Introduction
Humans live in a chemical environment and inhale, ingest, or absorb from the skin many of these chemicals. Toxicology is concerned with the deleterious effects of these chemical agents on all living systems. In the biomedical area, however, the toxicologist is primarily concerned with adverse effects in humans resulting from exposure to drugs and other chemicals as well as the demonstration of safety or hazard associated with their use.
Occupational Toxicology
Occupational toxicology deals with the chemicals found in the workplace. The major emphasis of occupational toxicology is to identify the agents of concern, define the conditions leading to their safe use, and prevent absorption of harmful amounts. Guidelines have been elaborated to establish safe ambient air concentrations for many chemicals found in the workplace. The American Conference of Governmental Industrial Hygienists periodically prepares lists of recommended threshold limit values (TLVs) for about 600 such chemicals. These guidelines are reevaluated as new information becomes available.
Environmental Toxicology
Environmental toxicology deals with the potentially deleterious impact of chemicals, present as pollutants of the environment, on living organisms. The term environment includes all the surroundings of an individual organism, but particularly the air, soil, and water. While humans are considered a target species of particular interest, other species are of considerable importance as potential biologic targets.
Air pollution is a product of industrialization, technologic development, and increased urbanization. Humans may also be exposed to chemicals used in the agricultural environment as pesticides or in food processing that may persist as residues or ingredients in food products. The Food and Agriculture Organization and the World Health Organization (FAO/WHO) Joint Expert Commission on Food Additives adopted the term acceptable daily intake (ADI) to denote the daily intake of a chemical which, during an entire lifetime, appears to be without appreciable risk. These guidelines are reevaluated as new information becomes available.
Ecotoxicology
Ecotoxicology is concerned with the toxic effects of chemical and physical agents on populations and communities of living organisms within defined ecosystems; it includes the transfer pathways of those agents and their interactions with the environment. Traditional toxicology is concerned with toxic effects on individual organisms; ecotoxicology is concerned with the impact on populations of living organisms or on ecosystems. It is possible that an environmental event, while exerting severe effects on individual organisms, may have no important impact on populations or on an ecosystem. Thus, the terms "environmental toxicology" and "ecotoxicology" are not interchangeable.
TOXICOLOGIC TERMS & DEFINITIONS
Hazard & Risk
Hazard is the ability of a chemical agent to cause injury in a given situation or setting; the conditions of use and exposure are primary considerations. To assess hazard, one needs to have knowledge about both the inherent toxicity of the substance and the amounts to which individuals are liable to be exposed. Humans can safely use potentially toxic substances when the necessary conditions minimizing absorption are established and respected.
Risk is defined as the expected frequency of the occurrence of an undesirable effect arising from exposure to a chemical or physical agent. Estimation of risk makes use of dose-response data and extrapolation from the observed relationships to the expected responses at doses occurring in actual exposure situations. The quality and suitability of the biologic data used in such estimates are major limiting factors.
Routes of Exposure
The route of entry for chemicals into the body differs in different exposure situations. In the industrial setting, inhalation is the major route of entry. The transdermal route is also quite important, but oral ingestion is a relatively minor route. Consequently, preventive measures are largely designed to eliminate absorption by inhalation or by topical contact. Atmospheric pollutants gain entry by inhalation, whereas for pollutants of water and soil, oral ingestion is the principal route of exposure for humans.
Duration of Exposure
Toxic reactions may differ qualitatively depending on the duration of the exposure. A single exposure¾or multiple exposures occurring over 1 or 2 days¾represents acute exposure. Multiple exposures continuing over a longer period of time represent a chronic exposure. In the occupational setting, both acute (eg, accidental discharge) and chronic (eg, repetitive handling of a chemical) exposures may occur, whereas with chemicals found in the environment (eg, pollutants in ground water), chronic exposure is more likely.
ENVIRONMENTAL CONSIDERATIONS
Certain chemical and physical characteristics are known to be important for estimating the potential hazard involved for environmental toxicants. In addition to information regarding effects on different organisms, knowledge about the following properties is essential to predict the environmental impact: The degradability of the substance; its mobility through air, water, and soil; whether or not bioaccumulation occurs; and its transport and biomagnification through food chains. (See Box: Bioaccumulation & Biomagnification.) Chemicals that are poorly degraded (by abiotic or biotic pathways) exhibit environmental persistence and thus can accumulate. Lipophilic substances tend to bioaccumulate in body fat, resulting in tissue residues. When the toxicant is incorporated into the food chain, biomagnification occurs as one species feeds upon others and concentrates the chemical. The pollutants that have the widest environmental impact are poorly degradable; are relatively mobile in air, water, and soil; exhibit bioaccumulation; and also exhibit biomagnification.
BIOACCUMULATION & BIOMAGNIFICATION
If the intake of a long-lasting contaminant by an organism exceeds the latter's ability to metabolize or excrete the substance, the chemical accumulates within the tissues of the organism. This is called bioaccumulation.
Although the concentration of a contaminant may be virtually undetectable in water, it may be magnified hundreds or thousands of time as the contaminant passes up the food chain. This is called biomagnification.
The biomagnification of polychlorinated biphenyls (PCBs) in the Great Lakes of North America is illustrated by the following residue values available from Environment Canada, a report published by the Canadian government, and other sources.
Thus, the biomagnification for this substance in the food chain, beginning with phytoplankton and ending with the herring gull, is nearly 50,000-fold. Domesticated animals and humans may eat fish from the Great Lakes, resulting in PCB residues in these species as well.
Source PCB Concentration (ppm)1 Concentration Relative to Phytoplankton
Phytoplankton 0.0025 1
Zooplankton 0.123 49.2
Rainbow smelt 1.04 416
Lake trout 4.83 1,932
Herring gull 124 49,600
1Sources: Environment Canada, The State of Canada's Environment, 1991, Government of Canada, Ottawa; and other
publications.
SPECIFIC CHEMICALS
AIR POLLUTANTS
INTRODUCTION
Five major substances account for about 98% of air pollution: carbon monoxide (about 52%), sulfur oxides (about 14%), hydrocarbons (about 14%), nitrogen oxides (about 14%), and particulate matter (about 4%). The sources of these chemicals include transportation, industry, generation of electric power, space heating, and refuse disposal. Sulfur dioxide and smoke resulting from incomplete combustion of coal have been associated with acute adverse effects, particularly among the elderly and individuals with preexisting cardiac or respiratory disease. Ambient air pollution has been implicated as a contributing factor in bronchitis, obstructive ventilatory disease, pulmonary emphysema, bronchial asthma, and lung cancer.
1. Carbon Monoxide
Introduction
Carbon monoxide (CO) is a colorless, tasteless, odorless, and nonirritating gas, a byproduct of incomplete combustion. The average concentration of CO in the atmosphere is about 0.1 ppm; in heavy traffic, the concentration may exceed 100 ppm. The recommended 2005 threshold limit values (TLV-TWA and TLV-STEL) are shown in Table 57-1.
Mechanism of Action
CO combines reversibly with the oxygen-binding sites of hemoglobin and has an affinity for hemoglobin that is about 220 times that of oxygen. The product formed, carboxyhemoglobin, cannot transport oxygen. Furthermore, the presence of carboxyhemoglobin interferes with the dissociation of oxygen from the remaining oxyhemoglobin, thus reducing the transfer of oxygen to tissues. The brain and the heart are the organs most affected. Normal nonsmoking adults have carboxyhemoglobin levels of less than 1% saturation (1% of total hemoglobin is in the form of carboxyhemoglobin); this level has been attributed to the endogenous formation of CO from heme catabolism. Smokers may exhibit 5-10% saturation, depending on their smoking habits. An individual breathing air containing 0.1% CO (1000 ppm) would have a carboxyhemoglobin level of about 50%.
Clinical Effects
The principal signs of CO intoxication are those of hypoxia and progress in the following sequence: (1) psychomotor impairment; (2) headache and tightness in the temporal area; (3) confusion and loss of visual acuity; (4) tachycardia, tachypnea, syncope, and coma; and (5) deep coma, convulsions, shock, and respiratory failure. There is great variability in individual responses to a given carboxyhemoglobin concentration. Carboxyhemoglobin levels below 15% rarely produce symptoms; collapse and syncope may appear around 40%; above 60%, death may ensue. Prolonged hypoxia and posthypoxic unconsciousness can result in irreversible damage to the brain and the myocardium. The clinical effects may be aggravated by heavy labor, high altitudes, and high ambient temperatures. The presence of cardiovascular disease is considered to increase the risks associated with CO exposure. Delayed neuropsychiatric impairment can occur after poisoning, and the resolution of behavioral consequences can be slow. While CO intoxication is usually thought of as a form of acute toxicity, there is some evidence that chronic exposure to low levels may lead to undesirable effects, including the development of atherosclerotic coronary disease in cigarette smokers. However, convincing experimental evidence is lacking. The fetus may be quite susceptible to the effects of CO exposure.
Treatment
In cases of acute intoxication, removal of the individual from the exposure source and maintenance of respiration is essential, followed by administration of oxygen¾the specific antagonist to CO¾within the limits of oxygen toxicity. With room air at 1 atm, the elimination half-time of CO is about 320 minutes; with 100% oxygen, the half-time is about 80 minutes; and with hyperbaric oxygen (2-3 atm), the half-time can be reduced to about 20 minutes. Questions still exist about the efficacy of hyperbaric oxygen in the treatment of CO poisoning, and absolute indications for its use have yet to be established.
2. Sulfur Dioxide
Introduction
Sulfur dioxide (SO2) is a colorless, irritant gas generated primarily by the combustion of sulfur-containing fossil fuels. The 2005 threshold limit values are given in Table 57-1.
Mechanism of Action
On contact with moist membranes, SO2 forms sulfurous acid, which is responsible for its severe irritant effects on the eyes, mucous membranes, and skin. It is estimated that approximately 90% of inhaled SO2 is absorbed in the upper respiratory tract, the site of its principal effect. The inhalation of SO2 causes bronchial constriction; parasympathetic reflexes and altered smooth muscle tone appear to be involved in this reaction. Exposure to 5 ppm for 10 minutes leads to increased resistance to airflow in most humans. Exposures to 5-10 ppm are reported to cause severe bronchospasm; 10-20% of the healthy young adult population is estimated to be reactive to even lower concentrations. The phenomenon of adaptation to irritating concentrations is a recognized occurrence in workers. Asthmatic individuals are especially sensitive to SO2.
Clinical Effects & Treatment
The signs and symptoms of intoxication include irritation of the eyes, nose, and throat and reflex bronchoconstriction. If severe exposure has occurred, delayed onset pulmonary edema may be observed. Cumulative effects from chronic low-level exposure to SO2 are not striking, particularly in humans. Chronic exposure, however, has been associated with aggravation of chronic cardiopulmonary disease. Treatment is not specific for SO2 but depends on therapeutic maneuvers utilized in the treatment of irritation of the respiratory tract.
3. Nitrogen Oxides
Introduction
Nitrogen dioxide (NO2) is a brownish irritant gas sometimes associated with fires. It is formed also from fresh silage; exposure of farmers to NO2 in the confines of a silo can lead to silo-filler's disease. The 2005 threshold limit values are shown in Table 57-1.
Mechanism of Action
NO2 is a deep lung irritant capable of producing pulmonary edema. The type I cells of the alveoli appear to be the cells chiefly affected on acute exposure. Exposure to 25 ppm is irritating to some individuals; 50 ppm is moderately irritating to the eyes and nose. Exposure for 1 hour to 50 ppm can cause pulmonary edema and perhaps subacute or chronic pulmonary lesions; 100 ppm can cause pulmonary edema and death.
Clinical Effects & Treatment
The signs and symptoms of acute exposure to NO2 include irritation of the eyes and nose, cough, mucoid or frothy sputum production, dyspnea, and chest pain. Pulmonary edema may appear within 1-2 hours. In some individuals, the clinical signs may subside in about 2 weeks; the patient may then pass into a second stage of abruptly increasing severity, including recurring pulmonary edema and fibrotic destruction of terminal bronchioles (bronchiolitis obliterans). Chronic exposure of laboratory animals to 10-25 ppm NO2 has resulted in emphysematous changes; thus, chronic effects in humans are of concern. There is no specific treatment for acute intoxication by NO2; therapeutic measures for the management of deep lung irritation and noncardiogenic pulmonary edema are employed. These measures include maintenance of gas exchange with adequate oxygenation and alveolar ventilation. Drug therapy may include bronchodilators, sedatives, and antibiotics.
4. Ozone
Introduction
Ozone (O3) is a bluish irritant gas that occurs normally in the earth's atmosphere, where it is an important absorbent of ultraviolet light. In the workplace, it can occur around high-voltage electrical equipment and around ozone-producing devices used for air and water purification. It is also an important oxidant found in polluted urban air. The effect of low ambient levels of ozone on admission to Ontario, Canada, hospitals for respiratory problems revealed a near-linear gradient between exposure (1-hour level, 20-100 ppb) and response. See Table 57-1 for 2005 threshold limit values.
Clinical Effects & Treatment
O3 is an irritant of mucous membranes. Mild exposure produces upper respiratory tract irritation. Severe exposure can cause deep lung irritation, with pulmonary edema when inhaled at sufficient concentrations. Ozone penetration in the lung depends on tidal volume; consequently, exercise can increase the amount of ozone reaching the distal lung. Some of the effects of O3 resemble those seen with radiation, suggesting that O3 toxicity may result from the formation of reactive free radicals. The gas causes shallow, rapid breathing and a decrease in pulmonary compliance. Enhanced sensitivity of the lung to bronchoconstrictors is also observed. Exposure around 0.1 ppm for 10-30 minutes causes irritation and dryness of the throat; above 0.1 ppm, one finds changes in visual acuity, substernal pain, and dyspnea. Pulmonary function is impaired at concentrations exceeding 0.8 ppm. Airway hyperresponsiveness and airway inflammation have been observed in humans.
Animal studies indicate that the response of the lung to O3 is a dynamic one. The morphologic and biochemical changes are the result of both direct injury and secondary responses to the initial damage. Long-term exposure in animals results in morphologic and functional pulmonary changes. Chronic bronchitis, bronchiolitis, fibrosis, and emphysematous changes have been reported in a variety of species exposed to concentrations above 1 ppm. There is no specific treatment for acute O3 intoxication. Management depends on therapeutic measures utilized for deep lung irritation and noncardiogenic pulmonary edema (see Nitrogen Oxides, above).
SOLVENTS
1. Halogenated Aliphatic Hydrocarbons
Introduction
These agents find wide use as industrial solvents, degreasing agents, and cleaning agents. The substances include carbon tetrachloride, chloroform, trichloroethylene, tetrachloroethylene (perchloroethylene), and 1,1,1-trichloroethane (methyl chloroform). See Table 57-1 for recommended threshold limit values.
Mechanism of Action & Clinical Effects
In laboratory animals, the halogenated hydrocarbons cause central nervous system depression, liver injury, kidney injury, and some degree of cardiotoxicity. These substances are depressants of the central nervous system in humans, although their relative potencies vary considerably; chloroform is the most potent and was widely used as an anesthetic agent. Chronic exposure to tetrachloroethylene can cause impaired memory and peripheral neuropathy. In 1994, evidence was presented suggesting that 1,1,1-trichloroethane used in some degreasing operations may be associated with peripheral neuropathy. This proposed association requires confirmation because of the widespread use of this agent. Hepatotoxicity is also a common toxic effect that can occur in humans after acute or chronic exposures, the severity of the lesion being dependent on the amount absorbed. Carbon tetrachloride is the most potent of the series in this regard. Nephrotoxicity can occur in humans exposed to carbon tetrachloride, chloroform, and trichloroethylene. With chloroform, carbon tetrachloride, trichloroethylene, and tetrachloroethylene, carcinogenicity has been observed in lifetime exposure studies performed in rats and mice. The potential effects of low-level, long-term exposures in humans are yet to be determined. However, a review of the epidemiologic literature on the occupational exposure of workers to tetrachloroethylene found no association between breast, prostate, skin, or brain cancer and exposure to the agent, while a relationship for cancer of the oral cavity, liver, pancreas, or lung appeared unlikely. Data indicate that the margin of safety for humans is very large with respect to the potential carcinogenic effect of household exposure to chloroform or environmentally relevant concentrations of trichloroethylene.
Treatment
There is no specific treatment for acute intoxication resulting from exposure to halogenated hydrocarbons. Management depends on the organ system involved.
2. Aromatic Hydrocarbons
Benzene is widely used for its solvent properties and as an intermediate in the synthesis of other chemicals. The 2005 recommended threshold limit values are given in Table 57-1. The acute toxic effect of benzene is depression of the central nervous system. Exposure to 7500 ppm for 30 minutes can be fatal. Exposure to concentrations larger than 3000 ppm may cause euphoria, nausea, locomotor problems, and coma; vertigo, drowsiness, headache, and nausea may occur at concentrations ranging from 250 to 500 ppm. No specific treatment exists for the acute toxic effect of benzene.
Chronic exposure to benzene can result in very serious toxic effects, the most significant being an insidious and unpredictable injury to the bone marrow; aplastic anemia, leukopenia, pancytopenia, or thrombocytopenia may occur. Bone marrow cells in early stages of development appear to be most sensitive to benzene. The early symptoms of chronic benzene intoxication may be rather vague (headache, fatigue, and loss of appetite). Epidemiologic data suggest an association between chronic benzene exposure and an increased incidence of leukemia in workers.
Toluene (methylbenzene) does not possess the myelotoxic properties of benzene, nor has it been associated with leukemia. It is, however, a central nervous system depressant. See Table 57-1 for the threshold limit values. Exposure to 800 ppm can lead to severe fatigue and ataxia; 10,000 ppm can produce rapid loss of consciousness. Chronic effects of long-term toluene exposure are unclear because human studies indicating behavioral effects usually concern exposures to several solvents, not toluene alone. In limited occupational studies, however, metabolic interactions and modification of toluene's effects have not been observed in workers also exposed to other solvents.
INSECTICIDES
1. Organochlorine Insecticides
Introduction
These agents are usually classified in four groups: DDT (chlorophenothane) and its analogs, benzene hexachlorides, cyclodienes, and toxaphenes (Table 57-2). They are aryl, carbocyclic, or heterocyclic compounds containing chlorine substituents. The individual compounds differ widely in their biotransformation and capacity for storage in tissues; toxicity and storage are not always correlated. They can be absorbed through the skin as well as by inhalation or oral ingestion. There are, however, important quantitative differences between the various derivatives; DDT in solution is poorly absorbed through the skin, whereas dieldrin absorption from the skin is very efficient.
Human Toxicology
The acute toxic properties of the organochlorine insecticides in humans are qualitatively similar. These agents interfere with inactivation of the sodium channel in excitable membranes and cause rapid repetitive firing in most neurons. Calcium ion transport is inhibited. These events affect repolarization and enhance the excitability of neurons. The major effect is central nervous system stimulation. With DDT, tremor may be the first manifestation, possibly continuing on to convulsions, whereas with the other compounds convulsions often appear as the first sign of intoxication. There is no specific treatment for the acute intoxicated state, management being symptomatic.
Chronic administration of some of these agents to laboratory animals over long periods has resulted in enhanced tumorigenicity; there is no agreement regarding the potential carcinogenic properties of these substances, and extrapolation of these observations to humans is controversial. Evidence of carcinogenic effects in humans has not been established. In a large epidemiologic study, no relationship was observed between the risk of breast cancer and serum levels of DDE, the major metabolite of DDT. Similarly, the results of a case-control study conducted to investigate the relation between DDE and DDT breast adipose tissue levels and breast cancer risk did not support a positive association.
Environmental Toxicology
The organochlorine insecticides are considered persistent chemicals. Degradation is quite slow when compared with other insecticides, and bioaccumulation, particularly in aquatic ecosystems, is well documented. Their mobility in soil depends on the composition of the soil; the presence of organic matter favors the adsorption of these chemicals onto the soil particles, whereas adsorption is poor in sandy soils. Once adsorbed, they do not readily desorb.
Because of their environmental impact, use of the organochlorine insecticides has been largely curtailed in North America and Europe. Some of them are still used, however, in equatorial countries.
2. Organophosphorus Insecticides
Introduction
These agents, some of which are listed in Table 57-3, are utilized to combat a large variety of pests. They are useful pesticides when in direct contact with insects or when used as plant systemics, where the agent is translocated within the plant and exerts its effects on insects that feed on the plant. Some of these agents are used in human and veterinary medicine as local or systemic antiparasitics (see Chapters 7 and 54). The compounds are absorbed by the skin as well as by the respiratory and gastrointestinal tracts. Biotransformation is rapid, particularly when compared with the rates observed with the chlorinated hydrocarbon insecticides. Current and suggested human inhalation occupational exposure limits for 30 organophosphate pesticides were reviewed by Storm and collaborators in 2000.
Human Toxicology
In mammals as well as insects, the major effect of these agents is inhibition of acetylcholinesterase through phosphorylation of the esteratic site. The signs and symptoms that characterize acute intoxication are due to inhibition of this enzyme and accumulation of acetylcholine; some of the agents also possess direct cholinergic activity. These effects and their treatment are described in Chapters 7 and 8 of this book. Altered neurologic and cognitive function, as well as psychological symptoms of variable duration, have been associated with exposure to high concentrations of these insecticides. Furthermore, there is some indication of an association of low arylesterase activity with neurologic symptom complexes in Gulf War veterans.
In addition to¾and independently of¾inhibition of acetylcholinesterase, some of these agents are capable of phosphorylating another enzyme present in neural tissue, the so-called neuropathy target esterase. This results in development of a delayed neurotoxicity characterized by polyneuropathy, associated with paralysis and axonal degeneration (organophosphorus ester-induced delayed polyneuropathy; OPIDP); hens are particularly sensitive to these properties and have proved very useful for studying the pathogenesis of the lesion and for identifying potentially neurotoxic organophosphorus derivatives. In humans, neurotoxicity has been observed with triorthocresyl phosphate (TOCP), a noninsecticidal organophosphorus compound, and is thought to occur with the insecticides dichlorvos, trichlorfon, leptophos, methamidophos, mipafox, and trichloronat. The polyneuropathy usually begins with burning and tingling sensations, particularly in the feet, with motor weakness following a few days later. Sensory and motor difficulties may extend to the legs and hands. Gait is affected, and ataxia may be present. There is no specific treatment for this form of delayed neurotoxicity.
Environmental Toxicology
Organophosphorus insecticides are not considered to be persistent pesticides because they are relatively unstable and break down in the environment. As a class they are considered to have a small impact on the environment in spite of their acute effects on organisms.
3. Carbamate Insecticides
These compounds (Table 57-4) inhibit acetylcholinesterase by carbamoylation of the esteratic site. Thus, they possess the toxic properties associated with inhibition of this enzyme as described for the organophosphorus insecticides. The effects and treatment are described in Chapters 7 and 8. The clinical effects due to carbamates are of shorter duration than those observed with organophosphorus compounds. The range between the doses that cause minor intoxication and those that result in lethality is larger with carbamates than with the organophosphorus agents. Spontaneous reactivation of cholinesterase is more rapid after inhibition by the carbamates. While the clinical approach to carbamate poisoning is similar to that for organophosphates, the use of pralidoxime is not recommended.
The carbamate insecticides are considered to be nonpersistent pesticides and are thought to exert only a small impact on the environment.
4. Botanical Insecticides
Insecticides derived from natural sources include nicotine, rotenone, and pyrethrum. Nicotine is obtained from the dried leaves of Nicotiana tabacum and N rustica. It is rapidly absorbed from mucosal surfaces; the free alkaloid, but not the salt, is readily absorbed from the skin. Nicotine reacts with the acetylcholine receptor of the postsynaptic membrane (sympathetic and parasympathetic ganglia, neuromuscular junction), resulting in depolarization of the membrane. Toxic doses cause stimulation rapidly followed by blockade of transmission. These actions are described in Chapter 7. Treatment is directed toward maintenance of vital signs and suppression of convulsions.
Rotenone (Figure 57-1) is obtained from Derris elliptica, D mallaccensis, Lonchocarpus utilis, and L urucu. The oral ingestion of rotenone produces gastrointestinal irritation. Conjunctivitis, dermatitis, pharyngitis, and rhinitis can also occur. Treatment is symptomatic.
Pyrethrum consists of six known insecticidal esters: pyrethrin I (Figure 57-1), pyrethrin II, cinerin I, cinerin II, jasmolin I, and jasmolin II. Synthetic pyrethroids account for about 30% of worldwide insecticide usage. Pyrethrum may be absorbed after inhalation or ingestion; absorption from the skin is not significant. The esters are extensively biotransformed. Pyrethrum insecticides are not highly toxic to mammals. When absorbed in sufficient quantities, the major site of toxic action is the central nervous system; excitation, convulsions, and tetanic paralysis can occur. Voltage-gated sodium, calcium, and chloride channels are considered targets, as well as peripheral-type benzodiazepine receptors. Symptomatic treatment is usually employed. Anticonvulsants are not consistently effective. The chloride channel agonist, ivermectin, is of use as are pentobarbital and mephenesin. The most frequent injury reported in humans results from the allergenic properties of the substance, especially contact dermatitis. Cutaneous paresthesias have been observed in workers spraying synthetic pyrethroids. Severe occupational exposures to synthetic pyrethroids in China resulted in marked effects on the central nervous system, including convulsions.
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Figure 57-1. Chemical structures of selected herbicides and pesticides. |
HERBICIDES
1. Chlorophenoxy Herbicides
2,4-Dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), and their salts and esters are the major compounds of interest as herbicides used for the destruction of weeds (Figure 57-1). They have been assigned toxicity ratings of 4 or 3, respectively, which place the probable human lethal dosages at 50-500 or 500-5000 mg/kg, respectively.
In humans, 2,4-D in large doses can cause coma and generalized muscle hypotonia. Rarely, muscle weakness and marked hypotonia may persist for several weeks. With 2,4,5-T, coma may occur, but the muscular dysfunction is less evident. In laboratory animals, signs of liver and kidney dysfunction have also been reported. There is limited evidence that occupational exposure to phenoxy herbicides is associated with an increased risk of non-Hodgkin's lymphoma; the evidence for soft-tissue sarcoma, however, is considered equivocal.
The toxicologic profile for these agents, particularly that of 2,4,5-T, has been confusing because of the presence of chemical contaminants (dioxins) produced during the manufacturing process (see below). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most important of these contaminants.
2. Bipyridyl Herbicides
Paraquat is the most important agent of this class (Figure 57-1). Its mechanism of action is said to be similar in plants and animals and involves single-electron reduction of the herbicide to free radical species. It has been given a toxicity rating of 4, which places the probable human lethal dosage at 50-500 mg/kg. Several lethal human intoxications (accidental or suicidal) have been reported. Paraquat accumulates slowly in the lung by an active process and causes lung edema, alveolitis, and progressive fibrosis.
In humans, the first signs and symptoms after oral exposure are attributable to gastrointestinal irritation (hematemesis and bloody stools). Within a few days, however, delayed toxicity occurs, with respiratory distress and the development of congestive hemorrhagic pulmonary edema accompanied by widespread cellular proliferation. Hepatic, renal, or myocardial involvement may also be evident. The interval between ingestion and death may be several weeks. Because of the delayed pulmonary toxicity, prompt removal of paraquat from the digestive tract is important. Gastric lavage, the use of cathartics, and the use of adsorbents to prevent further absorption have all been advocated; after absorption, treatment is successful in fewer than 50% of cases. Oxygen should be used cautiously to combat dyspnea or cyanosis, as it may aggravate the pulmonary lesions. Patients require prolonged observation, because the proliferative phase begins 1-2 weeks after ingestion.
ENVIRONMENTAL POLLUTANTS
1. Polychlorinated Biphenyls
The polychlorinated biphenyls (PCBs, coplanar biphenyls) have been used in a large variety of applications as dielectric and heat transfer fluids, plasticizers, wax extenders, and flame retardants. Their industrial use and manufacture in the USA was terminated by 1977. Unfortunately, they persist in the environment. The products used commercially were actually mixtures of PCB isomers and homologs containing 12-68% chlorine. These chemicals are highly stable and highly lipophilic, poorly metabolized, and very resistant to environmental degradation; they bioaccumulate in food chains. Food is the major source of PCB residues in humans.
A serious exposure to PCBs¾lasting several months¾occurred in Japan in 1968 as a result of cooking oil contamination with PCB-containing transfer medium (Yusho disease). Possible effects on the fetus and on the development of the offspring of poisoned women were reported. It is now known that the contaminated cooking oil contained not only PCBs but also polychlorinated dibenzofurans (PCDFs) and polychlorinated quaterphenyls (PCQs). Consequently, the effects that were initially attributed to the presence of PCBs are now thought to have been largely caused by the other contaminants. Workers occupationally exposed to PCBs have exhibited the following clinical signs: dermatologic problems (chloracne, folliculitis, erythema, dryness, rash, hyperkeratosis, hyperpigmentation), some hepatic involvement, and elevated plasma triglycerides.
The effects of PCBs alone on reproduction and development, as well as their carcinogenic effects, have yet to be established in humans¾whether workers or the general population¾even though some subjects have been exposed to very high levels of PCBs. Some adverse behavioral effects in infants are reported to have been observed, but the effects were dissimilar. An association between prenatal exposure to PCBs and deficits in childhood intellectual function was described for children born to mothers who had eaten large quantities of contaminated fish. The bulk of the evidence from human studies indicates that PCBs pose little hazard to human health except in situations where food is contaminated with high concentrations of these congeners.
The polychlorinated dibenzo-p-dioxins (PCDDs), or dioxins, have been mentioned above as a group of congeners of which the most important is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In addition, there is a larger group of dioxin-like compounds, including certain polychlorinated dibenzofurans (PCDFs) and coplanar biphenyls. While PCBs were used commercially, PCDDs and PCDFs are unwanted by-products that appear in the environment as contaminants because of improperly controlled combustion processes. PCDD and PCDF contamination of the global environment is considered to represent a contemporary problem produced by human activities. Like PCBs, these chemicals are very stable and highly lipophilic. They are poorly metabolized and very resistant to environmental degradation.
In laboratory animals, TCDD administered in suitable doses has produced a wide variety of toxic effects, including a wasting syndrome (severe weight loss accompanied by reduction of muscle mass and adipose tissue), thymic atrophy, epidermal changes, hepatotoxicity, immunotoxicity, effects on reproduction and development, teratogenicity, and carcinogenicity. Fortunately, most of these actions have not been observed in humans. The effects observed in workers involved in the manufacture of 2,4,5-T (and therefore presumably exposed to TCDD) consisted primarily of contact dermatitis and chloracne. In severely TCDD-intoxicated patients, only discrete chloracne may be present.
The presence of TCDD in 2,4,5-T is believed to be largely responsible for other human toxicities associated with the herbicide. There is some epidemiologic evidence indicating an association between occupational exposure to the phenoxy herbicides and an excess incidence of non-Hodgkin's lymphoma. The evidence of an association of increased soft tissue sarcomas with herbicides themselves, however, is considered equivocal. On the other hand, the TCDD contaminant in these herbicides may play a role in soft tissue sarcomas.
2. Endocrine Disruptors
The potential hazardous effects of some chemicals in the environment are receiving considerable attention because of their estrogen-like or antiandrogenic properties. Compounds that affect thyroid function are also of concern. Since 1998, the process of prioritization, screening, and testing of chemicals for such actions has been undergoing worldwide development. These chemicals mimic, enhance, or inhibit a hormonal action. They include a number of plant constituents (phytoestrogens) and some mycoestrogens as well as industrial chemicals, particularly persistent organochlorine agents such as DDT and PCBs. Some brominated flame retardants are now being investigated as possible endocrine disrupters. Concerns exist because of their increasing contamination of the environment, the appearance of bioaccumulation, and their potential for toxicity. In vitro assays alone are unreliable for regulatory purposes, and animal studies are considered indispensable. Modified endocrine responses in some reptiles and marine invertebrates have been observed. In humans, however, a causal relationship between exposure to a specific environmental agent and an adverse health effect due to endocrine modulation has not been established.
REFERENCES
Air Pollution
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Folinsbee LJ: Human health effects of air pollution. Environ Health Perspect 1993;100:45.
Raub JA et al: Carbon monoxide poisoning¾a public health perspective. Toxicology 2000;145:1.
Occupational Toxicology
House RA, Liss GM, Wills MC: Peripheral sensory neuropathy associated with 1,1,1-trichlorethane. Arch Environ Health 1994;51:196.
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Environmental Toxicology & Ecotoxicology
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Pesticides & Herbicides
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Clinical Toxicology
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