Excretion of toxicants

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CDC Public Health Image library ID 11162, James Gathany, via Wikimedia Commons

 

Introduction

Elimination from the body is very important in determining the potential toxicity of a xenobiotic. When a toxic xenobiotic (or its metabolites) is rapidly eliminated from the body, it is less likely that they will be able to concentrate in and damage critical cells. The terms excretion and elimination are frequently used to describe the same process whereby a substance leaves the body. Elimination, however, is sometimes used in a broader sense and includes the removal of the absorbed xenobiotic by metabolism as well as excretion. Excretion, as used here, pertains to the elimination or ejection of the xenobiotic and it's metabolites by specific excretory organs.

Except for the lung, polar (hydrophilic or water-soluble) substances have a definite advantage over lipid-soluble toxicants as regards elimination from the body. Chemicals must again pass through membranes in order to leave the body, and the same chemical and physical properties that governed passage across other membranes applies to excretory organs as well.

Toxicants or their metabolites can be eliminated from the body by several routes. The main routes of excretion are via urine, feces, and exhaled air. Thus, the primary organ systems involved in excretion are the urinary system, gastrointestinal system and respiratory system. A few other avenues for elimination exist but they are relatively unimportant, except in exceptional circumstances.

Urinary Excretion

Elimination of substances by the kidneys into the urine is the primary route of excretion of toxicants. The primary function of the kidney is the excretion of body wastes and harmful chemicals. The functional unit of the kidney responsible for excretion is the nephron. Each kidney contains about one million nephrons. The nephron has three primary regions that function in the renal excretion process, the glomerulus, proximal tubule, and the distal tubule. These are identified in the illustrations.

Three processes are involved in urinary excretion: filtration, secretion, and reabsorption. Filtration, the first process, takes place in the glomerulus, the very vascular beginning of the nephron. Approximately one-fourth of the cardiac output circulates through the kidney, the greatest rate of blood flow for any organ. A considerable amount of the blood plasma filters through the glomerulus into the nephron tubule. This results from the large amount of blood flow through the glomerulus, the relatively large pores (40 angstrom, an angstom is one one-hundred millionth of a centimeter) in the glomerular capillaries, and the hydrostatic pressure of the blood. Small molecules, including water, readily pass through the sieve-like filter into the nephron tubule. Both lipid-soluble and polar substances will pass through the glomerulus into the tubule filtrate. The amount of filtrate is very large, about 45 gallons/day in an adult human. About 99% of the water-like filtrate, small molecules, and lipid-soluble substances, are reabsorbed downstream in the nephron tubule. The urine, as eliminated, is thus only about one percent of the amount of fluid filtrated through the glomerulae into the renal tubules.

caption By Piotr Michał Jaworski; PioM EN DE PL (Own work) [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], via Wikimedia Commons
  1. Renal pyramid
  2. Interlobular artery
  3. Renal artery
  4. Renal vein
  5. Renal hylum
  6. Renal pelvis
  7. Ureter
  8. Minor calyx

Piotr Michał Jaworski via Wikimedia Commons

  1. Renal capsule
  2. Inferior extremity
  3. Superior extremity
  4. Interlobar vein
  5. Nephron
  6. Renal sinus
  7. Major calyx
  8. Renal column
  9. Renal papilla

Molecules with molecular weights greater than 60,000 (which include large protein molecules and blood cells) cannot pass through the capillary pores and remain in the blood. If albumen or blood cells are found in urine it is an indication that the glomerulae have been damaged. Binding to plasma proteins will influence urinary excretion. Polar substances usually do not bind with the plasma proteins and thus can be filtered out of the blood into the tubule filtrate. In contrast, substances extensively bound to plasma proteins remain in the blood.

Secretion, which occurs in the proximal tubule section of the nephron, is responsible for the transport of certain molecules out of the blood and into the urine. Secreted substances include potassium ions, hydrogen ions, and some xenobiotics. Secretion occurs by active transport mechanisms that are capable of differentiating among compounds on the basis of polarity. Two systems exist, one that transports weak acids (such as many conjugated drugs and penicillins) and the other that transports basic substances (such as histamine and choline).

Reabsorption takes place mainly in the proximal convoluted tubule of the nephron. Nearly all of the water, glucose, potassium, and amino acids lost during glomerular filtration reenter the blood from the renal tubules. Reabsorption occurs primarily by passive transfer based on concentration gradient, moving from a high concentration in the proximal tubule to the lower concentration in the capillaries surrounding the tubule.

A factor that greatly affects reabsorption and urinary excretion is the pH of the urine. This is especially the case with weak electrolytes. If the urine is alkaline, weak acids are more ionized and thus excreted to a great extent. If the urine is acidic, the weak acids (such as glucuronide and sulfate conjugates) are less ionized and undergo reabsorption with renal excretion reduced. Since the urinary pH is variable in humans, so are the urinary excretion rates of weak electrolytes. Examples are phenobarbital (an acidic drug), which is ionized in alkaline urine, and amphetamine (a basic drug), which is ionized in acidic urine. Treatment of barbiturate poisoning (such as an overdose of phenobarbital) may include changing the pH of the urine to facilitate excretion. Diet may have an influence on urinary pH and thus the elimination of some toxicants. For example, a high-protein diet results in acidic urine.

 

It can be seen that the ultimate elimination of a substance by the kidney is greatly affected by its physical properties (primarily molecular size) and its polarity in the urinary filtrate. Small toxicants (both polar and lipid-soluble) are filtered with ease by the glomerulus. In some cases, large molecules (including some that are protein-bound) may be secreted (by passive transfer) from the blood across capillary endothelial cells and nephron tubule membranes to enter the urine. The major difference in ultimate fate is governed by a substance's polarity. Those substances that are ionized remain in the urine and leave the body. Lipid-soluble toxicants can be reabsorbed and re-enter the blood circulation, which lengthens their half-life in the body and potential for toxicity.

Kidneys, which have been damaged by toxins, infectious diseases, or as a consequence of age, have diminished ability to eliminate toxicants thus making those individuals more susceptible to toxins that enter the body. The presence of albumin in the urine indicates that the glomerulus filtering system is damaged letting large molecules pass through. The presence of glucose in the urine is an indication that tubular reabsorption has been impaired.

Fecal Excretion

Elimination of toxicants in the feces occurs from two processes: excretion in bile, which then enters the intestine, and direct excretion into the lumen of the gastrointestinal tract. The biliary route is an important mechanism for fecal excretion of xenobiotics and is even more important for the excretion of their metabolites. This route generally involves active secretion rather than passive diffusion. Specific transport systems appear to exist for certain types of substances, e.g., organic bases, organic acids, and neutral substances. Some heavy metals are excreted in the bile, e.g., arsenic, lead, and mercury. However, the most likely substances to be excreted via the bile are comparatively large, ionized molecules, such as large molecular weight (greater than 300) conjugates.

caption By Mariana RuizLadyofHats, edited by Joaquim Alves Gaspar (i made it myself) [Public domain], via Wikimedia Commons
Mariana Ruiz, edited by Joaquim Alves Gaspar, via Wikimedia Commons

Once a substance has been excreted by the liver into the bile, and subsequently into the intestinal tract, it can then be eliminated from the body in the feces, or it may be reabsorbed. Since most of the substances excreted in the bile are water-soluble, they are not likely to be reabsorbed as such. However, enzymes in the intestinal flora are capable of hydrolyzing some glucuronide and sulfate conjugates, which can release the less-polar compounds that may then be reabsorbed. This process of excretion into the intestinal tract via the bile and reabsorption and return to the liver by the portal circulation is known as the enterohepatic circulation.

The effect of this enterohepatic circulation is to prolong the life of the xenobiotic in the body. In some cases, the metabolite is more toxic than the excreted conjugate. Continuous enterohepatic recycling can occur and lead to very long half-lives of some substances. In this case, drugs may be given orally to bind substances excreted in the bile. For example, a resin is administered orally which binds with the dimethylmercury (which had been secreted in the bile), preventing reabsorption, and further toxicity.

The efficiency of biliary excretion can be affected by changing the production and flow of bile in the liver. This can occur with liver disease, which usually causes a decrease in bile flow. In contrast, some drugs (e.g., phenobarbital) can produce an increase in bile flow rate. Administration of phenobarbital has been shown to enhance the excretion of methylmercury by this mechanism.

Another way that xenobiotics can be eliminated via the feces is by direct intestinal excretion. While this is not a major route of elimination, a large number of substances can be excreted into the intestinal tract and eliminated via feces. Some substances, especially those which are poorly ionized in plasma (such as weak bases), may passively diffuse through the walls of the capillaries, through the intestinal submucosa, and into the intestinal lumen to be eliminated in feces. Intestinal excretion is a relatively slow process and is therefore an important elimination route only for those xenobiotics that have slow biotransformation, or slow urinary or biliary excretion. Increasing the lipid content of the intestinal tract can enhance intestinal excretion of some lipophilic substances. For this reason, mineral oil is sometimes added to the diet to help eliminate toxic substances, which are known to be excreted directly into the intestinal tract.

Exhaled Air

The lungs represent an important route of excretion for xenobiotics (and metabolites) that exist in a gaseous phase in the blood. Blood gases are excreted by passive diffusion from the blood into the alveolus, following a concentration gradient. This occurs when the concentration of the xenobiotic dissolved in capillary blood is greater than the concentration of the substance in the alveolar air. Gases with a low solubility in blood are more rapidly eliminated than those gases with a high solubility. Volatile liquids dissolved in the blood are also readily excreted via the expired air. The amount of a liquid excreted by the lungs is proportional to its vapor pressure. Exhalation is an exception to most other routes of excretion in that it can be a very efficient route of excretion for lipid-soluble substances. This is due to the very close proximity of capillary and alveolar membranes, which are thin and allow for the normal gaseous exchange that occurs in breathing.

Other Routes of Excretion

Several minor routes of excretion exist, primarily via mother's milk, sweat, saliva, tears, and semen. Excretion into milk can be important since toxicants can be passed with milk to the nursing offspring. In addition, toxic substances may be passed from cow's milk to people. Toxic substances are excreted into milk by simple diffusion. Both basic substances and lipid-soluble compounds can be excreted into milk. Basic substances can be concentrated in milk since milk is more acidic (pH ~ 6.5) than blood plasma. Since milk contains 3-4% lipids, lipid-soluble xenobiotics can diffuse along with fats from plasma into the mammary gland and thus can be present in mother's milk. Substances that are chemically similar to calcium can also be excreted into milk along with calcium. Examples of substances that can be excreted in milk are DDT, polybrominated biphenyls, and lead (which follows calcium kinetics).

Excretion of xenobiotics in all other body secretions or tissues (including the saliva, sweat, tears, hair, and skin) are of only minor importance. Under conditions of great sweat production, excretion in sweat may reach a significant degree. Some metals, including cadmium, copper, iron, lead, nickel, and zinc, may be eliminated in sweat to some extent. Hair, in some cases, may be used as a biomonitoring tool for metals. Xenobiotics that passively diffuse into saliva may be swallowed and absorbed by the gastrointestinal system. The excretion of some substances into saliva is responsible for the unpleasant taste that sometimes occurs with time after exposure to a substance.

Disclaimer: This article is taken wholly from, or contains information that was originally published by, the National Library of Medicine. Topic editors and authors for the Encyclopedia of Earth may have edited its content or added new information. The use of information from the National Library of Medicine should not be construed as support for or endorsement by that organization for any new information added by EoE personnel, or for any editing of the original content.

 

Glossary

Citation

(2013). Excretion of toxicants. Retrieved from http://www.eoearth.org/view/article/51cbedc47896bb431f693c48

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