There has been much discussion in recent years regarding the most appropriate follow-up testing in vivo when positive results are obtained in vitro but the in vivo micronucleus (MN) test (traditionally the most widely-used test) is negative. Not all rodent carcinogens give positive results in the micronucleus test, and so it has been common practice to include a second in vivo assay such as the unscheduled DNA synthesis (UDS) test. This has proved useful but is usually limited to analysis of rodent (usually rat) liver. With the increased evaluation and use of other in vivo assays, e.g. for transgenic mutations (TG) and DNA damage (Comet assay) it was important to investigate their usefulness. We therefore examined the published in vivo UDS, TG and Comet-assay results for 67 carcinogens that were negative or equivocal in the micronucleus test. Between 30 and 41 chemicals were evaluated in each of the three in vivo tests, with some overlap. In general, the UDS test was disappointing and gave positive results with 50% of the carcinogens, but the Comet assay detected almost 90% of the micronucleus-negative or equivocal carcinogens. This pattern of results was virtually unchanged when the in vitro profile (gene mutagen or clastogen) was taken into account. High sensitivity (ability to detect carcinogens as positive) is only really useful when the specificity (ability to give negative results with non-carcinogens) is also high. Based on small numbers of publications with non-carcinogens, the TG and Comet assays gave negative results with non-carcinogens on 69 and 78% of occasions, respectively. Although further evaluation of the Comet and TG assays, particularly with non-carcinogens, is needed, these data suggest that they both should play a more prominent role in regulatory testing strategies than the UDS test.

Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens: III. Appropriate follow-up testing in vivo

Aldehydes are electrophilic compounds to which humans are pervasively exposed. Despite a significant health risk due to exposure, the mechanisms of aldehyde toxicity are poorly understood. This ambiguity is likely due to the structural diversity of aldehyde derivatives and corresponding differences in chemical reactions and biological targets. To gain mechanistic insight, we have used parameters based on the hard and soft, acids and bases (HSAB) theory to profile the different aldehyde subclasses with respect to electronic character (softness, hardness), electrophilic reactivity (electrophilic index), and biological nucleophilic targets. Our analyses indicate that short chain aldehydes and longer chain saturated alkanals are hard electrophiles that cause toxicity by forming adducts with hard biological nucleophiles, e.g., primary nitrogen groups on lysine residues. In contrast, α,β-unsaturated carbonyl derivatives, alkenals, and the α-oxoaldehydes are soft electrophiles that preferentially react with soft...

Molecular mechanisms of aldehyde toxicity: a chemical perspective.

β-Amyloid protein-induced Alzheimer's disease animal model

Organic solvents are known as carbon-based solvents and their general property is primarily based on their volatility, boiling point, the molecular weight and color. Having enormous hazards associated with the organic solvents, they are used for millions of purposes which alert us to think more on its toxicity points. Almost all of the solvents are hazardous to health, if swallowed or inhaled more than the limit quantity and on contact to the skin most of them cause irritation. Some of the common solvents are acetone, ethyl acetate, hexane, heptane, dichloromethane, methanol, ethanol, tetrahydrofuran, acetonitrile, dimethylformamide, toluene, dimethylsulfoxide etc. Researchers, scientists, workers in the chemical industry and research institutes use these solvents on regular basis leading them to be affected in major aspects. But also, the nearby persons are affected by the contamination to the soil, water, air etc. If constantly exposed with solvents, it will badly affect the function of CNS and other body parts. The level of impact, sign and symptoms will depend on concentration, time, duration, frequency and nature of solvents, leading to common effects like headache, dizziness, tiredness, blurred vision, behavioral changes, unconsciousness, and even(Zimmermann, Mayer et al. 1985) death. To overcome it, the green chemistry concept is growing rapidly, and the solvent selection guide is in practice in many big company and research institute. A researcher or chemical worker is the primary person who works with solvents and they need to consider throughout these things while performing their activities for their own good health and for the sake of the world. The purpose of this review is to provide needed basic knowledge about common organic solvents and their potential toxicities which will alert researchers to think twice and always think for their health as well as for the environment via safe and green practice.

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An Overview on Common Organic Solvents and Their Toxicity

Many chemical toxicants and/or their active metabolites are electrophiles that cause cell injury by forming covalent bonds with nucleophilic targets on biological macromolecules. Covalent reactions between nucleophilic and electrophilic reagents are, however, discriminatory since there is a significant degree of selectivity associated with these interactions. Over the course of the past few decades, the theory of Hard and Soft, Acids and Bases (HSAB) has proven to be a useful tool in predicting the outcome of such reactions. This concept utilizes the inherent electronic characteristic of polarizability to define, for example, reacting electrophiles and nucleophiles as either hard or soft. These HSAB definitions have been successfully applied to chemical-induced toxicity in biological systems. Thus, according to this principle, a toxic electrophile reacts preferentially with biological targets of similar hardness or softness. The soft/hard classification of a xenobiotic electrophile has obvious utility in ...

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Application of the hard and soft, acids and bases (hsab) theory to toxicant-target interactions

The reactivity of selected acrylate esters toward glutathione and deoxyribonucleosides in vitro: structure-activity relationships

Microsomal metabolism of acetonitrile to cyanide: Effects of acetone and other compounds

The purpose of these studies was to investigate the nature and mechanism of a toxicologic interaction between acetonitrile and acetone. Results of oral dose-response studies utilizing a 1:1 (w/w) mixture of acetonitrile and acetone, or varying doses of acetonitrile administered together with a constant dose of acetone, indicated that acetone potentiated acute acetonitrile toxicity three- to fourfold in rats. The onset of severe toxicity (manifested by tremors and convulsions) was delayed in the groups dosed with both solvents compared to the groups that received acetonitrile or acetone alone. Blood cyanide (a metabolite of acetonitrile) and serum acetonitrile and acetone concentrations were measured after oral administration of 25% aqueous solutions of acetonitrile, acetone, or acetonitrile plus acetone. Concentrations of cyanide in the blood of rats given acetonitrile plus acetone remained near baseline, in contrast to the high concentrations found in rats dosed with acetonitrile alone. At 34-36 h, high blood cyanide concentrations were found in rats dosed with both of the solvents. This delayed onset of elevation of blood cyanide coincided with the occurrence of clinical signs and with the disappearance of serum acetone. In further pharmacokinetic studies, blood cyanide concentrations were measured after similar dosage regimens of acetone and acetonitrile. Peak cyanide concentrations were found to be significantly greater in rats dosed with both solvents than in rats given only acetonitrile. Administration of either sodium thiosulfate or a second dose of acetone prevented the toxicity associated with exposure to both solvents. These results suggest that the effects of acetone on acetonitrile toxicity are due to a biphasic effect on the metabolism of acetonitrile to cyanide, that is, an initial inhibition followed by a stimulation of this metabolism upon acetone elimination.

Eileen P. Hayes

Papers

The reactivity of selected acrylate esters toward glutathione and deoxyribonucleosides in vitro: structure-activity relationships

Microsomal metabolism of acetonitrile to cyanide: Effects of acetone and other compounds

Acetone potentiation of acute acetonitrile toxicity in rats

The metabolism of acetonitrile to cyanide by isolated rat hepatocytes

Possible role of hydroxyl radicals in the metabolism of succinonitrile.