Target Organs
Organs as Targets of Chemical Compounds
Blood acts as the transport system for distribution of absorbed substances throughout the body. The distribution is often uneven. Adverse responses may occur if the concentration exceeds a critical concentration in the target organ. As stated previously, the target organ is not necessarily the same as the organ with the largest accumulation of the substance. Many compounds are stored in the skeleton and fatty tissue but critical effccts usually occur in other organs. Lipophilic organic materials are deposited in fatty tissue, whereas some inorganic materials accumulate in the bones due to their resemblance to calcium (e. g., lead) or their ability to bind with calcium (e. g., fluoride). 13M32
Water-soluble compounds are naturally easily transported in the blood. Non-soluble compounds are usually transported bound to plasma proteins (albumins). This binding is reversible in most cases but may vary remarkably. The degree of protein binding may vary between 50% and 99%. The proportion of the free (unbound) compound in the circulation is the amount of the compound that can reach the tissues and thus the target organs. Very lipid —
Soluble compounds are also easily transported in the blood, mainly bound to lipoproteins. They move freely from the circulation to the organs depending on the lipid content of various organs. Thus, at equilibrium, organs such as the brain and other lipid-containing organs have the highest concentration of the agent at equilibrium. Typical examples of very lipid-soluble components are aromatic solvents such as benzene, xylenes, toluene, styrene, and ethyi — benzene. Also, chlorinated hydrocarbons such as tri — and tetrachloroethyiene belong to this category.2-68
The reactivity of a compound greatly affects its distribution and, there fore, the potential target organs. For example, formaldehyde is a very reactive and irritating gas. Because of its reactivity, inhaled formaldehyde binds with mucus and proteins in the nasal and oral cavities and perhaps in the upper respiratory tract, but it does not reach the alveolar region or the systemic circulation through inhalational exposure. For this reason, the most serious health effects of formaldehyde, notably cancer, are only seen in the upper respiratory tract. In fact, a considerable amount of formaldehyde is being formed endogenously in normal metabolism. However, it does not cause any harm under these conditions because it is tightly bound to serum proteins. Thus, harmful reactions of formaldehyde with macromolecules such as DNA only occur in very limited areas in the body. Due to its reactivity, formaldehyde also readily forms protein adducts which in some cases can be used for biomonitoring of formaldehyde exposure.129
Toxicity to the Central and Peripheral Nervous Systems
The nervous system consists of two main categories of cells: neurons and glial cells. Neurons are the actual nerve cells, which are responsible for transmitting information. There are fewer nerve cells than glial cells present in the brain. Glial cells play a variety of supportive functions. The brain and spinal cord form the central nervous system (CNS). Most parts of the CNS are isolated from other parts of the body by the blood-brain barrier, which is a functional rather than a morphological entity that consists of tightly connected cell membranes. Some substances, however, pass through the blood-brain barrier due to their lipophilicity. In addition, there are active transport mechanisms for hydrophilic nutrients and minerals which are vital for CNS function. Some toxic compounds can use these mechanisms to cross the barrier. The remaining parts of the nervous system are called the peripheral nervous system (PNS). The PNS can be considered, in fact, as an extension of the CNS.1 :’-5
Neurons have three parts: the cell body and dendrites, the axon, and axon terminals. The cell body contains the nucleus and the organelles needed for metabolism, growth, and repair. The dendrites are branched extensions of the cell body membrane. The axon is a long, thin structure which transfers electrical impulses down to the terminals. The axon divides into numerous axon terminals and it is in this specialized region that neurotransmitters are released to transmit information from one neuron to its neighbors. The synapse has been defined as the space between two subsequent interrelated neurons.107
The glial cells support the neurons physically. Certain glial cells (oligoden — droglial cells) synthesize myelin, a fatty insulation layer wrapped around the axons. Myelin is necessary for the so-called saltatory conduction of electrical
Impulses. The myelin layer is not continuous but has breaks called the nodes of Ranvier. Action potentials occur only at those nonprotected nodes where they “jump” (the Latin verb saltare means “jump”) from one node to the next. The glial cells also have various maintenance functions (e. g., maintaining ionic equilibrium).136’157
The nervous system is vulnerable to attack from several directions. Neurons do not divide, and, therefore, death of a neuron always causes a permanent loss of a cell. The brain has a high demand for oxygen. Lack of oxygen (hypoxia) rapidly causes brain damage. This manifests itself both on neurons and oligodendroglial cells. Anoxic brain damage may result from ac utt carbon monoxide, cyanide, and hydrogen sulfide poisonings. Carbon mon de may also be formed in situ in the metabolism of dichloromethylene.107’1 ‘■
Organic solvents have acute narcotic effects. Aromatic and chlorinated hydrocarbons seem to be especially effective. As stated, the combined effect of several organic solvents is usually considered to be additive. However, there is some evidence that the combined effect may in fact be synergistic. The symptoms caused by organic solvents, often called prenarcotic symptoms, resemble those caused by the use of alcohol. A decrease in reaction time and impairment in various psychological performances can be observed. Acute neurotoxicity can also be detected as abnormalities in the electroencephalogram (EEG), which records the electrical activity of the brain.107
Chronic neurotoxic effects can be divided into four groups. Neuronopa- thv, where the whole neuron is destroyed, is the most dramatic of these four. In axonopathy, the axon partly degenerates. The damage usually begins from a certain site and progresses towards the terminal. One can imagine it as a break in the axon. Carbon disulfide and n-hexane are examples of chemicals causing this kind of damage. The toxic effect results in reactions with the amino groups in proteins. In the case of n-hexane, the toxic compound (2,5- hexadione) is formed via oxidative metabolism. The reactions cause precipitations of neurofilaments in the axons which hinder its transport capabilities. The sensomotoric neuropathy caused by n-hexane exposure appears in extremities as numbness, weakness, and muscle pain. Myelinopathy slows the velocity of nerve conduction. The damage cannot be easily rectified in the CNS. Demyelination may also occur in the PNS. Lead is the most common agent causing myelinopathy.107’139
Eye Toxicity
Vision is vital for human activities, and eyes are very sensitive to a number of toxic insults induced by chemical compounds. The most serious outcome is permanent eye damage which may be so severe as to cause loss of vision. The eye consists of the cornea and conjunctiva, the choroid, the iris, and the ciliary body. It also contains the retina, which is of neural origin, and the optic nerve. The retina contains photoreceptors, a highly specific light-sensitive type of neural tissue. The eye also contains the lens and a small cerebrospinal fluid system, the aqueous humor system, that is important for the maintenance of the steady state of hydration of the lens and thus the transparency of the eye.140
The cornea must be transparent to allow normal function of the eye. Therefore even a tiny degree of scar formation, commonly induced by exposure to acids or alkalies, in the cornea may seriously damage the visual system. Acid and alkali burns of the eye have to be washed immediately for at least 30 niin with water.41
A special feature of the iris is its autonomic innervation. Sympathetic activation widens the aperture of the iris whereas impulses from the parasympa thetic nervous system decrease the aperture size. Therefore adrenergic agonists and anticholinergic compounds both increase the aperture of the iris, i. e., cause mydriasis, and antiadrenergic and cholinergic agonists decrease it, i. e., cause miosis. The iris can thus be considered an excellent mirror reflecting the balance of the autonomic nervous system in the body.140
The eye has its own hydraulic system, and disturbances in it may cause serious damage to the eye. The normal eye pressure is 22 mm Hg, but when the pressure increases to 28-30 mm Hg, the optic nerve is squeezed and becomes hypoxic. This increase in the eye pressure may be due to acids or alkali causing inflammation in the anterior chamber of the eye, blocking the outflow of aqueous humor back into the systemic circulation.
The lens is an avascular transparent tissue surrounded by an elastic, collagenous capsule. Disturbances in the normal metabolism of the lens and rupture of the lens alter its optical characteristics, and may cause cataract, i. e., reduced transparency of the lens. For example exposure to a herbicide, 2,4- dichlorophenol, may cause cataract."
The retina is the part of the eye that belongs to the nervous system. Rods and cones are the photoreceptors of the retina that synapse with the cells in the bipolar layer in the retina, and these cells, in turn, make connections with ganglion cells. The metabolism of retina is very active and, therefore, the retina is sensitive to toxic insults. For example, natural retinols that were being used in skin therapies have provoked retinal damage, perhaps by replacing the retinoids of the photoreceptors. Hyperbaric oxygen can also cause serious retinal damage in immature newborn children that have had respiratory difficulties.107’137
Methanol intoxication can cause blindness due to damage to ganglion cells in the retina. The blindness results from the accumulation of formaldehyde and formic acid, which are metabolites of methanol. Chemical compounds can also damage the visual cortex, for example, visual damage was observed among the victims of organic mercury intoxication in Japan (the fishermen of Minamata Bay).107’137
Pulmonary Toxicity
The lungs are an important port of entry for toxic compounds into the body, and also an important target organ for chemical compounds. Gas exchange is the most important function of the lungs—oxygen enters the circulation through the lungs, and carbon dioxide and other products of metabolism are exhaled. In addition, the lungs are an important metabolizing organ. Lungs possess a number of non-specific defense systems, such as sneezing and coughing, active movement of the cilia of the pulmonary epithelial cells, and secretion of mucus in the airways. In addition, there are a number of specialized phagocytic cells such as neutrophils, eosinophils and macrophages, that destroy foreign particles through phagocytosis, i. e., they first engulf the particles and then destroy them by bombarding them with proteolytic enzymes. The immunological system is responsible for providing specific responses against specific antigens.4’41
Inhaled gaseous compounds are absorbed in all parts of the rt/spiraton system whereas particle size determines how deep into the airways the parti cles will be transported in the airstream. Shortness of breath is a typical sign ni a chemical exposure that has affected the lungs, and it may be evoked through immunological mechanisms (e. g., formaldehyde, ethyleneoxide), or through toxic irritation (formaldehyde, isocyanates, sulfur dioxide, nitrogen dioxide, ozone). Frequently the mechanism depends on the concentration of the i. on — pound in the inhaled air. The accident in Bhopal, India, is an example of ,i poisoning epidemic that caused serious lung injuries. There, an explosion of a large container led to poisoning of thousands of individuals by methylisocyan — ate, and subsequently to blindness, serious lung injuries, and deaths in the exposed population.41
Acute Lung Toxicity Toxic compounds can induce acute deleterious effects in various parts of the airway. Irritating compounds may cause bron — choconstriction within the bronchial tree, edema of its mucous membranes, and increased secretion of mucus. In addition, ciliar activity may decrease in the bronchial and bronchiolar regions, and thereby prevent the clearance of mucus and foreign particles ftom the airway.58,59’86
Bronchoconstriction may take place without any cellular injury. For example, low concentrations of sulfur dioxide induce bronchoconstriction. Asthmatics are especially sensitive; a concentration of sulfur dioxide as low as 0.4 ppm may induce bronchoconstriction.58’59 Cholinergic activation mediated via the vagal nerve is responsible for this reaction because it can be prevented with anticholinergic compounds.74 An inflammatory reaction may also cause bronchoconstriction. Inflammatory mediators, such as metabolites of arachidonic acid released from the epithelial cells of the airways, may increase the extent of the bronchoconstriction. Epithelial cells also produce relaxing compounds that antagonize bronchoconstriction, but in inflammation, there is reduced production of these compounds (e. g., prostaglandin E2). Also, exposure to inorganic particles may induce a dramatic acute inflammation in the lungs, leading to the ex cretion of a number of bioactive molecules from pulmonary’ phagocytic cells.
Compounds that induce bronchoconstriction include tobacco smoke, formaldehyde, and diethyl ether. Several other compounds, such as acidic fumes (e. g., sulfuric acid) and gases, such as ozone and nitrogen dioxide, as well as isocyanates, can cause bronchoconstriction. Also, cellular damage in the airways induces bronchoconstriction because of the release of vasoactive compounds. Frequently, different mechanisms work at the same time, provoking bronchoconstriction and increased secretion of mucus, both of which interfere with respiration.58’-9
T he alveolar surface is predominantly covered by alveolar type 1 cells. These cells are the primary targets of chemical compounds causing alveolar damage. Typically, alveolar type I cells are replaced by alveolar type II cells subsequent to alveolar damage induced by deep lung irritants (e. g., nitrogen dioxide and ozone).74 On the other hand, when small particles reach the alveolar region, specialized phagocytes, mainly macrophages, phagocytize the particles and are then removed from the lungs by the mucociliary escalator in the trachea, or by the lymphatic system. Alternatively they may persist in the lungs.58’59 When macrophages are phagocytizing the particles, they become activated and secrete large amounts of oxygen radicals. While the radicals may have no effect whatsoever on the particles, they may well damage the surrounding cells and tissues. It has been suggested that the mechanisms by which asbestos particles induce lung cancer and mesothelioma (a fatal cancer type in the pleura) may be associated with excessive production of reactive oxygen species by specialized phagocytes. ’ An important consequence of alveolar level damage is that it may sensitize the lungs to inflammation. Serious air pollution episodes are associated with increased incidence of lung inflammations, especially in the elderly.
Chronic Pulmonary Toxicity Chronic damage to the lungs may be due to several subsequent exposures or due to one large dose that markedly exceeds the capacity of pulmonary defense, clearance, and repair mechanisms. Chronic pulmonary toxicity includes emphysema, chronic bronchitis, asthma, lung fibrosis, and lung cancer. The single most important reason for chronic pulmonary toxicity is tobacco smoke, which induces all types of chronic pulmonary toxicity, with the exception of fibrosis.141
In developed countries, where the prevalence of chronic obstructive lung diseases has increased rapidly, the finger of suspicion is often pointed at the air quality, especially that in large cities.41 In emphysema, the walls separating alveoli from each other disappear, and this reduces the surface area for gas exchange. Chronic bronchitis is characterized by persistent cough and increased mucus secretion. In asthma, the lungs become sensitive to bronchoconstriction induced by environmental agents. In addition, asthma also involves inflammation of the airways.58
Lung Cancer Lung cancer is one of the most common cancers. In many countries, lung cancer is the most common cancer among the male population, and its incidence among females has shown a dramatic and alarming increase. The incidence of lung cancer has always carried a strong association with smoking in the past, i. e., the latency period of lung cancer is about 20 years after the beginning of the exposure to tobacco smoke. In addition to tobacco smoke, many chemicals can increase the risk of lung cancer. These include asbestos, radon, nickel, chromium and beryllium. Asbestos and radon are considered to be the next most important factors after tobacco smoke causing lung cancer. Both also have a synergistic effect with smoking. The number of asbestos-related diseases has remained high (these include pleural diseases, asbestosis, and cancers), even though the use of asbestos has dramatically decreased and is now totally banned in many countries. This is due to the long latency period of asbestos-induced diseases.41’58-59 Figure 5.48 provides epidemiological data on the relationship between smoking and lung cancer. See also Fig. 5.39 for the mechanism of asbestos toxicity.64
Several chemical compounds can have an adverse effect on the heart and the vascular system. The effect may first appear as a transient change in the cardiac function. However, prolonged exposure increases the risk of permanent effects. Occasionally, functional effects such as cardiac arrhythmias may even lead to death. Furthermore, in many cases the effects of chemicals
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FIGURE S.48 Epidemiological data defining the relationships between smoking of cigarettes and carcinoma of the lung, (a) Death rate from cancer of the lung and the rate of consumption of tobacco in the UK. The rates are based on three-year averages for all years except 1947. (b) Relationship between lung cancer mortality and previous cigarette consumption in sixteen countries. From left to right the solid dots below the line (lower incidence) are from Japan and USA and above the line (higher incidence) are from the Netherlands, Austria and England/Wales, (c) Death rate from lung cancer, standardized for age among doctors smoking different daily numbers of cigarettes, (d) Death from lung cancer among doctors who had given up smoking cigarettes for different periods (used with permission). | 1 indicates data for <5, 5-9, 10-14, and >15 years
Since stopping smoking.64,142-144 (Used with permission.)
On the cardiovascular system are secondary; i. e., a compound may affect lipid metabolism and thereby amplify atherosclerotic alterations in the circulatory system.
Mechanisms of Cardiotoxicity Chemical compounds often affect the cardiac conducting system and thereby change cardiac rhythm and force of contraction. These effects are seen as alterations in the heart rate, conduction velocity of impulses within the heart, and contractivity. For example, alterations of pH and changes in ionic balance affect these cardiac functions. In principle, cardiac toxicity can be expressed in three different ways: (1) pharma cological actions become amplified in an nonphysiological way; (2) rcactive metabolites of chemical compounds react covalently with vital macromolecules
In myocytes (cardiac muscle cells) causing permanent functional and morphological alterations; and (3) the reaction is mediated through immunological mechanisms. Also, a reactive intermediate of allylamine, acrolein, may cause cardiac damage. When cardiac injury is mediated through immunological mechanisms, the reaction is usually due to the formation of a complex of the chemical compound with some protein, also termed a hapten.14’
Mean arterial pressure and cardiac output, an expression of the amount of blood that the heart pumps each minute, are the key indicators of the normal functioning of the cardiovascular system. Mean arterial pressure is strictly controlled, but by changing the cardiac output, a person can adapt, e. g., to increased oxygen requirement due to increased workload. Blood flow in vital organs may vary for many reasons, but is usually due to decreased cardiac output. However, there can be very dramatic changes in blood pressure, e. g., blood pressure plummets during an anaphylactic allergic reaction. Also cytotoxic chemicals, such as heavy metals, may decrease the blood pressure.
Compounds Causing Cardiovascular Toxicity Alcohols are the most important compounds causing vascular toxicity. Ethanol depresses cardiac muscle and attenuates its contractivity when the concentration of ethanol in the blood exceeds 0.75 mg/100 mL. Ethanol also causes arrhythmias, and a metabolite of ethanol, acetaldehyde, also depresses the heart. Furthermore, high concentrations of acetaldehyde cause cardiac arrhythmias. The cardiovascular toxicity of methanol is about the same as that of ethanol, whereas al cohols with longer chains are more toxic than ethanol.
Halogenated hydrocarbons depress cardiac contractility, decrease heart rate, and inhibit conductivity in the cardiac conducting system. The cardiac toxicity of these compounds is related to the number of halogen atoms; it increases first as the number of halogen atoms increases, but decreases after achieving the maximum toxicity when four halogen atoms are present. Some of these compounds, e. g., chloroform, carbon tetrachloride, and trichloroeth — ylene, sensitize the heart to catecholamines (adrenaline and noradrenaline) and thus increase the risk of cardiac arrhythmia.
Some metals, such as cadmium, cobalt, and lead, are selectively car — diotoxic. They depress contractivity and slow down conduction in the cardiac system. They may also cause morphological alterations, e. g., cobalt, which was once used to prevent excessive foam formation in beers, caused cardiomyopathy among heavy’ beer drinkers. Some of the metals also block ion channels in myocytes. Manganese and nickel block calcium channels, whereas barium is a strong inducer of cardiac arrhythmia.
Several chemical compounds may cause inflammation or constriction of the blood vessel wall (vasoconstriction). Ergot alkaloids at high doses cause constriction and thickening of the vessel wall. Allylamine may also iuduce constriction of coronary arteries, thickening of their smooth muscle walls, and a disease state that corresponds to coronary heart disease. The culprit is a toxic reactive metabolite of allylamine, acrolein, that binds covalently to nu — cleophilic groups of proteins and nucleic acids in the cardiac myocytes. i45
Atherosclerosis is a degenerative disease which is characterized by cholesterol — containing thickening of arterial walls. Saturated fatty acids, high levels of cholesterol, elevated blood pressure, and elevated serum lipoprotein are well-known risk
Factors for atherosclerosis. Exposure to some chemical compounds, such as carbon disulfide (CS2) and CO may promote the development of the disease. 5"
Liver Toxicity
The liver is the most important metabolizing organ in the body. It is largely responsible for the biotransformation of chemicals and drugs to water-soluble forms that can be excreted in the urine or bile. The functional unit of the liver is die triangular-shaped acinus, the tip of which is located between the terminal vein and adjacent portal arteries (see Fig. 5.49).61 Liver damage may cause dramatic changes in the biotransformation of chemicals, and lead to alterations in metabolic pathways. Severe liver damage is characterized by fibrosis and scar formation and the loss of functional capacity of the organ. There are many chemical compounds capable of inducing liver damage.147 !4S
Yellow phosphorus was the first identified liver toxin. It causes accumulation of lipids in the liver. Several liver toxins such as chloroform, carbon tetrachloride, and bromobenzene have since been identified. The forms of acute liver toxicity are accumulation of lipids in the liver, hepatocellular necrosis, in — trahepatic cholestasis, and a disease state that resembles viral hepatitis. The types of chronic hepatotoxicity are cirrhosis and liver cancer.
Acute Liver Damage Several compounds (e. g., dimethyl nitrosoamine, carbon tetrachloride, and thioacetamide) cause necrosis of hepatocytes by inhibiting pro tein synthesis at the translational level, i. e., by inhibiting the addition of new amino acids into the protein chain being synthetized. This is not, however, the only mechanism. Ethionine is a compound which inhibits protein synthesis but does not induce
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Liver necrosis. Carbon tetrachloride, tetrachloroethylene, and yellow phosphorus induce lipid peroxidation, one common mechanism of liver necrosis. There are, however, a number of compounds (e. g., dimethyl nitrosoamine) that cause liver necrosis without causing lipid peroxidation. Recent findings suggest that neutrophil-mediated cytotoxicity may play a role in some forms of liver toxicity, perhaps due to inflammatory mediators or reactive oxygen species excreted by these inflammatory cells.147 l4S
Accumulation of lipids in the liver (steatosis) is one possible mechanism for liver toxicity. Several compounds causing necrosis of hepatocytes also cause steatosis. There are, however, some doubts that steatosis would be the primary cause of liver injury. Several compounds cause steatosis (e. g., puro — mycin, cycloheximide) without causing liver injury. Most of the accumulated lipids are triglycerides. In steatosis, the balance between the synthesis and excretion of these lipids has been disturbed (see Table 5.13).J47-J48
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TABLE 5.13 Examples of Drugs that Induce Intrahepatic Cholestasis or Liver Damage Resembling That Induced by Viral Hepatitis
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CHAPTER 5 PHYSIOLOGICAL AND TOXICOLOGICAL CONSIDERATIONS TABLE 5.14 Chemical Compounds that Induce Chronic Liver Damage
3 In experimental animals *’ * Is also a human carcinogen? Unknown — Does not cause any effect Source: Modified from Savolainen and Vahakangas.151 |
Chronic Liver Damage Cirrhosis is one the main forms of chronic liver damage. Formation of a collagen network that destroys the typical liver structure is characteristic of cirrhosis. In cirrhosis, the blood circulation to the liver is severely disturbed because of altered liver morphology. The underlying mechanism of this disruption is most likely necrosis of individual hepatocytes leading to scar formation. The same compounds that induce liver cancer also induce liver cirrhosis. In humans, the most important compound causing liver cirrhosis is ethyl alcohol.149’150 Table 5.14 lists chemical compounds that can induce acute liver damage.
Liver cancer can also be a consequence of exposure to hepatotoxic chemicals. Natural hepatocarcinogens include fungal aflatoxins. Synthetic hepato — carcinogens include nitrosoamines, certain chlorinated hydrocarbons, polychlorinated biphenyls (PCBs), chloroform, carbon tetrachloride, dimethyl — benzanthracene, and vinyl chloride.150 Table 5.15 lists the chemical compounds that induce liver cancer or cirrhosis in experimental animals or
Chemical compound
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Necrosis |
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Steatosis |
Natural Compounds Aflatoxin[3]
Ethanol’" [4]
Pyrrolizidine alkaloids SatfroSe
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} } X X X ? X X ? X |
Synthetic Compounds Anabolic androgens** Dialkvlnitroamines Organochlorine pesticides Polychlorinated hydrocarbons Carbon tetrachloride Chloroform Vinyl chloride** Dimethylaminobenzene Acetylaminofluorene Thioacetamide Urethane Ethiomine
Dimethylbenzanthrazene
Galactosamine
Balance. In addition, the kidney is responsible for the synthesis ot a number of hormones that regulate several systemic metabolic events. These hormones include 1,25-dihydroxyvitamin D3, erythropoietin, renin, and several vasoactive prostanoids and kinins. In addition to these physiologically important functions, the kidneys are also metabolically active organs that contribute to the biotransformation of xenobiotics.
The sensitivity of the kidneys to various toxic insults is due to large blood flow, ability to concentrate compounds to be excreted in the urine, and to mer — abolically activate xenobiotics. About 25% of cardiac output continuously flows through the kidneys even though the relative weight of the kidnes is only 0.5% of the human body mass. Due to the key role of the kidney in the excretion of metabolic wastes, it inevitably becomes exposed to high concentrations of metabolic endproducts. The primary urine filtrated in the glomeruli is concentrated 100-fold before its excretion. The amount of primary urine formed during a 24-hour period is about 100 L, and is being concentrated down to one liter. Therefore, the concentrations of several toxic compounds in the urine may become very high compared to their corresponding concentrations in the bloodstream. Furthermore, excretory and reabsorptive functions may expose kidney cells to high concentrations of harmful compounds.148
Alterations in the ability of the kidneys to excrete or reabsorb compounds from the proximal and distal tubules are immediately reflected in the amount of extracellular fluid in the mammalian organism. For example, reduced excretion in the glomeruli leads to increased volume of extracellular fluid, and this may contribute to cardiac insufficiency, in which the working capacity of the heart is exceeded. The kidneys are active metabolic organs; this ability has toxicological significance when it leads to the formation of toxic reactive metabolites that damage kidney cells.147,148
Mechanisms of Kidney Toxicity Alterations in the levels of free intracellular calcium in kidney cells are important in kidney toxicity caused by several chemical compounds since cell calcium participates in cell activation and the formation of reactive oxygen species that contribute to hypoxic cell injury.89 Kidney injury may also be due to an indirect mechanism: long-term hypotension may be a reason for kidney injuries, e. g., due to reduced oxygen supply. Immunological mechanisms may also play a role in kidney injuries, and for example, metallothionein, a protein synthesized by the liver to complex heavy metals, may accumulate in the kidneys as a protein-metal complex and cause kidney injury. The primary goal of the protein is to protect the mammalian organism against metal toxicity, but excessive accumulation of the metal-metallothionein complex in the kidneys leads to cellular damage and impaired kidney function, e. g., reduced formation of urine. Also accumulation of calcium oxalate, which occurs after exposure to ethylene glycol, the parent compound of the oxalate, may induce kidney injury.3b
Compounds that Cause Kidney Damage Several drugs and some anesthetic compounds such as methoxyflurane cause kidney damage when presenr at high doses. Kidney-toxic compounds found in occupational environments include mycotoxins, halogenated hydrocarbons, several metals, and solvents (see Table 5.16).
TABLE 5.16 Nephrotoxic Compounds in Occupational and General Environments
Il ycoroxms
Aflatoxin B Ochratoxin A Pyrrolizidine alkaloids Rubratoxin B V(>latilc hydrocarbons Gasoline Herbicides and Fungicides Paraquat Diquar Succinimides
2,4,5—trichlorophenoxyacetic acid Metals
Cadmium Gold Lead Nickel Mercury Chromium Uranium Organic solvents Hthvlene glycol Diethvlene glvcol Toluene
Halogenated aliphatic hydrocarbons Bromobenzene Carbondichloride Chlorofluoroethene Dibromoerhane Hexachlorobutad iene Trifluoroethenc Bromodichloromethane Chloroform
Dibromochioropropane Dichloroechene Pentachlotoethene Tnchloroethene Other compounds Benzidine /?-AminophenoI Ma lea te
Source: Modified from Savolamen and Vahakangas.151
Many metals are potent kidney toxins. These metals cause similar signs and symptoms. At low doses, the symptoms include leakage of sugars and amino acids into the urine due to glomerular damage and polyuria due to lack of concentrating capability of the kidney. Large doses cause cellular necrosis, anuria, increased concentrations of blood-urea-nitrogen, and subsequently the total breakdow n of kidney function and ultimately death. In addition to direct cell injury; some metals induce vasoconstriction in the kidney. Metals such as nickel and cadmium strongly induce the synthesis of metal binding proteins in the liver, notably metallothionein.’
Halogenated hydrocarbons may cause kidney damage in addition to liver damage. A nephrotoxic dose of carbon tetrachloride increases the relative weight of the kidneys, induces swelling of tubular epithelium in the kidneys, and causes lipid degeneration, tubular casts, and necrosis of the epithelium of the proximal tubulus. Several other halogenated hydrocarbons, e. g., tri-and tetrachloroethyiene, also induce this kind of kidney damage.153
Reproductive Toxicity
The reproductive system is a very complex, hormonally-controlled entity. The female endocrine system is more complex than that of the male, and toxic effects that are directed toward the female reproductive system are, therefore, more difficult to assess than those targeted at the male system. In addition, the effects of toxic compounds on the reproductive system clearly differ between females who are pregnant and those who are not, because pregnancy changes, female physiology and because the target of the toxic effects may also be the fetus. The effects of chemicals on the fetus will be discussed in the section on teratogenesis (see Section 5.3.4.5). The assessment of reproductive toxicity is further complicated by the fact that the timing of essential events, e. g., the process of organogenesis, is different in different species, and therefore extrapolating results obtained in animal experiments to predict the toxic effects of chemicals on human reproduction is problematic.
It needs to be noted that a toxic effect on the reproductive system may be mediated through alterations in normal functions of the central nervous system, gonads (ovaries, testicles), or on the pharmacokinetics of reproductive hormones.98’154’155
Compounds Affecting Reproduction Compounds that can affect reproductive function include several drugs and occupationally important chemicals such as solvents and pesticides as well as a number of environmentally relevant compounds. A group of chemical compounds that has received much attention recently is endocrine disruptors, many of which are halogenated hydrocarbons, e. g., PCBs. These are known to induce feminization in fish and other animal species.98’1561’’7 There is intense debate about the significance of these compounds to human health. Tobacco smoke and ethyl alcohol also have major effects on human reproduction, the effects of alcohol being especially important. Table 5.17 lists compounds that may disturb the functions of female and male reproductive functions.
Toxicity to Blood and Blood-Forming Tissues
Blood-forming tissues consist of bone marrow, spleen, lymph nodes and the reticuloendothelial system. These produce the elements of blood and are important for the immunological defense systems.
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TABLE 5.17 Examples of Chemical Compounds that Affect the Reproductive System
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There are undifferentiated stem cells of the blood elements in the bone marrow that differentiate and mature into erythrocytes, (red blood cells), thrombocytes (platelets), and white blood cells (leukocytes and lymphocytes). The production of erythrocytes is regulated by a hormone, erythropoietin (see the section on kidney toxicity), that is synthetized and excreted by the kidney. An increase in the number of premature erythrocytes is an indication of stimulation of erythropoiesis, i. e., increased production of erythrocytes in anemia due to continuous bleeding.
Toxic Effects on the Blood-Forming Tissues Reduced formation of erythrocytes and other elements of blood is an indication of damage to the bone marrow. Chemical compounds toxic to the bone marrow may cause pancytopenia, in which the levels of all elements of blood are reduced. Ionizing radiation, benzene, lindane, chlordane, arsenic, chloramphenicol, trinitrotoluene, gold salts, and phenylbutazone all induce pancytopenia. If the damage to the bone marrow is so severe that the production of blood elements is totally inhibited, the disease state is termed aplastic anemia. In the occupational environment, high concentrations of benzene can cause aplastic anemia.158
Platelets are essential as the first line of defense in clot formation to stop bleeding. Platelets gather quickly around the damaged vessel wall and clump together with fibrin filaments to form a clot that prevents bleeding. Platelets also become activated by exposure to adrenaline, thrombin, and collagen. Drugs and chemicals that disturb normal functioning of the bone marrow also decrease the number of circulating platelets, a state termed thrombocytopenia. Vinyl chloride is an example of a chemical which may cause this kind of disturbance.
Specialized phagocytes (i. e., actively phagocytizing cells of the immune system) include granulocytes (neutrophils, eosinophils, and basophils), monocytes, and macrophages, which often originate from circulating monocytes. Many environmental factors may decrease the number of these cells. Ionizing radiation and several drugs may cause granulocytopenia. Erythrocytes can be degraded if they are exposed to chemical compounds, the end result being hemolytic anemia. Hemolytic anemia reduces the capacity of blood to carry oxygen, and thereby prevents oxygenation of various tissues, especially the central nervous system and the heart, organs that are particularly sensitive due to their large oxygen need. Aniline and nitrobenzene cause hemolytic anemia, and several other nitrocompounds also induce this effect. Phenols and propylene glycol are also capable of inducing hemolytic anemia.158’159
Toxicity to the Skin
The skin is the largest organ in the human being. In particular, the surface layer of the outer epidermis, the stratum corneum, usually provides quite good protection against chemical compounds. Nevertheless, the skin is an important entry route for chemical compounds into the body.
Skin has several protective mechanisms in addition to its thick epidermis that prevent many chemical compounds from penetrating it. Eccrine (sweat) glands, phagocytic cells, skin metabolism, and melanin pigmentation (which protects the skin from ultraviolet irradiation from the sun) belong to the battery of the dermal defense systems. However, skin is exposed to many chemical compounds. Skin diseases account for a considerable percentage of all occupational diseases (20% in Finland). Among exposure-induced skin diseases, inflammations due to both irritation and sensitization are common.
Assessment of skin exposure continues to be relatively difficult because it: is difficult to measure or estimate the dose actually absorbed by the skin.
Toxic Reactions of the Skin Irritation is the most common reaction of the skin. Skin irritation is usually a local inflammatory reaction. The most common skin irritants are solvents; dehydrating, oxidizing, or reducing compounds; and cosmetic compounds.160 Acids and alkalies are common irritants. Irritation reactions can be divided into acute irritation and corrosion. Necrosis of the surface of the skin is typical for corrosion. Acids and alkalies also cause chemical burns. Phenols, organotin compounds, hydrogen fluoride, and yellow phosphorus may cause serious burns.161 Phenol also causes local anesthesia, in fact it has been used as a local anesthetic in minor ear operations such as puncture of the tympanous membrane in cases of otitis.36
The common skin reaction allergic contact dermatitis is evoked subsequent to exposure to a chemical compound via a cell-mediated type IV allergic reaction. Allergic contact dermatitis is also a common skin disease in the occupational environment. The reaction is compound-specific and re-exposure to very small amounts of chemical compounds provoke a severe reaction. Skin allergens often have small molecular size and are frequently haptens that become bound to a protein and in that way induce an immunological reaction. Many chemical compounds can induce allergic contact dermatitis (see Table 5.18).161 Especially important inducers of allergic contact dermatitis are metals (nickel) and metallic compounds (cobalt, chromium, and nickel salts as well as organic mercurial compounds). Also several cosmetic products, resins, a number of colors, rubber (latex) and leather additives, and pesticides (fungicides such as thi — urams and dithiocarbamates) are skin allergens. Compounds that belong to the same group of chemical compounds may cross-sensitize sensitive individuals. Thiurams and dithiocarbamates are good examples of this: if you are sensitive to one compound in this group you are allergic to all members of this group of chemicals.162’163 Table 5.19 lists common cross-reacting chemicals.161
Light and Toxic Reactions In many individuals, exposure to ultraviolet radiation from the sun causes skin reactions such as erythema, thickening of the epidermis, and darkening of existing pigment. Exposure to ultraviolet light also increases the risk of different forms of skin cancers, especially malignant melanoma.161
Chemical Acne Many chemical compounds induce skin lesions that are similar to acne. Oils, tar, creosote, and several cosmetic products induce chemical acne. These compounds induce keratinization of the sebaceous glands of the skin, obstruction of the glands, and formation of acne. Chloracne is a specific skin lesion that is induced by chemical compounds that are structurally similar to 2,3,7,8-tet — rachloro dibenzo-p-dioxin (TCDD). Chloracne is slow to heal and difficult to
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Source |
Common allergens |
Source |
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Topical medications/ |
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Hygiene products |
Antibiotics |
Therapeutics |
|
Bacitracin |
Benzocaine |
|
|
Neomycin |
Fluorouracil |
|
|
Polymyxin |
Idoxuridine |
|
|
Am inoglycosides |
A-Tocopherol (vitamin E! |
|
|
Sulfonamides |
Corticosteroids |
|
|
Preservatives |
Others |
|
|
Benzalkonium chloride |
Cinnamic aldehyde |
|
|
Formaldehyde |
Ethylenediamine |
|
|
Formaldehyde releasers |
Lanolin |
|
|
Quaternium 15 |
/>-PhenyIened iaminc |
|
|
Imidazolidinyl urea |
Propylene glycol |
|
|
Diazolidinyl urea |
Benzophenones |
|
|
DMDM Hydantoin |
Fragrances |
|
|
Methylchloroisothiazolone |
Thioglycolates |
|
|
Plants and trees |
Abietic acid |
Pentadecylcatechols |
|
Balsam of Peru |
Sesquiterpene lactone |
|
|
Rosin (colophony) |
Tuliposide A |
|
|
Antiseptics |
Chloramine |
Glutaraldehyde |
|
Chlorohexidine |
Hexachlorophene |
|
|
Chloroxylenol |
Thimerosal (Merthiolate) |
|
|
Dichlorophene |
Mercurials |
|
|
Dodecylaminoethyl glycine HC1 |
Triphenylmethane dyes |
|
|
Rubber products |
Diphenylguanidine |
Resorcinol monobenzoate |
|
Hydroguinone |
Benzothiazolesulfenamides |
|
|
Mercaptobenzothiazole |
Dithiocarbamates |
|
|
P-Phenylenediamine |
Thiurams |
|
|
Leather |
Formaldehyde Glutaraldehyde |
Potassium dichromate |
|
Paper products |
Abietic acid |
Rosin (colophony) |
|
Formaldehyde |
Triphenyl phosphate |
|
|
Nigrosine |
Dyes |
|
|
Glues and bonding |
Bisphenol A |
Epoxy resins |
|
Agents |
||
|
Epichlorohydrin |
P-(;-butyl)formaldehyde Resin |
|
|
Formaldehyde |
Toluene sulfonamide resins |
|
|
Acrylic monomers Cyanoacrylates |
Urea formaldehyde resins |
|
|
Metals |
Chromium |
Mercury |
|
Cobalt |
Nickel |
|
|
TABLE 5.19 Common Cross-Reacting Chemicals
|
Chemical |
Cross-Reactor
|
Abictic acid Balsam of Peru Bisphenol A Canaga oil Chlorocresol Diazolidinyl urea Ethylenediamine di-HCl Formaldehyde Hydroquinone Methyl hydroxybenzoate P-Aminobenzoic acid Phenvlenediamine Propyl hydroxybenzoate Phenol |
Pine resin (colophony)
Pine resin, cinnamates, benzoates Diethylstilbestrol, hydroquinone monobenzyl ether Benzyl salicylate Chloroxylenol
Imidazolidinyl urea, formaldehyde Aminophylline, piperazine
Arylsulfonamide resin, chloroallyl-hexammium chloride Resorcinol
Parabens, hydroquinone monobenzyl ether p-Aminosalicylic acid, sulfonamide Parabens, p-aminobenzoic acid Flydroquinone monobenzyl ether Resorcinol, cresols, hydroquinone
Tetramethylthiuram disulfide Tetraethylthiuram mono — and disulfide Source: Modified from Rice and Cohen.161
Treat. Chloracne is characterized by hyperplasia of the epithelial cells of the sebaceous glands associated with inflammatory skin changes typical of acne.164
TCDD is the most potent inducer of chloracne. This has been well known since the accident in Seveso, Italy, in 1976 in which large amounts of TCDD were distributed in the environment subsequent to an explosion in a factory that produced a chlorophenoxy herbicide, 2,4,5-T. TCDD is an impurity produced during the production of 2,4,5-T. The most common long-term effect of TCDD exposure was chloracne. Exposed individuals also suffered increased excretion of porphyrins, hyper-pigmentation, central nervous system effects, and liver damage and increased risk of cancer was a long-term consequence of the exposure. In addition to TCDD, polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans, and polychloronaphthalens cause chloracne as well as other effects typical of TCDD.51’150’165
Allergies
Allergies are diseases m which immune responses to antigens, compounds which otherwise would be innocuous, cause inflammation. The immune response occurs in two stages. First, the person becomes sensitized to an antigen. He or she will remain asymptomatic until there is a new exposure, which will provoke an inflammatory response. Hypersensitivity is often used as a synonym for allergy. Allergic disease can be classified according to the immunologic mechanism provoking it. Traditionally, a classification into four types is used, as first presented by Gell and Coombs.166
Type I allergies are mediated by immunoglobulin E (IgE). Unlike the other immunoglobulins (G, M,A, and D), which are part of the essential defense
mechanisms against foreign proteins, IgE is an antibody type that has virtually only adverse effects. Often allergy is defined to include only type I reactions. The symptoms due to IgE-mediated responses depend on the exposure route. In occupational environments, inhalation is usually the most important route and allergic rhinitis and asthma are common occupational diseases. Atopic dermatitis also belongs to this allergy type. The individual susceptibiliry for this kind of reaction varies considerably. Those persons who inherently are sensitive are called atopies. The allergens are usually proteins or glycoproteins with molecular weights ranging from 10 to 40 kDa. Common allergen sources include pollen, mites, molds, and animal dander,120
Sensitization is a consequence of a complex chain of events which includes presentation of the allergen by antigen-presenting cells (APC) to naive (ThO) lymphocytes, which then differentiate into Th2 lymphocytes. These lymphocytes then release a barrage of cytokines (particularly IL-4) that cause B lymphocytes (B cells) to differentiate into specialized plasma cells which secrete IgE antibodies (cytokines are chemical mediators, small soluble proteins that affect the specific receptors of other cells initiating and maintaining man) biological processes). Circulating IgE binds to the receptors on the surfaces of mast cells (located mainly in the mucosal and epithelial tissues).89120
When exposure is repeated, the allergen binds between two adjacent IgE molecules. This causes release of inflammatory mediators (histamine, leukotrienes, chemotactic factors). These act locally and cause smooth muscle contraction, increased vascular permeability, mucous gland secretion, and infiltration of inflammatory cells (neutrophils and eosinophils). However, histamine can also be released by non-IgE-mediated mechanisms (e. g., due to exposure to certain fungi).162’163
In addition to the proteins discussed above, a large number of reactive chemicals used in industry can cause asthma and rhinitis. Hypersensitivity’ pneumonias have also been described. Isocyanates and acid anhydrides are industrial chemicals that cause occupational asthma. Acid anhydrides, such as phthalic anhydride, seem to cause mainly type I reactions, whereas the IgE-mediated mechanism explains only a part of the sensitizations to isocyanates. Several mechanisms have been suggested, but despite intensive research no models have been generally accepted. The situation is even more obscure for other sensitizing chemicals; therefore, the term specific chemical hypersensitivity is often used for chemical allergies. This term should not be confused with multiple chemical sensitivity (MCS) syndrome, which is a controversial term referring to hypersusceptibility to very low levels of environmental chemicals.120
Type II reactions include cytotoxic reactions in which the antigen binds to the surface of certain cells (e. g., red blood cells) and B cells then produce IgG antibodies against these cells, which results in cytotoxic injury mediated by complement (a group of blood plasma proteins acting together) activation and an influx of inflammatory cells. For example, some drug allergies are caused by this mechanism. However, this is not an important mechanism in occupational allergies.120
In type III or immunocomplex-mediated allergy, IgG antibodies form complexes with antigen. At low exposures, the body is able to remove these complexes, but if there is a severe exposure, immiinocomplexes release a variety of proinflammatory cytokines. The involvement of this mechanism is clearest in serum sickness. This mechanism is also considered to be most important in the development of extrinsic allergic alveolitis (hypersensitivity pneumonitis, especially
The acute form) in persons having massive bioaerosol exposure. The symptoms include fever, cough, shortness of breath, and malaise. Prolonged exposure can result in lung fibrosis. The disease is common among farmers who handle moldy hay (the syndrome is also called farmers’ lung disease). Trimellitic anhydride is an example of a reactive chemical causing a type III response.120
Type IV reactions differ from the previous hypersensitivity reactions in that they are not immunoglobulin-mediated, but mediated by T cells. It is probable that this mechanism is also involved in the pathogenesis of extrinsic alveolar alveolitis, especially in the chronic form. Allergic contact dermatitis is the most common example of this allergy type. Allergic contact dermatitis is caused by substances with low molecular weights (below 500 Da). The small molecule (e. g., Ni and Co), called a haptene, cannot act as an allergen alone, but needs to bind to certain proteins (la-antigens) on the surface of Langerhans’ cells. This combined hapten and Ia-antigen forms the allergen. Langerhans’ cells then transfer the allergen to the small lymphocytes. This is carried by the lymphatic vessel to the lymph node where it initiates the production of activated T cells (Thl lymphocytes). When these encounter their antigens, cytokines are secreted (e. g., interferon y; IFNy). These activate the inflammatory cells leading to visible eczema usually within 1-4 days. T memory cells remain viable for a long time (a year or even longer), after which the sensitivity disappears.162’163 The mechanisms underlying type I-IV allergic reactions have been depicted in a simplified way in Fig. 5.50.
Over 3000 chemicals have been classified as contact allergens. Among them are some substances (so-called “superallergens”) that are so potent that they sensitize most exposed persons possibly on the first contact (e. g., dinitrochloroben — zene).120 In practice, it would be useful to be able to classify contact allergens according to their potency. In the Nordic countries, a classification system for skin-contact allergens resembling the criteria of LARC for the classification of carcinogenic substances has been proposed, but it is not yet widely accepted. However, allergenicity evaluation has become an important part of toxicity testing with experimental animals. The guinea pig is the most commonly used animal, and the guinea pig maximation test is probably the most sensitive method for detecting the sensitizing potential of a compound.
Many irritative chemicals may cause non-specific hyper-responsitivity of the airways and skin. The number of irritating chemicals is very large, several thousands. The symptoms caused by exposure to irritants may resemble allergic symptoms. In addition, exposure to irritating substances (such as sulfur dioxide or solvent vapors) often triggers the symptoms in individuals with allergic asthma.
5.3.4.4 Chemical Teratogenesis
A teratogen is a chemical compound that induces malformations in the fetus. The term can also be defined to have a wider meaning, that a teratogen is a compound that can permanently damage the fetus during pregnancy. In the latter case, teratogens include compounds that induce morphological and/or functional alterations in the fetus. Brain tissue is especially sensitive to the effects of chemical compounds, because unlike most other organs, which undergo most of their organogenesic development during the first trimester of the pregnancy, the brain continues to develop throughout the entire pregnancy, and even after birth, the brain continues to develop for a number of years.167
|
TYPE 1 (1) JgE-antibodv № binds to formation has basophilic and been initiated y masl <*№• by antigen*». ‘y J y — (3) Antigen ((4) Histamine binds to and other adjacent Sal • • . inflammatory * VX* ■ mediators are motcules, • being re — which leads * cascd. In to the release the prjck res^ pustular and of bioactive crythoma are induced. In compounds. allergic reaction, responses in the target organs. |
TYPE II (1) Antigen (e. g., a (2) Antibodies react chcmical) binds to with antigens bound a cell. to the cell. {y)r V Јt> (3) The cell is being destroyed due to complement activation and reactions (???) due to the responses of mononucleus cells. |
|
TYPE III (1) Formation of absolute antibody-anngen complexes. _______________________ A <2) Antibody-antigen complexes accumulate in vascular endothelium and basement membrane. (3) Local inflammatory reaction, thrombocyte aggregation, and activation at the complement system. |
TYPE IV (11 A compound binds to the skin proteins. ‘‘-•►A G3>A 1 V——— i (2) Reaction with a sensiti/.ed Lvmphokine T-cell releases lymphokines. (3) Local inflammation and swelling. |
|
FIGURE 5.50 Four allergic (types l-IV) reaction types based on Coomb’s classification. Type I reaction is an immediate allergic reaction. Type II reaction is an antibody-dependent cytotoxic reaction. In a type III reaction, injuries are due to soluble circulating antlbody-antlgen complexes. Type IV reactions are cell-mediated delayed allergic reactions. In the figure, the characteristics of different allergic reactions have been depicted in more detail.151 |
About three percent of children are born with some degree of morphological malformation. It is claimed that up to 16% of children may be malformed to some degree. However, most of the malformations are barely appreciable and, thus, the incidence of severe malformations is much lower. In about 30% of malformation cases, a genetic reason can be found, and in about 10% of cases, some external factor can be implicated. In most cases, however, the reason for the malformations remains unknown. It should be stressed that it is even extremely difficult to identify chemical compounds that cause functional damage, since regardless of the mechanism of the disturbance in development, the timing when it causes the damage is critical. Compounds with very different mechanisms can cause the same functional deficiency in a child. A chemical compound is rarely suspected as being the cause of a malformation.!fc7
Mechanisms of Chemical Teratogenesis
The effects of a teratogen on a fetus depend on the timing of the exposure, i. e., at which stage of organogenesis the exposure takes place. Exposure to a teratogen before implantation usually leads to death and abortion of the fetus. How
Ever, experimental animal data provide evidence that exposure even at this stage may lead to birth of a malformed pup. Organogenesis is the period between the 21st and 56th days of pregnancy in humans, when most organs are undergoing rapid development. This time is the most sensitive period for a teratogen to exert its effects. For example, the closure of the palate in humans takes place between 56th and 58th day of pregnancy. This is the time when the risk of cleft palate is the greatest for the fetus if exposure to a teratogen occurs. After the end of organogenesis, morphological malformations are unlikely, but biochemical and functional alterations are still possible.168
Several chemical carcinogens are also chemical teratogens. In these cases, both carcinogens and teratogens may have an ultimate common mechanism, DNA damage. In this context, both chemical carcinogens and teratogens require metabolic activation to be able to react with the nucleic acids in DNA. Like chemical carcinogenesis, chemical teratogenesis constitutes a cascade of complex events, and is rarely induced by a single factor. This is exemplified by the fact that, depending on the dose and timing of exposure, a chemical ter atogen may cause death of the fetus, induce a malformation, or result in growth retardation of the fetus. If the dose is large, the fetus dies. If the dose is lower than the lethal dose and exposure takes place during an early phase of a critical period, compensatory hyperplasia may replace the dead cells in the damaged organ, resulting in growth retardation in a morphologically normal fetus. However, even a small dose of a teratogen may lead to specific malformations when the exposure takes place during a critical period of organogenesis of a given organ. In addition to chemical compounds, ionizing radiation may also cause DNA damage potentially leading to teratogenesis.169
In addition to direct effects of chemical compounds on the fetus, metabolic disturbances in the mother, such as diabetes or hyperthermia, or deficiencies of calories or specific nutrients such as vitamin A, zinc, and folic acid may lead to teratogenesis. Compounds that inhibit placental functions may also induce malformations, e. g., by inhibiting placental circulation. For example, hydroxyurea disrupts the placental circulation and induces malformations. In addition, it also induces DNA damage.170“173
Chemical Teratogens
IMore than 900 teratogens have been identified in experimental animals. However, only about 30 human teratogens have been identified. Human teratogens have been listed in Table 5.20. In this section, some of the best-known teratogenic compounds are briefly described.167
Thalidomide was introduced in 1956 as a sedative which also prevented nausea and vomiting. Since the compound was effective and did not induce addiction, and because its acute side-effects were minor, it became popular to prevent the nausea associated with early pregnancy. Within a few years after its introduction, there was an outbreak of an epidemic of very rare malformations of the extremities, hands, and legs. Typical malformations due to thalidomide were lack of extremities (anamely), a shortening of long bones of the extremities (phocomelia or seal-like limbs), and malformations of the heart, eyes, intestine, external ears, and kidney. The sale of thalidomide was prohibited in 1961, and within a year no more children were born with its tragic trademark deformities.174 Had the malformations induced by thalidomide been less spectacular and
CHAPTER 5 PHYSIOLOGICAL AND TOXICOLOGICAL CONSIDERATIONS TABLE 5.20 Human Developmental Toxicants
Radiation Therapeutic Radioiodine Atomic fallout infections Rubella virus Cytomegalovirus Herpes virus hominis Toxoplasmosis
Venezuelan equine encephalitis virus Syphilis
Parvovirus B-19 Maternal metabolic imbalances Alcoholism Cretinism Diabetes
Folic acid deficiency Hyperthermia Phenylketonuria Rheumatic disease Virilizing tumors Drugs and chemicals Androgenic chemicals Angiotensin-converting enzyme inhibitors Captopril, enalapril Antibiotics
Tetracyline Anticancer drugs
Aminopterin, methylaminopterine, cyclophosphamide, busulfan Anticonvulsants
Phenytoin, trimethadione, valproic acid Antithyroid drugs Methimazole Chelators
Penicillamine Chlorohiphenyls Cigarette smoke Cocaine
Coumarm anticoagulants Warfarin Diethylstilbesterol Ethanol Ethylene oxide Iodides Lithium Metals
Mercury (organic)
Lead
Retinoids
13-cts-retinoic acid Etretinate Thalidomide
Rare (e. g., if it had induced cleft palate), it would have taken much longer to identify the causal relationship between the use of thalidomide and the malformations. In the case of thalidomide, the causal relationship was clear; about 84% of mothers whose children had limb malformations had taken thalidomide. It is estimated that thalidomide damaged about 7000-10 000 children, mainly in Western European countries.
Another well-known chemical teratogen is methyl mercury. Environmental health disasters in Japan, in Minamata Bay and Nigeta in the 1950s, and in Iraq in 1971, have provided detailed information of the effects of methyl mercury on fetuses.175 Exposure to methyl mercury during pregnancy affected mainly the central nervous system of the children, and these changes were permanent. The most im portant sign was progressive retardation of psychomotor development of a child that seemed to be normal at birth. In addition, the exposure may also have caused blindness, deafness, and convulsions which appeared as the child grew (see Fig. 5.51). Methyl mercury seriously disturbs the normal organization of various brain structures during organogenesis. It binds to SH groups of proteins and also disturbs DNA and RNA synthesis. It used to be thought that the mother could somehow’ protect the growing fetus from chemical insults. Methyl mercury is a compound which reveals the fallacy of the claim that doses of methyl mercury which do not damage the mother cannot be teratogenic to the fetus. Furthermore, male fetuses seem to be more sensitive than female fetuses to the effects of this compound.176
|
6 16 40 78 156 312 Estimated body burden of mercury (mg) FIGURE 5.51 Dose-response relationships for methyl mercury.176 (Used with permission.) |
Fetal alcohol syndrome (FAS) was only defined in 1973, even though harmful effects of ethyl alcohol on the fetus have been known for a long time. During the past 25 years, the estimates of the dose required to damage the fetus have decreased, and today the consumption of ethyl alcohol during pregnancy is not recommended at aSJ. The incidence of FAS has been found in different epidemiological studies to be about 2-7 cases/1000 live births,177
FAS is normally characterized by growth retardation, anomalies of the head and face, and psychomotor dysfunctions. Excessive consumption of ethyl alcohol may lead to malformations of the heart, extremities, and kidneys. Sincc consumption of ethyl alcohol is socially acceptable and prevalent even in pregnant women, the risks associated with the use of ethyl alcohol are remarkable. However, it should be kept in mind that there are several chemical compounds in the <xcupa — tional environment that may also cause malformations even at low do^es. The oc — cupationally-important known human teratogens include methyl mercury, ethyl alcohol, PCB compounds, tobacco smoke, lead, TCDD, 2,4,5-1, carbon monoxide, nitrogen dioxide, gasoline, and fluoride. lh7
5.3.4.5 Carcinogens and Mutagens
A mutagen is a chemical that can induce alterations in the DNA. Mutations occurring in germ cells are inheritable and may lead to genetic diseases. If mutations take place in somatic cells, carcinogenesis may be initiated.
The International Agency for Research on Cancer (IARC) classifies carcinogens into five groups: human carcinogens (Category I), probable human carcinogens (Category 2A), possible human carcinogens (Category’ 2B), not classified (Category 3), and compounds with no evidence of carcinogenicity for humans (Category 4). Before an agent can be classified as a human carcinogen, there must be sufficient epidemiological evidence for a causal association between exposure to this agent and cancer. Probable human carcinogens include agents for which the epidemiological evidence is more limited and/or animal test carcinogenicity evidence is available. A compound is classified as possible human carcinogen when there is limited evidence of animal carcinogenicity. If the animal evidence is inadequate, the agent belongs to the not classified category. The final category includes agents with no evidence of carcinogenicity as determined by adequate animal testing or epidemiological studies. By the year 1993, IARC had classified the carcinogenicity of 763 chemical compounds, groups of chemical compounds, and mixtures of chemical compounds. Of these, 58 were placed in Category 2A, and 205 compounds were placed in Category 2B. The number of chemical compounds belonging to Category 3 was 405, and only one compound was classified as Category 4. These figures reveal some of the difficulties associated with the assessment of the carcinogenicity of chemical compounds: (1) usually only a limited number of studies on the carcinogenicity of chemicals are available; (2) human carcinogenicity is difficult to demonstrate; and (3) experimental or epidemiological evidence of the lack of carcinogenicity is practically impossible to obtain. This is the reason for not having a “not carcinogenic in humans” category in the IARC classification.150 Some of the difficulties in assessing the carcinogenicity of chemical compounds are discussed below.178 Table 5.21 lists categories of human carcinogens according to IARC.
|
TABLE 5.21 Classification of Carcinogenicity of Chemicals According to the International Agency on Research on Cancer
|
|
Source: Modified from Vаhаkangas and Savolainen.17-9 |
Since animals are biological systems which differ from humans in many ways, epidemiological evidence on the carcinogenicity of chemicals is naturally much stronger than that derived from experimental animal studies. However, it is often difficult to obtain conclusive evidence due to several problems which are characteristic of epidemiological studies (see Section 5.3 IPR, pages 3-5). It should also be noted that agents causing very rare types of cancer are much easier to detect than those causing more common cancers. Angiosarcoma of the liver and adenocarcinoma of the nose are rare cancers (annual incidences about one per million in the general population); therefore, the human carcinogenicity of vinyl chloride (angiosarcoma) and wood dust (adenocarcinoma of nasal cavity) was identified on the basis of a few cases, whereas increased risk of lung cancer (annual incidence about 400-500 per million) is much more difficult to demonstrate. However, when the evidence derived from experimental animal studies on the carcinogenicity of a given chemical is utilized in assessing human risks of chemical carcinogenesis, several new difficulties are encountered.178,180-182
The biotransformation of a given chemical compound in experimental animals and in humans may differ. Furthermore, high doses of chemical compounds are used in studies with experimental animals, and this may cause alterations in biotransformation of the tested chemicals that do not occur at the lower doses relevant to the human exposure situation. For example, a metabolic pathway dominating at low doses may become saturated, and a salvage metabolic pathway, e. g., one that produces reactive intermediates of the compound, may become involved in the biotransformation of the chemical. Since this intermediate could never be produced at the exposure levels encountered in humans, the overall result of such a carcinogenicity trial is irrelevant. It has also been ai ^ued that high doses of chemicals used in animal carcinogenicity bioassavs induce mitogenesis (increased rate of cell division), and thus carcinogenesis, and are therefore not specific to the compound itself.182183
Mechanisms of Chemical Carcinogenesis
Carcinogens can be divided into two broad classes based on their mechanism of chemical carcinogenicity: genotoxic and epigenetic carcinogens. Geno — toxic carcinogens initiate the process of chemical carcinogenesis by acting as mutagens. All other carcinogens belong to the group epigenetic carcinogens, which includes foreign compound carcinogens, carcinogens acting through a hormonal mechanism, carcinogens that amplify the carcinogenic effects of true carcinogens when they are given after the true carcinogen, and cocarcinogens that stimulate chemical carcinogenesis when delivered in conjunction with a true carcinogen. Chemical carcinogenesis is a very complex cascade of events, this being typical of all forms of carcinogenesis, such that the alterations leading to cancer take place in a stepwise and usually subtle fashion. In fact, it is difficult if not impossible to find the point at which one step is over and the next one begins.178-180
Experimental animal studies have played a key role in the understanding of the mechanisms of chemical carcinogenesis. The duration of development of a cancer in humans may be several decades, and the development probably includes several steps. Furthermore, individual susceptibility is also important for the disease. Therefore, it has been extremely difficult to make the required observations in exposed individuals.
Most genotoxic carcinogens require metabolic activation. The most important group of enzymes that participates in these processes are the P-450 enzymes, of which CYP1A1 is involved in the activation of polycyclic aromatic hydrocarbons, CYP2 in the activation of aromatic amines, and CYP.3A in the activation of aflatoxins.131 An activated compound binds to several macromolecules within cells, and an important event in chemical carcinogenesis is binding to the genetic material, i. e., the formation of carcinogen-DN A adducts which lead to alterations in the genes. Typically, activated compounds favor guanine as the base to which they bind. In addition to the balance between the activity of enzymes that activate chemicals and the activity of enzymes that repair the chemical-induced damage to DNA, the stability of the adducts and the amount of the adducts in the cells are important factors in the initial stages of chemical carcinogenesis induced by genotoxic carcinogens.184-186
If enzymes responsible for DNA repair are unable to remove the DNA ad — duct, or if an error takes place in the repair, then the error in the genetic code remains when the cell divides. Thus, cellular proliferation is also required, in addition to a mutation, for there to be a permanent effect of a chemical compound. Accumulation of genetic errors, i. e., mutations, has been suspected to be an important factor in chemical carcinogenesis.183’185
Recently a number of genes that are important in chemical carcinogenesis have been identified. These include oncogenes (genes that promote carcinogenesis) and tumor suppressor genes (genes that prevent carcinogenesis). A mutation of a proto-oncogene may be required for the transformation of a
Proto-oncogene to an oncogene, which then amplifies the carcinogenic process. On the other hand, mutations that inactivate tumor suppressor genes also greatly amplify carcinogenesis induced by exposure to chemical compounds.187’188 In fact, inactivating mutations in tumor suppressor genes may be vital for the initiation and progression of the carcinogenic process. For example, mutations of ras-, raf-, jun-, fur-, and myc-oncogenes are known to be crucial in the development of lung cancer.189 Table 5.22 lists important oncogenes and tumor suppressor genes that may be involved in human carcinogenesis.
A few tumor suppressor genes have also been identified. The most important of these are the p53 tumor suppressor gene and the retinoblastoma gene.190 When functioning normally, the p53 tumor suppressor gene will stop cell division after DNA damage to give the cell time to repair the damage. Inactivating mutations in the p53 tumor suppressor gene may, therefore, amplify carcinogenesis by preventing the cell from repairing damage to its genetic material. In fact, mutations of p53 tumor suppressor gene are the most usual genetic changes in human cancers, and it seems that some chemical carcinogens
TABLE 5.22 Important Oncogenes and Tumor Suppressor Genes in Human Cancers
Tissues associated with the cancer
|
|
|
|
Tumor suppressor gene
|
Rb P.53 WT-1 APC DCC BRCA HNPCC |
Retina (retinoblastoma), lung Lung, urinary bladder, intestine, breast Kidney (Wilms’ tumor;
Colon
Colon
Breast
Colon
Induce typical and very specific mutations in the p53 tumor suppressor gene. One example is the aflatoxin-induced mutation in codon 249 in the p53 gene.191 In contrast, benzo(a)pyrene, present in tobacco smoke, does not bind to this codon, but does bind to other areas of the gene, so-called hot spots. Exposure to UV light also seems to induce typical and specific mutations in thep53 gene. In addition, there are other typical mutations of the p53 gene that seem to be associated with cancer that are induced by environmental or occupational chemical carcinogens.190
Transplacental Carcinogenesis
Transplacental carcinogenesis indicates that exposure of the mother during pregnancy may induce cancer in the child as it grows. In animals, more than 50 transplacental carcinogens have been found, but in humans only one such compound has been identified, diethylstilbesterol, a synthetic estrogen that was used to prevent spontaneous abortions. However, there is data to suggest that several chemical compounds that are important in the occupational environment may also mediate their effect transplacentaliy. Such compounds include polycyclic aromatic hydrocarbons, nitrosoamines, hydrazines, and isoniazide. Thus, exposure to these compounds should be strictly controlled due to the potential hazard they pose to the developing fetus.5
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