INTRODUCTION TO TOXICOLOGY in Visual Studio .NET

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INTRODUCTION TO TOXICOLOGY
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DOSE-RESPONSE RELATIONSHIPS
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As mentioned previously, toxicity is a relative event that depends not only on the toxic properties of the chemical and the dose administered but also on individual and interspeci c variation in the metabolic processing of the chemical. The rst recognition of the relationship between the dose of a compound and the response elicited has been attributed to Paracelsus (see Section 1.1.3). It is noteworthy that his statement includes not only that all substances can be toxic at some dose but that the right dose differentiates a poison from a remedy, a concept that is the basis for pharmaceutical therapy. A typical dose-response curve is shown in Figure 1.2, in which the percentage of organisms or systems responding to a chemical is plotted against the dose. For many chemicals and effects there will be a dose below which no effect or response is observed. This is known as the threshold dose. This concept is of signi cance because it implies that a no observed effect level (NOEL) can be determined and that this value can be used to determine the safe intake for food additives and contaminants such as pesticides. Although this is generally accepted for most types of chemicals and toxic effects, for chemical carcinogens acting by a genotoxic mechanism the shape of the curve is controversial and for regulatory purposes their effect is assumed to be a no-threshold phenomenon. Dose-response relationships are discussed in more detail in 21 on toxicity testing.
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SOURCES OF TOXIC COMPOUNDS
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Given the enormous number of toxicants, it is dif cult to classify them chemically, either by function or by mode of action, since many of them would fall into several classes. Some are natural products, many are synthetic organic chemicals of use to society, while others are by-products of industrial processes and waste disposal. It is useful, however, to categorize them according to the expected routes of exposure or according to their uses.
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A typical dose-response curve.
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MOVEMENT OF TOXICANTS IN THE ENVIRONMENT
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Exposure Classes
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Exposure classes include toxicants in food, air, water, and soil as well as toxicants characteristic of domestic and occupational Settings. Toxicant exposure classes are described in detail in 4.
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1.3.2 Use Classes
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Use classes include drugs of abuse, therapeutic drugs, agricultural chemicals, food additives and contaminants, metals, solvents, combustion products, cosmetics, and toxins. Some of these, such as combustion products, are the products of use processes rather than being use classes. All of these groups of chemicals are discussed in detail in 5.
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1.4 MOVEMENT OF TOXICANTS IN THE ENVIRONMENT
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Chemicals released into the environment rarely remain in the form, or at the location, of release. For example, agricultural chemicals used as sprays may drift from the point of application as air contaminants or enter runoff water as water contaminants. Many of these chemicals are susceptible to fungal or bacterial degradation and are rapidly detoxi ed, frequently being broken down to products that can enter the carbon, nitrogen, and oxygen cycles. Other agricultural chemicals, particularly halogenated organic compounds, are recalcitrant to a greater or lesser degree to metabolism by microorganisms and persist in soil and water as contaminants; they may enter biologic food chains and move to higher trophic levels or persist in processed crops as food contaminants. This same scenario is applicable to any toxicant released into the environment for a speci c use or as a result of industrial processes, combustion, and so on. Chemicals released into the environment are also susceptible to chemical degradation, a process often stimulated by ultraviolet light. Although most transport between inanimate phases of the environment results in wider dissemination, at the same time dilution of the toxicant in question and transfer among living creatures may result in increased concentration or bioaccumulation. Lipid soluble toxicants are readily taken up by organisms following exposure in air, water, or soil. Unless rapidly metabolized, they persist in the tissues long enough to be transferred to the next trophic level. At each level the lipophilic toxicant tends to be retained while the bulk of the food is digested, utilized, and excreted, thus increasing the toxicant concentration. At some point in the chain, the toxicant can become deleterious, particularly if the organism at that level is more susceptible than those at the level preceding it. Thus the eggshell thinning in certain raptorial birds was almost certainly due to the uptake of DDT and DDE and their particular susceptibility to this type of toxicity. Simpli ed food chains are shown in Figure 1.3. It is clear that such transport can occur through both aquatic and terrestrial food chains, although in the former, higher members of the chains, such as sh, can accumulate large amounts of toxicants directly from the medium. This accumulation occurs because of the large area of gill laments, their intimate contact with the water and the high ow rate of water over them. Given these characteristics and a toxicant with a high partition coef cient between lipid membranes and water, considerable uptake is inevitable.
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