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Effects of abnormal renal function on body fluid
The structural framework of membranes is a bilayer of lipid molecules phospholipids, sphyngolipids, cholesterol. The backbone of a phospholipid molecule is glycerol with two of its -OH groups esterified by aliphatic fatty acids with 16 to 18 carbon atoms, and the third group esterified by a phosphate group and a nitrogenous compound choline, ethanolamine, serine. In sphyngolipids, sphyngosine is the base.
The lipid bilayer is arranged so that the hydrophilic heads constitute the outer and inner surface of membrane and lipophilic tails are stretched toward the membrane interior, which contains water, various ions and molecules.
Proteins and glycoproteins are inserted into the lipid bilayer intrinsic proteins or attached to the membrane surface extrinsic proteins. These proteins contribute to the structural integrity of the membrane, but they may also perform as enzymes, carriers, pore walls or receptors. The membrane represents a dynamic structure which can be disintegrated and rebuilt with a different proportion of lipids and proteins, according to functional needs.
Regulation of transport of substances into and out of the cell represents one of the basic functions of outer and inner membranes. Some lipophilic molecules pass directly through the lipid bilayer. Hydrophilic molecules and ions are transported via pores. Membranes respond to changing conditions by opening or sealing certain pores of various sizes. The following processes and mechanisms are involved in the transport of substances, including toxicants, through membranes:.
Difference in concentration or electric charge is the driving force influencing the intensity of the flux in both directions.
In the equilibrium state, influx will be equal to efflux. Small lipophilic molecules pass easily through the lipid layer of membrane, according to the Nernst partition coefficient.
Large lipophilic molecules, water soluble molecules and ions will use aqueous pore channels for their passage. Size and stereoconfiguration will influence passage of molecules. For ions, besides size, the type of charge will be decisive. The protein molecules of pore walls can gain positive or negative charge. This filtration is a consequence of the osmotic gradient. This requires the presence of a carrier in the membrane, usually a protein molecule permease.
The carrier selectively binds substances, resembling a substrate-enzyme complex. Similar molecules including toxicants can compete for the specific carrier until its saturation point is reached. Toxicants can compete for the carrier and when they are irreversibly bound to it the transport is blocked. The rate of transport is characteristic for each type of carrier. If transport is performed in both direction, it is called exchange diffusion. The carrier is very stereospecific and can be saturated.
For uphill transport, energy is required. Toxicants can interfere with this transport by competitive or non-competitive inhibition of the carrier or by inhibition of ATP-ase activity. Endocytosis is defined as a transport mechanism in which the cell membrane encircles material by enfolding to form a vesicle transporting it through the cell. When the material is liquid, the process is termed pinocytosis. In some cases the material is bound to a receptor and this complex is transported by a membrane vesicle.
This type of transport is especially used by epithelial cells of the gastrointestinal tract, and cells of the liver and kidneys. People are exposed to numerous toxicants present in the work and living environment, which can penetrate into the human organism by three main portals of entry:.
In the case of exposure in industry, inhalation represents the dominant way of entry of toxicants, followed by dermal penetration. In agriculture, pesticides exposure via dermal absorption is almost equal to cases of combined inhalation and dermal penetration. The general population is mostly exposed by ingestion of contaminated food, water and beverages, then by inhalation and less often by dermal penetration.
Absorption in the lungs represents the main route of uptake for numerous airborne toxicants gases, vapours, fumes, mists, smokes, dusts, aerosols, etc. The respiratory tract RT represents an ideal gas-exchange system possessing a membrane with a surface of 30 m 2 expiration to m 2 deep inspiration , behind which a network of about 2, km of capillaries is located.
The system, developed through evolution, is accommodated into a relatively small space chest cavity protected by ribs. Anatomically and physiologically the RT can be divided into three compartments:. Hydrophilic toxicants are easily absorbed by the epithelium of the nasopharingeal region.
The whole epithelium of the NP and TB regions is covered by a film of water. Lipophilic toxicants are partially absorbed in the NP and TB, but mostly in the alveoli by diffusion through alveolo-capillary membranes. The absorption rate depends on lung ventilation, cardiac output blood flow through lungs , solubility of toxicant in blood and its metabolic rate. In the alveoli, gas exchange is carried out.
The alveolar wall is made up of an epithelium, an interstitial framework of basement membrane, connective tissue and the capillary endothelium. The diffusion of toxicants is very rapid through these layers, which have a thickness of about 0. In alveoli, toxicant is transferred from the air phase into the liquid phase blood. The rate of absorption air to blood distribution of a toxicant depends on its concentration in alveolar air and the Nernst partition coefficient for blood solubility coefficient.
From the very beginning of exposure in the lungs, two opposite processes are occurring: The equilibrium between these processes depends on the concentration of toxicant in alveolar air and blood.
With continuation of exposure, an equilibrium between absorption and desorption is attained. Hydrophilic toxicants will rapidly attain equilibrium, and the rate of absorption depends on pulmonary ventilation rather than on blood flow. Lipophilic toxicants need a longer time to achieve equilibrium, and here the flow of unsaturated blood governs the rate of absorption.
Deposition of particles and aerosols in the RT depends on physical and physiological factors, as well as particle size. In short, the smaller the particle the deeper it will penetrate into the RT. Relatively constant low retention of dust particles in the lungs of persons who are highly exposed e. In the upper part of the RT tracheo-bronchial a mucociliary blanket performs the clearance. In the pulmonary part, three different mechanisms are at work.: The first 17 of the 23 branchings of the tracheo-bronchial tree possess ciliated epithelial cells.
By their strokes these cilia constantly move a mucous blanket toward the mouth. Particles deposited on this mucociliary blanket will be swallowed in the mouth ingestion. A mucous blanket also covers the surface of the alveolar epithelium, moving toward the mucociliary blanket.
Toxicants can be ingested in the case of accidental swallowing, intake of contaminated food and drinks, or swallowing of particles cleared from the RT.
The entire alimentary channel, from oesophagus to anus, is basically built in the same way. A mucous layer epithelium is supported by connective tissue and then by a network of capillaries and smooth muscle. The active area for absorption in the intestines is about m 2. Some toxic metal ions use specialized transport systems for essential elements: Many factors influence the rate of absorption of toxicants in various parts of the GIT:. It is also necessary to mention the enterohepatic circulation.
Here the enzymes of the microflora perform hydrolysis and liberated products can be reabsorbed and transported by the portal vein into the liver. This mechanism is very dangerous in the case of hepatotoxic substances, enabling their temporary accumulation in the liver. In the case of toxicants biotransformed in the liver to less toxic or non-toxic metabolites, ingestion may represent a less dangerous portal of entry.
After absorption in the GIT these toxicants will be transported by the portal vein to the liver, and there they can be partially detoxified by biotransformation. It represents a barrier against physical, chemical and biological agents, maintaining the body integrity and homeostasis and performing many other physiological tasks. Basically the skin consists of three layers: From the toxicological point of view the epidermis is of most interest here.
It is built of many layers of cells. A horny surface of flattened, dead cells stratum corneum is the top layer, under which a continuous layer of living cells stratum corneum compactum is located, followed by a typical lipid membrane, and then by stratum lucidum, stratum gramulosum and stratum mucosum. The lipid membrane represents a protective barrier, but in hairy parts of the skin, both hair follicles and sweat gland channels penetrate through it.
Therefore, dermal absorption can occur by the following mechanisms:. After absorption by any of these portals of entry, toxicants will reach the blood, lymph or other body fluids. The blood represents the major vehicle for transport of toxicants and their metabolites. Blood is a fluid circulating organ, transporting necessary oxygen and vital substances to the cells and removing waste products of metabolism. Blood also contains cellular components, hormones, and other molecules involved in many physiological functions.
Blood flows inside a relatively well closed, high-pressure circulatory system of blood vessels, pushed by the activity of the heart. Due to high pressure, leakage of fluid occurs. The lymphatic system represents the drainage system, in the form of a fine mesh of small, thin-walled lymph capillaries branching through the soft tissues and organs.
Plasma contains proteins albumins, globulins, fibrinogen , organic acids lactic, glutamic, citric and many other substances lipids, lipoproteins, glycoproteins, enzymes, salts, xenobiotics, etc. Blood cell elements include erythrocytes Er , leukocytes, reticulocytes, monocytes, and platelets. Toxicants are absorbed as molecules and ions.
Some toxicants at blood pH form colloid particles as a third form in this liquid. Molecules, ions and colloids of toxicants have various possibilities for transport in blood:.
Most of the toxicants in blood exist partially in a free state in plasma and partially bound to erythrocytes and plasma constituents. The distribution depends on the affinity of toxicants to these constituents. All fractions are in a dynamic equilibrium. Toxicants can be adsorbed on the surface of Er, or can bind to the ligands of stroma.
If they penetrate into Er they can bind to the haem e. Some toxicants transported by Er are arsenic, cesium, thorium, radon, lead and sodium. Hexavalent chromium is exclusively bound to the Er and trivalent chromium to the proteins of plasma.
For zinc, competition between Er and plasma occurs. Organic mercury is mostly bound to Er and inorganic mercury is carried mostly by plasma albumin. Small fractions of beryllium, copper, tellurium and uranium are carried by Er.
The majority of toxicants are transported by plasma or plasma proteins. Many electrolytes are present as ions in an equilibrium with non-dissociated molecules free or bound to the plasma fractions. This ionic fraction of toxicants is very diffusible, penetrating through the walls of capillaries into tissues and organs. Gases and vapours can be dissolved in the plasma.
Plasma proteins possess a total surface area of about to km 2 offered for absorption of toxicants. Albumin molecules possess about cationic and anionic ligands at the disposal of ions. Many ions are partially carried by albumin e. Globulin molecules alpha and beta transport small molecules of toxicants as well as some metallic ions copper, zinc and iron and colloid particles. Fibrinogen shows affinity for certain small molecules. Many types of bonds can be involved in binding of toxicants to plasma proteins: Van der Waals forces, attraction of charges, association between polar and non-polar groups, hydrogen bridges, covalent bonds.
Plasma lipoproteins transport lipophilic toxicants such as PCBs. The other plasma fractions serve as a transport vehicle too. The affinity of toxicants for plasma proteins suggests their affinity for proteins in tissues and organs during distribution. Organic acids lactic, glutaminic, citric form complexes with some toxicants.
Alkaline earths and rare earths, as well as some heavy elements in the form of cations, are complexed also with organic oxy- and amino acids. All these complexes are usually diffusible and easily distributed in tissues and organs. Physiologically chelating agents in plasma such as transferrin and metallothionein compete with organic acids and amino acids for cations to form stable chelates. Diffusible free ions, some complexes and some free molecules are easily cleared from the blood into tissues and organs.
The free fraction of ions and molecules is in a dynamic equilibrium with the bound fraction. The concentration of a toxicant in blood will govern the rate of its distribution into tissues and organs, or its mobilization from them into the blood. The human organism can be divided into the following compartments.
This classification is mostly based on the degree of vascular blood perfusion in a decreasing order. The well-perfused internal organs generally achieve the highest concentration of toxicants in the shortest time, as well as an equilibrium between blood and this compartment. The uptake of toxicants by less perfused tissues is much slower, but retention is higher and duration of stay much longer accumulation due to low perfusion.
Three components are of major importance for the intracellular distribution of toxicants: The above-mentioned order of compartments also follows closely a decreasing water content in their cells. Hydrophilic toxicants will be more rapidly distributed to the body fluids and cells with high water content, and lipophilic toxicants to cells with higher lipid content fatty tissue. The organism possesses some barriers which impair penetration of some groups of toxicants, mostly hydrophilic, to certain organs and tissues, such as:.
As previously noted only the free forms of toxicants in plasma molecules, ions, colloids are available for penetration through the capillary walls participating in distribution. This free fraction is in a dynamic equilibrium with the bound fraction. Concentration of toxicants in blood is in a dynamic equilibrium with their concentration in organs and tissues, governing retention accumulation or mobilization from them. The condition of the organism, functional state of organs especially neuro-humoral regulation , hormonal balance and other factors play a role in distribution.
Retention of toxicant in a particular compartment is generally temporary and redistribution into other tissues can occur. Retention and accumulation is based on the difference between the rates of absorption and elimination. The duration of retention in a compartment is expressed by the biological half-life.
Biotransformation processes occur during distribution and retention in various organs and tissues. Biotransformation produces more polar, more hydrophilic metabolites, which are more easily eliminated. A low rate of biotransformation of a lipophilic toxicant will generally cause its accumulation in a compartment. The toxicants can be divided into four main groups according to their affinity, predominant retention and accumulation in a particular compartment:.
Toxicants soluble in the body fluids are uniformly distributed according to the water content of compartments. Many monovalent cations e.
Lipophilic toxicants show a high affinity for lipid-rich organs CNS and tissues fatty, adipose. Toxicants forming colloid particles are then trapped by specialized cells of the reticuloendothelial system RES of organs and tissues. Tri- and quadrivalent cations lanthanum, cesium, hafnium are distributed in the RES of tissues and organs. Toxicants showing a high affinity for bones and connective tissue osteotropic elements, bone seekers include divalent cations e.
However, this lipid fraction is not uniformly distributed. The brain CNS is a lipid-rich organ, and peripheral nerves are wrapped with a lipid-rich myelin sheath and Schwann cells. All these tissues offer possibilities for accumulation of lipophilic toxicants.
Numerous non-electrolytes and non-polar toxicants with a suitable Nernst partition coefficient will be distributed to this compartment, as well as numerous organic solvents alcohols, aldehydes, ketones, etc. Adipose tissue will accumulate toxicants due to its low vascularization and lower rate of biotransformation. However, potential danger for the organism is always present due to the possibility of mobilization of toxicants from this compartment back to the circulation. Deposition of toxicants in the brain CNS or lipid-rich tissue of the myelin sheath of the peripheral nervous system is very dangerous.
The neurotoxicants are deposited here directly next to their targets. Toxicants retained in lipid-rich tissue of the endocrine glands can produce hormonal disturbances. Despite the blood-brain barrier, numerous neurotoxicants of a lipophilic nature reach the brain CNS: In each tissue and organ a certain percentage of cells is specialized for phagocytic activity, engulfing micro-organisms, particles, colloid particles, and so on. This system is called the reticuloendothelial system RES , comprising fixed cells as well as moving cells phagocytes.
These cells are present in non-active form. An increase of the above-mentioned microbes and particles will activate the cells up to a saturation point. Toxicants in the form of colloids will be captured by the RES of organs and tissues. Distribution depends on the colloid particle size. For larger particles, retention in the liver will be favoured. With smaller colloid particles, more or less uniform distribution will occur between the spleen, bone marrow and liver.
Clearance of colloids from the RES is very slow, although small particles are cleared relatively more quickly. Elements representing or replacing physiological constituents of the bone. Twenty such elements are present in higher quantities. The others appear in trace quantities. Under conditions of chronic exposure, toxic metals such as lead, aluminium and mercury can also enter the mineral matrix of bone cells. Alkaline earths and other elements forming cations with an ionic diameter similar to that of calcium are exchangeable with it in bone mineral.
Also, some anions are exchangeable with anions phosphate, hydroxyl of bone mineral. Elements forming microcolloids rare earths may be adsorbed on the surface of bone mineral. The surface area of mineral available for adsorption is about m 2 per g of bone. Metabolic activity of the bones of the skeleton can be divided in two categories:.
With age this percentage of metabolic bone decreases. Incorporation of toxicants during exposure appears in the metabolic bone and in more slowly turning-over compartments.
For ions, an ion exchange occurs with physiologically present calcium cations, or anions phosphate, hydroxyl. For toxicants forming colloid particles, adsorption on the mineral surface occurs. The bone mineral, hydroxyapatite, represents a complex ion-exchange system. Calcium cations can be exchanged by various cations. The anions present in bone can also be exchanged by anions: Ions which are not exchangeable can be adsorbed on the mineral surface.
When toxicant ions are incorporated in the mineral, a new layer of mineral can cover the mineral surface, burying toxicant into the bone structure. Ion exchange is a reversible process, depending on the concentration of ions, pH and fluid volume. Thus, for example, an increase of dietary calcium may decrease the deposition of toxicant ions in the lattice of minerals. It has been mentioned that with age the percentage of metabolic bone is decreased, although ion exchange continues.
With ageing, bone mineral resorption occurs, in which bone density actually decreases. At this point, toxicants in bone may be released e. Mobilization and excretion of this fraction shows a biological half-life of 2. Colloid particles are adsorbed as a film on the mineral surface m 2 per g by Van der Waals forces or chemisorption. This layer of colloids on the mineral surfaces is covered with the next layer of formed minerals, and the toxicants are more buried into the bone structure. The rate of mobilization and elimination depends on remodelling processes.
The hair and nails contain keratin, with sulphydryl groups able to chelate metallic cations such as mercury and lead. Recently the distribution of toxicants, especially some heavy metals, within cells of tissues and organs has become of importance. With ultracentrifugation techniques, various fractions of the cell can be separated to determine their content of metal ions and other toxicants. Animal studies have revealed that after penetration into the cell, some metal ions are bound to a specific protein, metallothionein.
This low molecular weight protein is present in the cells of liver, kidney and other organs and tissues. Its sulphydryl groups can bind six ions per molecule. Increased presence of metal ions induces the biosynthesis of this protein. Ions of cadmium are the most potent inducer. Metallothionein serves also to maintain homeostasis of vital copper and zinc ions. Metallothionein can bind zinc, copper, cadmium, mercury, bismuth, gold, cobalt and other cations.
During retention in cells of various tissues and organs, toxicants are exposed to enzymes which can biotransform metabolize them, producing metabolites. The elimination of an absorbed toxicant depends on the portal of entry. Elimination of toxicants absorbed by other paths of entry is prolonged and starts after transport by blood, eventually being completed after distribution and biotransformation. During absorption an equilibrium exists between the concentrations of a toxicant in the blood and in tissues and organs.
Excretion decreases toxicant blood concentration and may induce mobilization of a toxicant from tissues into blood. Many factors can influence the elimination rate of toxicants and their metabolites from the body:. Here we distinguish two groups of compartments: A toxicant can be excreted simultaneously by two or more excretion routes.
However, usually one route is dominant. Scientists are developing mathematical models describing the excretion of a particular toxicant. These models are based on the movement from one or both compartments exchange systems , biotransformation and so on.
Elimination via the lungs desorption is typical for toxicants with high volatility e. Gases and vapours with low solubility in blood will be quickly eliminated this way, whereas toxicants with high blood solubility will be eliminated by other routes. Organic solvents absorbed by the GIT or skin are excreted partially by exhaled air in each passage of blood through the lungs, if they have a sufficient vapour pressure. The Breathalyser test used for suspected drunk drivers is based on this fact.
The radioactive gas radon appears in exhaled air due to the decay of radium accumulated in the skeleton. Elimination of a toxicant by exhaled air in relation to the post-exposure period of time usually is expressed by a three-phase curve. The first phase represents elimination of toxicant from the blood, showing a short half-life. The second, slower phase represents elimination due to exchange of blood with tissues and organs quick-exchange system.
The third, very slow phase is due to exchange of blood with fatty tissue and skeleton. If a toxicant is not accumulated in such compartments, the curve will be two-phase. In some cases a four-phase curve is also possible. Determination of gases and vapours in exhaled air in the post-exposure period is sometimes used for evaluation of exposures in workers.
The kidney is an organ specialized in the excretion of numerous water-soluble toxicants and metabolites, maintaining homeostasis of the organism. Each kidney possesses about one million nephrons able to perform excretion. Renal excretion represents a very complex event encompassing three different mechanisms:. Excretion of a toxicant via the kidneys to urine depends on the Nernst partition coefficient, dissociation constant and pH of urine, molecular size and shape, rate of metabolism to more hydrophilic metabolites, as well as health status of the kidneys.
The kinetics of renal excretion of a toxicant or its metabolite can be expressed by a two-, three- or four-phase excretion curve, depending on the distribution of the particular toxicant in various body compartments differing in the rate of exchange with the blood.
The toxicants are then swallowed, reaching the GIT, where they can be reabsorbed or eliminated by faeces. Many non-electrolytes can be partially eliminated via skin by sweat: This pathway can represent a danger for nursing infants. Analysis of hair can be used as an indicator of homeostasis of some physiological substances. Also exposure to some toxicants, especially heavy metals, can be evaluated by this kind of bioassay.
Application of chelating agents is often used for elimination of heavy metals from the body of exposed workers in the course of their medical treatment. This method is also used for evaluation of total body burden and level of past exposure. Also it is necessary to take into consideration that some persons use medications, smoke, consume alcohol and food containing additives and so on. That means that usually multiple exposure is occurring. Each agent produces a different effect due to a different mechanism of action.
The combined effect is greater than that of each single agent. Here we differentiate two types: The combined effect is lower than additive. However, studies on combined effects are rare. This kind of study is very complex due to the combination of various factors and agents. We can conclude that when the human organism is exposed to two or more toxicants simultaneously or consecutively, it is necessary to consider the possibility of some combined effects, which can increase or decrease the rate of toxicokinetic processes.
The priority objective of occupational and environmental toxicology is to improve the prevention or substantial limitation of health effects of exposure to hazardous agents in the general and occupational environments. The effects of a chemical on particular systems and organs are related to the magnitude of exposure and whether exposure is acute or chronic.
In view of the diversity of toxic effects even within one system or organ, a uniform philosophy concerning the critical organ and critical effect has been proposed for the purpose of risk assessment and development of health-based recommended concentration limits of toxic substances in different environmental media. From the point of view of preventive medicine, it is of particular importance to identify early adverse effects, based on the general assumption that preventing or limiting early effects may prevent more severe health effects from developing.
Such an approach has been applied to heavy metals. Although heavy metals, such as lead, cadmium and mercury, belong to a specific group of toxic substances where the chronic effect of activity is dependent on their accumulation in the organs, the definitions presented below were published by the Task Group on Metal Toxicity Nordberg The definition of the critical organ as proposed by the Task Group on Metal Toxicity has been adopted with a slight modification: Whether a given organ or system is regarded as critical depends not only on the toxicomechanics of the hazardous agent but also on the route of absorption and the exposed population.
At an exposure level lower than that giving a critical concentration of metal in the critical organ, some effects may occur that do not impair cellular function per se, yet are detectable by means of biochemical and other tests. Such effects are defined as subcritical effects. The latter possibility can be particularly significant in view of prophylactic activities.
Lung cancer unit risk 4. A number of other definitions have been formulated which may better reflect the meaning of the notion. Adverse effects, such as cancer, with no defined threshold concentration are often regarded as critical. Decision on whether an effect is critical is a matter of expert judgement. The latter definition has been formulated directly for the purpose of evaluating the health-based exposure limits in the general environment.
In this context the most essential seems to be determining which effect can be regarded as an adverse effect. Decision on whether or not any effect is adverse requires expert judgement. In the case of exposure to lead, A can represent a subcritical effect inhibition of erythrocyte ALA-dehydratase , B the critical effect an increase in erythrocyte zinc protoporphyrin or increase in the excretion of delta-aminolevulinic acid, C the clinical effect anaemia and D the fatal effect death.
For lead exposure there is abundant evidence illustrating how particular effects of exposure are dependent on lead concentration in blood practical counterpart of the dose , either in the form of the dose-response relationship or in relation to different variables sex, age, etc. Determining the critical effects and the dose-response relationship for such effects in humans makes it possible to predict the frequency of a given effect for a given dose or its counterpart concentration in biological material in a certain population.
The critical effects can be of two types: Whenever possible, appropriate human data should be used as a basis for the risk assessment. In order to determine the threshold effects for the general population, assumptions concerning the exposure level tolerable intake, biomarkers of exposure have to be made such that the frequency of the critical effect in the population exposed to a given hazardous agent corresponds to the frequency of that effect in the general population.
In general, if data from well-conducted human population studies defining a no observed adverse effect level are the basis for safety evaluation, then the uncertainty factor of ten has been considered appropriate.
In the case of occupational exposure the critical effects may refer to a certain part of the population e. Both these values are under consideration for lowering, in many countries, at the present time i. There is no clear consensus on appropriate methodology for the risk assessment of chemicals for which the critical effect may not have a threshold, such as genotoxic carcinogens. A number of approaches based largely on characterization of the dose- response relationship have been adopted for the assessment of such effects.
Owing to the lack of socio-political acceptance of health risk caused by carcinogens in such documents as the Air Quality Guidelines for Europe WHO , only the values such as the unit lifetime risk i.
Presently, the basic step in undertaking activities for risk assessment is determining the critical organ and critical effects. The definitions of both the critical and adverse effect reflect the responsibility of deciding which of the effects within a given organ or system should be regarded as critical, and this is directly related to the subsequent determination of recommended values for a given chemical in the general environment-for example, Air Quality Guidelines for Europe WHO or health-based limits in occupational exposure WHO Determining the critical effect from within the range of subcritical effects may lead to a situation where the recommended limits on toxic chemicals concentration in the general or occupational environment may be in practice impossible to maintain.
Regarding as critical an effect that may overlap the early clinical effects may bring about the adoption of the values for which adverse effects may develop in some part of the population. The decision whether or not a given effect should be considered critical remains the responsibility of expert groups who specialize in toxicity and risk assessment. There are often large differences among humans in the intensity of response to toxic chemicals, and variations in susceptibility of an individual over a lifetime.
The possible contributions of the aforementioned factors in either increasing or decreasing susceptibility to adverse health effects, as well as the mechanisms of their action, are specific for a particular chemical. Therefore only the most common factors, basic mechanisms and a few characteristic examples will be presented here, whereas specific information concerning each particular chemical can be found in elsewhere in this Encyclopaedia. According to the stage at which these factors act absorption, distribution, biotransformation or excretion of a particular chemical , the mechanisms can be roughly categorized according to two basic consequences of interaction: The most common mechanisms of either type of interaction are related to competition with other chemical s for binding to the same compounds involved in their transport in the organism e.
However, both toxicokinetic and toxicodynamic interactions may influence individual susceptibility to a particular chemical. The influence of several concomitant factors can result in either: The quantity of a particular toxic chemical or characteristic metabolite at the site s of its effect in the human body can be more or less assessed by biological monitoring, that is, by choosing the correct biological specimen and optimal timing of specimen sampling, taking into account biological half-lives for a particular chemical in both the critical organ and in the measured biological compartment.
However, reliable information concerning other possible factors that might influence individual susceptibility in humans is generally lacking, and consequently the majority of knowledge regarding the influence of various factors is based on experimental animal data. Some of these differences can be attributed to the fact that the transportation, distribution and biotransformation pathways of various chemicals are greatly dependent on subtle changes in the tissue pH and the redox equilibrium in the organism as are the activities of various enzymes , and that the redox system of the human differs considerably from that of the rat.
This is obviously the case regarding important antioxidants such as vitamin C and glutathione GSH , which are essential for maintaining redox equilibrium and which have a protective role against the adverse effects of the oxygen- or xenobiotic-derived free radicals which are involved in a variety of pathological conditions Kehrer Humans cannot auto-synthesize vitamin C, contrary to the rat, and levels as well as the turnover rate of erythrocyte GSH in humans are considerably lower than that in the rat.
Humans also lack some of the protective antioxidant enzymes, compared to the rat or other mammals e. These examples illustrate the potentially greater vulnerability to oxidative stress in humans particularly in sensitive cells, e. Compared to adults, very young children are often more susceptible to chemical toxicity because of their relatively greater inhalation volumes and gastrointestinal absorption rate due to greater permeability of the intestinal epithelium, and because of immature detoxification enzyme systems and a relatively smaller excretion rate of toxic chemicals.
The central nervous system appears to be particularly susceptible at the early stage of development with regard to neurotoxicity of various chemicals, for example, lead and methylmercury. For example, the cytochrome P enzymes involved in the biotransformation pathways of almost all toxic chemicals can be either induced or have lowered activity because of the influence of various factors over a lifetime including dietary habits, smoking, alcohol, use of medications and exposure to environmental xenobiotics.
Gender-related differences in susceptibility have been described for a large number of toxic chemicals approximately , and such differences are found in many mammalian species. It appears that males are generally more susceptible to renal toxins and females to liver toxins. The causes of the different response between males and females have been related to differences in a variety of physiological processes e.
Adequate intake of essential metals including metalloids and proteins, especially the sulphur-containing amino acids, is necessary for the biosynthesis of various detoxificating enzymes and the provision of glycine and glutathione for conjugation reactions with endogenous and exogenous compounds. Lipids, especially phospholipids, and lipotropes methyl group donors are necessary for the synthesis of biological membranes.
Carbohydrates provide the energy required for various detoxification processes and provide glucuronic acid for conjugation of toxic chemicals and their metabolites. Selenium an essential metalloid , glutathione, and vitamins such as vitamin C water soluble , vitamin E and vitamin A lipid soluble , have an important role as antioxidants e.
In addition, various dietary constituents protein and fibre content, minerals, phosphates, citric acid, etc. However, diet itself can be an additional source of individual exposure to various toxic chemicals e. The habit of smoking can influence individual susceptibility to many toxic chemicals because of the variety of possible interactions involving the great number of compounds present in cigarette smoke especially polycyclic aromatic hydrocarbons, carbon monoxide, benzene, nicotine, acrolein, some pesticides, cadmium, and, to a lesser extent, lead and other toxic metals, etc.
For example, several cigarette smoke constituents can induce cytochrome P enzymes, whereas others can depress their activity, and thus influence the common biotransformation pathways of many other toxic chemicals, such as organic solvents and some medications. Consumption of alcohol ethanol can influence susceptibility to many toxic chemicals in several ways. The effect of possible aforementioned events can be augmented due to the fact that alcoholic beverages can contain an appreciable amount of lead from vessels or processing Prpic-Majic et al.
Another common reason for ethanol-related changes in susceptibility is that many toxic chemicals, for example, various organic solvents, share the same biotransformation pathway involving the cytochrome P enzymes. Depending on the intensity of exposure to organic solvents as well as the quantity and frequency of ethanol ingestion i. The common use of various medications can influence susceptibility to toxic chemicals mainly because many drugs bind to serum proteins and thus influence the transport, distribution or excretion rate of various toxic chemicals, or because many drugs are capable of inducing relevant detoxifying enzymes or depressing their activity e.
Characteristic for either of the mechanisms is increased urinary excretion of trichloroacetic acid the metabolite of several chlorinated hydrocarbons when using salicylate, sulphonamide or phenylbutazone, and an increased hepato-nephrotoxicity of carbon tetrachloride when using phenobarbital.
In addition, some medications contain a considerable amount of a potentially toxic chemical, for example, the aluminium-containing antacids or preparations used for therapeutic management of the hyperphosphataemia arising in chronic renal failure. The changes in susceptibility to adverse health effects due to interaction of various chemicals i. Relevant epidemiological and clinical studies are lacking. This is of concern particularly considering the relatively greater intensity of response or the variety of adverse health effects of several toxic chemicals in humans compared to the rat and other mammals.
The possibility of various additive, synergistic or antagonistic effects of exposure to various metals and metalloids in humans can be illustrated by basic examples related to the main toxic elements see table The main cause of all these interactions is the competition of various metals and metalloids for the same binding site especially the sulphhydryl group, -SH in various enzymes, metalloproteins especially metallothionein and tissues e.
Decreases the absorption rate of Ca and impairs the metabolism of Ca; deficient dietary Ca increases the absorption rate of Al. Data on interactions with Fe, Zn and Cu are equivocal i. Affects the distribution of Cu an increase of Cu in the kidney, and a decrease of Cu in the liver, serum and urine. Impairs the metabolism of Fe an increase of Fe in the liver with concomitant decrease in haematocrit. Decreases the absorption rate of Ca and impairs the metabolism of Ca; deficient dietary Ca increases the absorption rate of Cd.
Impairs the metabolism of Fe; deficient dietary Fe increases the absorption rate of Cd. Affects the distribution of Zn; Zn decreases the toxicity of Cd, whereas its influence on the absorption rate of Cd is equivocal.
Data on the interaction with Cu are equivocal i. Cd increases the concentration of Hg in the kidney, but at the same time decreases the toxicity of Hg in the kidney the influence ofthe Cd-induced metallothionein synthesis. Impairs the metabolism of Ca; deficient dietary Ca increases the absorption rate of inorganic Pb and increases the toxicity of Pb. Impairs the metabolism of Fe; deficient dietary Fe increases the toxicity of Pb, whereas its influence on the absorption rate of Pb is equivocal.
Impairs the metabolism of Zn and increases urinary excretion of Zn; deficient dietary Zn increases the absorption rate of inorganic Pb and increases the toxicity of Pb. Data on interactions with Cu and Mg are equivocal i. Nebert and Ross A. The recent explosion in molecular biology and genetics has brought a clearer understanding about the molecular basis of such variability. Major determinants of individual response to chemicals include important differences among more than a dozen superfamilies of enzymes, collectively termed xenobiotic- foreign to the body or drug-metabolizing enzymes.
Although the role of these enzymes has classically been regarded as detoxification, these same enzymes also convert a number of inert compounds to highly toxic intermediates. Recently, many subtle as well as gross differences in the genes encoding these enzymes have been identified, which have been shown to result in marked variations in enzyme activity.
It is the complex interplay of these many different enzyme superfamilies which ultimately determines not only the fate and the potential for toxicity of a chemical in any given individual, but also assessment of exposure.
In this article we have chosen to use the cytochrome P enzyme superfamily to illustrate the remarkable progress made in understanding individual response to chemicals. The development of relatively simple DNA-based tests designed to identify specific gene alterations in these enzymes, is now providing more accurate predictions of individual response to chemical exposure.
We hope the result will be preventive toxicology. In other words, each individual might learn about those chemicals to which he or she is particularly sensitive, thereby avoiding previously unpredictable toxicity or cancer. Although it is not generally appreciated, human beings are exposed daily to a barrage of innumerable diverse chemicals. Many of these chemicals are highly toxic, and they are derived from a wide variety of environmental and dietary sources.
The relationship between such exposures and human health has been, and continues to be, a major focus of biomedical research efforts worldwide.
What are some examples of this chemical bombardment? More than chemicals from red wine have been isolated and characterized. At least 1, chemicals are estimated to be produced by a lighted cigarette. There are countless chemicals in cosmetics and perfumed soaps. Another major source of chemical exposure is agriculture: Two other sources of large concentrations of chemicals taken into the body include a drugs taken chronically and b exposure to hazardous substances in the workplace over a lifetime of employment.
It is now well established that chemical exposure may adversely affect many aspects of human health, causing chronic diseases and the development of many cancers. In the last decade or so, the molecular basis of many of these relationships has begun to be unravelled. In addition, the realization has emerged that humans differ markedly in their susceptibility to the harmful effects of chemical exposure.
Current efforts to predict human response to chemical exposure combine two fundamental approaches figure Although both of these approaches are extremely important, it should be emphasized that the two are distinctly different from one another.
This article will focus on the genetic factors underlying individual susceptibility to any particular chemical exposure. This field of research is broadly termed ecogenetics, or pharmacogenetics see Kalow and Many of the recent advances in determining individual susceptibility to chemical toxicity have evolved from a greater appreciation of the processes by which humans and other mammals detoxify chemicals, and the remarkable complexity of the enzyme systems involved.
However, how do these doses affect each of us on an individual basis? In other words, a highly sensitive individual may be times more affected or times more likely to be affected than the most resistant individual in a population; for these people, the LD 50 and MTD 50 and ED 50 values would have little meaning.
This generic diagram might represent bronchogenic carcinoma in response to the number of cigarettes smokes, chloracne as a function of dioxin levels in the workplace, asthma as a function of air concentrations of ozone or aldehyde, sunburn in response to ultraviolet light, decreased clotting time as a function of aspirin intake, or gastrointestinal distress in response to the number of jalapeño peppers consumed.
Generally, in each of these instances, the greater the exposure, the greater the toxic response. Most of the population will exhibit the mean and standard deviation of toxic response as a function of dose. The "resistant outlier" lower right in figure These outliers, with extreme differences in response compared to the majority of individuals in the population, may represent important genetic variants that can help scientists in attempting to understand the underlying molecular mechanisms of a toxic response.
Using these outliers in family studies, scientists in a number of laboratories have begun to appreciate the importance of Mendelian inheritance for a given toxic response. How does the body respond to the myriad of exogenous chemicals to which we are exposed? Humans and other mammals have evolved highly complex metabolic enzyme systems comprising more than a dozen distinct superfamilies of enzymes. Almost every chemical to which humans are exposed will be modified by these enzymes, in order to facilitate removal of the foreign substance from the body.
Collectively, these enzymes are frequently referred to as drug-metabolizing enzymes or xenobiotic-metabolizing enzymes. Actually, both terms are misnomers. First, many of these enzymes not only metabolize drugs but hundreds of thousands of environmental and dietary chemicals. Second, all of these enzymes also have normal body compounds as substrates; none of these enzymes metabolizes only foreign chemicals. For more than four decades, the metabolic processes mediated by these enzymes have commonly been classified as either Phase I or Phase II reactions figure Phase I reactions are primarily mediated by a superfamily of highly versatile enzymes, collectively termed cytochromes P, although other enzyme superfamilies can also be involved figure Phase II reactions involve the coupling of a water-soluble endogenous molecule to a chemical parent chemical or Phase I metabolite in order to facilitate excretion.
The enzyme superfamilies catalyzing Phase II reactions are generally named according to the endogenous conjugating moiety involved: Although the major organ of drug metabolism is the liver, the levels of some drug- metabolizing enzymes are quite high in the gastrointestinal tract, gonads, lung, brain and kidney, and such enzymes are undoubtedly present to some extent in every living cell.
As we learn more about the biological and chemical processes leading to human health aberrations, it has become increasingly evident that drug-metabolizing enzymes function in an ambivalent manner figure In the majority of cases, lipid-soluble chemicals are converted to more readily excreted water-soluble metabolites. However, it is clear that on many occasions the same enzymes are capable of transforming other inert chemicals into highly reactive molecules. These intermediates can then interact with cellular macromolecules such as proteins and DNA.
Thus, for each chemical to which humans are exposed, there exists the potential for the competing pathways of metabolic activation and detoxification. In human genetics, each gene locus is located on one of the 23 pairs of chromosomes. The two alleles one present on each chromosome of the pair can be the same, or they can be different from one another. For example, the B and b alleles, in which B brown eyes is dominant over b blue eyes: For a gene to be polymorphic, the gene product must not be essential for development, reproductive vigour or other critical life processes.
Genetic differences in the metabolism of various drugs and environmental chemicals have been known for more than four decades Kalow and These differences are frequently referred to as pharmacogenetic or, more broadly, ecogenetic polymorphisms. These polymorphisms represent variant alleles that occur at a relatively high frequency in the population and are generally associated with aberrations in enzyme expression or function.
Historically, polymorphisms were usually identified following unexpected responses to therapeutic agents. More recently, recombinant DNA technology has enabled scientists to identify the precise alterations in genes that are responsible for some of these polymorphisms. As more and more polymorphisms are identified, it is becoming increasingly apparent that each individual may possess a distinct complement of drug-metabolizing enzymes. It is the complex interplay of the various drug- metabolizing enzyme superfamilies within any individual that will ultimately determine his or her particular response to a given chemical Kalow and ; Nebert ; Gonzalez and Nebert ; Nebert and Weber How might we develop better predictors of human toxic responses to chemicals?
Advances in defining the multiplicity of drug-metabolizing enzymes must be accompanied by precise knowledge as to which enzymes determine the metabolic fate of individual chemicals. Data gleaned from laboratory rodent studies have certainly provided useful information. However, significant interspecies differences in xenobiotic-metabolizing enzymes necessitate caution in extrapolating data to human populations. To overcome this difficulty, many laboratories have developed systems in which various cell lines in culture can be engineered to produce functional human enzymes that are stable and in high concentrations Gonzalez, Crespi and Gelboin This system provides easy access to networks of scientific journals.
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