The biological system may be exposed to the high amounts/concentration of xenobiotics, but if the concentration at the specific sites remain low due to any reason viz., defensive mechanism, there appears little or no effect. In order to produce a measurable effect, a xenobiotic must be transported from the site of exposure to the specific sites of action. The process of transport of xenobiotics (toxicants) from the site of their application to the specific site of action or more diffused sites of action is designated as translocation of xenobiotics.
In other words, dynamics of movement of xenobiotics in the living system from its penetration into the blood to its final elimination from the body is termed translocation. The factors which bring translocation are referred to as translocation factors including absorption, distribution, binding and excretion.
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The process of translocation involves four principal steps:
i. Absorption from the site of action via skin or GIT or lungs.
ii. Transport of xenobiotics by blood to- (a) The biotransformation sites, (b) Other tissues.
iii. Accumulation of xenobiotics and their release into the blood.
iv. Elimination from the body mainly through- (a) G.I.T. (b) Kidney
The entire process of translocation is represented in the Fig. 14.1. The major routes by which xenobiotics enter the body are skin, G.I.T. and lungs. Xenobiotics thus absorbed are eliminated from the circulation by metabolism and circulation. The quantification and determination of the time course of absorption, distribution, biotransformation and excretion of xenobiotics are referred to as toxicokinetics.
1. Absorption:
The process by which xenobiotics cross body membranes and enter the blood stream is referred to as absorption. There are no specific systems or pathways for the sole purpose of absorbing toxicants. Xenobiotics penetrate membranes during absorption by the same processes, as do biologically essential substances such as oxygen, foodstuff and other nutrients.
The main sites of absorption are the GIT, the lungs, and the skin. However, absorption may also occur from other sites, such as the sub-cutis, peritoneum, or muscle, if a chemical is administered by special routes. Experimentalists often distinguish between parenteral and enteral administration of drugs and other xenobiotics. It shall not be out of place to mention that enteral administration includes all routes pertaining to the alimentary canal (sublingual, oral, and rectal), whereas parenteral administration involves all other routes (intravenous, intraperitoneal, intramuscular, subcutaneous) etc.
Overall, the absorption of xenobiotics may take place through 4 ways:
A. Absorption by the skin (Dermal absorption)
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B. Absorption by the lungs (Pulmonary absorption)
C. Absorption by gastro-intestinal tract (Gastro-intestinal absorption)
D. Absorption through special routes.
A. Absorption by the Skin:
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The body’s primary barrier to the toxic chemicals is the skin, which has a surface area of about 18,000 cm2 in humans and constitutes about 10% of body weight. Thus, dermal absorption is very important in view of the surface area of skin. A xenobiotic entering through the skin would normally have to penetrate several layers of intact cells to reach the systemic blood circulation.
Lipid-soluble molecules such as tetraethyl lead and benzene are more easily absorbed via the skin than water-soluble polar molecules and ions (e.g., inorganic leads, H2SO4). Solvents such as CCl4, highly lipid soluble, absorbed percutaneously exert systemic toxic effect following absorption by this route. Small hydrophilic xenobiotics such as hydrazine is sufficiently absorbed through skin, causes local as well as systemic toxic effect.
B. Absorption by the Lungs:
Humans breathe 22,000 times a day taking in 16 kg of oxygen. Thus pulmonary absorption can be the principal route of entry for gaseous and particulate air pollutants and volatile organic chemicals. The large surface area of lungs makes it particularly vulnerable to the toxic injuries caused by inhaled gases and particulates.
The most frequent cause of death from poisoning by CO and occupational disease silicosis are the consequences and the results of absorption of air-borne poisons by the lungs. Bhopal Gas Tragedy may be considered as an extreme example of absorption of MIC gas through the lungs.
The air-borne particulate matters deposited in the lungs are absorbed by processes known as ‘pinocytosis’ (a special type of transport, in which cells engulf small droplets of extracellular fluid) and ‘phagocytosis’ (a specialized transport process that involves the engulfing of a particle or colloidal material by the cells) and moved by the action of cilia into the pharynx from where it may be swallowed in.
But the soluble chemical molecules could penetrate the epithelium and enter the blood circulation directly. Pinocytosis and phagocytosis may also be referred to as cell-drinking and cell-eating, respectively.
C. Absorption by the Gastro-Intestinal Tract:
The oral uptake is the most important pathway at least for the water-borne and food-borne pollutants. The absorption of xenobiotic molecules along the gastrointestinal (G.I.) tract (consisting of stomach, small intestine and colon) is characteristically due to the epithelial wall of the G. I. Tract, which exhibits the properties of the lipoid membrane. Hence, un-ionized polar toxicants are more readily absorbed, the absorption rates for these chemicals being influenced by their relative octanol- water partition coefficients.
The substances ingested by oral route do not produce systemic effects unless they are absorbed. The stomach having a pH 1 to 3 represents the most significant site of absorption for xenobiotics that are actually acidic or near neutral. Along the small intestines and colon (whose pH lies in the range of 6 to 8), weak acids and bases are more efficiently absorbed, the rate of absorption being inversely related to their water solubilities.
D. Absorption through Special Routes:
Generally the xenobiotics enter the blood stream following absorption through skin, lungs and gastrointestinal tract.
But, sometimes, the toxicants are administered in the body of experimental animals through special routes such as:
(1) Intraperitoneal
(2) Subcutaneous
(3) Intramuscular, and
(4) Intravenous.
The toxicants are directly administered into the blood stream through intravenous route. Administration of toxicants through intraperitoneal route results in rapid absorption of toxicants primarily through the portal circulation because of the large surface area and rich blood supply to the peritoneal cavity. Toxicants administered subcutaneously and intramuscularly are absorbed at slow rate. This can be altered by changing the blood flow to the area and the medium in which the toxicant is administered.
Most of the toxicant administered intra-peritoneally enters the liver via portal circulation before it reaches the general circulation of the animals. Sometimes the xenobiotics may be completely bio-transformed and eliminated into the bile and consequently it never reaches the target sites.
2. Distribution:
A xenobiotic after entering the blood by absorption or intravenous administration is ready for distribution throughout the body. Distribution usually occurs rapidly. The rate of distribution to organs or tissues is determined primarily by blood flow and the rate of diffusion out of the capillary bed into the cells of a particular organ or tissues. The final distribution depends largely on the affinity of a xenobiotic for various tissues. In general, the initial phase of distribution is dominated by the blood flow, whereas the eventual distribution is determined largely by affinity.
Some toxicants do not readily cross plasma membranes and, therefore, have restricted distribution; whereas other xenobiotics rapidly pass through plasma membranes and are distributed throughout the body. During the course of distribution, the xenobiotics may get concentrated in a particular tissue or organ and such tissues or sites are termed storage depots. The site of accumulation of toxicant may be its site of major toxic action, but more often it is not.
Actually xenobiotics (toxicant) accumulate at a site other than the target organ or tissue. The accumulation may be viewed as a protective process. Xenobiotics enter the systemic blood circulation as a result of the absorption processes. Since the blood-stream passes through all the body tissues, it can distribute the chemical throughout the body. Among the body fluids, plasma water is relatively more important than the interstitial or intra-cellular water. In humans, the blood plasma accounts for 4% of the total body weight and for about 53% of the total blood volume.
The concentration of a chemical (xenobiotic) in blood plasma, is very important since it determines the amount of the chemical- (1) That can reach the site of toxic action (i.e., target organ), (2) That might be directed to a storage depot (e.g., bone, adipose tissue) and (3) That is transported to the liver where the process of biotransformation to activate or inactivate an organic pollutant occurs.
The concentration of a toxicant in blood is primarily dependent on its volume of distribution.
The volume of distribution can be quantified by the following formula –
VD = [Dose (mg)/Plasma concentration (mg/l)]
The volume of distribution sometimes indicates that the xenobiotic compound is localized in a particular tissue or is mainly confined to the plasma.
Various factors influence the distribution of toxicants from the blood stream; of prime importance is the binding of chemical molecules in blood to the plasmatic proteins, particularly, the serum albumins. The chemical molecules that are bound to the plasmatic proteins are rendered unavailable for distribution or for immediate toxic action (until dissociated, or competitively displaced by another chemical molecule). Only the free and unbound chemical forms are susceptible for metabolic alterations and are responsible for the elimination of toxic effects.
Several organophosphorus insecticides and also the organo-chlorine insecticides, dieldrin, for example, are known to be firmly bound to plasmatic proteins. Problems could emerge when a second substance is introduced into the blood-stream, especially if the latter replaces the previously bound substance(s) from the binding sites on the plasma proteins. This can result in unpredictable increase of the unbound fraction of the first substance in the plasma, leading to serious toxicological consequences.
Storage-Depots or Store-House (Storage of Toxicants in Certain Tissues):
Xenobiotics often are concentrated in a specific tissue. Some xenobiotics attain their highest concentrations at the site of toxic action and in fact such substances prove to be highly deleterious. For example, CO, which keeps a high degree of affinity for hemoglobin and paraquet shows high affinity for the lungs, hence it accumulates in the lung. Other xenobiotics get concentrated at sites other than the target organ. For example, lead is accumulated in bone, but its poisoning appears in soft tissues.
Likewise, organochlorines, which are well known neurotoxicants, accumulate in tissue having high lipid content. The compartments where xenobiotics get concentrated or accumulated are denoted as storage depots or store house of toxicants. The storage may be viewed as a protective device, which prevents the deposition or accumulation or storage of xenobiotics (toxicants) at the site of their action, and consequently minimize their toxic actions. Elimination of the toxicants of storage depots takes place through biotransformation and excretion.
Effect of Accumulation and Retention of Xenobiotics:
Some xenobiotics (toxicants) do not readily cross plasma membrane and, therefore, have restricted distribution. Whereas, other toxicants rapidly pass through plasma membrane and are distributed throughout the body. Some toxicants accumulate in certain parts of the body as a result of protein binding, active transport, or high solubility in fat. The site of accumulation of a toxicant also may be its site of major toxic action but more often it is not.
If a toxicant accumulates at a site other than the target organ or tissue, the accumulation may be viewed as a protective process in that plasma levels and, consequently, the concentration of a toxicant at the site of action, are diminished. In this case, it is assumed that the xenobiotic in the storage depot is toxicologically inactive. However, because any chemical in a storage depot is in equilibrium with the free fraction of toxicant in plasma, it is released into the circulation as the unbound fraction of toxicant is eliminated, for example, by biotransformation.
The following are the toxic effects due to accumulation and retention of xenobiotics:
1. Accumulation of high concentration of various xenobiotics viz., 1,000 ppm of organochlorinated hydrocarbons in liver may cause cytoplasmic vacuolation, swelling, necrosis and fatty degeneration of liver.
2. In lungs aldrin, dieldrin etc. causes congestion.
3. Lindane and BHC cause fatty degeneration of kidney, congestion of the bladder and also nephritis. These xenobiotics also cause hemorrhage of GIT.
4. Metallic xenobiotics, after accumulating in the glomerular basement membrane of kidney produce nephritis.
5. Chlorinated hydrocarbons, after accumulating in the axon sheath, disrupt impulse transmission.
6. Xenobiotics, after crossing placental barrier, accumulate in the fetus and produce deleterious effects. For example — thalidomide causes phocomelia i.e., absence of limbs in fetus.
3. Biotransformation:
Biocatalytical conversion of xenobiotics (toxicants) into hydrophilic forms to facilitate their excretion from the body is termed biotransformation. In other words, biochemical modification of xenobiotics (toxicants) into non-toxic form may be termed as biotransformation. It is also called metabolic transformation. In principle, biotransformation may be defined as a process which converts the lipophilic compounds to more hydrophillic metabolites. In simple words, the conversion of toxic xenobiotics into less toxic metabolites and then forming conjugates may be termed biotransformation.
The principal site of biotransformation is the liver, the other being the lungs, stomach, intestine, skin and kidneys. Actually almost all parts of the body possess some activity against xenobiotic substances, but the major enzyme systems are found mainly in the liver.
4. Excretion:
Actually elimination of the xenobiotics from the body system is a bi-phasic process. First the xenobiotics reach blood from various routes of entry, then they are distributed by blood to different organs of the body, from where the toxic molecules re-enter blood for redistribution to the organs of elimination or deposition. The rate of elimination of xenobiotics from blood stream, therefore, depends on the rate of their distribution and redistribution by the blood and the organs of elimination.
The principal organs of the elimination (excretion) of xenobiotics and their metabolites are:
1. Kidneys (urinary or renal excretion)
2. GIT
3. Liver (Biliary excretion)
4. Lungs
5. Sweat glands on skin
6. Mammary glands
7. Vagina (Vaginal secretion)
8. Salivary glands.
Kidneys are the organs that seem to be especially designed for the excretion of xenobiotics and their metabolites. Toxicants and their metabolites are steadily removed from the blood as they pass through the kidneys. Blood, amounting to one- fourth of the cardiac output, actually flows via the/kidneys, which filter an estimated 180 liters of plasma every day. The filtration of toxic substances (of molecule weight < 70,000) from the blood is carried out at the glomeruli; the remaining filtrate passes into proximal tubules where re-absorption of lipophilic substances takes place.
Toxicants may also be excreted into the urine by a process called active secretion. The urinary excretion of xenobiotics is influenced primarily by the pH of urine; the bases are more readily eliminated if the urine is acidic, and vice versa. Conversely, acidic urines may exhibit a high capacity of re-absorption for organic acids. The various conditions that affect the kidney would eventually influence the urinary excretion of metabolites.
To sum up, kidney excretes xenobiotics/their metabolites by the following three mechanisms:
i. Passive glomerular filtration
ii. Active tubular secretion
iii. Passive diffusion across tubules.
All ionized and polar forms of xenobiotics, example — organophosphates, alcohol etc., and also weak acids and weak bases are completely excreted by glomerular filtration. Organic bases and weak electrolytes are secreted into tubular lumen. Polar and lipophilic substances are not excreted at all from kidney.
Many insoluble molecules and molecules in colloidal form are eliminated through fecal content. The excretion may be due to the agent/compound not absorbed after oral ingestion. Some ionized xenobiotics may be excreted into the gut, if concentration gradient is favourable. Heavy metal ions in the form of metallo-protein are eliminated through feces.
Generally, the free and conjugated forms of toxicants or their metabolites of molecular weight < 300 are conveniently excreted through the kidneys. But the biliary excretion represents a relatively more important route for the elimination of compounds with higher molecular mass (300 – 700). This route is indeed a prominent route of elimination. This route provides way for the elimination of metabolites formed in the liver, directly into the bile without entering the systemic blood circulation.
Some xenobiotics may undergo entero-hepatic circulation, the mechanism by which a compound excreted in the bile is re-absorbed from the intestine and returned to the liver. Recirculation of non-polar toxicants in this manner might lead to the cumulative poisoning of the liver cells.
The biliary route of excretion is important in elimination of anions, cations and non-ionized molecules. Liver also secretes organic cations. Non-ionized molecules are also secreted in bile and perhaps liver has also a transport system for the excretion of metallic xenobiotics.
Biliary excretion of xenobiotics varies with species, and is generally maximum in dogs and rats. Hepatic excretion system is not fully developed in infants and, therefore, some xenobiotics are more toxic to infants than adults.
Many volatile compounds like alcohol and paraldehydes are eliminated through expiration from lungs. Lungs also excrete Flurobenzene and CO. Gases with low blood/gas solubility, such as benzene and nitrous oxide, are excreted at rapid rates.
Many water-soluble toxic molecules, entering sweat glands, are excreted with the sweat. Generally, sweat glands excrete very small amounts of xenobiotics. However, drugs used for leprosy, viz., diethyl dithioliosphthalate, are largely excreted through sweat.
Certain xenobiotics are partly excreted into milk of lactating mothers. Several xenobiotics as DDT, thiouracil, tetracycline, morphine, heroin, sedatives like barbiturates, tranquilizers like diazepam and phenothiazine, oral anticoagulants and purgatives etc. have been reported to be excreted in milk.
7. Vagina (Vaginal Secretion):
Though the role of vagina is not much understood, hippuric and glycine conjugates of benzoic acid have been reported in the estrus secretions of cow.
Water-soluble toxic molecules enter salivary glands from the GIT and are eliminated through saliva. Example — iodides, fluorides, sulphonamides. Drugs like pentobarbitone are excreted in higher concentration in the saliva of ruminants.
Many xenobiotics get deposited in the dead tissues of the body and are eliminated.
For example:
i. Metallic ions viz. arsenic get deposited in nails and hair follicles.
ii. Toxic molecules that are highly lipophilic, for example, dieldrin, get deposited in the carcass of ruminates.
iii. Some metals like lead and cadmium get deposited in bones.