mutagenicity of the studied water samples. The phytotoxic activitywas observed in the water of the River Esik, manifested in the inhibition of onion root growth. Cytotoxicactivity in the water of the rivers Esik, Turgen, and Lake Esik was manifested in a statistically significantdecrease (p≤0.05) in the mitotic index compared to the negative control (distilled water). A weak mutagenic activity was established in water samples from the river. Esik, Turgen and Lake Esik, manifested ina statistically significant increase in the level of chromosomal aberrations in the cells of the root meristemof onions when germinating in water from these water bodies, compared with negative control (p≤0.05).Thus, the obtained results of the study of the toxic and mutagenic potential of natural surface waters fromwater bodies located on the territory of the Enbekshikazakh district of the Almaty region indicate theircontamination with environmentally hazardous factors that pose a threat to biota and human health.Key words: natural surface waters, heavy metals, Allium test, mitotic index, chromosomalaberrations.

Determining the mutagenic activity of a tar, its vapors and aerosols

Furan is a volatile compound that is formed in foods during thermal processing. It is classified as a possible human carcinogen by international authorities based on sufficient evidence of carcinogenicity from studies in experimental animals. Although a vast number of studies both in vitro and in vivo have been performed to investigate furan genotoxicity, the results are inconsistent, and its carcinogenic mode of action remains to be clarified. Here, we address the mutagenic and clastogenic activity of furan and its prime reactive metabolite cis-2 butene-1,4-dial (BDA) in mammalian cells in culture and in mouse animal models in a search for DNA lesions responsible of these effects. To this aim, Fanconi anemia-derived human cell lines defective in the repair of DNA inter-strand crosslinks (ICLs) and Ogg1−/− mice defective in the removal of 8-hydroxyguanine from DNA, were used. We show that both furan and BDA present a weak (if any) mutagenic activity but are clear inducers of clastogenic damage. ICLs are strongly indicated as key lesions for chromosomal damage whereas oxidized base lesions are unlikely to play a critical role.

New investigations into the genotoxicity of cobalt compounds and their impact on overall assessment of genotoxic risk

The oral LD50 values of an antipsoriatic drug, dithranol, were 1542 mg/kg in NMRI mice and 3216 mg/kg in Wistar rats. Three 10-acyl analogues of dithranol (10-acetyl, 10-propionyl and 10-butyryl dithranol or butantrone) were more toxic both in mice and rats. They were mutagenic only in TA1537 of the five Salmonella typhimurium strains tested. None of them were mutagenic in two Escherichia coli strains. Butantrone was least toxic to test bacteria and had the lowest mutagenic activity on TA1537. In metaphase analysis of in vitro treated human lymphocytes, dithranol, 10-acetyl dithranol and 10-propionyl dithranol produced significant increases in the number of chromosome and chromatid gaps but without a clear dose-response relationship, and without inducing significant breaks. Butantrone did not cause significant increases in gaps or breaks. In the mouse micronucleus test, dithranol and butantrone caused no increases in micronucleated polychromatic or normochromatic erythrocytes, indicating lack of clastogenic activity in vivo at maximum tolerated doses. Hence, dithranol and its 10-acyl analogues have a weak mutagenic activity in vitro. The mutagenic activity of butantrone is lower than that of the other analogues and dithranol.

We investigated mutations of the Tp53 tumor suppressor gene (formerly known as p53) in the lung tumors induced in rats after inhalation of plutonium dioxide ((239)PuO(2)) aerosols. Exons 5, 6, 7 and 8 of the Tp53 gene were examined for mutations by single-strand conformation polymorphism (SSCP) analysis of polymerase chain reaction (PCR)-amplified fragments and direct sequencing analysis. Almost all the mutations were guanine (G) to adenine (A) transitions and were distributed in exons 5 and 6. The Tp53 mutations occurred in lung tumors of various phenotypes and levels of immunohistochemical staining of Tp53 nuclear protein. These results indicate that the Tp53 mutations are not associated with tumor phenotype and nuclear accumulation of Tp53 protein, and that the G to A transition could be a common point mutation in the lung tumors seen after the inhalation of plutonium dioxide. The point mutations in the Tp53 gene seem to play a role in the development of lung tumors in rats after inhalation exposures to plutonium dioxide.

Diesel engines play a vital role in world economy, especially in transportation. Exhaust from traditional diesel engines using high-sulfur fuel contains high concentrations of respirable carbonaceous particles with absorbed organic compounds. Recognition that some of these compounds are mutagenic has raised concern for the cancer-causing potential of diesel exhaust exposure. Extensive research addressing this issue has been conducted during the last three decades. This critical review is offered to facilitate an updated assessment of the carcinogenicity of diesel exhaust and to provide a rationale for future animal research of new diesel technology. Life-span bioassays in rats, mice, and Syrian hamsters demonstrated that chronic inhalation of high concentrations of diesel exhaust caused lung tumors in rats but not in mice or Syrian hamsters. In 1989, the International Agency for Research on Cancer (IARC) characterized the rat findings as “sufficient evidence of animal carcinogenicity,” and, with “limited” evidence from epidemiological studies, classified diesel exhaust Category 2A, a “probable human carcinogen.” Subsequent research has shown that similar chronic high concentration exposure to particulate matter generally considered innocuous (such as carbon black and titanium dioxide) also caused lung tumors in rats. Thus, in 2002, the U.S. Environmental Protection Agency (EPA) concluded that the findings in the rats should not be used to characterize the cancer hazard or quantify the cancer risk of diesel exhaust. Concurrent with the conduct of the health effects studies, progressively more stringent standards have been promulgated for diesel exhaust particles and NOx. Engine manufacturers have responded with new technology diesel (improved engines, fuel injection, fuels, lubricants, and exhaust treatments) to meet the standards. This review concludes with an outline of research to evaluate the health effects of the new technology, research that is consistent with recommendations included in the U.S. EPA 2002 health assessment document. When this research has been completed, it will be appropriate for IARC to evaluate the potential cancer hazard of the new technology diesel.

Lung Cancer Rates in Carbon-Black Workers Are Discordant with Predictions from Rat Bioassay Data

The Production of Lung Tumours in Rats by 3:4 Benzpyrene, Methylcholanthrene and the Condensate from Cigarette Smoke