Mechanism of toxic action

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). 

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. 

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... 

Information concerning the mechanism of toxic action is incomplete... 

Special tools are needed to study those underlying processes, and a significant fraction of scientists in the toxicology community are involved in such research. Sometimes the phrase mechanism of toxic action is used to describe these various underlying processes, although it is often used to describe only the pharmacodynamic piece of the picture. It is extraordinarily difficult to uncover all relevant mechanistic processes, but significant pieces of the puzzle of toxicity are known for many substances. 

Richburg JH, Johnson KJ, Schoenfeld HA et al. Defining the cellular and molecular mechanisms of toxicant action in the testis. Toxicol Lett 2002 135 167-183. 

Investigative toxicology Determine sequence and mechanisms of toxic action. Discover the genes, proteins, pathways involved. Develop new methods for assessing toxicity use computer-assisted modeling. 

The number of possible mechanisms by which a chemical can exert a toxic effect on humans and other species is staggering. As shown here, some are well understood, but further elucidation of mechanisms of toxic action is direly needed to propagate the field of safe chemical design. However, this cannot be a reason for molecular designers not to attempt to consider the most likely reactivity of a chemical inside an organism, and to make an effort to minimize rationally either its bioavailability, metabolic activation, or ligand binding interactions with biomolecules. 

We will explore these three approaches briefly in order. Ideally, all three should be applied simultaneously, but lack of data often does not allow this. A mechanistic method would stem from a systematic understanding of all known, suspected, or plausible biochemical mechanisms of toxic action, and therefore must include considerations at the levels of ecosystem, organism, organ, tissue, cell, and finally molecules. 

Careful control of the conditions of synthesis of chlorinated phenols will reduce the formation of dioxins, and this is now the rule for avoiding their formation. Likewise, macro-contaminants, such as inactive isomers, are now recognized as unwanted components of chemicals that may cause harm in the environment or to humans. However, a good understanding of the mechanism of toxic action and how the chemical interacts with the receptor is needed to be able to recognize that toxicity is isomer-specific and to then use this in the intelligent design of low-risk products. 

The mechanism of toxic action of PBBs is not completely understood and no methods exist to block the toxic response due to exposure to PBBs. A more complete characterization of the cytosolic Ah receptor protein, to which some PBB congeners are thought to bind, and understanding of physiological effects of receptor blockage would be useful for the possible identification of blockers of Ah receptor-mediated toxic effects. Further studies aimed at elucidating the nonreceptor-mediated mechanism of action of some PBBs would also be valuable. 

Polybrominated Diphenyl Ethers. The mechanism by which PBDEs enter the blood stream is not known, there are no established methods for reducing body burden of PBDEs, and the mechanisms of toxic action of PBDEs are incompletely understood. Types of studies that could address these data gaps and possibly provide information on reducing to dc effects of PBDEs are discussed in the preceding subsection on PBBs. 

Molecular modification can be used to eliminate the potential for toxicity from a candidate drug. This requires knowledge of the chemical mechanisms of toxic action, both direct and indirect (via metabolic activation), so that one may recognize the potential toxophore. 

One of the intricate problems of the interface function of concentration techniques is to arrive at completely standardized tests, both in technical and biological aspects. The mechanism of toxic action of compounds can be different for different organisms because susceptibility of many organisms is distinctly pollutant-specific. Consequently, not only should a set of tests be carried out with different test systems, but the concentration procedure must be a reproducible interface between the environment and the various test systems. This situation can be achieved by careful analysis of all coherent steps in the whole procedure from sampling to analysis. 

A. Modes of Toxic Action. This includes the consideration, at the fundamental level of organ, cell and molecular function, of all events leading to toxicity in vivo uptake, distribution, metabolism, mode of action, and excretion. The term mechanism of toxic action is now more generally used to describe an important molecular event in the cascade of events leading from exposure to toxicity, such as the inhibition of acetylcholinesterase in the toxicity of organophosphorus and carbamate insecticides. Important aspects include the following ... 

Gene structure and any of the processes involved in DNA expression including transcription, mRNA processing and translation and protein synthesis (Figure 2.2) can all be examined by molecular techniques. In toxicology this may include toxic effects on these processes or the role of the processes in the mechanism of toxic action. 

It should be emphasized that all of these activities proceed simultaneously, and that increased emphasis and interest in any particular area is often preceded by the development of new techniques—for example, the tremendous increase in specificity and sensitivity of chemical methods has proceeded simultaneously with the introduction of molecular biologic techniques into studies of mechanisms of toxic action. 

The enormous cost of multiple-species, multiple-dose, lifetime evaluations of chronic effects has already made the task of carrying out hazard assessments of all chemicals in commercial use impossible. At the same time, quantitative structure activity relationship (QSAR) studies are not yet predictive enough to indicate which chemicals should be so tested and which chemicals need not be tested. In exposure assessment, continued development of analytical methods will permit ever more sensitive and selective determinations of toxicants in food and the environment, as well as the effects of chemical mixtures and the potential for interactions that affect the ultimate expression of toxicity. Developments in QSARs, in short-term tests based on the expected mechanism of toxic action and simplification of chronic testing procedures, will all be necessary if the chemicals to which the public and the environment are exposed are to be assessed adequately for their potential to cause harm. 

Organophosphates are characterized by their similar mechanism of toxic action in insects and mammals, resulting in the irreversible inhibition of the enzyme cholinesterase, and the accumulation of acetylcholine at nerve endings (synapses). The primary mechanism is phosphorylation of the enzyme critical to normal transmission of nerve impulses from fibers to innervated tissues. A critical fraction of tissue enzyme must be inactivated before the symptoms of toxicity appear. At sufficient dose, the loss of enzyme function results in... 

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