Introduction to Toxicology: Occupational & Environmental: 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, identify the acute and chronic diseases that they cause, define the conditions under which they may be used safely, and prevent absorption of harmful amounts of these chemicals. Occupational toxicologists may also define and carry out programs for the surveillance of exposed workers and the environment in which they work. Regulatory limits and voluntary guidelines have been elaborated to establish safe ambient air concentrations for many chemicals found in the workplace. Governmental and supragovernmental bodies throughout the world have generated workplace health and safety rules, including short- and long-term exposure limits for workers. These permissible exposure limits (PELS) have the power of law. Copies of the United States Occupational Safety and Health Administration (OSHA) standards may be found on OSHA's website at http://www.osha.gov. Copies of the United States Mine Safety and Health Administration (MSHA) standards may be found at http://www.msha.gov.

Voluntary organizations such as the American Conference of Governmental Industrial Hygienists (ACGIH) periodically prepares lists of recommended threshold limit values (TLVs) for many chemicals. These guidelines are periodically updated, but regulatory imperatives in the United States are not updated except under certain extraordinary circumstances. These TLV guidelines are useful as reference points in the evaluation of potential workplace exposures. Copies of current TLV lists may be obtained from the ACGIH at http://www.acgih.org.

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. Although 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. Air contaminants are regulated in the United States by the Environmental Protection Agency (EPA) based on both health and esthetic considerations. Tables of regulated air contaminants and other regulatory issues that relate to air contaminants in the United States may be found at http://www.epa.gov. Many states also have individual air contaminant regulations that may be more rigorous than those of the EPA. Many other nations and some supragovernmental organizations regulate air contaminants.

The United Nations 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 from food that, during an entire lifetime, appears to be without appreciable risk. These guidelines are reevaluated as new information becomes available. In the United States, the Food and Drug Administration (FDA) and the Department of Agriculture are responsible for the regulation of contaminants such as pesticides, drugs, and chemicals in foods. Major international problems have occurred because of traffic among nations in contaminated or adulterated foods from countries whose regulations and enforcement of pure food and drug laws are lax or nonexistent.

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.

*The author thanks Gabriel L. Plaa, PhD, the previous author of this chapter, for his contributions.

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 may be able to use potentially toxic substances when the necessary conditions minimizing absorption are established and respected. However, hazard is often a description based on subjective estimates rather than objective evaluation.

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, primary prevention should be designed to reduce or eliminate absorption by inhalation or by topical contact. Atmospheric pollutants gain entry by inhalation and by dermal contact. Water and soil pollutants are absorbed through inhalation, ingestion, and dermal contact.

Duration of Exposure

Toxic reactions may differ qualitatively depending on the duration of the exposure. A single exposure—or multiple exposures occurring over a brief period from seconds to 1 or 2 days—represents acute exposure. Multiple exposures continuing over a longer period of time represent chronic exposure. In the occupational setting, both acute (eg, accidental discharge) and chronic (eg, repetitive handling of a chemical) exposures occur. Exposures to chemicals found in the environment such as air and water pollutants often cause chronic exposure, but sudden large chemical releases may result in acute massive population exposure with serious or lethal consequences.

Environmental Considerations

Certain chemical and physical characteristics are 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 Bioaccumulation & Biomagnification.) Chemicals that are poorly degraded (by abiotic or biotic pathways) exhibit environmental persistence and thus can accumulate. Typical examples of such chemicals include the persistent organic pollutants (POP) such as polychlorinated biphenyls and similar substances. Lipophilic substances such as the once-widespread organochlorine pesticides (eg, DDT) tend to bioaccumulate in body fat, resulting in tissue residues. Slowly released over time, these residues and their metabolites may have chronic adverse effects such as endocrine disruption. When the toxicant is incorporated into the food chain, biomagnification occurs as one species feeds on others and concentrates the chemical. Humans stand at the apex of the food chain. They may be exposed to highly concentrated pollutant loads as bioaccumulation and biomagnification occurs. 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.

Specific Chemicals

Air Pollutants

Five major substances account for about 98% of air pollution: carbon monoxide (CO, 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. EPA standards for these substances apply to the general environment, and OSHA standards apply to workplace exposure.

Carbon Monoxide

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 2008 threshold limit values (TLV-TWA and TLV-STEL) are shown in Table 56–1.

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. A person 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% may produce headache and malaise; at 25% many workers complain of headache, fatigue, decreased attention span, and loss of fine motor coordination. Collapse and syncope may appear at around 40%; with levels above 60%, death may ensue as a result of irreversible damage to the brain and myocardium. The clinical effects may be aggravated by heavy labor, high altitudes, and high ambient temperatures. Although 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. 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 are essential, followed by administration of oxygen—the specific antagonist to CO—within 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. If a hyperbaric oxygen chamber is readily available, it should be used in the treatment of CO poisoning for severely poisoned patients; however, there remain questions about its effectiveness. Progressive recovery from effectively treated CO poisoning, even of a severe degree, is often complete, although some patients demonstrate persistent impairment for a prolonged period of time.

Sulfur Dioxide

Sulfur dioxide (SO₂) is a colorless, irritant gas generated primarily by the combustion of sulfur-containing fossil fuels. The 2008 TLVs are given in Table 56–1. A recently published assessment for oxides of sulfur is available at: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=198843.

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. 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. Exposure to 5 ppm SO₂ for 10 minutes leads to increased resistance to airflow in most humans. Exposures of 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 has been reported in workers. However, current studies have not confirmed this phenomenon. 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. In asthmatic subjects, exposure to SO₂ may result in an acute asthmatic episode. 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 but these effects have been associated with aggravation of chronic cardiopulmonary disease. When combined exposure to high respirable particulate loads and SO₂ occurs, the mixed irritant load may increase the toxic respiratory response. Treatment is not specific for SO₂ but depends on therapeutic maneuvers used in the treatment of irritation of the respiratory tract and asthma.

Nitrogen Oxides

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 2008 TLVs are shown in Table 56–1.

Mechanism of Action

NO₂ is a relatively insoluble 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. At higher exposure, both type I and type II alveolar cells are damaged. Exposure to 25 ppm of NO₂ 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 used. These measures include maintenance of gas exchange with adequate oxygenation and alveolar ventilation. Drug therapy may include bronchodilators, sedatives, and antibiotics.

Ozone

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. There is a near-linear gradient between exposure (1-hour level, 20–100 ppb) and response. See Table 56–1 for 2008 TLVs.

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 O₃ 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.

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, including humans, exposed to concentrations above 1 ppm. There is no specific treatment for acute O₃ intoxication. Management depends on therapeutic measures used for deep lung irritation and noncardiogenic pulmonary edema (see Nitrogen Oxides, above).

Solvents

Halogenated Aliphatic Hydrocarbons

These agents once found 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). However, because of the likelihood that halogenated aliphatic hydrocarbons are carcinogenic to humans, carbon tetrachloride and trichloroethylene have largely been removed from the workplace. Perchloroethylene and trichloroethane are still in use for dry cleaning and solvent degreasing, but it is likely that their use will be very limited in the future. Dry cleaning as an occupation is listed as a class 2B carcinogenic activity by the International Agency for Research Against Cancer (IARC). Fluorinated aliphatics such as the freons and closely related compounds have also been used in the workplace and in consumer goods, but because of the severe environmental damage they cause, their use has been limited or eliminated by international treaty agreements. The common halogenated aliphatic solvents also create serious problems as persistent water pollutants. They are widely found in both groundwater and drinking water as a result of poor disposal practices.

See Table 56–1 for recommended TLVs.

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. Several are also carcinogenic in animals and are considered probable carcinogens in humans. Trichloroethylene and tetrachloroethylene are listed as "reasonably anticipated to be a human carcinogen" by the US National Toxicology Program, and as class 2A probable human carcinogens by IARC. These substances are depressants of the central nervous system in humans; chloroform is the most potent. Chronic exposure to tetrachloroethylene and possibly 1,1,1-trichloroethane can cause impaired memory and peripheral neuropathy. Hepatotoxicity is also a common toxic effect that can occur in humans after acute or chronic exposures; carbon tetrachloride is the most potent of the series. 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 and in some human epidemiologic studies. Reviews of the epidemiologic literature on the occupational exposure of workers to various halogenated aliphatic hydrocarbon solvents including trichloroethylene and tetrachloroethylene have found significant associations between exposure to the agent and renal, prostate, and testicular cancer. Other cancers have been found to be increased but their incidence has not reached statistical significance.

Treatment

There is no specific treatment for acute intoxication resulting from exposure to halogenated hydrocarbons. Management depends on the organ system involved.

Aromatic Hydrocarbons

Benzene is used for its solvent properties and as an intermediate in the synthesis of other chemicals. The 2008 recommended TLVs are given in Table 56–1. Benzene remains an important component of gasoline and may be found in premium gasolines at concentrations as high as 2%. In cold climates such as Alaska, benzene concentrations in gasoline may reach 5%. The PEL promulgated by OSHA is 1 ppm in the air and a 5 ppm limit for skin exposure. The National Institute for Occupational Safety and Health (NIOSH) and others have recommended that the exposure limits for benzene be further reduced to 0.1 ppm because excess blood cancers occur at the current PEL. 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 of which is bone marrow injury. Aplastic anemia, leukopenia, pancytopenia, and thrombocytopenia occur at higher levels of exposure, as does leukemia. Chronic exposure to much lower levels has been associated with leukemia of several types as well as lymphomas, myeloma, and myelodysplastic syndrome. Recent studies have shown the occurrence of leukemia following exposures as low as 2 ppm-years. The pluripotential bone marrow stem cells appear to be a target of benzene or its metabolites and other stem cells may also be targets. Epidemiologic data confirm a causal association between benzene exposure and an increased incidence of leukemia in workers. Most organizations now classify benzene as a known human carcinogen.

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 and a skin and eye irritant. It is also fetotoxic. See Table 56–1 for the TLVs. 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. In limited occupational studies, however, metabolic interactions and modification of toluene's effects have not been observed in workers also exposed to other solvents. Less refined grades of toluene contain benzene.

Xylene (dimethylbenzene) has been substituted for benzene in many solvent degreasing operations. Like toluene, the three xylenes do not possess the myelotoxic properties of benzene, nor have they been associated with leukemia. Xylene is a central nervous system depressant and a skin irritant. Less refined grades of xylene contain benzene. See Table 56–1 for the TLVs.

Pesticides

Organochlorine Pesticides

These agents are usually classified into four groups: DDT (chlorophenothane) and its analogs, benzene hexachlorides, cyclodienes, and toxaphenes (Table 56–2). 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. Organochlorine pesticides have largely been abandoned because they cause severe environmental damage. DDT continues to have very restricted use for domestic mosquito annihilation in malaria-infested areas of Africa. This use is controversial, but it is very effective and is likely to remain in place for the foreseeable future. Organochlorine pesticide residues in humans, animals, and the environment present long-term problems that are not yet fully understood.

Human Toxicology

The acute toxic properties of all the organochlorine pesticides 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 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, and management is symptomatic.

The potential carcinogenic properties of organochlorine pesticides have been extensively studied, and results indicate that chronic administration to laboratory animals over long periods results in enhanced tumorigenicity. Endocrine pathway disruption is the postulated mechanism. Extrapolation of the animal observations to humans is controversial. However, several large epidemiologic studies found no significant association 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. In contrast, recent work supports an association between prepubertal exposure to DDT and brain cancer. In addition, recent studies suggest that the risk of testicular cancer is increased in persons with elevated DDE levels. The risk of non-Hodgkin's lymphoma (NHL) also seems to be increased in persons with elevated oxychlordane residues. Therefore, increased cancer risk in people exposed to the halogenated hydrocarbon pesticides is of concern.

Environmental Toxicology

The organochlorine pesticides are considered persistent chemicals. Degradation is quite slow when compared with other pesticides, 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. These compounds induce significant abnormalities in the endocrine balance of sensitive animal and bird species, in addition to their adverse impact on humans, and their use is appropriately banned in most areas.

Organophosphorus Pesticides

These agents, some of which are listed in Table 56–3, are used 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. These agents are based on compounds such as soman, sarin, and tabun, which were developed for use as war gases. Some of the less toxic organophosphorus compounds are used in human and veterinary medicine as local or systemic antiparasitics (see Chapters 7 and 53). 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 hydrocarbonpesticides. Storm and collaborators reviewed current and suggested human inhalation occupational exposure limits for 30 organophosphate pesticides (see References).

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 functions, as well as psychological symptoms of variable duration, have been associated with exposure to these pesticides. Furthermore, there is some indication of an association of low arylesterase activity with neurologic symptom complexes in Gulf War veterans.

In addition to—and independently of—inhibition 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 progressive demyelination of the longest nerves. Associated with paralysis and axonal degeneration, this lesion is sometimes called organophosphorus ester-induced delayed polyneuropathy (OPIDP). Delayed central and autonomic neuropathy may occur in some poisoned patients. 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. It is also thought to occur with the pesticides dichlorvos, trichlorfon, leptophos, methamidophos, mipafox, trichloronat, and others. The polyneuropathy usually begins with burning and tingling sensations, particularly in the feet, with motor weakness a few days later. Sensory and motor difficulties may extend to the legs and hands. Gait is affected, and ataxia may be present. Central nervous system and autonomic changes may develop even later. There is no specific treatment for this form of delayed neurotoxicity. The long-term prognosis of neuropathy target esterase inhibition is highly variable. Reports of this type of neuropathy (and other toxicities) in pesticide manufacturing workers and in agricultural pesticide applicators have been published.

Environmental Toxicology

Organophosphorus pesticides are not considered to be persistent pesticides. They are relatively unstable and break down in the environment as a result of hydrolysis and photolysis. As a class they are considered to have a small impact on the environment in spite of their acute effects on organisms.

Carbamate Pesticides

These compounds (Table 56–4) 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 pesticides. 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. Although the clinical approach to carbamate poisoning is similar to that for organophosphates, the use of pralidoxime is not recommended.

The carbamates are considered to be nonpersistent pesticides. They exert only a small impact on the environment.

Botanical Pesticides

Pesticides 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 56–1) 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 56–1), pyrethrin II, cinerin I, cinerin II, jasmolin I, and jasmolin II. Synthetic pyrethroids account for an increasing percentage of worldwide pesticide usage. Pyrethrum may be absorbed after inhalation or ingestion; absorption from the skin is not significant. The esters are extensively biotransformed. Pyrethrum pesticides 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. Treatment of exposure is usually directed at management of symptoms. Anticonvulsants are not consistently effective. The chloride channel agonist, ivermectin, is of use, as are pentobarbital and mephenesin. The pyrethroids are highly irritating to the eyes, skin, and respiratory tree. They may cause irritant asthma and, potentially, reactive airways dysfunction syndrome (RADS) and even anaphylaxis. The most common injuries reported in humans result from their allergenic and irritant effects on the airways and skin. Cutaneousparesthesias have been observed in workers spraying synthetic pyrethroids. The use of persistent synthetic pyrethroids for aircraft disinfection to comply with international rules regarding prevention of transfer of insect vectors has resulted in respiratory and skin problems, as well as some neurologic complaints in flight attendants and other aircraft workers. Severe occupational exposures to synthetic pyrethroids in China resulted in marked effects on the central nervous system, including convulsions.

Herbicides

Chlorophenoxy Herbicides

2,4-Dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), and their salts and esters are compounds of interest as herbicides used for the destruction of weeds (Figure 56–1). 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.

Because 2,4,5-T is often contaminated with dioxins and other polychlorinated compounds, it is no longer used. It was the compound used in "Agent Orange" and proved to be an agricultural and social disaster.

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. In laboratory animals, signs of liver and kidney dysfunction have also been reported with chlorphenoxy herbicides. Several epidemiologic studies performed by the US National Cancer Institute confirmed the causal link between 2,4-D and non-Hodgkin's lymphoma. Evidence for a causal link to soft tissue sarcoma, however, is considered equivocal.

The toxicologic profile for these agents, particularly that of 2,4,5-T, is complicated by the presence of chemical contaminants (dioxins ) produced during the manufacturing process (see below). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin, TCDD) is the most important of these contaminants. Dioxin is a potent animal carcinogen and a likely human carcinogen.

Glyphosate

Glyphosate (N-[phosphonomethyl] glycine, Figure 56–1) is now the most widely used herbicide in the world. It functions as a contact herbicide and is absorbed through the leaves and roots of plants. Because it is nonselective, it may damage important crops even when used as directed. Therefore, genetically modified plants such as soybean, corn, and cotton that are glyphosate-resistant have been developed and patented. They are widely grown throughout the world.

Glyphosate-related poisoning incidents are commonly reported. Most injuries are minor, although some lethal outcomes have been reported.

Glyphosate is a significant eye and skin irritant. It has caused lethal outcomes, although it is far less potent than the bipyridyl herbicides. Although the pure chemical seems to have little persistence and lower toxicity than other herbicides, the commercial formulations of glyphosate often contain surfactants and other active compounds that complicate the toxicity of the product. No specific treatment is available for glyphosate toxicity.

Bipyridyl Herbicides

Paraquat is the most important agent of this class (Figure 56–1). 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. 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. It probably inhibits superoxide dismutase, resulting in intracellular free radical oxygen toxicity.

In humans, the first signs and symptoms after oral exposure are 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, because it may aggravate the pulmonary lesions. Patients require prolonged observation, because the proliferative phase begins 1–2 weeks after ingestion. Management of severe paraquat poisoning is complex and largely symptomatic. Many approaches have been used, including immunosuppressive therapy to slow or stop the progressive pulmonary fibrosis. None of the currently proposed methods of treatment is universally successful.

Environmental Pollutants

Polychlorinated Biphenyls

The polychlorinated biphenyls (PCBs, coplanar biphenyls) have been used in a large variety of applications as dielectric and heat transfer fluids, lubricating oils, plasticizers, wax extenders, and flame retardants. Their industrial use and manufacture in the USA were terminated by 1977. Unfortunately, PCBs 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 PCBs—lasting several months—occurred 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 caused by a mixture of 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 humans—whether workers or the general population—even though some subjects have been exposed to very high levels of PCBs. Repeated epidemiologic studies have found some increases in various cancers including melanoma, breast, pancreatic, and thyroid cancers, but the small number of cases and uncertain exposure status have left the carcinogenicity question unclear. In 1977, the IARC recommended that PCBs be regarded as likely carcinogenic to man, although the evidence for this classification was lacking. Some adverse behavioral effects in infants have been reported. 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 polychlorinated dibenzo-p-dioxins (PCDDs) , or dioxins , have been mentioned 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 and in manufactured products 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. The effects observed in workers involved in the manufacture of 2,4,5-T (and therefore presumably exposed to TCDD) consisted of contact dermatitis and chloracne. In severely TCDD-intoxicated patients, discrete chloracne may be the only manifestation.

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 epidemiologic evidence indicating an association between occupational exposure to the phenoxy herbicides and an excess incidence of non-Hodgkin's lymphoma. The TCDD contaminant in these herbicides seems to play a role in a number of cancers such as soft tissue sarcomas, lung cancer, Hodgkin's lymphomas, and others.

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 relation between exposure to a specific environmental agent and an adverse health effect due to endocrine modulation have not been established. Epidemiologic studies of populations exposed to higher concentrations of endocrine disrupting environmental chemicals are underway. There are indications that breast and other reproductive cancers are increased in these patients. Prudence dictates that exposure to environmental chemicals that disrupt endocrine function should be reduced.

Asbestos

Asbestos in many of its forms has been widely used in industry for over 100 years. All forms of asbestos that have been used in industry have been shown to cause progressive lung disease that is characterized by a fibrotic process. Higher levels of exposure produce the process called asbestosis. Lung damage develops even at low concentrations of shorter fibers, whereas higher concentrations of longer fibers are required to cause lung damage. Every form of asbestos, including chrysotile asbestos, causes an increase in lung cancer. Lung cancer occurs in people exposed at fiber concentrations well below concentrations that produce asbestosis. Cigarette smoking and exposure to radon daughters increase the incidence of asbestos-caused lung cancer in a synergistic fashion.

All forms of asbestos also cause mesothelioma of the pleura or peritoneum at very low doses. Other cancers including colon cancer, laryngeal cancer, stomach cancer, and perhaps even lymphoma are increased in asbestos-exposed patients. The mechanism for asbestos-caused cancer is not yet delineated. Arguments that chrysotile asbestos does not cause mesothelioma are contradicted by many epidemiologic studies of worker populations. Recognition that all forms of asbestos are dangerous and carcinogenic has led many countries to ban all uses of asbestos. Countries such as Canada, Zimbabwe, and others that still produce asbestos argue that asbestos can be used safely with careful workplace environmental controls. However, studies of industrial practice make the "safe use" of asbestos highly improbable.

Metals

Occupational and environmental poisoning with metals, metalloids, and metal compounds is a major health problem. Exposure in the workplace is found in many industries, and exposure in the home and elsewhere in the nonoccupational environment is widespread. The classic metal poisons (arsenic, lead, and mercury) continue to be widely used. (Treatment of their toxicities is discussed in Chapter 57.) Occupational exposure and poisoning due to beryllium, cadmium, manganese, and uranium are relatively new occupational problems, which present new and previously unaddressed problems.

Beryllium

Beryllium (Be) is a light alkaline metal that confers special properties on the alloys and ceramics in which it is incorporated. One attractive property of beryllium is its nonsparking quality, which makes it useful in such diverse applications as the manufacture of dental appliances and of nuclear weapons. Beryllium-copper alloys find use as components of computers, in the encasement of the first stage of nuclear weapons, in devices that require hardening such as missile ceramic nose cones, and in the space shuttle heat shield tiles. Because of the use of beryllium in dental appliances, dentists and dental appliance makers are often exposed to beryllium dust in toxic concentrations.

Beryllium is highly toxic by inhalation and is classified by IARC as a class 1, known human carcinogen. Inhalation of beryllium particles produces progressive pulmonary fibrosis and may lead to cancer. Skin disease also develops in workers overexposed to beryllium. The pulmonary disease is called chronic beryllium disease (CBD) and is a chronic granulomatous pulmonary fibrosis. In the 5–15% of the population that is sensitive to beryllium, chronic beryllium disease is the result of activation of an autoimmune attack on the skin and lungs. The disease is progressive and may lead to severe disability and death. Although some treatment approaches to the management of chronic beryllium disease show promise, the prognosis is poor in most cases.

The current permissible exposure levels for beryllium of 0.01 mcg/m³ averaged over a 30-day period or 2 mcg/m³ over an 8-hour period are insufficiently protective to prevent chronic beryllium disease. Both NIOSH and the ACGIH have recommended that the PEL and TLV be reduced to 0.05 mcg/m³. These recommendations have not yet been implemented.

Environmental beryllium exposure is not generally thought to be a hazard to human health except in the vicinity of industrial sites where air, water and soil pollution have occurred.

Cadmium

Cadmium (Cd) is a transition metal widely used in industry. Workers are exposed to cadmium in the manufacture of nickel cadmium batteries, pigments, low-melting-point eutectic materials, in solder, television phosphors, and in plating operations. It is also used extensively in semiconductors and in plastics as a stabilizer. Cadmium smelting is often done from residual dust from lead smelting operations, and cadmium smelter workers often face both lead and cadmium toxicity.

Cadmium is toxic by inhalation and by ingestion. When metals that have been plated with cadmium or welded with cadmium-containing materials are vaporized by the heat of torches or cutting implements, the fine dust and fumes released produce an acute respiratory disorder called cadmium fume fever. This disorder, common in welders, is usually characterized by shaking chills, cough, fever, and malaise. Although it may produce pneumonia, it is usually transient. However, chronic exposure to cadmium dust produces a far more serious progressive pulmonary fibrosis. Cadmium also causes severe kidney damage, including renal failure if exposure continues. Cadmium is a human carcinogen and is listed as a group 1, known human carcinogen by the IARC.

The current OSHA PEL for cadmium is 5 mcg/m³. This PEL, considered by OSHA to be the lowest feasible limit for the dust, is insufficiently protective of worker health.

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