Subject toxic mechanisms

Before we embark on a descriptive survey of toxic and carcinogenic phenomena, the subjects of the next three chapters, it will be useful to provide a broad outline of the ways in which toxic injuries can be produced, and the ways in which they manifest themselves. This type of discussion will help to place into a unified context the descriptive material to come, and it will also aid in understanding concepts of toxic mechanisms as they relate to understanding human risk. The topic is presented in broad outline only details are far more complex than is suggested here. 

Little is known about the specific biochemical mechanism(s) by which selenium and selenium compounds exert their acute toxic effects. Long-term effects on the hair, skin, nails, liver, and nervous system are also well documented, and a general theory has been developed to explain the toxicity of exposure to excess selenium, as discussed below. Generally, water-soluble forms are more easily absorbed and are generally of greater acute toxicity. Mechanisms of absorption and distribution for dermal and pulmonary uptake are unknown and subject to speculation, but an active transport mechanism for selenomethionine absorption in the intestine has been described (Spencer and Blau 1962). The mechanisms by which selenium exerts positive effects as a component of glutathione peroxidase, thioredoxin reductase, and the iodothyronine 5 -deiodinases are better understood, but the roles of other selenium-containing proteins in mammalian metabolism have not been clarified. 

The hypersensitive and toxic mechanisms are not mutually exclusive. In some instances, a combined effect might by operating, with antigens being produced only in some subjects because of altered drug metabolism (Klatskin 1974). In addition, a direct toxic mechanism might also alter an immune response, exposing the cell to further injury. 

Successful predictive models in toxicology exist - however, they are of a rather local nature. Effects considered in toxicology can be caused by different mechanisms. Efforts to get away from a class perspective to one that is more consistent regarding modes of toxic action are still a subject of ongoing research. 

There are three types of TAP emissions continuous, intermittent, and accidental. Both routine emissions associated with a batch process or a continuous process that is operated only occasionally can be intermittent sources. A dramatic example of an accidental emission was the release of methyl isocyanate [624-83-9] in Bhopal, India. As a result of this accident, the U.S. Congress created Tide III, a free-standing statute included in the Superfund Amendments and Reauthorization Act (SARA) of 1986. Title III provides a mechanism by which the pubHc can be informed of the existence, quantities, and releases of toxic substances, and requires the states to develop plans to respond to accidental releases of these substances. Eurther, it requires anyone releasing specific toxic chemicals above a certain threshold amount to aimuaHy submit a toxic chemical release form to EPA. At present, there are 308 specific chemicals subject to Title III regulation (37). 

Unrestricted use of reclaimed wastewater for drinking water, however, requires careful examination. While practically a complete barrier to viruses, bacteria, and other toxic entities that must be kept out of a potable supply, RO membranes could pose serious problems should any defect develop in their separation mechanism. Given the purity and clarity of RO-treated wastewaters, however, it might be advantageous to use RO and then subject the product to well-established disinfection procedures. 

Coelenterates and Echinoderms. In the phylla Coelenterata and Echinodermata approximately 90 species have been investigated for toxicity (see Tables II and IH). Only 20 or so have been extensively studied (e.g., sea anemones, sea cucumber, and jellyfish). Even so, while relatively complete studies have been made on isolation, characterization, and elucidation of mechanisms of action, in no one species have all of the toxins present been identified. Thousands of species have not been subjected to even the most cursory examination. 

An inadequate intake in the diet of those food chemicals that are essential nutrients results in health risks. Indeed these risks are by far the most important in terms of the world s population where malnutrition is a major public health problem. But, unlike the toxic chemicals, they would show a very different dose-response if they were subject to similar animal bioassays. At very low doses there would be a high risk of disease that would decrease as the dose was increased, the curve would then plateau until exposure was at such a level that toxicity could occur. Figure 11.2 shows this relationship which is U- or J-shaped rather than the essentially linear dose-response that is assumed for chemicals that are only toxic. The plateau region reflects what is commonly regarded as the homeostatic region where the cell is able to maintain its function and any excess nutrient is excreted, or mechanisms are induced that are completely reversible. 

Alcohol abuse is a major clinical problem in many countries and has been the subject of investigation for many years by those interested in determining the molecular basis of ethanol-induced liver dam e (see Lieber, 1990). These intensive and extended efforts have revealed much about the metabolism of ethanol in the liver and about the toxicity of its primary oxidative product, acetaldehyde. They have not, however, folly elucidated the molecular mechanisms that lead to the typical features of alcoholic liver injury steatosis, necrosis and eventually cirrhosis. 

Alterations in blood heme metabolism have been proposed as a possible indicator of the biological effects of hydrogen sulfide (Jappinen and Tenhunen 1990), but this does not relate to the mechanism of toxicity in humans. The activities of the enzymes of heme synthesis, i.e., delta-aminolevulinic acid synthase (ALA-S) and heme synthase (Haem-S), were examined in 21 cases of acute hydrogen sulfide toxicity in Finnish pulp mill and oil refinery workers. Subjects were exposed to hydrogen sulfide for periods ranging from approximately 1 minute to up to 3.5 hours. Hydrogen sulfide concentrations were considered to be in the range of 20-200 ppm. Several subjects lost consciousness for up to 3 minutes. 

Data adequacy The key study was well designed, conducted, and documented used 20 human subjects and utilized a range of concentrations and exposure durations. Occupational exposures support the 8-h AEGL value. The mechanism of headache induction (vasodilation) is well understood and occurs following therapeutic administration of nitrate esters to humans. Animal studies utilized several mammalian species and addressed metabolism, neurotoxicity, developmental and reproductive toxicity, and potential carcinogenicity. ... 

The toxicity of fullerene is at present one of the most widely discussed subjects. Though commonplace, it should be noted that toxicity is an extreme manifestation of biological activity leading to the death of biological object. One can conclude that the mechanisms of toxicity of any substance reflect the mechanisms of its biological activity. 

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