Absorption and Distribution of Toxicants

As illustrated in the previous chapter, the human body can be exposed to a variety of toxicants that may be present in various environmental media such as air, soil, water, or food. However, just simply being exposed to these hazardous chemicals does not necessarily translate into a toxicological response. The mammalian body has several inherent defense mechanisms and membrane barriers that tend to prevent the entry or absorption and distribution of these toxicants once an exposure event has occurred. However, if the toxicant is readily absorbed into the body, there are still other anatomical and physiological barriers that may prevent distribution to the target tissue to elicit a toxic response. As the toxicological response is often related to the exposed dose, interactions between the toxicant and the body s barriers and defense mechanisms will have an effect on toxicant movement in the body, and ultimately modulate the rate and extent of toxicant absorption and distribution to the target tissue. 

The skin represents the largest organ in the human body, and one of its primary functions can be seen as a physical barrier to absorption of toxicants. The other major routes of toxicant entry into the body are through the respiratory and gastrointestinal tract, which can be seen to offer less resistance to toxicant absorption than the skin. In general, the respiratory tract offers the most rapid route of entry, and the dermal the least rapid. One reason for this major difference is primarily because membrane thickness, which is really the physical distance between the external environment (skin surface, air in the lung, or lumen of the gut) and the blood capillaries, varies across these portals of entry. The overall entry depends on both the amount present and the saturability of the transport processes involved. 

A Textbook of Modern Toxicology, Third Edition, edited by Ernest Hodgson ISBN 0-471-26508-X Copyright 2004 John Wiley Sons, Inc. 

The lipid constituents in the membrane permit considerable movement of macromolecules, and membrane constituents may move appreciably within membranes. Membrane fluidity, a function of lipid composition, can be altered by temperature and chemicals 

Proteins, which have many physiological roles in normal cell function, are intimately associated with lipids and may be located throughout lipid bilayers. These proteins may be located on either the surface or traverse the entire structure. Hydrophobic forces are responsible for maintaining the structural integrity of proteins and lipids within membranes, but movement within the membranes may occur. External and internal membrane proteins can function as receptors. Many proteins that traverse the membrane are transport proteins, and are involved in translocation of ligands that is, they are involved in active and facilitated transport. 

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P-glycoprotein, a plasma membrane transport protein, is present in the gut, brain, liver, and kidneys 42 This protein provides a biologic barrier by eliminating toxic substances and xenobiotics that may accumulate in these organs. P-glycoprotein plays an important role in the absorption and distribution of many medications. Medications that are CYP3A4 substrates, inhibitors, or inducers are also often affected by P-glycoprotein therefore, the potential for even more DDIs exists in transplant recipients.42... 

Methods for Reducing Toxic Effects. The mechanism of absorption and distribution of aluminum... 

Synergism A phenomenon where exposure to more than one chemical can result in health effects greater than expected when the effects of exposure to each chemical are added together. In simple terms, 1 + 1 = 3. If chemicals have synergistic properties, the potential hazards of the chemicals should be reevaluated, taking their synergistic properties into consideration Systemic effects Effects that require absorption and distribution of the toxicant to a site distant from its entry point... 

Local toxicity occurs at the site of first contact between the biological system and the toxicant. Systemic toxicity requires absorption and distribution of the toxicant most substances, with the exception of highly reactive chemical species, produce systemic toxic effects. The two categories are not mutually exclusive. Tetraethyl lead, for example, injures skin at the site of contact and deleteriously affects the CNS after it is absorbed into the circulation (see Chapter 65). 

Systemic—pertaining to or affecting the body or organism as a whole Systemic effects—effects requiring absorption and distribution of a toxicant to a site within the body distant from its entry point Tachycardia—excessively rapid heartbeat Temporal—relating or pertaining to time... 

MacKenzie RD, Byerrum RU, Decker CF, Hoppert CA, Langham RF (1958) Chronic toxicity studies. II. Hexavalent and trivalent chromium administered in drinking water to rats. AMA Arch Ind Health 18 232-234 MacKenzie RD, Anwar RA, Byerrum RU, Hoppert CA (1959) Absorption and distribution of Cr in the albino rat. Arch Biochem Biophys 79 200-205 Mertz W (1969) Chromium occurrence and function in biological systems. Physiol Rev 49 163-239... 

The kinetic properties of chemical compounds include their absorption and distribution in the body, theit biotransformation to more soluble forms through metabolic processes in the liver and other metabolic organs, and the excretion of the metabolites in the urine, the bile, the exhaled air, and in the saliva. An important issue in toxicokinetics deals with the formation of reactive toxic intermediates during phase I metabolic reactions (see. Section 5.3.3). 

Toxicokinetic—The study of the absorption, distribution and elimination of toxic compounds in the living organism. 

No studies were located regarding toxicokinetic data in humans. Limited information is available regarding the toxicokinetic differences among animal species. Rats, mice, mink, and dogs showed rapid absorption, wide distribution, and over 90% urinary excretion of diisopropyl methylphosphonate or its metabolites. However, the rates of absorption and patterns of distribution varied (Hart 1976 Weiss et al. 1994). The mechanism of toxicity is also undetermined. From the limited data available, it is not possible to determine the degree of correlation between humans and animals. 

As far as man and animals are concerned, the economic poisons exert their harmful and deleterious effect after absorption and distribution through the blood stream. Relatively few agents are irritating or corrosive in their action, and their effect on the intact skin may be considered secondary (5, 8). Toxic action of economic poisons is exerted by alteration in physiologic or biochemical activity of various systems, organs, and cells. 

Second, meanwhile, no international guidelines have been provided for the manufacture, marketing, and distribution of household insecticides on such a level as those of agricultural chemicals, and not even manufacturing registration is required in some countries. Of course, the minimal required toxicity studies are conducted with synthetic pyrethroids for household insecticides to examine absorption, distribution, metabolism, and genotoxicity in animals. 

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