The excretion of toxic substances

The organism eliminates toxic substances or their metabolites through the kidneys, bile, lungs, saliva, stools and skin. The excretion by the kidneys is of the main importance. This mechanism is the same as that during the excretion of final products of primary and secondary metabolic pathways. Substances absorbed in the gastrointestinal tract are eliminated from the blood by the liver. These substances can be removed by the liver prior to reaching the circulation system. Substances which enter the body by inhalation are also eliminated from the lung (carbon monoxide, alcohol, volatile substances). The excretion system is not specialized and it operates on the basis of a simple diffusion [7-9]. 

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

Manahan, S. E. Environmental Chemistry, 4th ed. Willard Grant Press, Boston 1984. 

DuBois, K. P. and Gelling, E. M. K. Textbook of Toxicology. Oxford University Press, Oxford 1959. 

Goldstein, A., Aronow, L. and Kalman, S. H. Principles of Drug Action. Harper and Row, New York 1968. 

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Pyrrolidine is the simple five-membered cyclic amine and pyrrolidine alkaloids contain this ring somewhere in their structure. Both nicotine and atropine contain a pyrrolidine ring as do hygrine and tropinone. All are made in nature from ornithine. Ornithine is an amino acid not usually found in proteins but most organisms use it, often in the excretion of toxic substances. If birds are fed benzoic acid (PI1CO2H) they excrete dibenzoyl ornithine. When dead animals decay, the decarboxylation of ornithine leads to putrescine which, as its name suggest, smells revolting. It is the smell of death . 

Mannitol is an osmotic diuretic that has been used in acute oliguric renal insufficiency, acute cerebral edema, and the short-term management of glaucoma, especially to reduce intraocular pressure before ophthalmic surgery. Other indications include promotion of the excretion of toxic substances by forced diuresis, bladder irrigation during transurethral resection of the prostate, and oral administration as an osmotic laxative for bowel preparation. Mannitol is used as a diluent and excipient in pharmaceutical formulations and as a bulk sweetener. 

The kidney is an important organ for the excretion of toxic materials and their metaboHtes, and measurement of these substances in urine may provide a convenient basis for monitoring the exposure of an individual to the parent compound in his or her immediate environment. The Hver has as one of its functions the metaboHsm of foreign compounds some pathways result in detoxification and others in metaboHc activation. Also, the Hver may serve as a route of elimination of toxic materials by excretion in bile. In addition to the Hver (bile) and kidney (urine) as routes of excretion, the lung may act as a route of elimination for volatile compounds. The excretion of materials in sweat, hair, and nails is usually insignificant. 

The major routs and sites of absorption, metabolism, binding, and excretion of toxic substances in the body are shown in Figure 10... 

Toxicokinetics describes the biokinetics of toxic substances. It includes the kinetic processes for toxic substances which govern the movement into, within, and from the bodies of human populations. The overall lead toxicoki-netic process includes (1) the uptake, i.e., absorption rate, of lead into the bloodstream from various body compartments such as the lung or G1 tract (2) movement within the bloodstream followed by transport internally to target tissues and their cellular components (3) retention within one or more tissues and finally (4) excretion from the body by various systemic pathways. Older literature made incorrect reference to lead toxicokinetics as lead metabolism, but the latter term is more correctly employed with toxic substances undergoing actual chemical transformation within such processes as addition or removal of chemical groups and oxidative or reductive changes. 

Excretion. Excretion of toxic substances is a function of a critical balance between intake, body burden, and turnover in the storage tissues. Assuming repeated exposure to a substance, there is a steady increase of concentration until the storage tissues are saturated or at least until uptake and excretion are equal. For some toxic substances, such as carbon monoxide, the substance can be excreted completely between successive days of low-level exposure. 

The major routes and sites of absorption, metabolism, binding, and excretion of toxic substances in the body are illustrated in Figure 23.1. Toxicants in the body are metabolized, transported, and excreted they have adverse biochemical effects and they cause manifestations of poisoning. It is convenient to divide these processes into two major phases, a kinetic phase and a dynamic phase. 

In Chapter 2 we explained how chemicals foreign to the body can enter the circulatory system and be transported to various parts of the body. If the concentrations of these substances or their metabolic products reach sufficiently high levels, systemic toxicity can result. Different chemicals affect different organs and systems of the body because of differences in the rate and manner of their absorption, distribution, metabolism, and excretion. Some chemicals are directly toxic to the elements of the blood. Others bring about changes in certain elements of the blood that become detrimental to other systems of the body. 

Despite this clearly outlined procedure, scientific progress in the field has been slow, as very few authors have as yet attempted environmental risk assessment of PhCs in water, focussing their attention, furthermore, mainly on parent compounds rather than their metabolites, on the effects of individual substances rather than mixtures on target organisms and on acute rather than chronic toxicity. In particular, metabolite analysis tended to be disregarded as their exposure is very difficult to assess due to a lack of consensus in the literature regarding excreted metabolite fractions moreover, analysis has shown that their relative contribution to the overall risk is typically low [99]. 

The main routes of excretion for a substance as well as for its metabohtes are in the urine and bile (feces). For some substances, exhalation is also an important excretion route. In addition, excretion may also take place via biological fluids such as sahva, sweat, and nulk. Although the amounts excreted by these routes are relatively small, the presence of a substance in these fluids, particularly breast milk, may be the underlying cause of toxic effects. 

Waste products from the degradation of organic substances in animal metabolism include carbon dioxide (CO2), water (H2O), and ammonia (NH3). In mammals, the toxic substance ammonia is incorporated into urea and excreted in this form (see p. 182). 

Toxicity is the ability of a substance to cause injury to biological tissue. The hazard or risk of a substance is the probability that it will cause injury in a given environment or situation. The hazard of a substance depends on several factors, including its toxicity how it is absorbed, metabolized, and excreted how rapidly it acts its warning properties and its potential for fire and explosion. 

The excretion of a foreign substance can also be a major factor in its toxicity and a determinant of the plasma and tissue levels. All these considerations are modified by species differences, genetic effects, and other factors. The response of the organism to the toxic insult is influenced by similar factors. The route of administration of a foreign compound may determine whether the effect is systemic or local. 

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). 

Endogenous substances other than metallothionein may be involved in minimizing the effects of heavy metals and excreting them from the body. Hepatic (liver) glutathione, discussed as a phase II conjugating agent in Section 7.4, plays a role in the excretion of several metals in bile. These include the essential metals copper and zinc toxic cadmium, mercury(II), and lead(II) ions and organometallic methyl mercury. 

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. 

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