Mutation Research/Reviews in Genetic Toxicology最新文献

The genetic toxicity of atrazine, a member of the s-triazine herbicides, was reviewed with the objective of classifying the chemical. Atrazine has been subjected to a broad range of genetic tests with predominantly negative results. Some publications, specifically those measuring dominant lethality in mice and bone marrow clastogenicity in rodents, reported conflicting results across two or more independent tests. Two approaches were employed to evaluate and interpret the results. The first approach attempts to classify each type of genetic endpoint as positive or negative and resolve test conflicts by critical assessment of the study and detailed data. This is the more traditional “expert judgment” approach to hazard assessment. The second approach employs a computer-assisted weight-of-evidence method of data analysis. This approach does not require resolution of conflicts but uses all data sets to arrive at a classification of hazard. The first approach was able to resolve some conflicts but not all. Use of the “expert judgement” results in an equivocal conclusion and classification. Use of the weight-of-evidence method resulted in a conclusion that atrazine does not pose a mutagenic hazard. The weight-of-evidence scheme is proposed to be a more practical and relevant approach for assessing complex data sets.

Ethylene thiourea (ETU) is a common contaminant, metabolite and degradation product of the fungicide class of ethylene bisdithiocarbamates (EBDCs); as such, they present possible exposure and toxicological concerns to exposed individuals. ETU has been assayed in many different tests to assess genotoxicity activity. While a great number of negative results are found in the data base, there is evidence that demonstrates ETU is capable of inducing genotoxic endpoints. These include responses for gene mutations (e.g. Salmonella), structural chromosomal alterations (e.g. aberrations in cultured mammalian cells as well as a dominant lethal assay) and other genotoxic effects (e.g. bacterial rec assay and several yeast assays).

It is important to consider the magnitude of the positive responses as well as the concentrations/doses used when assessing the genotoxicity of ETU. While ETU induces a variety of genotoxic endpoints, it does not appear to be a potent genotoxic agent. For example, it is a weak bacterial mutagen in the Salmonella assay without activation in strain TA1535 at concentrations generally above 1000 μg/plate. Weak genotoxic activity of this sort is usually observed in most of the assays with positive results. Since ETU does not appear very potent and is not extremely toxic to test cells and organisms, it is not surprising to find that ETU does not produce consistent effects in many of the assays reviewed. Consequently, in many instances, mixed results for the same assay type are reported by different investigators, but as reviewed herein, these results may be dependent upon the test conditions in each individual laboratory. A primary shortcoming with many of the reported negative results is that the concentrations or doses used are not high enough for an adequate test for ETU activity. There are also problems with many of the negative assays generally in protocol or reporting, particularly with the in vivo studies (e.g. inappropriate sample number and/or sampling times; inadequate top dose employed).

Overall, while ETU does not appear to be a potent genotoxic agent, it is capable of producing genotoxic effects (e.g. gene mutations, structural chromosomal aberrations). This provides a basis for weak genotoxic activity by ETU. Furthermore, based on a suggestive dominant lethal positive result, there may be a concern for heritable effects. Due to the many problems with the conduct and assessment of the in vivo assays, it is worth repeating in vivo

Coffee and caffeine are mutagenic to bacteria and fungi, and in high concentrations they are also mutagenic to mammalian cells in culture. However, the mutagenic effects of coffee disappear when bacteria or mammalian cells are cultured in the presence of liver extracts which contain detoxifying enzymes. In vivo, coffee and caffeine are devoid of mutagenic effects. Coffee and caffeine are able to interact with many other mutagens and their effects are synergistic with X-rays, ultraviolet light and some chemical agents. Caffeine seems to potentiate rather than to induce chromosomal aberrations and also to transform sublethal damage of mutagenic agents into lethal damage. Conversely, coffee and caffeine are also able to inhibit the mutagenic effects of numerous chemicals. These antimutagenic effects depend on the time of administration of coffee as compared to the acting time of the mutagenic agent. In that case, caffeine seems to be able to restore the normal cycle of mitosis and phosphorylation in irradiated cells. Finally, the potential genotoxic and mutagenic effects of the most important constituents of coffee are reviewed. Mutagenicity of caffeine is mainly attributed to chemically reactive components such as aliphatic dicarbonyls. The latter compounds, formed during the roasting process, are mutagenic to bacteria but less to mammalian cells. Hydrogen peroxide is not very active but seems to considerably enhance mutagenic properties of methylglyoxal. Phenolic compounds are not mutagenic but rather anticarcinogenic. Benzopyrene and mutagens formed during pyrolysis are not mutagenic whereas roasting of coffee beans at high temperature generates mutagenic heterocyclic amines. In conclusion, the mutagenic potential of coffee and caffeine has been demonstrated in lower organisms, but usually at doses several orders of magnitude greater than the estimated lethal dose for caffeine in humans. Therefore, the chances of coffee and caffeine consumption in moderate to normal amounts to induce mutagenic effects in humans are almost nonexistent.

Two antimutagenicity databases were prepared by applying a co-treatment procedure to the Salmonella reversion assay. Ninety compounds belonging to various chemical classes were quantitatively tested for antimutagenicity towards the direct-acting mutagen 4-nitroquinoline 1-oxide (4NQO) in strain TA100 of S. typhimurium and 63 of them were additionally tested for antimutagenicity towards unfractionated mainstream cigarette smoke (CS) in strain TA98, in the presence of S9 mix. Twelve compounds (13.3%) inhibited 4NQO mutagenicity by at least 50%, with a MID₅₀ (dose inhibiting 50% of mutagenicity) varying over a 1226-fold range. Twenty-six compounds (41.3%) inhibited CS mutagenicity, with a MID₅₀ varying over a 520-fold range. Three compounds only, i.e., bilirubin, curcumin and myricetin, were capable of inhibiting the mutagenicities of both 4NQO and CS. However, myricetin and the other flavonoid rutin were at the same time mutagenic by inducing frameshift mutations following metabolic activation. There was a rather rigorous selectivity of antimutagenicity data depending on the chemical class of inhibitors and it was possible to discriminate protective effects within several pairs or series of structurally related compounds. For instance, all eight thiols and aminothiols inhibited 4NQO mutagenicity, which contrasted with the inactivity of the remaining 17 sulfur compounds tested, all of them lacking a free sulfhydryl group. The mutagenicity of CS was consistently inhibited by the majority of phenols (eight out of 10 tested) and by all two isothiocyanates, two dithiocarbamates, three indole derivatives, three tetrapyrrole compounds and three flavonoids tested. Although the results obtained cannot be extrapolated to other mutagens or test systems, they may provide a useful source of information for research in the area of antimutagenesis and for the development of chemopreventive agents.

Cyclosporine is an important therapeutic agent for transplant recipients and for a growing number of autoimmune diseases. Experimental animal and human data has indicated that cyclosporine is unlikely to be genotoxic. In contrast, azathioprine, an agent often given with cyclosporine, is considered to be genotoxic making the assessment of the independent effects of cyclosporine difficult. Cyclosporine does appear to be related to the development of tumors, primarily lymphomas, in animals and humans, but the basis of its potential carcinogenicity is not completely understood. In terms of reproductive and developmental toxicity, cyclosporine produces some adverse effects in both experimental animals and humans. In animals, the effects are seen at high doses sufficient to cause maternal toxicity. In humans, outcomes such as growth retardation have been noted, but the confounding effects of renal toxicity and resultant pregnancy complications cloud the interpretation. An increase in congenital anomalies and genetic disease have not been found reported in human studies that are limited in sample size.

This paper discusses (a) data on the epidemiological and etiological aspects of human congenital abnormalities, (b) the multifactorial threshold model and other models which have been proposed to explain their inheritance patterns and recurrence risks in families and (c) current concepts on mechanisms on the prevalence of heritable variation for quantitative traits in populations.

Congenital abnormalities, which afflict an estimated 6% of all live births, are etiologically heterogeneous. The majority of these do not follow Mendelian transmission patterns, but do ‘run’ in families. The multifactorial threshold model is an extension of genetic principles developed for quantitative traits to all-or-none traits; in its simplest formulation, it assumes the existence in the population of an underlying normally distributed ‘liability’ (which is due to numerous genetic and environmental factors acting additively, each contributing a small amount of liability) and of a ‘threshold’ beyond which the individual is affected. For most congenital abnormalities, the nature of these factors remains unknown. Other models assume fewer causal factors although, again, these remain to be identified.

The question of how considerable heritable variation for most quantitative / polygenic traits has come to exist is a long-standing one in evolutionary population genetics. Models postulating that its existence is consistent with a balance between recurrent mutation and stabilizing selection or suggesting the possible operation of other mechanisms have been published in the literature.

Nitrogen oxides (NO_x) are formed in combustion processes and are major pollutants in urban air. Relatively few studies on the genotoxicity of NO₂ and NO have been performed. These studies indicate that NO₂ is genotoxic in vitro, but the effect of NO seems to be very slight.

One in vivo study showed chromosome aberrations and mutations in lung cells after inhalation of NO₂ (and NO), but tests for chromosome aberrations in lymphocytes and spermatocytes or micronuclei in bone marrow were negative after inhalation of NO₂. Based on present studies, there is no clear evidence of a carcinogenic potential of NO₂, although lung adenomas were induced in the susceptible strain A/J mouse.

The primary metabolites of NO_x are nitrite and nitrate. Nitrate seems to be devoid of genotoxic properties, but nitrite is genotoxic in vitro, and there are also positive in vivo results. Cancer studies have been mainly negative. However, carcinogenic nitrosamines have been shown to be formed in vivo after inhalation of NO₂.

Nitrogen oxides are key components in atomospheric smog formation, which may lead to secondary effects. Strongly mutagenic nitro-PAH compounds are easily formed, and mutagenic reaction products may be formed photochemically from alkenes.

This article reviews literature data concerning the genotoxicity of 29 mercury-containing agents, including laboratory compounds as well as ingredients of preparations used as fungicides, dyes, disinfectants and drugs. A variety of genetic end-points were investigated in bacteria, yeasts, moulds, plants, insects, cultured cells from fishes, rodents or humans, aquatic organisms, amphibians, mammalia and exposed humans. The overall evaluation is quite complex. Mercury compounds failed to induce point mutations in bacteria but often exerted clastogenic effects in eukaryotes, especially by binding SH groups and acting as spindle inhibitors, thereby causing c-mitosis and consequently aneuploidy and/or polyploidy. Inorganic mercury compounds were also found to induce the generation of reactive oxygen species and glutathione depletion in cultured mammalian cells. Although different mercury compounds tended to produce qualitatively comparable genetic effects, which suggests the involvement of a common toxic entity, methylmercury derivatives and other ionizable organomercury compounds were more active in short-term tests than either non-ionizable mercury compounds (e.g., dimethylmercury) or inorganic mercury salts (e.g., mercuric chloride). The results of cytogenetic monitoring in peripheral blood lymphocytes of individuals exposed to elemental mercury or mercury compounds from accidental, occupational or alimentary sources were either negative or borderline or uncertain as to the actual role played by mercury in some positive findings. Both genotoxic and non-genotoxic mechanisms may contribute to the renal carcinogenicity of mercury, which so far has been convincingly demonstrated only in male rodents treated with methylmercury chloride.

The mutagenic, carcinogenic and teratogenic effects of vanadium and its compounds are reviewed. It is concluded that vanadium is not clastogenic and only weakly mutagenic; it has marked mitogenic activity affecting the distribution of chromosomes during mitosis and possibly causing aneuploidy. The few positive data on effects of vanadium during development leave it open whether direct effects on the embryo or fetus or physiological disturbances in the mother are responsible. No data exist indicating that vanadium is carcinogenic in animals or man, but since it interferes with mitosis and chromosome distribution, the possibility that vanadium might be carcinogenic under certain conditions cannot be dismissed offhand.