Dr Noor Kamil

Environmental & Occupational Toxicology

Toxicology is the branch of pharmacology that concerns

the study, regulation, and treatment of adverse effects in
humans resulting from exposure to chemicals
encountered at work or in the general environment.
Polychlorinated biphenyls
Term Definition
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
Biomagnification Although the concentration of a contaminant may be virtually undetectable in
water, it may be magnified hundreds or thousands of times as the contaminant
passes up the food chain
Ecotoxicology Study of the toxic effects of chemical and physical agents on populations and
communities of living organisms within defined ecosystems
Endocrine Chemicals in the environment that have estrogen-like or antiandrogen activity or
disruptors disrupt thyroid function. There is concern that exposure to endocrine disruptors may
increase reproductive cancers, impair fertility, and have teratogenic effects
Environmental The area of toxicology that deals with the effects of agents found in the
toxicology environment (air, soil, water); regulated by the Environmental Protection Agency
(EPA) in the United States. The FDA regulates exposure in food
Occupational The area of toxicology that deals with the toxic effects of chemicals found in the
toxicology workplace; regulated by the Occupational Safety and Health Administration
(OSHA) in the United States
Threshold limit The amount of exposure to a given agent that is deemed safe for a stated time
value period. It is higher for shorter periods than for longer periods
AIR POLLUTANTS

 Major air pollutants include

 carbon monoxide (50%)
 sulfur oxides (18%)
 hydrocarbons (12%)
 particulate matter (eg, smoke particles, 10%)
 nitrogen oxides (6%)
 contributing factor in bronchitis, obstructive pulmonary disease,
and lung cancer
 B. Carbon Monoxide

 Carbon monoxide (CO) is an odorless, colorless gas has affinity for hemoglobin more
than 200-fold greater than that of oxygen.
 Threshold limit of 8-h workday is 25 ppm
 Heavy motor vehicle traffic exceed 100 ppm
 1. Effects
 Causes tissue hypoxia. Headache occurs first, followed by confusion, decreased visual
acuity, tachycardia, syncope, coma, seizures, and death.
 Collapse and syncope occur when 40% of hemoglobin converted to
carboxyhemoglobin
 Hypoxia can result in irreversible damage to the brain and the myocardium.
 May cause fetal death or serious and irreversible but survivable birth defects.
 2. 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.
 1. 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 individuals with asthma) is the primary sign 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.
 2. 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.
 1. 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.
 Today, the most common source of human exposure to oxides of
nitrogen, including NO2, is automobile and truck traffic emissions.
 2. 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.
 1. 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.
 2. 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.
 A. Halogenated Aliphatic Hydrocarbons
 This group includes halogenated solvents such as carbon tetrachloride, chloroform,
and trichloroethylene.
 1. 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.
 2. Treatment—Removal from exposure is the only specific treatment available.
Serious CNS depression must be treated with support of vital signs
Aromatic Hydrocarbons

 Benzene, toluene, and xylene are important aromatic hydrocarbons.

 1. 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.
 Most national and international organizations classify benzene as a known
human carcinogen. Toluene (methylbenzene) and xylene (dimethylbenzene) are
not carcinogenic.
 2. Treatment—Removal from exposure is the only specific way to reduce toxicity.
CNS depression is managed by support of vital signs.
PESTICIDES

 A. 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).
PESTICIDES

 B. Chlorinated Hydrocarbons
 These agents are persistent, poorly metabolized, lipophilic
chemicals that exhibit significant bioaccumulation.
 1. 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.
PESTICIDES

 B. Chlorinated Hydrocarbons
 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 non-Hodgkin’s lymphoma
and testicular cancer.
 2. 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.
PESTICIDES

 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.
 1. Effects— Cholinesterase inhibitors increase muscarinic and
nicotinic cholinergic 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.
PESTICIDES

 Cholinesterase Inhibitors
 2. Treatment—Atropine is used in large doses to control muscarinic
excess; pralidoxime is used to regenerate cholinesterase.
Mechanical ventilation may be necessary until sufficient
cholinesterase has been regenerated.
PESTICIDES

 Botanical Insecticides
 1. 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.
 2. Rotenone—This plant alkaloid pesticide causes gastrointestinal
distress when ingested and conjunctivitis and dermatitis after direct
contact with exposed body surfaces. Treatment is supportive.
PESTICIDES

 Botanical Insecticides
 3. 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 supportive with
anticonvulsants if necessary.
HERBICIDES

 A. 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 no longer used because it is often contaminated during
manufacturing with dioxin and other polychlorinates.
 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.
HERBICIDES

 B. Glyphosate
 Glyphosate is the principal ingredient in Roundup brand weed killer
and is now the most widely used herbicide in the world. Its target, 5-
enolpyruvylshikimate-3-phosphate synthase, is a key enzyme
involved in aromatic amino acid biosynthesis in plants.
 1. Effects—Glyphosate exposure causes significant eye and skin
irritation and can be fatal when ingested in large quantities.
 2. Treatment—Supportive, no specific treatment is available.
 HERBICIDES
 Paraquat
 Paraquat, a bipyridyl herbicide, is used extensively to kill weeds on farms
and for highway maintenance.
 1. 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.
 2. Treatment—No specific antidote is available. Because of the delayed
pulmonary toxicity, prompt prevention of absorption is important (activated
charcoal, Fuller’s earth). Gastric lavage is not recommended, as it may
promote aspiration from the stomach into the lungs.
HERBICIDES

 Once the paraquat is absorbed, treatment is successful in fewer

than 50% of cases.
 Pulmonary fibrosis starts 1–2 weeks after ingestion.
Immunosuppression with corticosteroids and cyclophosphamide
are commonly used. Antioxidants such as acetylcysteine and
salicylate might be beneficial through free radical-scavenging,
anti-inflammatory actions.
 However, the best supportive treatment, including dialysis, still results
in less than 50% survival after ingestion of as little as 50–500 mg/kg.
ENVIRONMENTAL POLLUTANTS

 Include the polychlorinated biphenyls, dioxins, asbestos, and the heavy metals.
 A. Polychlorinated Biphenyls
 1. 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.
 Due to their estrogen-like effects, PCBs are endocrine disruptors.
ENVIRONMENTAL POLLUTANTS

 A. Polychlorinated Biphenyls
 2. 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.
 Food is the major source of PCBs in humans.
 Epidemiologic studies have established a correlation with increases
in various cancers.
ENVIRONMENTAL POLLUTANTS

 Dioxins
 1. 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
byproducts of the chemical industry.
 They are chemically stable and highly resistant to environmental
degradation.
ENVIRONMENTAL POLLUTANTS

 Dioxins
 2. 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 (a rare skin condition), 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.
ENVIRONMENTAL POLLUTANTS

 C. Asbestos
 1. 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.
ENVIRONMENTAL POLLUTANTS

 C. Asbestos
 2. 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.