PHARMACOLOGY: OCCUPATIONAL & ENVIRONMENTAL TOXICOLOGY

Erwin P. Carabeo, M.D., FPCP

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Occupational Toxicolgy The pollutants that have the widest environmental impact
Chemicals found in the workplace are poorly degradable
are relatively mobile in air, water and soil
Major emphasis of occupational toxicolgy: exhibit bioaccumulation
1. identify agents of concern exhibit biomagnification
LE 1

2. identify the diseases they cause (acute & chronic)

3. define conditions under which they could be used safely Bioaccumulation accumulation of chemical within the tissues of an
organism that occurs when the intake of a long-lasting contaminant
4. prevent absorption of harmful amounts of these chemicals exceeds the organisms ability to metabolize or excrete the substance

Workplace Regulations
Biomagnification exponential increase in the concentration of a
contaminant as it passes up the food chain
PELS
permissible exposure limits Air Pollutants
5 Major Air Pollutants
have the power of law
carbon monoxide (CO) 52%
OSHA
sulfur oxides 14%
TLV
hydrocarbons 14%
threshold limit values
nitrogen oxides 14%
reference points in the evaluation of potential workplace
exposures particulate matter 4%

Environmental Toxicology Sources of Air Pollutants

Deals with the potentially deleterious impact of chemicals (pollutants) transportation

on living organisms industry
environment: air, soil and water generation of electricity

ADI
space heating

acceptable daily intake

refuse disposal

daily intake of chemical from food that during an entire lifetime appears Carbon Monoxide
to be without an appreciable risk
colorless, odorless, tasteless and non-irritating gas
FAO/WHO
by product of incomplete combustion
Ecotoxicology average concentration in atmosphere: 0.1 ppm
toxic effects of chemical and physical agents on populations and in heavy traffic: > 100 ppm
communities of living organisms
Mechanism of Action
includes the transfer pathways of agents and interactions with the
environment combines reversibly with O2 binding sites of hemoglobin
carboxyhemoglobin failure of oxygen transport and transfer of
traditional toxicology: toxic effects on individual organism
oxygen to tissues
Toxicologic Terms affinity for hemoglobin is 220X that of O2
Hazard ability of the chemical to cause injury in a given situation or brain and heart are the most affected
setting; assessment is based inherent toxicity of the substance and the
amounts to which individuals are liable to be exposed Principal Signs of CO Intoxication:
Risk the expected frequency of the occurrence of an undesirable psychomotor impairment
effect arising from exposure to chemical or physical agent headache
Routes of Exposure route of entry of chemicals into the body confusion and loss of visual acuity
industrial setting: inhalational is the major route of entry tachycardia, tachypnea syncope and coma
atmospheric pollutants: inhalation and transdermal routes deep coma, convulsions, shock and respiratory failure
water and soil pollutants: inhalation, ingestion and dermal contact
Treatment
Duration of Exposure length of exposure to chemicals
acute exposure: single or multiple exposures lasting from seconds
for acute intoxication: removal from exposure source and maintenance
of respiration
to 1 or 2 days
chronic exposure: multiple exposures continuing over a longer
oxygen administration:
period of time room air: elimination half time of CO 320 min
100% oxygen: 80 minutes
Chemical and Physical Characteristics that Determine Environmental Impact
of Toxicants: hyperbaric oxygen (2-3 atm): 20 minutes

1. degradability of the substance Sulfur Dioxide

2. its mobility through air, water and soil SO2
3. whether or not bioaccumulation occurs colorless irritant gas
4. transport and biomagnification through food chains generated by the combustion of sulfur-containing fossil fuels
Transcribed by: KC 1
Mechanism of Action Mechanism of Action & Clinical Effects
on contact with moist membranes sulfurous acid severe irritant CNS depression; chloroform most potent
effects on eyes, mucus membranes and skin chronic exposure: impaired memory and peripheral neuropathy
inhalation of SO2: bronchoconstriction hepatotoxicity; CCl4 most potent
Clinical Effect and Treatment nephrotoxicity
irritation of the eyes, nose and throat carcinogenicity
reflex bronchoconstriction Treatment
in asthmatics: acute asthmatic attack no specific treatment for acute intoxication
no specific treatment for SO2; treatment of the irritation of respiratory management depends on the organ system involved
tract and asthma
Aromatic Hydrocarbons
Nitrogen Oxides BENZENE
nitrogen dioxide (NO2) component of premium gasoline
brownish irritant gas associated with fires acute toxic effect: CNS depression
Mechanism of Action 250-500 ppm: vertigo, drowsiness, headache
insoluble deep lung irritant capable of producing pulmonary edema >3000 ppm: euphoria, nausea, locomotor problems, coma
50 ppm: moderately irritating to the eyes and nose 7500 ppm for 30 min: fatal
50 ppm for 1 hour: pulmonary edema or chronic pulmonary lesions chronic exposure: bone marrow toxicity aplastic anemia, leukemia,
lymphoma, myeloma
100 ppm: pulmonary edema and death
TOLUENE (Methylbenzene)
CNS depressant, skin and eye irritant,
Clinical Effects fetotoxic
acute exposure: irritation of the eyes and nose, cough, mucoid or frothy at 800 ppm: severe fatigue and ataxia
sputum, dyspnea, chest pain
at 10,000 ppm: rapid loss of consciousness
clinical signs may subside in about 2 weeks
second stage: abruptly increasing severity, recurring pulmonary edema XYLENE (Dimethylbenzene)
and fibrotic destruction of terminal bronchioles substitute for benzene in degreasing operations

Treatment
no myelotoxic properties of benzene

no specific treatment for acute intoxication

CNS depressant and skin irritant

management of deep lung irritation and pulmonary edema: adequate Pesticides

oxygenation and alveolar ventilation Organochlorine Pesticides
drugs: bronchodilators, sedatives and antibiotics DDT (chlorophenotane)

Ozone
benzene hexachlorides

O3
cyclodienes

bluish irritant gas normally occurring in the atmosphere

toxaphenes

absorbent of UV light Human Toxicology

workplace: ozone producing devices for air and water purification, high interfere with activation of sodium channels and inhibition of Calcium
voltage electrical equipment ion transport enhanced excitability of neurons CNS stimulation
also found in polluted urban air DDT: tremors convulsions

Clinical Effects
no specific treatment of acute intoxication

effects resemble that of radiation

0.1 ppm for 10-30 min: irritation and dryness of the throat
>0.1 ppm: changes in visual acuity, substernal pain and dyspnea
>0.8 ppm: impairment of pulmonary function
Treatment
similar to treatment of Nitrogen Oxide exposure
increased cancer risk exposed to halogenated hydrocarbon pesticides:
brain cancer (DDE), testicular cancer (DDE), non-Hodgkins lymphoma
Environmental Toxicology
considered as persistent chemicals because of slow degradation
bioaccumulation in aquatic ecosystems
induce significant abnormalities in the endocrine balance of sensitive
animal and bird species

Solvents Organophosphorus Pesticides

Halogenated Aliphatic Hydrocarbons
used to combat a wide variety of pets
used as: industrial solvents, degreasing agents, cleaning agents
based on compounds which were developed for use as war gases
carbon tetrachloride, chloroform, trichloroethylene, (soman, sarin and tabun)
tetrachloroethylene, methyl chloroform
absorbed by the skin, respiratory and GI tracts
CCl4 and trichloroethylene have been removed from the workplace
undergoes rapid biotransformation
Transcribed by: KC 2
 most widely used herbicide in the world
Human Toxicology
contact herbicide: absorbed through the leaves and roots
mechanism of action: inhibition of acetylcholinesterase accumulation
of acetyl choline; some may have direct cholinergic activity significant eye and skin irritant
altered cognitive and neurologic functions have little persistence and lower toxicity than other herbicides
inhibition of neuropathy target esterase progressive demyelination of no specific treatment for glyphosate toxicity is available
neurons paralysis
Bipyridil Herbicides
Environmental Toxicology Paraquat most important agent in this class
not considered as persistent pesticides mechanism of action: reduction to free radical species
relatively unstable and breakdown in the environment as a result of toxicity rating of 4 (human lethal dose of 50-500 mg/kg)
hydrolysis and photolysis
after oral exposure: hematemesis and bloody stools
small impact on the environment
delayed toxicity: lung edema, alveolitis and progressive fibrosis
Carbamate Pesticides hepatic, renal or myocardial involvement
mechanism of action: inhibition of acetylcholinesterase interval between ingestion and death may be several weeks
possess the toxic properties associated with organophosphorus treatment: gastric lavage, use of cathartics, use of adsorbents
pesticides after absorption, treatment is successful in less than 50% of cases
clinical effects are of shorter duration than those of organophosphorus
pesticides Environmental Pollutants
Polychlorinated Biphenyls
considered to be nonpersistent pesticides
PCBs, coplanar biphenyls
Botanical Pesticides uses: heat transfer fluids, lubricating oils, plasticizers, wax extenders
pesticides derived from natural sources and flame retardants
nicotene, rotenone, pyrethrum industrial use and manufacture was terminated in the US in 1977
persist in the environment: highly stable, highly lipohilic, poorly
Nicotene metabolized, very resistant to degradation, bioaccumulation in food
obtained from the dried leaves of Nicotiana tabacum and Nicotiana chains
rustica foods: major source of PCB residues in humans
rapidly absorbed from mucosal surfaces occupational exposure to PCBs: dermatologic problems, hepatic
reacts with the acetylcholine receptor of the postsynaptic membrane involvement and elevated plasma triglycerides
depolarization of the membrane increase in various cancers: melanoma, breast, pancreas and thyroid
treatment directed at maintenance of vital signs and suppression of deficits in childhood intellectual function was seen in children born to
convulsions mothers who had eaten large quantities of fish contaminated with PCBs

Rotenone Asbestos
obtained from Derris elliptica, D mallaccensis, Lonchorpus utilis, L urucu has been used widely for over 100 years
oral ingestion: GI irritation has been shown to cause progressive lung disease characterized by
conjunctivitis, dermatitis, pharyngitis and rhinitis can also occur fibrotic process
treatment is symptomatic higher levels of exposure: asbestosis
cigarette smoking increases the incidence of asbestos caused lung
Pyrethrum cancer
may be absorbed after ingestion or inhalation; absorption from skin is other cancers: mesothelioma, colon cancer, laryngeal cancer, stomach
not significant cancer, lymphomas
not highly toxic to mammals
Metals
CNS effects: excitation, convulsions, tetanic paralysis
treatment directed at management of symptoms; ivermectin,
occupational and environmental poisoning with metals is a major health
problem
pentobarbital, mephenesin
classic metal poisons: arsenic, lead and mercury
Herbicides new occupational exposure and poisoning: beryllium, manganese,
Chlorophenoxy Herbicides cadmium and uranium
2,4 Dichlorophenoxyacetic acid (2,4-D),2,4,5-trichlorophenoxyacetic
acid (2,4,5-T) Beryllium
used for the destruction of weeds light alkaline metal; non sparking quality
toxicity ratings: uses: dental appliances, nuclear weapons, computer components
4 human lethal dose 50 500 mg/kg highly toxic by inhalation
3 human lethal dose 500 5000 mg/kg inhalation of beryllium particles progressive pulmonary fibrosis
(chronic beryllium disease) and cancer
large doses: coma and generalized hypotonia
confirmed link with non Hodgkins lymphoma
prognosis is poor

Cadmium
Glyphosate
Transcribed by: KC 3
 uses: batteries, pigments, solder, television, plating operations,
semiconductors, plastics
toxic by inhalation and ingestion
cadmium fume fever: acute respiratory disorder common in welders;
shaking chills, cough, fever and malaise
chronic exposure: pulmonary fibrosis, severe kidney damage

Transcribed by: KC 4