Mechanism of toxicity

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

Health and Safety Factors. Carbonyl sulfide is dangerously poisonous, more so because it is practically odorless when pure. It is lethal to rats at 2900 ppm. Studies show an LD q (rat, ip) of 22.5 mg/kg. The mechanism of toxic action appears to iavolve breakdowa to hydrogea sulfide (36). It acts principally on the central nervous system with death resulting mainly from respiratory paralysis. Little is known regarding the health effects of subacute or chronic exposure to carbonyl sulfide a 400-p.g/m max level has been suggested until more data are available (37). Carbon oxysulfide has a reported inhalation toxicity in mice LD q (mouse) = 2900 ppm (37). 

Synergism is appHed to a situation where the effect of two or more chemicals that have common mechanism of toxicity, given together, is significantly greater than that expected from considerations on the toxicity of each material alone. This differs from potentiation in that both materials contribute to the toxic injury, and the net effect is always greater than additive. 

Gregiis. Z., and Klaa,ssen, C. D. (1996). Mechanisms of toxicity. In Casarett and Doull s Toxicology The Basic Science of Poisons [C. D. Klaassen, Ed.), pp. 35-74. McGraw-Hill, New York. 

Sources of Toxicity. There are three contributing mechanisms of toxicity in drilling fluids, chemistry of mud mixing and treatment, storage/disposal practices, and drilled rock. The first group conventionally has been known the best because it includes products deliberately added to the system to build and maintain the rheology and stability of drilling fluids. 

Saxitoxin (STX) is a toxin which is found in marine microorganisms. It is most likely synthesized by bacteria which live in symbiosis with dinoflagellates, a component of phytoplankton. Through the marine food chain, it can lead to poisoning of humans. The mechanism of toxicity of saxitoxin is vety similar to that of tetrodotoxin. Saxitoxin binds from the outside of the membrane to various forms of voltage-sensitive Na+channels and blocks the channel in an activation state-independent manner. 

Almost all systemic effects of methyl parathion are related to the action of this compound on the nervous system or are secondary to this primary action. It is therefore necessary to preface a description of the mechanisms of toxicity of methyl parathion with a brief discussion of the nervous system and neuro-humoral transmitters (excerpted from Lefkowitz et al. 1996). 

Lopes VICF, Antunes-Madeira MC, Madeira VMC. 1997. Effects of methylparathion on membrane fluidity and its implications for the mechanisms of toxicity. Toxicol in Vitro 11 337-345. 

Acute exposure to large amounts of endosulfan results in frank effects manifested as hyperactivity, muscle tremors, ataxia, and convulsions. Possible mechanisms of toxicity include (a) alteration of neurotransmitter levels in brain areas by affecting synthesis, degradation, and/or rates of release and reuptake, and/or (b) interference with the binding of those neurotransmitter to their receptors. 

The mechanism of toxic action of some important organic pollutants is described and related, where possible, to ecotoxicological effects. 

Neither of these mechanisms of toxic action is susceptible to the kind of QSAR analysis referred to earlier, the employment of which depends on knowledge of the structure of particular binding sites. 

Mechanistic biomarker A biomarker that provides a measure of a toxic effect (some biomarkers only measure exposure). In the simplest case, this involves the direct measurement of the operation of a mechanism of toxicity (e.g., of acetylcholinesterase inhibition). 

Lipnick, R.L. (1991). Outliers Their origin and use in the classification of molecular mechanisms of toxicity. Science of the Total Environment 109/110, 131-153. 

Luo W, Fan W, Xie H, ling L, Ricicki E, Vouros P, et al. Phenotypic anchoring of global gene expression profiles induced by A -hydroxy-4-acetylaminobiphenyl and benzo[a]pyrene diol epoxide reveals correlations between expression profiles and mechanism of toxicity. Chem Res Toxicol 2005 18 619-29. 

As the name implies, the odor of urine in maple syrup urine disease (brancbed-chain ketonuria) suggests maple symp or burnt sugar. The biochemical defect involves the a-keto acid decarboxylase complex (reaction 2, Figure 30-19). Plasma and urinary levels of leucine, isoleucine, valine, a-keto acids, and a-hydroxy acids (reduced a-keto acids) are elevated. The mechanism of toxicity is unknown. Early diagnosis, especially prior to 1 week of age, employs enzymatic analysis. Prompt replacement of dietary protein by an amino acid mixture that lacks leucine, isoleucine, and valine averts brain damage and early mortality. 

Croni MT et al. (2000) Structure-toxicity relationships for aliphatic compounds encompassing a variety of mechanisms of toxic action to Vibrio fischeri. SAR QSAR Environ Res 11(3-4) 301-312... 

Graham, D.G. Tiffany, S.M. Bell, W.R., Jr. and Gutknecht, W.F. Autooxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine and related compounds toward C1300 neuroblastoma cells in vitro. Mol Pharmacol 14 644-653, 1978. 

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