Genotoxicity of arsenical compounds

With respect to global human health hazard, arsenic (As) is one of the most important environmental single substance toxicants. Currently, millions of people all over the world are exposed to the ubiquitous element in exposure levels leading to long-term toxicity, in particular cancer. Unfortunately, it has not been elucidated up to now how As mechanistically leads to the induction of neoplasia. Besides its tumorigenic potential, As has been shown to be genotoxic in a wide variety of different experimental set-ups and biological endpoints. In vitro, the element was shown to induce chromosomal mutagenicity like micronuclei, chromosome aberrations, and sister chromatid exchanges. It mainly acts clastogenic but also has an aneugenic potential. Instead, its potential to induce point mutations is very low in bacterial as well as in mammalian cell systems. However, in combined exposure with point mutagens in vitro, As was shown to enhance the frequency of chemical mutations in a synergistic manner. Additionally, As was shown to induce chromosome aberrations and micronuclei in vivo in experiments with mice. After long-term exposure to As-contaminated drinking water, the great majority of human biomonitoring studies found elevated frequencies of DNA lesions like micronuclei or chromosome aberrations. Respective occupational studies are few. Like it is the case for As carcinogenicity, it is not known through which mechanism the genotoxicity of As is mediated, although the data available indicate that As may act indirectly on DNA, i.e. via mechanisms like interference of regulation of DNA repair or integrity. Because of the indirect mode of action, it has been discussed as well that As's genotoxicity may underlie a sublinear dose-response relationship. However, various problems like non-standardized test systems and experimental variability make it impossible to prove such statement. Basically, to be able to improve risk assessment, it is of crucial importance to scientifically approach the mechanistic way of induction of As's genotoxicity and carcinogenicity.     

Ubiquitous perfluorinated compounds

Perfluorinated compounds are derivatives of hydrocarbons, in which all or most of hydrogen atoms are substitiuted by fluorine atoms. These compounds are commonly used in many branches of industry. Perfluorinated compounds are in the limelight because of numerous reports concerning their toxicity and negative effects on human health as well as contradictory information about their cancerogenic effect. The above compounds are used in production of many commonly used products including such brand names as Gore-Tex, Teflon, Stainmaster. The most common ways of penetrating these compounds into a human organism are: via food, inhalation and skin contact. Perfluorooctanesulfonate (PFOS) has been added to the list of persistent organic pollutants (POPs).     

Mutagenicity of aliphatic and aromatic nitro compounds. Industrial materials and related compounds

Mutagenicity of 102 aliphatic and aromatic nitro compounds, industrial materials and related chemicals were tested by pre-incubation method using Salmonella typhimurium TA100 and TA98 strains with and without S9 mix. Escherichia coli WP2uvrA/pKM101 was also used in the mutagenicity assay of aliphatic nitro compounds. Four chemicals out of 8 aliphatic nitro compounds tested were mutagenic to TA100, TA98 and/or WP2 strains. Sixty-one out of 94 nitrobenzene derivatives were mutagenic to TA100 and/or TA98 strains. Thirty-seven chemicals among the 65 mutagens showed higher mutagenic activity than 1,000 rev./mg. The following 15 chemicals showed higher activity than 10,000 rev./mg: tetranitromethane, chloropicrin, 1,3,5-trinitrobenzene, 2,4-dinitrochlorobenzene, 2,3-dinitrophenol, 2,6-dinitroaniline, 3,5-dinitroaniline, 2-bromo-4,6-dinitroaniline, 2,4-dinitrofluorobenzene, p-nitrobenzylchloride, 3,5-dinitrobenzylchloride, p-nitrophenylhydrazine, 2,4-dinitrophenylhydrazine, 2,4-dinitrophenylthiocyanate and nitramine. Nitrobenzene was not mutagenic, but mono-substituted nitrobenzenes having-CH2Cl, -COCl, -NO2, -NH-NH2, -COOH, -OCH3, -NH2, -Br, -OH, -NH-NH2HCl, -OP(OC2H5)2S or -CHO group showed mutagenic. Introduction of-Cl, -CH3, -C2H5 or -SO3H group to nitrobenzene did not contribute to mutagenicity. Mutagenicity of dinitrobenzene was enhanced by the introduction of -F, -SCN, -NH2, -Cl, -CH2Cl, -NO2, -NH-NH2 or -COCl group, and suppressed by the introduction of -COOH or -CH3 group. Twenty-three out of 45 chemicals for which "exposure limits" are established from the stand point of industrial hygiene in many countries in the world, were mutagenic to TA100, TA98 and/or WP2 strains. Furthermore, 42 out of 57 chemicals for which "exposure limits" are not established were also mutagenic. The following three carcinogens, that is, 2-nitropropane, 2,4-dinitrotoluene and 2,6-dinitrotoluene, were all mutagenic, but their mutagenic activity was weak. Many chemicals were found to have a stronger mutagenic activity and a chemical structure similar to carcinogenic dinitrotoluenes. This fact suggests the necessity of conducting carcinogenic assay of these chemicals.     

Mutagenicity of nitroaromatic degradation compounds

The mutagenicity of 2,4-dinitrotoluene (24DNT), and 2,6-dinitrotoluene (26DNT), and their related transformation products such as hydroxylamine and amine derivatives, which are formed by Clostridium acetobutylicum, were tested in crude cell extracts using Salmonella typhimurium TA100. A previous publication already reported the mutagenic activities of 2,4,6-trinitrotoluene (TNT) and its related hydroxylamine derivatives in this test system. A time course of the mutagenicity during the anaerobic transformation of TNT, 24DNT, and 26DNT was also investigated under the same conditions to compare with the results from the pure compounds. The monohydroxylamino intermediates 2-hydroxylamino-4-nitrotoluene (2HA4NT), 4-hydroxylamino-2-nitrotoluene (4HA2NT) and 2-hydroxylamino-6-nitrotoluene (2HA6NT) formed during anaerobic transformation of dinitrotoluenes were proven to be mutagenic in the Ames test using Salmonella typhimurium TA100. This study reports that 4HA2NT is the most stable derivative, whereas 2HA4NT and 2HA6NT are less stable and these intermediates are mutagenic in the Ames test. Both 24DNT and 26DNT and their final metabolites 2,4-diaminotoluene (24DAT) and 2,6-aminotoluene (26DAT) appeared nonmutagenic. In a time-course study of TNT degradation, the temporal sample containing 85% of 2,4-dihydroxylamino-6-nitrotoluene (24HA6NT) is most mutagenic. These observations suggest that the bioremediation approach for treatment of 24DNT and 26DNT should be carried past the hydroxylamino intermediate.     

Percutaneous absorption of uranium compounds

Percutaneous absorption of soluble and insoluble uranium compounds has been induced in order to obtain information on penetration routes and the tissue injury produced by uranium salts. The high electron density of uranium provided a reliable way to visualize, by electron microscopy, the precise localization of the heavy compounds within the tissues. Few minutes after topical application of uranyl nitrate, dense deposits of uranium were observed at the epidermal barrier level. A few hours later, dense deposits were seen filling the intercellular spaces and were also scattered in the cytoplasm and nucleus. Mortality and body weight measurements indicated the high toxicity of uranyl nitrate and ammonium uranyl tricarbonate; uranyl acetate and ammonium diuranate were less toxic. As no penetration was achieved after uranium dioxide, no variations were detected on these parameters.     

Physiological modelling of organic compounds

In pharmacokinetic modelling the body is represented as a set of compartments. The characteristics of these compartments are defined either by fitting predetermined mathematical equations to the data ('data-based compartments') or by defining compartments based on the actual biological structure of the animal ('physiologically based compartments'). Physiological models of chemical disposition are developed using these physiologically based compartments. These models then consist of sets of organs or types of tissue compartments whose characteristics are based as far as possible on the anatomy and physiology of the test species. Individual organs or types of tissue are defined with respect to their blood flow, volume, kinetic constants for metabolism, storage capacity for the compound involved, protein binding and other relevant characteristics. Linking these compartments together in a proper anatomical arrangement yields the physiological model for compound disposition. This paper provides an overview of the basics for constructing physiological models for organic compounds, focusing on the structure of individual compartments in these models and the data required for model development. Some past applications of physiological models are reviewed and speculation offered on future developments in this field.     

Carcinogenicity of N-nitroso compounds]

The toxic, carcinogenic and mutagenic effects of N-nitroso compounds are briefly discussed with reference to recent reviews. These adverse biological effects are discussed in relation to the necessity of metabolic activation by microsomal enzymes for the nitrosamins but not for the nitrosamides.     

Benzodiazepines as appetite-enhancing compounds

There is consistent evidence that benzodiazepines may enhance appetite for food by relatively direct means. However, the evidence that they overcome food neophobia, and thereby increase food intake as a secondary effect, fails to be conclusive. Recent food selection studies nevertheless point to two dissociable actions of the drugs. At lower dose levels, benzodiazepines may act relatively selectively to mimic the effects of increased hunger. At higher dose levels, however, they display effects which are consistent with an action to reduce food neophobia. These behavioural studies indicate that appetitive effects of benzodiazepines are distinguishable from their anxiolytic effects. Clinically, this may point to an effective use of benzodiazepines in the treatment of feeding disorders.