Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 56. Environmental and Occupational Toxicology

Environmental and Occupational Toxicology: Introduction

Toxicology is the branch of pharmacology that encompasses the deleterious effects of chemicals on biologic systems. A number of chemicals in the environment (eg, atmosphere, home, workplace) pose important health hazards.

High-Yield Terms to Learn

Bioaccumulation The increasing concentration of a substance in the environment as the result of environmental persistence and physical properties (eg, lipid solubility) that leads to accumulation in biologic tissues Endocrine disruptors Chemicals in the environment that have estrogen-like or antiandrogen activity or disrupt thyroid function. There is concern that exposure to endocrine disruptors may increase reproductive cancers, impair fertility, and have teratogenic effects Environmental toxicology The area of toxicology that deals with the effects of agents found in the environment; regulated by the Environmental Protection Agency (EPA) in the United States Occupational toxicology The area of toxicology that deals with the toxic effects of chemicals found in the workplace; regulated by the Occupational Safety and Health Administration (OSHA) in the United States Threshold limit value The amount of exposure to a given agent that is deemed safe for a stated time period. It is higher for shorter periods than for longer periods

Air Pollutants

Classification and Prototypes

The major air pollutants in industrialized countries include carbon monoxide (which accounts for about 50% of the total amount of air pollutants), sulfur oxides (18%), hydrocarbons (12%), particulate matter (eg, smoke particles, 10%), and nitrogen oxides (6%). Air pollution appears to be a contributing factor in bronchitis, obstructive pulmonary disease, and lung cancer.

Carbon Monoxide

Carbon monoxide (CO) is an odorless, colorless gas that competes avidly with oxygen for hemoglobin. The affinity of CO for hemoglobin is more than 200-fold greater than that of oxygen. The threshold limit value of CO for an 8-h workday is 25 parts per million (ppm); in heavy traffic, the concentration of CO may exceed 100 ppm.

Effects

CO causes tissue hypoxia. Headache occurs first, followed by confusion, decreased visual acuity, tachycardia, syncope, coma, seizures, and death. Collapse and syncope occur when approximately 40% of hemoglobin has been converted to carboxyhemoglobin. Prolonged hypoxia can result in irreversible damage to the brain and the myocardium.

Treatment

Removal of the source of CO and 100% oxygen are the main features of treatment. Hyperbaric oxygen accelerates the clearance of carbon monoxide.

Sulfur Dioxide

Sulfur dioxide (SO2) is a colorless, irritating gas formed from the combustion of fossil fuels.

Effects

SO2 forms sulfurous acid on contact with moist mucous membranes; this acid is responsible for most of the pathologic effects. Conjunctival and bronchial irritation (especially in persons with asthma) are the primary signs of exposure. Presence of 5-10 ppm in the air is enough to cause severe bronchospasm. Heavy exposure may lead to delayed pulmonary edema. Chronic low-level exposure may aggravate cardiopulmonary disease.

Treatment

Removal from exposure to SO2 and relief of irritation and inflammation constitute the major treatment.

Nitrogen Oxides

Nitrogen dioxide (NO2), a brownish irritant gas, is the principal member of this group. It is formed in fires and in silage on farms.

Effects

NO2 causes deep lung irritation and pulmonary edema. Farm workers exposed to high concentrations of the gas within enclosed silos may die rapidly of acute pulmonary edema. Irritation of the eyes, nose, and throat is common.

Treatment

No specific treatment is available. Measures to reduce inflammation and pulmonary edema are important.

Ozone

Ozone (O3) is a bluish irritant gas produced in air and water purification devices and in electrical fields.

Effects

Exposure to 0.01-0.1 ppm may cause irritation and dryness of the mucous membranes. Pulmonary function may be impaired at higher concentrations. Chronic exposure leads to bronchitis, bronchiolitis, pulmonary fibrosis, and emphysema.

Treatment

No specific treatment is available. Measures that reduce inflammation and pulmonary edema are emphasized.

Solvents

Solvents used in industry and solvents to clean clothing are a major source of direct exposure to hydrocarbons and also contribute to air pollution.

Aliphatic Hydrocarbons

This group includes halogenated solvents such as carbon tetrachloride, chloroform, and trichloroethylene.

Effects

Solvents are potent CNS depressants. The acute effects of excessive exposure are nausea, vertigo, locomotor disturbances, headache, and coma. Chronic exposure leads to hepatic dysfunction and nephrotoxicity. Long-term exposure to tetrachloroethylene or to trichloroethane has caused peripheral neuropathy.

Treatment

Removal from exposure is the only specific treatment available. Serious CNS depression must be treated with support of vital signs (see Chapter 58).

Aromatic Hydrocarbons

Benzene, toluene, and xylene are important aromatic hydrocarbons.

Effects

Acute exposure to any of these hydrocarbons leads to CNS depression with ataxia and coma. Long-term exposure to benzene is associated with hematotoxicity (thrombocytopenia, aplastic anemia, pancytopenia) and various types of hematologic cancers, especially leukemia.

Treatment

Removal from exposure is the only specific way to reduce toxicity. CNS depression is managed by support of vital signs.

Skill Keeper: Safety of New Drugs

(See Chapter 5)

The FDA requires evidence of the relative safety of a new drug before its clinical evaluation. If a new drug is destined for chronic systemic administration, what animal toxicity testing is required? The Skill Keeper Answer appears at the end of the chapter.

Pesticides

Classification and Prototypes

The 3 major classes of pesticides are chlorinated hydrocarbons (DDT and its analogs), acetylcholinesterase inhibitors (carbamates, organophosphates), and botanical agents (nicotine, rotenone, pyrethrum alkaloids).

Chlorinated Hydrocarbons

These agents are persistent, poorly metabolized, lipophilic chemicals that exhibit significant bioaccumulation.

Effects

Chlorinated hydrocarbons block physiologic inactivation in the sodium channels of nerve membranes and cause uncontrolled firing of action potentials. Tremor is usually the first sign of acute toxicity and may progress to seizures. Chronic exposure of animals to these pesticides is tumorigenic. The toxicologic impact of long-term exposure in humans is unclear. Although no relationship has been shown in humans between the risk of breast cancer and serum levels of DDT metabolites, recent evidence suggests an association with brain and testicular cancer.

Treatment

No specific treatment is available for the acute toxicity caused by chlorinated hydrocarbons. Because of their extremely long half-lives in organisms and in the environment (years), their use in North America and Europe has been curtailed.

Cholinesterase Inhibitors

The carbamates (eg, aldicarb, carbaryl) and organophosphates (eg, dichlorvos, malathion, parathion) are effective pesticides with short environmental half-lives. These inexpensive drugs are heavily used in agriculture.

Effects

As described in Chapter 7, cholinesterase inhibitors increase muscarinic and nicotinic activity. The signs and symptoms include pinpoint pupils, sweating, salivation, bronchoconstriction, vomiting and diarrhea, CNS stimulation followed by depression, and muscle fasciculations, weakness, and paralysis. The most common cause of death is respiratory failure. Chronic exposure to some organophosphates (not carbamates) has resulted in a delayed neurotoxicity with axonal degeneration.

Treatment

Atropine is used in large doses to control muscarinic excess; pralidoxime is used to regenerate cholinesterase. Mechanical ventilation may be necessary.

Botanical Insecticides

Nicotine

Nicotine has the same effects on nicotinic cholinoceptors in insects as in mammals and probably kills by the same mechanism (ie, excitation followed by paralysis of ganglionic, CNS, and neuromuscular transmission). Treatment is supportive.

Rotenone

This plant alkaloid pesticide causes gastrointestinal distress when ingested and conjunctivitis and dermatitis after direct contact with exposed body surfaces. Treatment is symptomatic.

Pyrethrum

The most common toxic effect of this mixture of plant alkaloids is contact dermatitis. Ingestion or inhalation of large quantities may cause CNS excitation (including seizures) and peripheral neurotoxicity. Treatment is symptomatic, with anticonvulsants if necessary.

Herbicides

Chlorophenoxy Acids

The 2 most important members of this group are 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid, the compound in Agent Orange. 2,4,5-Trichlorophenoxyacetic acid is longer used because it is often contaminated during manufacturing with dioxin and other polychlorinates (see following text). Large doses of these drugs cause muscle hypotonia and coma. Long-term exposure has been associated with an increased risk of non-Hodgkin's lymphoma.

Glyphosate

Glyphosate is the most widely used herbicide in the world. It a key enzyme involved in aromatic amino acid biosynthesis in plants.

Effects

Glyphosate exposure causes significant eye and skin irritation.

Treatment

No specific treatment is available.

Paraquat

Paraquat, a bipyridyl herbicide, is used extensively to kill weeds on farms and for highway maintenance.

Effects

The compound is relatively nontoxic unless ingested. After ingestion, the initial effect is gastrointestinal irritation with hematemesis and bloody stools. Within a few days, signs of pulmonary impairment occur and are usually progressive, resulting in severe pulmonary fibrosis and often death.

Treatment

No antidote is available; the best supportive treatment, including gastric lavage and dialysis, still results in less than 50% survival after ingestion of as little as 50-500 mg/kg.

Environmental Pollutants

Chemical compounds that contribute to environmental pollution include the polychlorinated biphenyls, dioxins, asbestos, and the heavy metals discussed in Chapter 57.

Polychlorinated Biphenyls

Source

The polychlorinated biphenyls (PCBs) were used extensively in manufacturing electrical equipment until their potential for environmental damage was recognized. PCBs are among the most stable organic compounds known. They are poorly metabolized and lipophilic. They are therefore highly persistent in the environment, and they accumulate in the food chain.

Effects

In workers exposed to PCBs, the most common effect is dermatotoxicity (acne, erythema, folliculitis, hyperkeratosis). Less frequently, mild increases in plasma triglycerides and elevated liver enzymes have been observed.

Dioxins

Source

The polychlorinated dibenzo-p-dioxins (dioxins) are a large group of related compounds of which the most important is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The dioxins have appeared in the environment as unwanted by-products of the chemical industry. They are chemically stable and highly resistant to environmental degradation.

Effects

In laboratory animals, exposure to TCDD causes a wasting syndrome, hepatotoxicity, immune dysfunction, teratogenicity, and cancer. In humans, the most common signs of toxicity are dermatitis and chloracne, which are cystic acneiform lesions that typically form on the face and upper body. Epidemiologic evidence suggests that the dioxins also have carcinogenic and teratogenic effects in humans.

Asbestos

Source

Asbestos is a group of naturally occurring long, flexible mineral fibers, most commonly containing silicon. Asbestos has been used widely in manufacturing and building. Because it is poorly metabolized and lipophilic, it is highly persistent in the environment and accumulates in the food chain. Many countries have banned all use of asbestos because of its toxicity and strictly regulate handling of preexisting asbestos building products.

Effects

Inhalation of asbestos fibers can cause a fibrotic lung disorder called asbestosis, which is characterized by shortness of breath. Asbestos is also associated with several cancers including lung cancer, mesothelioma, and cancers of the gastrointestinal tract.

Skill Keeper Answer: Safety of New Drugs

(See Chapter 5)

Acute toxicity studies in 2 animal species are required by the FDA for all new drugs before their use in humans. Subacute and chronic toxicity studies are required for drugs that are intended for chronic systemic use. Toxicity testing in animals usually involves the determination of lethal dose, monitoring of blood, hepatic, renal, and respiratory functions, gross and histopathologic examination of tissues, and tests of reproductive effects and potential carcinogenicity.

Checklist

When you complete this chapter, you should be able to:

 List the major air pollutants and their clinical effects.

 Describe the signs and symptoms of carbon monoxide poisoning.

 Identify the major organ system toxicities of common solvents.

 Describe the signs, symptoms, and treatment of toxicity resulting from cholinesterase inhibitor insecticides.

 Identify the toxic effects of chlorinated hydrocarbons and botanical insecticides.

 List 2 important herbicides and their major toxicities.

 Appreciate the toxicologic significance of environmental pollution resulting from dioxins and polychlorinated biphenyls (PCBs).



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