Distribution of toxicants in the body
Distribution is the process whereby an absorbed chemical moves away from the site of absorption to other areas of the body. In this section we will answer the following questions:
- How do chemicals move through the body?
- Does distribution vary with the route of exposure?
- Is a chemical distributed evenly to all organs or tissues?
- How fast is a chemical distributed?
- Why do some chemicals stay in the body for a long time whereas others are eliminated quickly?
When a chemical is absorbed it passes through cell linings of the absorbing organ (skin, lung, or gastrointestinal tract) into the interstitial fluid (fluid surrounding cells) of that organ. Interstitial fluid represents about 15% of the total body weight. The other body fluids are the intracellular fluid (fluid inside cells), about 40% of the total body weight and blood plasma which accounts for about 8% of the body weight. However, the body fluids are not isolated but represent one large pool. The interstitial and intracellular fluids, in contrast to fast-moving blood, remain in place with certain components (e.g., water and electrolytes) moving slowly into and out of cells. A chemical, while immersed in the interstitial fluid, is not mechanically transported as it is in blood.
A toxicant can leave the interstitial fluid by:
- entering local tissue cells
- entering blood capillaries and the blood circulatory system
- entering the lymphatic system
If the toxicant gains entrance into the blood plasma, it travels along with the blood, either in a bound or unbound form. Blood moves rapidly through the body via the cardiovascular circulatory system. In contrast, lymph moves slowly through the lymphatic system. The major distribution of an absorbed chemical is by blood with only minor distribution by lymph. Since virtually all tissues have a blood supply, all organs and tissues of the body are potentially exposed to the absorbed chemical.
Distribution of a chemical to body cells and tissues requires that the toxicant penetrate a series of cell membranes. It must first penetrate the cells of the capillaries (small blood vessels) and later the cells of the target organs. The factors previously described pertaining to passage across membranes apply to these other cell membranes as well. For example, concentration gradient, molecular weight, lipid solubility, and polarity are important, with the smaller, nonpolar toxicants, in high concentrations, most likely to gain entrance.
The distribution of a xenobiotic is greatly affected by whether it binds to plasma protein. Some toxicants may bind to these plasma proteins (especially albumin), which "removes" the toxicant from potential cell interaction. Within the circulating blood, the non-bound (free) portion is in equilibrium with the bound portion. However, only the free substance is available to pass through the capillary membranes. Thus, those substances that are extensively bound are limited in terms of equilibrium and distribution throughout the body. Protein-binding in the plasma greatly affects distribution, prolongs the half-life within the body, and affects the dose threshold for toxicity.
The plasma level of a xenobiotic is important since it generally reflects the concentration of the toxicant at the site of action. The passive diffusion of the toxicant into or out of these body fluids will be determined mainly by the toxicant's concentration gradient. The total volume of body fluids in which a toxicant is distributed is known as the apparent volume of distribution (VD), expressed in liters.
If a toxicant is distributed only in the plasma fluid, a high VD results; however, if a toxicant is distributed in all sites (blood plasma, interstitial and intracellular fluids) there is greater dilution and a lower VD will result. Binding in effect reduces the concentration of "free" toxicants in the plasma or VD. The VD can be further affected by toxicants that undergo rapid storage, biotransformation, or elimination. Toxicologists determine the VD of a toxicant in order to know how extensively a toxicant is distributed in the body fluids. The volume of distribution can be calculated by the formula:
The volume of distribution may provide useful estimates as to how extensive the toxicant is distributed in the body. For example, a very high apparent VD may indicate that the toxicant has distributed to a particular tissue or storage area such as adipose tissue. In addition, the body burden for a toxicant can be estimated from knowledge of the VD by using the formula:
Once a chemical is in the blood stream it may be:
- biotransformed into different chemicals (metabolites)
- its metabolites may be excreted or stored
- the chemical or its metabolites may interact or bind with cellular components
Most chemicals undergo some biotransformation. The degree with which various chemicals are biotransformed and the degree with which the parent chemical and its metabolites are stored or excreted varies with the nature of the exposure (dose level, frequency and route of exposure).
Influence of Route of Exposure
The route of exposure is an important factor that can affect the concentration of the toxicant (or its metabolites) at any specific location within the blood or lymph. This can be important since the degree of biotransformation, storage, and elimination (and thus toxicity) can be influenced by the time course and path taken by the chemical as it moves through the body. For example, if a chemical goes to the liver before going to other parts of the body, much of it may be biotransformed quickly. In this case, the blood levels of the toxicant "downstream" may be diminished or eliminated. This can dramatically affect its potential toxicity.
This is exactly what often happens with toxicants that are absorbed through the gastrointestinal (GI) tract. The absorbed toxicants that enter the vascular system of the gastrointestinal tract are carried by the blood directly to the liver by the portal system. This is also true for those rare drugs that are administered by intraperitoneal injection. Blood from most of the peritoneum also enters the portal system and goes immediately to the liver. Blood from the liver then flows to the heart and then on to the lung, before going to other organs. Thus, toxicants entering from the GI tract or peritoneum are immediately subject to biotransformation or excretion by the liver and elimination by the lung. This is often referred to as the "first pass effect." For example, first-pass biotransformation of the drug propranolol (cardiac depressant) is about 70% when given orally. Thus, the blood level is only about 30% of that of a comparable dose administered intravenously.
Toxicants that are absorbed through the lung or skin enter the blood and go directly to the heart and systemic circulation. The toxicant is thus distributed to various organs of the body before it goes to the liver, and not subject to this first-pass effect. The same is true for intravenously or intramuscularly injected drugs.
A toxicant that enters the lymph of the intestinal tract will not go to the liver first but will slowly enter the systemic circulation. The proportion of a toxicant moving by lymph is much smaller than that transported by the blood.
The blood level of a toxicant not only depends on the site of absorption but also the rate of biotransformation and excretion. Some chemicals are rapidly biotransformed and excreted whereas others are slowly biotransformed and excreted.
Disposition is the term often used to integrate all the processes of distribution, biotransformation, and elimination. Disposition models have been derived to describe how a toxicant moves within the body with time (also known as kinetic models). The disposition models are named for the number of areas of the body (known as compartments) that the chemical may go to. For example, blood is a compartment. Fat (adipose) tissue, bone, liver, kidneys, and brain are other major compartments.
Kinetic models may be a one-compartment open model, a two-compartment open model, or a multiple compartment model. The one-compartment open model (Figure 1) describes the disposition of a substance that is introduced and distributed instantaneously and evenly in the body, and eliminated at a rate and amount that is proportional to the amount left in the body. This is known as a "first-order" rate, and represented as the logarithm of concentration in blood as a linear function of time.
The half-life of the chemical that follows a one-compartment model is simply the time required for half the chemical to be lost from the plasma. Only a few chemicals actually follow the simple, first-order, one compartment model.
For most chemicals, it is necessary to describe the kinetics in terms of at least a two-compartment model (Figure 2). In the two-compartment open model, the chemical enters and distributes in the first compartment, which is normally blood. It is then distributed to another compartment from which it can be eliminated or it may return to the first compartment. Concentration in the first compartment declines smoothly with time. Concentration in the second compartment rises, peaks, and subsequently declines as the chemical is eliminated from the body.
A half-life for a chemical whose kinetic behavior fits a two-compartment model is often referred to as the "biological half-life." This is the most commonly used measure of the kinetic behavior of a xenobiotic.
Frequently the kinetics of a chemical within the body can not be adequately described by either of these models since there may be several peripheral body compartments that the chemical may go to, including long-term storage. In addition, biotransformation and elimination of a chemical may not be simple processes but subject to different rates as the blood levels change.
Structural Barriers to Distribution
Organs or tissues differ in the amount of a chemical that they receive or to which they are exposed. This is primarily due to two factors, the volume of blood flowing through a specific tissue and the presence of special "barriers" to slow down toxicant entrance. Organs that receive larger blood volumes can potentially accumulate more of a given toxicant. Body regions that receive a large percentage of the total cardiac output include the liver (28%), kidneys (23%), heart muscle, and brain. Bone and adipose tissues have relatively low blood flow, even though they serve as primary storage sites for many toxicants. This is especially true for those that are fat soluble and those that readily associate (or complex) with minerals commonly found in bone.
Tissue affinity determines the degree of concentration of a toxicant. In fact, some tissues have a higher affinity for specific chemicals and will accumulate a toxicant in great concentrations in spite of a rather low flow of blood. For example, adipose tissue, which has a meager blood supply, concentrates lipid-soluble toxicants. Once deposited in these storage tissues, toxicants may remain for long periods of time, due to their solubility in the tissue and the relatively low blood flow.
During distribution, the passage of toxicants from capillaries into various tissues or organs is not uniform. Structural barriers exist that restrict entrance of toxicants into certain organs or tissues. The primary barriers are those of the brain, placenta, and testes.
The blood-brain barrier protects the brain from most toxicants. Specialized cells called astrocytes possess many small branches, which form a barrier between the capillary endothelium and the neurons of the brain. Lipids in the astrocyte cell walls and very tight junctions between adjacent endothelial cells limit the passage of water-soluble molecules. The blood-brain barrier is not totally impenetrable, but slows down the rate at which toxicants cross into brain tissue while allowing essential nutrients, including oxygen, to pass through.
The placental barrier protects the developing and sensitive fetus from most toxicants distributed in the maternal circulation. This barrier consists of several cell layers between the maternal and fetal circulatory vessels in the placenta. Lipids in the cell membranes limit the diffusion of water-soluble toxicants. However, nutrients, gases, and wastes of the developing fetus can pass through the placental barrier. As in the case of the blood-brain barrier, the placental barrier is not totally impenetrable but effectively slows down the diffusion of most toxicants from the mother into the fetus.
Storage of toxicants in body tissues sometimes occurs. Initially, when a toxicant enters the blood plasma, it may be bound to plasma proteins. This is a form of storage since the toxicant, while bound to the protein, does not contribute to the chemical's toxic potential. Albumin is the most abundant plasma protein that binds toxicants. Normally, the toxicant is only bound to the albumen for a relatively short time.
The primary sites for toxicant storage are adipose tissue, bone, liver and kidneys. Lipid-soluble toxicants are often stored in adipose tissues. Adipose tissue is located in several areas of the body but mainly in subcutaneous tissue. Lipid-soluble toxicants can be deposited along with triglycerides in adipose tissues. The lipids are in a continual exchange with blood and thus the toxicant may be mobilized into the blood for further distribution and elimination, or redeposited in other adipose tissue cells.
Another major site for storage is bone. Bone is composed of proteins and the mineral salt hydroxyapatite. Bone contains a sparse blood supply but is a live organ. During the normal processes that form bone, calcium and hydroxyl ions are incorporated into the hydroxyapatite-calcium matrix. Several chemicals, primarily elements, follow the same kinetics as calcium and hydroxyl ions and therefore can be substituted for them in the bone matrix. For example, strontium (Sr) or lead (Pb) may be substituted for calcium (Ca), and fluoride (F-) may be substituted for hydroxyl (OH-) ions. Bone is continually being remodeled under normal conditions. Calcium and other minerals are continually being resorbed and replaced, on the average about every 10 years. Thus, any toxicants stored in the matrix will eventually be released to reenter the circulatory system.
The liver is a storage site for some toxicants. It has a large blood flow and its hepatocytes (i.e., liver cells) contain proteins that bind to some chemicals, including toxicants. As with the liver, the kidneys have a high blood flow, which preferentially exposes these organs to toxicants in high concentrations. Storage in the kidneys is associated primarily with the cells of the nephron (the functional unit for urine formation).
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