Distribution of Toxic Substances

The sites of entry of toxicants into the body and their subsequent distribution have a major influence on their toxic effects. It was noted in Section 2.9.1 that the pulmonary route affords direct access of toxicants to the bloodstream and the effects of a direct-acting toxicant may be manifested very rapidly. Absorption through the skin affords similar direct access of toxicants to the blood and lymph systems. (Advantage is taken of this route through the use of skin patches worn to continuously deliver low doses of pharmaceuticals to the bloodstream, for example, a combination of norelgestro-min and ethinyl estradiol hormones that function as contraceptives.) 

Toxicants that are ingested generally are absorbed through the small intestine walls and are transported to the liver. The liver is the main site of toxicant metabolism and is where some poisonous substances are converted to less toxic forms more readily eliminated from the body whereas other substances are converted to toxic species. Toxic species are distributed around the body by the blood and lymph system, which can lead to systemic poisoning at sites remote from the entry of the substance into the body. Bone and adipose tissue (fat) are major sites of storage of toxicants. Bone accumulates heavy metals including lead and some radioactive materials, especially strontium-90, which biochemically behaves like calcium. Radioactive iodine accumulates in the thyroid and can cause thyroid cancer. Lipophilic toxicants, such as polychlorinated biphenyls (PCBs), that are poorly soluble in water tend to accumulate in adipose tissue. 

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Jaffe PR, Parker FL, Wilson DJ. 1982. Distribution of toxic substances in rivers. Journal of Environmental Engineers 108 639-649. 

Water on and beneath the surface of the geosphere plays a strong role in pollution and the distribution of toxic substances. Toxic substances from wastes improperly disposed to the geosphere can leach into groundwater and contaminate water supplies. Radioactive radium resulting from the decay of uranium in aquifer formations has caused some groundwater sources of drinking water to be abandoned. 

Livestock production practices may result in the distribution of toxic substances to the environment. This has been especially true with concentrated livestock feeding operations that produce large amounts of waste products in small areas. The crowding of animals in these kinds of operations is conducive to the spread of disease so that antibiotics and other agents are often fed to the animals, and these materials and their metabolites appear in livestock wastes. 

Biosphere The greatest direct effect is from the distribution of toxic substances as the result of industrial activities. There may also be significant indirect effects resulting from deterioration of the atmosphere, hydrosphere, and geosphere. 

A pioneer study of the distribution of this substance in the tissues of rats to which it had been fed was made by Laug (3). He evaporated ether extracts in Erlenmeyer flasks, so that a deposit was left over the bottom. Female houseflies were confined in the flasks, and the mortalities after 20 hours were compared to those obtained with known amounts of 7-hexachlorocyclohexane. Because most of the inner surface of the flask was untreated, the flies were out of contact with the toxicant during an unknown fraction of the exposure period. The exposure period was so long that the insects had to be fed dur-... 

For a limited number of exposure pathways (primarily inhalation of air in the vicinity of sources), pollutant fate and distribution models have been adapted to estimate population exposure. Examples of such models include the SAI and SRI methodologies developed for EPA s Office of Air Quality Planning and Standards (1,2), the NAAQS Exposure Model (3), and the GEMS approach developed for EPA s Office of Toxic Substances (4). In most cases, however, fate model output will serve as an independent input to an exposure estimate. 

A systemic effect is an effect that is normally observed distantly from the site of first contact, i.e., after the substance has passed through a physiological barrier (mucous membrane of the gastrointestinal tract or of the respiratory tract, or the skin) and becomes systemically available. It should be noted, however, that toxic effects on surface epithelia may reflect indirect effects as a consequence of systemic toxicity or secondary to systemic distribution of the substance or its active metabolite(s). 

Changes in plasma pH may also affect the distribution of toxic compounds by altering the proportion of the substance in the nonionized form, which will cause movement of the compound into or out of tissues. This may be of particular importance in the treatment of salicylate poisoning (see chap. 7) and barbiturate poisoning, for instance. Thus, the distribution of phenobarbital, a weak acid (pKa 7.2), shifts between the brain and other tissues and the plasma, with changes in plasma pH (Fig. 3.22). Consequently, the depth of anesthesia varies depending on the amount of phenobarbital in the brain. Alkalosis, which increases plasma pH, causes plasma phenobarbital to become more ionized, alters the equilibrium between plasma and brain, and causes phenobarbital to diffuse back into the plasma (Fig. 3.22). Acidosis will cause the opposite shift in distribution. Administration of bicarbonate is therefore used to treat overdoses of phenobarbital. This treatment will also cause alkaline diuresis and therefore facilitate excretion of phenobarbital into the urine (see below). 

Toxic Substances Control Act (TSCA) Law passed in 1976 that governs the regulation of toxic substances in commerce, with the objective of preventing human health and environmental problems before they occur. The manufacturing, processing, or distribution in commerce of toxic substances may be limited or banned if EPA finds, based on results of toxicity testing and exposure assessments, that there is an unreasonable risk of injury to human health or the environment. Important hazardous chemicals regulated under TSCA include, for example, dioxins, PCBs, and asbestos. 

The two main pathways for the uptake of toxic substances by plants are through their root systems and across their leaf cuticles. Stomata, the specialized openings in plant leaves that allow carbon dioxide required for photosynthesis to enter the leaves and oxygen and water vapor to exit, are also routes by which toxic substances may enter plants. The mechanisms by which plants take up systemic pesticides and herbicides, which become distributed within the plant, have been studied very intensvively. 

Figure 6.2 Major sites of exposure, metabolism, and storage, and routes of distribution and elimination of toxic substances in the body. 

Toxicokinetics. The process of the uptake of potentially toxic substances by the body, the biotransformation they undergo, the distribution of the substances and their metabolites in the tissues, and the elimination of the substances and their metabolites from the body. Both the amounts and the concentrations of the substances and their metabolites are studied. (Pharmacokinetics is the term used to study pharmaceutical substances.)... 

A toxicant must be present at its cellular site of action in sufficient amounts to exert its deleterious effects. When the concentration is too small it is said that the threshold has not been reached therefore, the material does not exert any adverse action. The distribution of active substances in the body is not uniform, and certain cells can exhibit preferentially high affinities for particular agents. Pharmacokinetic thresholds determine the effective dose of a chemical at its biological target site based on the absorption, distribution, biotransformation, and excretion of the particular chemical. 

Acute bioassays are designed to assess the effects of toxic substances that occur within a relatively short period after exposure (48-96 h). The effluent toxicity elicited by test organisms is often fatal and rarely reversible. The relevant information to be gained from this type of test is the distribution of the exposure-response relationship and the nature and potency of the toxic effects, such as immobility, percentage mortality, and time interval to mortality. 

Distribution of Toxicity in the RSTS The toxicity of the substances in the RSTS should be distributed as uniformly as possible across the range of interest. This is important because a nonuniform distribution of test substance toxicity in an RSTS may not allow an effective assessment of alternative method performance. Potential effects of nonuniform test substance distribution are illustrated in Figure 4. The ideal situation is shown in Figure 4b. In this example, the test substances are uniformly distributed across the range of possible toxicity. If such results were... 

Figure 4 The effects of nonuniform data distributions in the reference set of test substances (RSTS). This series of figures illustrates why the irritancy of the materials in the RSTS must be uniformly distributed across the range of toxicity of interest, (a) includes test substances that are not uniformly distributed across the range of toxicity observed in the in vivo method. In this case, it is impossible to determine whether the method is useful for predicting the toxicity of moderately toxic materials. If moderately toxic materials were to be evaluated in the assay shown in part (a), it may be found that the performance of the alternative method is similar to that shown in part (b), (c), or (d). The ideal situation is shown in part (b) where there is a useful relationship between the in vivo and alternative method results across the entire range of toxicity assessed. The less satisfactory outcomes shown in parts (c) and (d) are also possible. The only way to determine whether the relationship between the alternative method results and in vivo toxicity is useful is to assess an RSTS with a uniform distribution of toxicity across the entire range of interest. Reproduced from Toxicology In Vitro 10 479-501, 1996, Bruner, L. Proctor Gamble.

EPA. 1976a. PCBs in the United States Industrial use and environmental distribution. Washington, DC U.S. Environmental Protection Agency, Office of Toxic Substances. NTIS PB252012. 

The low concentration of protein in the interstitial fluid has been suggested as another factor which may reduce the distribution of some substances in the central nervous system. Lipid soluble compounds, such as methyl mercury which is toxic to the central nervous system (see Chapter 7). can enter the brain readily, the facility being reflected by the partition coefficient. Another example which illustrates the importance of the lipophilicity in the tissue distribution and duration of action of a foreign compound is afforded by a comparison of the drugs thiopental and pentobarbital (figure 3,5). These drugs are very similar in structure, only differing by one atom. Their pKa values are similar and consequently the... 

Changes in plasma pH may also affect the distribution of toxic compounds by altering the proportion of the substance in the nonionized form, which will cause movement of the compound into, or out of tissues. This may be of particular importance in the treatment of salicylate poisoning (see Chapter 7) and barbiturate poisoning for instance. Thus the distribution of phenobarbital, a weak acid (pKa 7.2), shifts... 

Procedures Waste Minimization in Metal Finishing Industry California Department of Toxic Substances Control, 1991 distributed by U.S. Environmental Protection Agency, Pollution Prevention Information Clearinghouse. 

Only circumstantial evidence is available that supports the supposition that wildlife species are exposed to explosive compounds. Studies conducted at U.S. Army ammunition plants and other areas of known soil contamination have failed to detect body burdens of suspected explosive compounds in mice, deer, and some bird species [4-7] (see Chapter 10 in this book for a more complete review). Given the relatively rapid metabolic potential of many explosives in vivo, the heterogeneous distribution of these substances in the environment, and the potential for bioaccumulation of some nitramines in plants, body burden analysis may not adequately describe exposure potential. Therefore, the data reviewed in this chapter will focus on controlled laboratory toxicity studies conducted to evaluate the effects in wildlife species, many of which were designed for specific risk assessment applications. 

The focal areas of this book have relatively minor relationships to the primary formation of the Earth s crust which has caused a certain distribution of the chemical elements. They mainly deal with products of the alteration of the crust in geologic processes. We can presently still observe the weathering of solid rocks, the erosion of mountain ridges, and the transport of eroded materials as suspended and dissolved constituents in river and rain water, in ice and wind. In-situ weathering forms soils, and soils are the basis of food production for human nutrition. Therefore, soUs need special protection against the impact of toxic substances (see Part I, Chapters 4 and 5). 

The effects of toxic substances are acutely dependent upon the absorption, distribution and secretion of the toxicants [1]. Another important factor is the rate of metabolism, or biochemical transformation, of the toxic substances in the body. 

Fig. 9.1. Absorption, distribution and excretion paths of toxic substances... 

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