MT6314: PHARMACOLOGY & TOXICOLOGY DMT 2023

CHAPTER 56: INTRODUCTION TO TOXICOLOGY

OUTLINE Asbestos
Occupational and Environmental Toxicology Endocrine Disruptors
*Toxicology *Cyanotoxins
Generalities Metals
Occupational Toxicology Beryllium
Environmental Toxicology Cadmium
*Ecotoxicology Nanomaterials
Terms Others
Hazard versus Risk IARC Classification
Routes of Exposure High-Yield Terms to Learn
Quantity, Duration and Intensity of Exposure
Legend: Sources:
Environmental Considerations
Colored – Lecturer • PPT and YT Vid Discussion
Hierarchy of Controls
* – from book (Dr. Karl Ablola)
Air Pollutants
• Book by Katzung (15th Ed)
Carbon Monoxide
• Reviewer by Katzung (12th
Mechanism of Action of CO
Ed.)
Clinical Effects of CO
Treatment for CO OCCUPATIONAL AND ENVIRONMENTAL
Sulfur Dioxide TOXICOLOGY
Mechanism of Action of SO2 1. Great London Smog (1952)
Clinical Effects & Treatment of SO2 • Its inhabitants used unusually large quantities of coal to
Nitrogen Oxides heat their homes. Soot poured out of their chimneys,
Mechanism of Action of NO 2 mixing with factory and powerplant emissions to form an
Clinical Effects & Treatment of NO2 acrid(?) smelling fog that hovered over the city from
Ozone and other oxides December 5 to December 9.
Mechanism of Action of O3 • Trapped in by a high-pressure weather system, as well
Clinical Effects & Treatment of O3 as the lack of wind, this toxic reduced visibility to near
Solvents zero.
Halogenated Aliphatic Hydrocarbons • Abandoned cars dotted the roads, movie theaters closed
Clinical Effects of “ “ “ because no one could see the screen, some people even
Aromatic Hydrocarbons accidentally stumbled into the Thames River. Worst of all,
Benzene about 4,000 people died of respiratory ailments over a
Toluene few days (Dec. 5 – Dec. 9) and up to 8,000 more would
Xylene come in the months that followed.
Pesticides 2. Minimata Disease (1950s)
Organochlorine Pesticides • In the early 1950s, the residents of Minimata, a small
Mechanism of Action & Clinical Effects of “ “ coastal city in southern Japan, began observing some
Organophosphorus Pesticides animal behavior from cats, birds, dogs, and soon enough
Mechanism of Action & Clinical Effects of OP humans too were suffering from what became known as
Carbamate Pesticides your Minimata Disease.
*Botanical Pesticides • Patients started developing slurring of their speech,
*Nicotine stumbling, tremors, having trouble with simple tasks and
*Rotenone cognitions.
*Pyrethrum • In 1959, it was determined that the chemical company
*Herbicides Chisso Corporation and one of Minimata’s biggest
*Chlorophenoxy Acids employers was dumping mercury into the sea as part of
2,4-D its manufacturing process and that this toxin was
2,4,5-T poisoning people and animals that ate the local seafood.
Glyphosate • Chisso continued releasing mercury-tainted wastewater
Bipyridyl Herbicides until 1968 reporting at least 2,000 deaths as well as birth
Environmental Pollutants defects, paralysis, and other diseases.
Polychlorinated and Polybrominated 3. Chernobyl (1986)
Biphenyls • On April 26, a turbine test on one of the reactors at the
*PCB Chernobyl Nuclear Power Station went wrong leading to
*PBBs and PBDEs a series of explosions that spewed massive amounts of
Polychlorinated dibenzo-p-dioxins radioactive material into the atmosphere.
Perfluorinated Compounds

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• The accident which the Soviet Authorities attempted
to cover up initially claimed only 31 lives (2 plant
workers who died in the blast, a 3rd who reportedly
killed over a heart attack, and 28 first responders
who contracted acute radiation syndrome during the
frantic early stages of the clean-up. However,
Chernobyl also unleashed a Thyroid Cancer epidemic
and likely caused additional cancer cases as well.
• In 2005, a United Nations Back (?) Panel calculated
that the eventual death toll is up to 4,000. Other
organizations put this number significantly higher.
• For centuries to come, an exclusion zone set up
around the plant following the forced evacuations of
tens of thousands of area residents will be off-limits
to human habitation.
*TOXICOLOGY
• 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.
• Toxicology plays a crucial role in the healthcare
system of not only an individual but a community and
a nation.
Toxic Chemicals in the environment:
• Pollutants
– Air
o CO, SO2, NO2, O3
– Environmental
o PCBs, dioxins, asbestos, metals
• Agricultural chemicals
– Pesticides
o Chlorinated hydrocarbons, cholinesterase
inhibitors, botanical
– Herbicides
o Chlorophenoxy acids, glyphosate, bipyridyl
• Solvents
– Halogenated aliphatic, hydrocarbons, aromatic
hydrocarbons
GENERALITIES
• Exposure to chemicals maybe through the
environment (air, water, soil, food) and/or
occupational.
• Most common chemicals are those used in
households, personal care and consumer products;
those used in agriculture and industry.
• There are various effects of chemicals depending on
the dose, duration of exposure and vulnerability of
the individuals. It may affect the different organ
systems such as the central nervous system, effects
on the liver and the kidneys, reproductive system,
among others.
• Signs and symptoms for acute chemical poisoning of
chemicals maybe non-specific and may manifest as
headaches, nauseas, vomiting, dizziness, irritation of the
skin, eyes, mucous membrane.
• Occupational Medicine Specialists and Toxicologists
handles cases involving these
• Treatment is available.
OCCUPATIONAL TOXICOLOGY
• Deals with chemical found in workplace
• (Occupational Toxicologists and Occupational Medicine
Specialists) are Responsible for the following:
– Identification of Agents
– Acute and Chronic Diseases
– Conditions that warrant their use safely
– Preventive Measures
– Treatment of Disease
– Surveillance
o Follow-up
– *Other Functions
o May be called to treat diseases if he/she is a
physician
o May define and carry out programs for surveillance
o Usually work hand-in-hand with Occupational
hygienists, Certified safety professionals, and
Occupational Health Nurses
• *Terms that may be encountered in Other Countries
– Permissible Exposure Limit (PEL)
o The concentration of a substance allowed for
workers
o Drafted by the US Occupational Safety and Health
Administration (OSHA)
o Holds power of law in the U.S.
– Threshold Limit Values (TLVs)
o The level of a chemical substance based on
exposure to workers on a life-time without adverse
effects
o Updated and prepared by American Conference of
Governmental Industrial Hygienists (ACGIH)
o Does not have a force of law
• RA 11058
• Occupational Safety and Health Standards (OSHS)
• Occupational = Work
ENVIRONMENTAL TOXICOLOGY
• Deals with chemicals or pollutants found in the
environment that has detrimental effects on living
organisms.
– *Environment refers to all surroundings of individual
organism
o Air, Soil and Water
o *Air Pollution
◼ Usually a product of industrialization,
technologic development, and increased
urbanization
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 ◼ Rarely, natural phenomena – volcanic
eruptions result in air pollution with gas,
vapor or particulates harmful to humans
◼ Environmental Protection Agency (EPA)
regulates air contaminants based on both
health and esthetic considerations
o *Agricultural
◼ E.g. Pesticides, and Food processing that
persists as residues or ingredients
◼ U.S. Food and Drug Administration (FDA)
– responsible for regulation of
contaminants such as pesticides, drugs
and chemicals in food
o *Maritime contamination
◼ Raised concern about oceanic pollution
and had an impact on fisheries of some
countries
o *Contaminated Food Traffic
◼ major international problems from traffic
among nations in contaminated or
adulterated food from other countries
whose regulation/ enforcement of pure
food and drug laws are lax or nonexistent
◼ Ex. Human and Animal illnesses from
ingestion of products imported from China
that contained melamine
– *Other nonhuman species are of considerable
importance as potential biologic targets
• The signal occurrence in animals are important as
early warning for impending human events.
– Ex. Minimata Disease, first affected dogs, cats, and
birds
• *Acceptable Daily Intake (ADI)
– daily intake of a chemical from food that, during
an entire lifetime, appears to be without
appreciable risk
– This term is adopted by the United Nations Food
and Agriculture Organization (FAO) and World
Health Organization (WHO) Joint Expert
Commission on Food Additives
– Guidelines are reevaluated as new information is
available
*ECOTOXICOLOGY
• Concerned with toxic effects of chemical and physical
agents on populations and communities of living
organisms within defined ecosystems
– Includes transfer pathways of those agents and
their interactions with the environment
• Ecotoxicology Research has become one of the
foremost areas of study for toxicologists
• Difference with Traditional Toxicology
– Traditional Toxicology – concerned with toxic
effects on individual organisms
– Ecotoxicology – concerned with impacts on
population of living organisms or on ecosystems
HAZARD VERSUS RISK
• Hazard
– Ability of chemical agent to cause injury/disease in a
given situation or setting.
o Often based on subjective estimates
o Something that can potentially cause harm.
o Is the potential to cause harm
– *To assess hazard, one needs to know:
o Inherent toxicity of substance; and
o Amounts to which individuals are liable to be
exposed
– Example:
o When crossing a road, cars are a hazard.
• Risk
– Expected frequency of the of the occurrence of an
undesirable effect arising from exposure to a chemical
or physical agent.
– Likelihood that a hazard will cause harm.
– Risk = hazard + exposure
– Is the likelihood of harm taking place
– Examples:
o When crossing a road, cars are a hazard.
◼ When crossing a highway, the risk of an
accident is high.
◼ When crossing a country road, the risk of an
accident is low.
o In the beach, the scorching hot sun is the hazard
for people.
◼ It only becomes a risk when people are
exposed to it for a long period of time.
◼ The risk of harm is the likelihood that these
people may develop skin cancers or skin
diseases under the sun.
– *Risk Assessment has become an integral part of the
regulatory process in most countries
o Estimating the risks uses:
◼ Dose-Response data; and
◼ Extrapolation from observed relationships to
expected responses at doses occurring in
actual exposure situations
– *Major Limiting Factors
o Quality and Suitability of biologic data used in such
estimates
ROUTES OF EXPOSURE
• Inhalational, Transdermal Route are quite common in
the industry.
• *Atmospheric pollutants gain entry by inhalation and
dermal contact
• Water and soil pollutants are absorbed through
inhalational, ingestion or transdermal
• Other examples are contact, ingestion, and inhalation.
• Oral can still happen, not as common as inhalational or
transdermal. Common cases of oral are mix-ups of some
mineral water bottles with those of chemical substances
(ex., Chlorox).
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 QUANTITY, DURATION AND INTENSITY OF
EXPOSURE
• An exposure to a toxic substance that is absorbed by
the target human or animal results in a dose.
• Acute Exposure
– Single exposure or multiple exposure over a brief
period of time (e.g. accidental discharge)
o *Over a brief period from seconds to 1-2 days
– *Intense, rapidly absorbed acute doses
normally detoxified may overwhelm the body’s
ability to detoxify the substance and may result in
serious or fatal toxicity
o Ex. In cyanide exposure, Rhodanese
(mitochondrial enzyme) is overwhelmed by
large, rapidly encountered cyanide doses, with
lethal effect
– *Slowly absorbed acute doses (same
substance), may result in little or no toxicity
o Ex. In cyanide exposure, Rhodanese effectively
detoxifies cyanide to relatively nontoxic
thiocyanate when cyanide is present in small
amounts
– *Examples
o Ex. Methyl isocyanate in the Bhopal, India
released in a crowded population resulting in
almost 4000 deaths and more than half a
million injuries
• Take note: Intense rapidly absorbed acute doses of
substances that may be detoxified in small amounts
can overwhelm the metabolic functions or
biotransformative properties of the person and
therefore produce serious or fatal toxicity. The same
amount when absorbed slowly may result to little or
no toxicity.
• Chronic Exposure
– Single or multiple exposure over a longer period of
time (e.g. repetitive handling of chemical)
– *Examples
o Ex. Chronic diseases arose from the Methyl
Mercury disaster in Minamata Bay, Japan
o Ex. Massive oil spill caused by the explosion of
BP’s Deepwater Horizon drilling rig in the Gulf
of Mexico which highlights the potential for
long-term ecotoxic impacts involving
widespread geographic areas
• *Both Chronic and Acute Example
– Ex. the release of dioxin in Seveso, Italy which
contaminated a populated area with a persistent
organic chemical
*ENVIRONMENTAL CONSIDERATIONS
• Poorly degraded chemicals, either by abiotic or biotic
pathways, exhibit environmental persistence and can
accumulate
– Ex. Persistent Organic Pollutants (POPs),
Polychlorinated biphenyls, Dioxins, Furans and
other similar substances
– Bioaccumulation
o Process where the intake of a long-lasting
contaminant by an organism, that cannot
metabolize or excrete the substance, ends up with
the contaminant accumulating in the tissues of the
organism instead of being expelled
– Biomagnification
o Magnification of the concentration of contaminant
as it passes up the food chain
o Ex. There is an increasing concentration of PCB as
it is passed from one predator/prey to another
predator
◼ The biomagnification for PCB beginning with
phytoplankton and ending with herring gull is
nearly 50,000-fold
◼ Domestic animals and humans may eat fish
from the Great Lakes, which would result in
PCB residues in these species as well
• The Human Scenario
– Lipophilic substances like organochlorine pesticides
tend to bioaccumulate in body fat, where tissue
residues are released slowly in the circulation, which
cause Chronic effects such as endocrine disruption
– When this toxicant is placed in the food chain,
biomagnification occurs as one species feeds on the
other
– This process results to the toxicant to be concentrated
in the upper food chain, and humans stand at the top
of the food chain
• The pollutants with the widest environmental impact are:
– Poorly degradable
– Relatively mobile in air, water, soil
– Exhibit bioaccumulation
– Exhibit biomagnification
HIERARCHY OF CONTROLS
• Elimination
– Physically remove the hazard
– Most effective
• Substitution
– Replace the hazard
• Engineering
– Isolate people from the hazard
– Walls, Machines
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• Administrative – Banning of Tetraethyl lead eliminated a major source
– Change the way people work of lead contamination and childhood lead poisoning in
– Policies in the workplace that we can limit, we urban environments
change the behavior of people who work around – “Clean, low-sulfur” diesel” helps to reduce urban and
these chemicals or substances highway pollutants such as sulfur oxides
• PPE • *Clinical Setting
– Protect the worker with Personal Protective – Sulfur dioxide and smoke from incomplete combustion
Equipment of coal
– Least effective o Associated with acute adverse effects among
– Suits, Masks children, the elderly, and individuals with
• We cannot totally avoid these hazards in the preexisting cardiac or respiratory disease
workplace, homes, and in the environment. That’s
– Ambient air pollution
why we instituted preventive measures on how to
o Cause of Cardiac disease, Bronchitis, Obstructive
decide whether a hazard can be removed and if can’t
ventilatory disease, Pulmonary emphysema,
be removed, what can we do to limit exposure.
Bronchial asthma, and Lung cancer
o Published Basic science and Clinical Epidemiologic
AIR POLLUTANTS
• contributing factor in bronchitis, obstructive literature on air pollutant toxicology led to
pulmonary disease, and lung cancer modifications of regulatory standards for air
• Vapors, Aerosols, Smokes, Particulates and pollutants
Individual Chemicals ◼ EPA standards apply to the general
• 92% of these major substances account for the air environment
pollutants we experience today. ◼ OSHA standards apply to workplace exposure
• Major Substances:
– Carbon Monoxide (52%) EXAMPLES OF PERMISSIBLE EXPOSURE LIMIT
– Sulfur Oxides (14%) VALUES (PELs) OF SOME COMMON AIR
– Hydrocarbons (14%) POLLUANTS AND SOLVENTS IN PARTS PER
– Nitrogen products (14%) MILLION (ppm)
– Ozone (4%) and ozone derivatives Examples of PEL in some common Chemicals
• *Classification and Prototypes Compounds PEL (ppm)
– Major air pollutants in industrialized countries Benzene 1.0
include: Carbon monoxide 50
o carbon monoxide (50%) Carbon tetrachloride 10
o sulfur oxides (18%) Chloroform 50
o hydrocarbons (12%) Nitrogen dioxide 5
o particulate matter (eg, smoke particles, 10%) Ozone 0.1
o nitrogen oxides (6%) Sulfur dioxide 5
• Air contaminants are regulated in the United States Tetrachloroethylene 100
by the Environmental Protection Agency (EPA) Toluene 200
• *Sources of Pollutants 1,1,1-Trichloroethane 350
– Agriculture especially industrial-scale farming Trichloroethylene 100
contributes a variety of air pollutants: • These exposure limits can be found at
o Ex. Particulates, Pesticidal chemicals, Hydrogen http://www.osha.gov, 1910.1000, Tables Z-1 and Z-2.
sulfide, etc. The OSHA standards are updated frequently and readers
– Fossil fuel burning, Transportation, manufacturing, are referred to the website for the most current
other industrial activities, generation of electric information.
power, space heating, refuse disposal, etc. • PELs are 8-hour TWA (time-weighted average) values for
– Uncatalyzed automobile traffic emissions are a normal 8-hour workday to which workers may be
larger contributors to ground-level air pollution repeatedly exposed without adverse effects.
than any other source (Studies in Helsinki)
o Catalytic converters on automobiles – greatly CARBON MONOXIDE (CO)
reduced automobile-released air pollution • Colorless, tasteless, odorless and non-irritating gas
– Two-cycle engines in emerging countries, creates • Byproduct of incomplete combustion
heavy ground-level air pollution in very crowded • Unvented kerosene and gas space heaters; leaking
cities chimneys and furnaces; back-drafting from furnaces, gas
• *Changes water heaters, wood stoves, and fireplaces; gas stoves;
generators and other gasoline powered equipment;
automobile exhaust from attached garages; and tobacco
smoke.

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 – *Smokers have a 5-10% CO saturation (depending
on smoking habits]
– *Normal nonsmoking adults have levels of less
than 1% saturation of carboxyhemoglobin
[endogenous CO from heme catabolism]
• Easily absorbed through the lungs
– *A person who breathes air that contains 0.1% CO
[1000ppm] would have a carboxyhemoglobin level
of about 50% in a short period of time
• Exposure may be acute or chronic
• Has teratogenic potential
• Sources of Carbon Monoxide in a Home:
1. Car Left Running Attached Garage
2. Clogged chimney Left: Hemoglobin with attached O molecules in their
3. Corroded or Disconnected Water heater Vent oxygen binding site
Pipe Right: CO binds very tightly to hemoglobin, O and CO2
4. Gas or Wood-Burning Fireplace can no longer be carried through of the body
5. Cracked or Loose Furnace Exchanger
6. Improperly Installed Kitchen Range or Vent CLINICAL EFFECTS OF CARBON MONOXIDE
7. Operating a Grill Indoors or in Garage • *Hypoxia is the principal sign of intoxication
8. Portable Kerosene or Gas Heaters • *Progression/ Symptoms of hypoxia
• *competes avidly with oxygen for hemoglobin – Psychomotor impairment
• *threshold limit value of CO for an 8-h workday is 25 – Headache occurs first and tightness in the temporal
parts per million (ppm); in heavy motor vehicle traffic, area
the concentration of CO may exceed 100 ppm – Confusion and loss of visual acuity
• Carbon Monoxide Poisoning in the Car – Tachycardia, tachypnea, syncope, and coma
– The internal combustion engine produces a lot of – Deep coma, convulsions, shock and respiratory failure
toxic gases which is disposed of through the • Aggravated by:
exhaust system of the vehicle. The most common – Heavy labor
way of carbon monoxide poisoning is when the – High Altitude
car’s air conditioning system is on and it’s parked – High Ambient Temperature
in a garage or space with very limited air – Smoking exposure
movement. – Cardiorespiratory diseases
– The car’s intake pulls in the air which is mixed with • *Collapse and syncope occur when approximately 40%
the exhaust gases. Carbon monoxide is odorless of hemoglobin has been converted to
and colorless, therefore it goes undetected by the carboxyhemoglobin
human and slowly kills the occupants of the car. • *Prolonged hypoxia can result in irreversible damage to
the brain and the myocardium
MECHANISM OF ACTION OF CARBON • *Acute
MONOXIDE – CO intoxication is usually thought of as a form of acute
• CO combines tightly but reversibly with the oxygen- toxicity
binding site of hemoglobin (Hb) • *Chronic
• *The product formed with this reaction is called – There is evidence that chronic exposure to low CO
Carboxyhemoglobin levels may lead to adverse cardiac effects, neurologic
– Carboxyhemoglobin disturbance, and emotional disorders
o interferes with the dissociation of oxygen from • *Fetal
the remaining oxyhemoglobin as a result of – developing fetus is susceptible to effects of CO
Bohr effect exposure
o reduces the transfer of oxygen to tissues – Exposure of a pregnant woman to elevated CO levels
• CO has affinity of about 220 times that of oxygen at critical periods of fetal development may cause
• Reduced oxygen transfer to the tissues (deleterious Fetal Death or Serious and Irreversible, but survivable
effect) birth defects
• Organs with the highest oxygen demand are most
seriously affected (Brain, Heart and Kidneys) *CONCENTRATION OF CARBOXYHEMOGLOBIN
Concentration and Individual Responses
Carboxy-
hemoglobin
concentration Effects

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 Below 15% Headache and Malaise
Headache, Fatigue, Decreased
25% attention span, Loss of fine motor
coordination
40% Collapse and Syncope
Death as a result of irreversible
Above 60% damage to the brain and
myocardium
*There is great variability in individual responses to
carboxyhemoglobin concentration
TREATMENT FOR CARBON MONOXIDE
• First step: Remove from source immediately
• (*100%) Oxygen is the specific antagonist for CO
• High concentrations of oxygen for a short amount of
time only
– High concentrations have a deleterious effect
– *High concentrations of oxygen may be toxic and
may contribute to acute respiratory distress
syndrome
• *Elimination Half-time
– Room air at 1atm: 320 minutes
– With 100% Oxygen: 80 minutes
– Hyperbaric Oxygen: 20 minutes
o Concentration is at 2-3atm
o Oxygen at pressurized chamber
o Some controversies exist about hyperbaric
oxygen for CO poisoning, but may still be used
o Recommended for pregnant women exposed to
CO
• Hyperbaric oxygen accelerates the clearance of
carbon monoxide
• Hypothermic therapy
– *for reduction of metabolic demand, has also been
useful
• *Progressive recovery from treated CO poisoning,
even of a severe degree, can be complete
– Neuropsychological and motor dysfunction persists
for a long time after treatment.
• *Cerebral edema by this intoxication does not
respond to either mannitol or steroid therapy and
may be persistent
SULFUR DIOXIDE (SO2)
• Colorless irritant gas
• *High solubility in water
– 200g SO2/L at room temperature
• Generated primarily by the combustion of sulfur-
containing fossil fuel
• The principal source of urban SO2 is the burning of
coal, domestic heating, high-sulfur transportation
and coal-fired power plants.
MECHANISM OF ACTION OF SULFUR DIOXIDE
• Site of Principal Effect: Upper Respiratory Tract
• Because of its high solubility, when SO2 contacts
moist membranes, it transiently forms sulfurous acid.
• Sulfurous acid
– severe irritant on the eyes, mucous membranes,
respiratory tract and skin.
• 90% of inhaled form is absorbed in the Upper
Respiratory tract causing Acute Irritant Asthma.
– Causes bronchial constriction and produces profuse
bronchorrhea
– Involves parasympathetic reflexes and altered smooth
muscle tone
• *Exposures
– Exposure for 5ppm for 10 minutes: increased
resistance to airflow in most humans
– Exposure to 5-10ppm: causes severe bronchospasm
– In Healthy Population: 10-20% of healthy young
adult population is estimated to be reactive to even
lower concentrations
– Asthmatic Individuals: especially sensitive to SO2
• The phenomenon of adapting to irritating concentrations
has been reported in workers.
– Evidence remain to be limited.
CLINICAL EFFECTS AND TREATMENT SULFUR
OXIDE (SO2)
• *forms sulfurous acid on contact with moist mucous
membranes; this acid is responsible for most of the
pathologic effects
• *Signs and Symptoms
– Irritation of Eyes, Nose and Throat
– Bronchoconstriction
– Increased Bronchial secretions
– *In Asthmatic Subjects
o Acute asthmatic episode
– *Severe Exposure
o Delayed-onset pulmonary edema
• *Cumulative Effects (Chronic low-level)
– Not striking in humans, but effects have been
associated with aggravation of Chronic
cardiopulmonary disease
• *Combination with Particulates
– Combined exposure to high respirable particulate
loads and SO2 increases toxic respiratory response
• *Greatest at Risk
– Children and Elderly
• *Presence of 5–10 ppm in the air is enough to cause
severe bronchospasm
• *Heavy exposure may lead to delayed-onset pulmonary
edema
• *Chronic low-level exposure may aggravate
cardiopulmonary disease
• May initiate or exacerbate Bronchial Asthma
• Treatment is supportive, non-specific
– Give what the patients need depending on the
symptoms
– Removal from exposure, relief of irritation and
inflammation
– *Depends on Therapeutic maneuvers used to treat
irritation of the respiratory tract and asthma
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 NITROGEN OXIDES (NO2)
• Brownish irritant gas associated with fires
• Farmers exposed to fresh silage
• Miners exposed to diesel equipment
• Today, the common causes are automobile and truck
traffic emissions.
MECHANISM OF ACTION OF NITROGEN OXIDE
• Relatively insoluble deep lung irritant
• Inhalation damages the lung infrastructure that
produces the surfactant necessary to allow smooth
and low-effort lung alveolar expansion.
– Type I alveolar cells: chiefly affected by acute
low to moderate inhalation exposure
o After exposure, treatment with modern
ventilation equipment and medications will
result in recovery
o Some patients develop nonallergic asthma, or
“twitchy airway” disease after respiratory insult
– Type I and II alveolar cells: both are damaged
at higher exposure
o In severe damage to both, replacement of the
type I cells may be impaired
o Progressive fibrosis may ensue that eventually
leads to Bronchial ablation and Alveolar
collapse
o Results to permanent restrictive respiratory
disease
– Long-term Exposure at lower concentrations is
linked to Cardiovascular disease, increased
incidence of Stroke, and other chronic diseases
• Exposures
– Exposure to 25 ppm: irritating to some individuals
– Exposure to 50 ppm: moderately irritating to the
eyes and nose
– Exposure to 50 ppm for 1 hour: cause Pulmonary
edema and perhaps Subacute or Chronic
pulmonary lesions
– Exposure to 100 ppm – cause Pulmonary edema
and Death
• Surfactant – fluid inside the lungs
CLINICAL EFFECTS AND TREATMENT (NO2)
• causes deep lung irritation*
• Farm workers exposed to high concentrations of the
gas within enclosed silos may die rapidly
• of acute pulmonary edema*
• Silo-Filler’s Disease, Non-allergic Asthma, “Twitchy-
airway disease” (associated diseases)
• Acute: Irritation of eyes and nose, cough, mucoid or
frothy sputum production, dyspnea and chest pain;
Pulmonary edema, fibrotic destruction of terminal
bronchioles
– *Clinical signs may subside in about 2 weeks and
patient may then pass into a second stage of
abruptly increasing severity
– *2nd Stage
o Recurring pulmonary edema
o Fibrotic destruction of terminal bronchioles
(bronchiolitis obliterans)
– *Silo-Filler’s Disease – severe and potentially lethal
form of acute respiratory distress syndrome
o Results from the exposure of farmers to NO2 in the
confines of a silo
o The disorder is uncommon today
• Miners who are regularly exposed to diesel equipment
exhaust have been particularly affected with nitrogen
oxide emissions with serious respiratory effects
• A variety of disorders of the respiratory system,
cardiovascular system and other problems have been
linked to NO2 exposure
• Chronic: Emphysematous changes
• Treatment: Supportive, non-specific
– *Measures to reduce inflammation and pulmonary
edema are important
– *Drug Therapy may include bronchodilators, sedatives,
and antibiotics
– *New approaches to the management of NO2-induced
ARDS have been developed and considerable
controversy now exists about the precise respiratory
control to use in any given patient.
OZONE (O3) AND OTHER OXIDES
• Bluish irritant gas naturally found in the earth’s
atmosphere.
• *Produced in air and water purification devices and in
electrical fields
• Produced primarily when fossil fuel are burned or when
some chemicals evaporate.
• Emitted from power plants, motor vehicles and other
sources of high-heat compounds
• Ozone in the workplace is generated by high-voltage
electrical equipment and around ozone producing
devices like air and water purification systems.
• Found in agriculture as well.
MECHANISM OF ACTION OF OZONE (O3) AND
OTHER OXIDES
• Irritant of mucous membranes
• There is a near-linear gradient between exposure to
ozone (1-hour level, 20-100 ppb) and bronchial smooth
muscle response
• Produces upper respiratory tract irritation to deep lung
irritation with pulmonary edema
• Formation of reactive free radicals.
• Exposures
– Mild Exposure: Upper respiratory tract irritation
– Severe Exposure: Deep lung irritation, with
pulmonary edema when inhaled at sufficient
concentrations
– Ozone Penetration in Lungs: depend on Tidal
volume
o I.e., exercise can increase the amount of ozone
reaching the distal lung
– Exposure around 0.1 ppm, 10-30 minutes: Irritation
and dryness of throat
Oloteo, Perales, Qua, Rubio, Santos |8
 – Exposure above 0.1 ppm: changes in visual acuity,
substernal pain, and dyspnea
– Exceeding 0.8ppm: Pulmonary function is
impaired
CLINICAL EFFECTS AND TREATMENT OZONE
(O3) AND OTHER OXIDES
• *Exposure to 0.01–0.1 ppm may cause irritation and
dryness of the mucous membranes
• *The response of the lung to O3 is dynamic
– Morphologic and biochemical changes are results
of both direct injury and secondary responses to
the initial damage
• Shallow, rapid breathing and decrease in pulmonary
compliance
– Pulmonary Compliance – the ability of the lungs to
expand and flatten during inhalation and
exhalation
– Pulmonary compliance is decreased
• Acute: Irritation and dryness to throat, changes to
visual acuity, substernal pain and dyspnea, ARDS
• Chronic (*above 1ppm on Animals): Chronic
Bronchitis, Bronchiolitis, Emphysema
• *Other Observations
– Airway hyperresponsiveness
– Airway inflammation
– Bronchoconstrictors have an enhanced sensitivity
of the lung
• Treatment: Supportive, non-specific
– *Measures that reduce inflammation and
pulmonary edema are emphasized
– *Management depends on therapeutic measures
used for Deep lung irritation and noncardiogenic
pulmonary edema that have resulted in ARDS
SOLVENTS
• *used in industry and solvents to clean clothing are
a major source of direct exposure to hydrocarbons
and also contribute to air pollution
2 Groups:
• Halogenated Aliphatic Hydrocarbons
• Aromatic Hydrocarbons
HALOGENATED ALIPHATIC HYDROCARBONS
• Also called Halohydrocarbons
• Once found in industrial solvents, degreasing agents
and cleaning agents
• Carbon tetrachloride, trichloroethylene, chloroform,
tetrachloroethylene and 1,1,1-trichloroethane
(divided into these 5 groups)
• Most classified as known or probable human
carcinogens
– Some are already removed from the workplace
– Ex. Carbon tetrachloride and trichloroethylene
o These remain to be used as dry cleaning and
degreasing agents
• Freon, a fluorinated aliphatic, causes severe damage
in the ozone layer in the troposphere
– Limited or banned in other countries
– Air conditioners made since 2010 no longer rely on
Freon
– Most air conditioning units now use a refrigerant called
R-410A or Puron
o A hydrofluorocarbon
o Been shown not to harm the ozone layer
o Has been the standard for residential ari
conditioning units since 2015
– By 2020, Freon is expected to be banned
• *Water pollution is the common halogenated aliphatic
solvents also create serious problems as persistent water
pollutants
– Found in both groundwater and drinking water as a
result of poor disposal practices
CLINICAL EFFECTS OF HALOGENATED ALIPHATIC
HYDROCARBONS
• Human Carcinogens
– some are associated with renal, prostate and testicular
cancer
– CNS depression, kidney injury, liver injury,
cardiotoxicity, arrythmia
• *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
• Chronic Exposure in the Workplace: Impaired memory,
peripheral neuropathy
• *Hepatotoxicity – common toxic effect after acute or
chronic halohydrocarbon exposure
• *Nephrotoxicity – can occur in humans exposed to the
three:
– Carbon tetrachloride
– Chloroform
– Trichloroethylene
• Treatment: Supportive, non-specific
– *Serious CNS depression must be treated with support
of vital signs
– Management depends on the organ system involved
• *Dichloromethane [Methylene chloride] –Potent
neurotoxin, CO generator in humans, and probably
human carcinogen
– Widely used as paint stripper, plastic glue, and for
other purposes
AROMATIC HYDROCARBONS
• Benzene, Toluene, Xylene
• *Effects: exposure to any of these hydrocarbons leads
to CNS depression with ataxia and coma
• *Treatment: Removal from exposure, CNS depression
is managed by support of vital signs
BENZENE
• *Human carcinogen
• Important component of gasoline
Oloteo, Perales, Qua, Rubio, Santos |9
• One of the most widely used industrial chemicals in
the world
– Relationships with other hydrocarbons
o Benzene is contained in less refined grades of
toluene
o Benzene is also contained in less refined grades
of xylene
o Benzene has been substituted for Xylene in
many solvent degreasing operations
• Used for its solvent properties
• Exposures
– at 7500 ppm for 30 minutes: fatal
– Greater than 3000 ppm: Euphoria, Nausea,
Locomotor problems, Coma
– At 250-500 ppm: Vertigo, Drowsiness, Headache,
Nausea
• Acute Exposure:
– CNS Depression, Nausea
– at certain doses, Euphoria, Locomotor Problems
and Coma; Vertigo, Drowsiness and Headache
• Chronic Exposure:
– Bone Marrow Injury (Aplastic Anemia, Leukopenia,
Pancytopenia, Thrombocytopenia etc.)
– *Various hematologic cancers especially Leukemia
o Low levels: Leukemia of several types;
Lymphomas, Myeloma, Myelodysplastic
syndrome
o Occurrence of Leukemia is at exposure as low
as 2 ppm-years
• Pluripotent Bone Marrow Stem Cells are the target
– In chronic exposure
– Cause injury in the long run
• Potent Clastogen
– Clastogen – mutagen that acts by causing
chromosomal breakage
– *Studies have suggested specific chromosome
reorganization and genomic patterns that are
associated with benzene-induced leukemia
o *Causal association between benzene
exposure and leukemia and other bone marrow
cancers are confirmed via epidemiology
• Treatment: Supportive, non-specific, removal from
exposure
TOLUENE
• *Not carcinogenic
• Also known as Methylbenzene
– Derivative of benzene
• Paint thinners, nail polish remover, glues, and
correction fluid; explosives
• No myelotoxic properties
– Unlike for benzene
• Fetotoxic
• Exposure
– At 800 ppm – Severe fatigue and ataxia
– At 10,000 ppm – rapid loss of consciousness
• CNS depressant, skin and eye irritant, fetotoxic
(acute phase)
• Associated with rapid loss of consciousness, severe
fatigue, ataxia (in large doses)
• Chronic Effects are unclear because human studies
indicating behavioral effects usually concern exposure to
several solvents
– In limited occupational studies, there are no
observations for metabolic interactions and
modification of toluene’s effects
XYLENE
• *Not carcinogenic
• Also known as dimethylbenzene
• Colorless, sweet-smelling agent
• Substitute for benzene in solvent degreasing operations
• No myelotoxic properties
– Like toluene
• Not associated with leukemia
• CNS depressant, skin irritant
PESTICIDES
1. Organochlorine Pesticides
2. Organophosphorus Pesticides
3. Carbamate Pesticides
4. Botanical Pesticides
*3 Major classes:
• Chlorinated hydrocarbons (DDT and its analogs)
– persistent, poorly metabolized, lipophilic chemicals
that exhibit significant bioaccumulation
– Effects: blocks physiologic inactivation in the sodium
channels of nerve membranes and cause uncontrolled
firing of action potentials
o Acute: tremor (1st sign), may progress to seizures)
o Chronic exposure of animals: tumorigenic
o Long-term exposure in humans: unclear toxicologic
impact
◼ evidence suggests an association with non-
Hodgkin’s lymphoma and testicular cancer
– Treatment: non-specific
– Because of their extremely long half- lives in organism,
their use in North America and Europe has been
curtailed
• Acetylcholinesterase inhibitors (carbamates,
organophosphates)
– Carbamates: aldicarb, carbaryl
– Organophosphates: dichlorvos, malathion, parathion
– effective pesticides with short environmental half-lives,
inexpensive drugs are heavily used in agriculture
– Effects: Increase muscarinic and nicotinic cholinergic
activity
– Signs and symptoms: pinpoint pupils, sweating,
salivation, bronchoconstriction, vomiting and diarrhea,
CNS stimulation followed by depression, and muscle
fasciculations, weakness, and paralysis
– Most common cause of death is respiratory failure
– Treatment: Atropine is used in large doses to control
muscarinic excess; pralidoxime is used to regenerate
cholinesterase
Oloteo, Perales, Qua, Rubio, Santos |10
 o Mechanical ventilation may be necessary until – Each compound differs widely in biotransformation
sufficient cholinesterase has been regenerated and capacity for storage in tissues
• Botanical agents (nicotine, rotenone, pyrethrum – Toxicity and storage are not always correlated
alkaloids) • Four Classes:
– Nicotine: same effects on nicotinic cholinoceptors – DDT (chlorphenothane) and analogs
in insects as in mammals and probably kills by the – Benzene hexachlorides
same mechanism (ie, excitation followed by – Cyclodienes
paralysis of ganglionic, CNS, and neuromuscular – Toxaphenes
transmission) • Largely abandoned due to severe environmental damage
o Treatment: supportive due to persistence in environment
– Rotenone: plant alkaloid pesticide that causes • Known endocrine disruptors in humans and animals
gastrointestinal distress when ingested and • DDT
conjunctivitis and dermatitis after direct contact – Continues to be used in domestic mosquito elimination
with exposed body surfaces in malaria-infested regions of Africa
o Treatment: supportive • Long-term effects poorly understood
– Pyrethrum: plant alkaloid, most common toxic
effect is dermatitis. Ingestion or inhalation of large TABLE OF ORGANOCHLORINE PESTICIDES
quantities may cause CNS excitation (including Chemical Compounds Toxicity ADI
Class Rating
seizures) and peripheral neurotoxicity Dichlorodiphenyltrichloroethane
o Treatment: supportive with anticonvulsants if 4 0.005
DDT and (DDT)
necessary analogs Methoxychlor 3 0.1
Tetrachlorodiphenylethane (TDE) 3 -
Benzene hexachloride (BHC;
Benzene 4 0.008
CHEMICAL STRUCTURES OF SOME hexachlorides
hexachlorocyclohexane)
HERBICIDES AND PESTICIDES Lindane 4 0.008
Aldrin 5 0.0001
Chlordane 4 0.0005
Cyclodienes
Dieldrin 5 0.0001
Heptachlor 4 0.0001
Toxaphenes Toxaphene (camphechlor) 4 -
• Toxicity rating: Probable human oral lethal dosage for
class 3 = 500 – 5000 mg/kg, class 4 = 50-500 mg/kg,
and class 5 = 5 – 50 mg/kg. (See Gosselin et al, 1984.)
• ADI, acceptable daily intake (mg/kg/d).

• Organophosphates are already discontinued

• Based on environmental studies, they persist in the
• Paraquat dichloride environment because they are very slow to degrade
• Dichlorodiphenyltrichloroethane (DDT) • Bioaccumulation happens
• Rotenone – Organochlorine pesticides persist in the air, water and
• Pyrethrin I soil sediment
• 2,3,7,8-Tetrachlorodibenzodioxin (TCDD) – In the air, it can be transported back to the soil and
• 2,4-Dichlorophenoxyacetic acid (2,4-D) from the soil, it will lead to the ground water.
• 2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) – To make it worse, volatilization from water occurs and
• Glyphosate then rain occurs
– They are discharged through flow networks and then
ORGANOCHLORINE PESTICIDES go back to the fishes of the sea
• Aryl, carbocyclic or heterocyclic compounds with – The biota, whether in land or sea, take up the
chlorine substituents organochlorine pesticide, and they continue to persist
in nature and environment

Oloteo, Perales, Qua, Rubio, Santos |11

 – It eventually leads back to humans
– Its bioaccumulation and persistence in nature is
what led to the decision of discontinuing the use
of those pesticides
MECHANISM OF ACTION AND CLINICAL
EFFECTS OF ORGANOCHLORINE PESTICIDES
• *Acute Toxic Properties of all organochlorine
pesticides in humans are qualitatively similar
– Major Effect: CNS stimulation
– Interfere with the inactivation of the Sodium
channel in excitable membranes and cause rapid
repetitive firing in most neurons
• These events affect repolarization and enhance
excitability of neurons
• First Manifestation
– DDT – tremor, possibly continuing to convulsions
– Others – Convulsions
• Treatment – there is no specific treatment for the
acute intoxicated state
– Management is symptomatic
• MOA: Interfere with inactivation of the sodium
channel in excitable membranes and cause rapid
repetitive firing in most neurons; calcium ion
transport is inhibited
– These functions/MOA are responsible for the first
or many manifestations of DDT drugs which is
tremor
• DDT – Tremor is the first manifestation
• Carcinogenic potential but more long-term studies
• are required.
• *Carcinogenic
– Has been extensively studied
– Laboratory Animals: chronic administration
over long periods results in enhanced
carcinogenesis
– Postulated Mechanism – Endocrine pathway
disruption
o Xenoestrogen [i.e., Estrogen-like]
carcinogenesis mechanisms have been
postulated
– No Connection, However, epidemiologic studies
in humans have not found a significant association
between risk of cancer and specific compounds or
serum levels or organochlorine pesticide
metabolites
o Several studies demonstrate elevated
concentrations in various human cancer tissues,
but causality is uncertain
– No Association, a case-control study
investigated relation of DDE [metabolite of DDT]
and DDT breast adipose tissue levels and breast
cancer risk, but did not confirm positive association
– Some associations
o There were works that supported association
between prepubertal exposure to DDT and
brain cancer
o Another study suggested risk of testicular cancer
and non-Hodgkin lymphoma is increased in
persons with elevated organochlorine levels
o Noncancer endpoints are also of concern
– Cryptorchidism and Hypospadias in Newborns are
related to maternal adipose levels of chlordane
metabolites
o These residues are also linked to testicular cancer
• The electrophysiology of neurons is seen in the
presynaptic and postsynaptic cells
• The presynaptic cells must depolarize to release
acetylcholine which will react with the postsynaptic cell.
Once this is achieved, repolarization of presynaptic cell
must occur so that release of acetylcholine is
discontinued.
• However, DDT inhibits sodium channels and to a certain
extent, calcium channels. This prevents repolarization of
presynaptic cells therefore acetylcholine continues to be
released. This causes continued repetitive firing in the
neurons. They become more excitable.
• Initial manifestation of patients exposed to DDT is
tremors because of this principle
• *Environmental Toxicology
– These pesticides are considered persistent chemicals
– *Compared with Other Pesticides
o Slow degradation
o Bioaccumulation is well documented
– Particularly, aquatic ecosystem
– *Mobility in Soil – depends on the composition of
the soil and presence of organic matter which favors
adsorption of these chemicals in soil particles
o Adsorption is poor in sandy soil
o Once adsorbed, they do not readily desorb
– *To Animals – these compounds induce significant
abnormalities in the endocrine balance of sensitive
animal and bird species
o *Silent Spring – a book that brought attention to
the issue
Oloteo, Perales, Qua, Rubio, Santos |12
 ◼1960s by Rachel Carson – Products of repetitive firing because of lack of
◼Recognition of organochlorine pesticides acetylcholinesterase
as pernicious environmental toxins • If not reversed, patients will develop neuromuscular
– Banned in most jurisdictions in U.S. transmission failure – cardiorespiratory failure, weakness
of respiratory muscles and death.
ORGANOPHOSPHORUS PESTICIDES • *Other Effects Associated with Exposure
• Used against large variety of pests – Altered neurologic and cognitive functions
• Either via direct contact or via plant systemics – Psychological symptoms of variable duration
– agent is translocated within the plant and exerts – There is some indication of association of low
its effects on insects that feed on the plant Arylesterase activity with neurologic symptom
• Based on warfare chemicals like sarin, soman and complexes in Gulf War veterans
tabun (G compounds)
– *Developed in Germany as insecticides and were
later weaponized for use as war gas
– *Later, British scientists developed VX, a nerve has
20 times more potent than the G series
compounds
– *Many of these [including VX] were manufactured
in the U.S.
– Less Toxic than Military Grade
o many Organophosphorus compounds are
widely used in agriculture throughout the world
o E.g., Parathion, Malathion, Azinphos, and other
OP compounds
o In the U.S., there are concerns of food
contamination, occupational health and safety
issues
◼ Several laws regulate its use
◼ To reduce use of the more toxic OP
compounds on food crops Specific treatment and useful antagonists are available (i.e.
o Problems with Cotton boll weevil required these physostigmine, pralidoximine)
farmers to rely more heavily on aerially sprayed • *Neuropathy Target Esterase (NTE)
parathion and its derivatives in recent years – Present in neural tissue and can be phosphorylated by
– Antiparasitic some of OP agents
o Some of the less toxic OP are used in human – Phosphorylation results in progressive
and veterinary medicine as local or systemic demyelination of the longest nerves
antiparasitics o Paralysis
• Biotransformation is rapid, compared with o Axonal degeneration or OPIDP
chlorinated hydrocarbon pesticide – *Poisoned patients: delayed central and autonomic
• Absorbed via the skin, respiratory and GI tract neuropathy
• In the environment, not considered a persistent – Hens are particularly sensitive to these properties and
pesticide been used to study the pathogenesis of the lesion and
– Unlike the previous chemicals for identifying potentially neurotoxic
organophosphorus derivatives
MECHANISM OF ACTION AND CLINICAL – *Treatment: there is no treatment for NTE toxicity
EFFECTS OF ORGANOPHOSPHORUS • *Progressive Chronic Axonal Neurotoxicity
PESTICIDES – Chronic neuropathy from continued NTE
• MOA: Inhibition of acetylcholinesterase (found in phosphorylation
synapses) through phosphorylation of the esteratic
o Long-term prognosis of NTE inhibition is highly
state.
variable
– True for mammals and insects
– Observed with triorthocresyl phosphate (TOCP), which
– Signs and symptoms are due to the inhibition of
is a noninsecticidal organophosphorus compound
this enzyme and accumulation of Acetylcholine
o Also thought to occur with Dichlorvos, Trichlorfon,
– Some of the agents also possess direct cholinergic
Leptophos, Methamidophos, Mipafox, Trichloronat,
activity
etc.
• M-U-D-D-L-E-S: miosis, urination, diarrhea,
diaphoresis, lacrimation, excitation of the central
nervous system, and salivation

Oloteo, Perales, Qua, Rubio, Santos |13

 – This polyneuropathy usually begins as burning and
tingling sensations, particularly in the feet, with
motor weakness a few days later
o Sensory and motor difficulties may extend to
legs and hands
o Gait [syn. manner of walking] is affected;
Ataxia may be present
o CNS and Autonomic changes may develop still
later
– *Treatment: no specific treatment for this form
of delayed neurotoxicity
• *Intermediate syndrome in severely poisoned
patients has been identified
– Neuromuscular transmission failure, Cardiac
failure that is typical of nicotinic that muscarinic
poisoning
– Progressive neuromuscular failure leads to
weakness of the respiratory muscles and
eventually to death
– *Physiologic abnormalities
o these abnormalities are complex but involve a
TABLE OF ORGANOPHOSPHORUS PESTICIDES
progressive decrement in neuromuscular
Compound Toxicity Rating ADI
junction transmission efficiency
Azinphos-methyl 5 0.005
– Patients who develop this intermediate syndrome Chlorfenvinphos - 0.02
are at great risk of cardiorespiratory failure and Diazinon 4 0.02
may require mechanical ventilation Dichlorvos - 0.04
– Because OP poisoning frequently occurs in less Dimethoate 4 0.01
developed countries, this syndrome is frequently a Fenitrothion - 0.005
lethal complication Malathion 4 0.02
– Treatment – Not effectively treated with usual Parathion 6 0.005
management protocol for OP pesticide poisoning Parathion-methyl 5 0.02
Trichlorfon 4 0.01

• Green Box – normal current; Acetylcholine signaling

at synapse
• Yellow Box – Ach stops signaling process. After the
release of acetylcholine, acetycholinesterases
normally appear at the synapse to stop the signaling
process. When drugs such as organophosphates or
pesticides are introduced, they inhibit
acetylcholinesterases and therefore acetylcholine
continues to be released and attach to the
postsynaptic neurons. This continues indefinitely.
Organophosphates are antiesterase insecticides and
exert their acute effects by causing overstimulation
at the cholinergic nerve terminals. This process
occurs in both insects and humans. Normally,
acetylcholinesterase catalyzes the degradation of the
neurotransmitter acetylcholine in the synapse.
Organophosphate pesticides phosphorylate
acetylcholine thereby reducing the ability of the
enzymes to break down the neurotransmitter. This
produces an accumulation of acetylcholine in the
central and peripheral nervous systems. This then
results in acute cholinergic syndrome via acute
neurotransmission. The onset of acute cholinergic
overstimulation can vary from instantaneous to
several hours after exposure
• Toxicity rating: Probable human oral lethal dosage for
class 3 = 500 – 5000 mg/kg, class 4 = 50-500 mg/kg,
and class 5 = 5 – 50 mg/kg. (See Gosselin et al, 1984.)
• ADI, acceptable daily intake (mg/kg/d).
• Most famous are malathion and parathions, and their
derivatives
CARBAMATE PESTICIDES
• Inhibits acetylcholinesterase by carbamoylation of the
esteratic site
– Like previous pesticides
• Shares toxic properties with organophosphorus
pesticides
– Because of mechanism of action
– MOA: Inhibit acetylcholinesterase by carbamoylation
of the esteratic site
o Possess toxic properties associated with inhibition
of this enzyme as described for the
organophosphorus pesticides
• Compared to OP agents
– Binding is relatively weak compared to OP compounds
o Dissociates in minutes to hours
o Clinical effects are shorter
– Therapeutic index is larger with carbamates

Oloteo, Perales, Qua, Rubio, Santos |14

 – Although clinical approach to carbamate poisoning • Conjunctivitis, dermatitis, pharyngitis, and rhinitis can
is similar, use of pralidoxime is not recommended also occur
– Spontaneous reactivation of cholinesterase is more • Treatment – Symptomatic
rapid after inhibition by the carbamates
• However, binding is relatively weak, dissociation *PYRETHRUM
occurs after minutes to hours • Consists of six known insecticidal esters:
• Treatment: similar clinical approach to – Pyrethrin I and II,
Organophosphates, use of pralidixomine is not – Cinerin I and II
recommended – Jasmolin I and II
• Nonpersistent pesticide • Synthetic pyrethroids account for an increasing
– Exert only a small impact on the environment percentage of worldwide pesticide usage
• Absorption: inhalation or ingestion
TABLE OF CARBAMATE PESTICIDES • Major site of toxic action: CNS
Compound Toxicity Rating ADI – Excitation, Convulsions, Tetanic paralysis can occur
Aldicarb 6 0.005 • Targets: Voltage-gated Sodium, Calcium and Chloride
Aminocarb 5 - channels; as well as Peripheral-type benzodiazepine
Carbaryl 4 0.01 receptors
Carbofuran 5 0.01 • Irritation – pyrethroids are highly irritating to the eyes,
Dimetan 4 - skin and respiratory tree
Dimetilan 4 - • Effects – may cause irritant asthma and, potentially,
Isolan 5 - Reactive airways dysfunction syndrome (RADS) and
Methomyl 5 - even Anaphylaxis
Propoxur 4 0.02 • Treatment – directed at management of symptoms
Pyramat 4 - – Anticonvulsants are not consistently effective
Pyrolan 5 - – Ivermectin [chloride channel agonist] is used as well
Zectran 5 - as Pentobarbital and Mephenesin
• The most common injuries in humans result from their
*BOTANICAL PESTICIDES allergenic and irritant effects on the airways and skin
• Pesticides derived from natural sources include • Cutaneous paresthesias – observed in workers
nicotine, rotenone, pyrethrum spraying synthetic pyrethroids
– Used to exterminate insects on aircraft has caused
*NICOTINE respiratory and skin problems as well as some
• Obtained from dried leaves of Nicotiana tabacum and neurologic complaints in flight attendants and other
N. rustica aircraft workers
• Absorption • Severe occupational exposures to synthetic pyrethroids
– Rapidly absorbed from mucosal surfaces in China resulted in marked effects on the CNS, including
– Free alkaloid [not the salt] is readily absorbed from convulsions
the skin • Other previously unreported toxic manifestations have
• *Mechanism: Reacts with the acetylcholine been observed in pyrethrin-exposed individuals
receptor of the postsynaptic membrane [sympathetic
and parasympathetic ganglia, neuromuscular *HERBICIDES
junction] • Chlorophenoxy Acids
– Results to membrane depolarization • Glyphosate
• Toxic dose causes stimulation rapidly followed by • Bipyridyl Herbicides
blockade of transmission
• *Treatment is directed toward maintenance of vital *CHLOROPHENOXY ACIDS
signs and suppression of convulsions • Important members: 2,4-dichlorophenoxyacetic acid
• Nicotine analogs have developed for use as (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T;
agricultural pesticides and have been implicated in compound in Agent Orange)
bee colony collapse – 2,4-D, 2,4,5-T and their salts and esters have been
– E.g., Neonicotinoids used as herbicides for the destruction of weeds
• Large doses of these drugs cause muscle hypotonia and
*ROTENONE coma. Long-term exposure has been associated with an
• Obtained from Derris elliptica, D. mallaccensis, increased risk of non-Hodgkin’s lymphoma
Lonchocarpus utilis, and L. urucu
• Oral Ingestion – Gastrointestinal irritation

Oloteo, Perales, Qua, Rubio, Santos |15

 *2,4-DICHLOROPHENOXYACETIC ACID
• Remains in wide commercial and domestic use for
lawn weed control
– *Large doses – Coma, Generalized muscle
hypotonia
– *Rarely – muscle weakness and marked
hypotonia may persist for several weeks
– *Laboratory Animals – signs of liver and kidney
dysfunction with chlorophenoxy herbicides
– Several studies by US National Cancer Institute
confirmed causal link between 2,4-D and non-
Hodgkin lymphoma
– Causal link to soft tissue sarcoma, however, is
considered equivocal
• Dichlorophenoxy and related Herbicides
– Found to contain and generate
dimethylnitrosamine (NDMA; N-
nitrosodimethylamine) which is a potent human
carcinogen
o Used during environmental transformation as
well as non-chlorine water disinfection
o *Studies
◼ Environment Canada and others have
questioned the use of this compound
because of water contamination
◼ Studies of related nitrosamine-forming
herbicidal compounds raised questions
about suitability of these compounds for
general weed control
o Due to high economic value of herbicides to
agriculture, long-term decisions on their use
have been delayed
*2,4,5-TRICHLOROPHENOXYACETIC ACID
• is longer used because it is often contaminated
during manufacturing with dioxin and other
polychlorinates
• Agent Orange was contaminated with 2,3,7,8-
tetrachlorodibenzo-p-dioxin [potent animal and likely
human carcinogen] and other toxic, persistent and
undesirable polychlorinated compound
– When this was discovered, US Department of
Agriculture canceled the domestic pesticide for
trichlorophenoxy herbicides, and are now no
longer used
*GLYPHOSATE
• 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
– Functions as a contact herbicide
o Absorbed through leaves and roots
o Formulated with surfactant to enhance its
intended effect on noxious plants
• Nonselective and may damage important crops and
desirable ornamental plants even when used as directed
• To reduce economic impact, genetically modified
(GMO) species have been developed and patented
– E.g., Soybean, corn, cotton that are glyphosate-
resistant and are widely grown around the world
– Almost all soybean and corn today are of this resistant
type
– Highly controversial in some jurisdictions
– There is no evidence that GMO are toxic and
dangerous to humans and animals, but agricultural
impact of widespread glyphosate herbicide use on
resistant crops is undetermined
• Effective weed elimination on food supply and habitat of
critical insect species [e.g., bees, butterflies; some
migrating birds] has been a source of increasing concern
• Glyphosate-surfactant poisonings are common
• Many observed ingestions and poisoning are from
developing countries where suicide by pesticide is
common
• *Ingestion
– Causes mild to moderate esophageal erosion
– Other Effects
o Also causes Aspiration pneumonia and Renal
failure
• Occupational
– There are some reports of teratogenic outcomes in
workers who handle and apply glyphosate; but
epidemiologic evidence is not clear
• Many injuries are minor, but some serious and lethal
poisonings have been reported
• Effects: causes significant eye and skin irritation and can
be fatal when ingested in large quantities
• Treatment: supportive, non-specific
– Hemodialysis has been used with success in cases of
renal failure
• Potential Carcinogenic
– concern about its potential has increased in recent
years and is still in active study
– Scientific evidence in both man and animals has been
uncertain, various interpretations and
reinterpretations
– Probably carcinogenic to humans
o Based on animal and mechanistic studies
– Classified as 2A in several lawsuits against
manufacturers – herbicide caused plaintiff’s lymphoma
– Zhang demonstrated statistically significant
association between glyphosate exposure and non-
Hodgkin lymphoma n humans
• Glyphosate seems to have little persistence and lower
toxicity than other herbicides
– However, Commercial formulations often contain
surfactants and other active compounds that
complicate the toxicity of the product
Oloteo, Perales, Qua, Rubio, Santos |16
 o Some toxic effects are related to the surfactant
material
*BIPYRIDYL HERBICIDES
• *Paraquat
– The most important agent in this class
– a bipyridyl herbicide, is used extensively to kill
weeds on farms and for highway maintenance
– Ingestion of Paraquat
o accidental or suicidal, is among the most
serious and potentially lethal pesticide
poisonings
o Paraquat accumulates slowly in the lungs by an
active process
◼ Lung edema, alveolitis, progressive
fibrosis
– *Effect: 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.
o *First Signs & Symptoms: Hematemesis,
Bloody stools
o *Delayed toxicity occurs, with respiratory
distress and development of congestive
hemorrhagic pulmonary edema accompanied
by widespread cellular proliferation
o During acute period, oxygen should be used
cautiously to combat dyspnea or cyanosis
because it may aggravate the pulmonary
lesions
o *Other Effects: Hepatic, Renal, or Myocardial
involvement may develop
o Interval between ingestion and death may be
several weeks
– Treatment: no antidote. Because of the delayed
pulmonary toxicity, prompt prevention of
absorption is important
o Adsorbents [e.g., Activated charcoal, Fuller’s
earth] are routinely given to bind the paraquat
and minimize its absorption
o Gastric lavage is not recommended, as it may
promote aspiration from the stomach into the
lungs.
o Once the paraquat is absorbed, treatment is
successful in fewer than 50% of cases.
o Pulmonary fibrosis starts 1–2 weeks after
ingestion.
o Immunosuppression with corticosteroids and
cyclophosphamide are commonly used; it is
widely practiced, but evidence for efficacy is
weak
o 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
• Prognosis
– Monitoring of plasma and urine paraquat
concentrations for prognostic assessment
– Computed tomography scanning has also been used
to follow the pulmonary lesions as they develop
• Case Fatality Rate
– High in all centers despite large variations in treatment
– Patients require prolonged observation and treatment
for respiratory and renal insufficiency if they survive
the acute stage of poisoning
ENVIRONMENTAL POLLUTANTS
• Polychlorinated and Polybrominated Biphenyls
– Polychlorinated dibenzo-p-dioxins (PCDDs)
• Perfluorinated Compounds
• Endocrine Disruptors
• Asbestos
• *Dioxins
• *Heavy metals
POLYCHLORINATED AND POLYBROMINATED
BIPHENYLS
• Highly halogenated biphenyl compounds
• *most stable organic compounds known
• *poorly metabolized and lipophilic, therefore highly
persistent in the environment, and they accumulate in
the food chain
• Used for insulation, fire retardancy
• *Mass production during 20th century resulted in
enormous environmental problems
• Very toxic and now banned for use
• Potent endocrine disruptors (due to their estrogen-like
effect*); associated with reproductive and teratogenic
effects on animal studies
• *Effects: most common effect is dermatotoxicity (acne,
erythema, folliculitis, hyperkeratosis). Less frequently,
mild increases in plasma triglycerides and elevated liver
enzymes have been observed
– *Epidemiologic studies have established a correlation
with increases in various cancers
*POLYCHLORINATED BIPHENYLS (PCB)
• Also called coplanar biphenyls
• Used in dielectric and heat transfer fluids, lubricating oils,
plasticizers, wax extenders and flame retardants
– Chlorinated products used commercially were actually
mixtures of PCB isomers and homologs containing 12-
68% chlorine
– Stable, highly lipophilic, poorly metabolized, very
resistant to environmental degradation
– Bioaccumulates in food chains
• Food is the major sources of PCB Residues in humans
• *Yusho Disease – Japan [several months] in 1968 as a
result of cooking oil contamination with PCB-containing
transfer medium
– Not only PCB but also Polychlorinated dibenzofurans
(PCDFs) and Polychlorinated quaterphenyls (PCQs)
Oloteo, Perales, Qua, Rubio, Santos |17
 – Linked effects were actually due to the mixture of
contaminants
• *Yucheng Disease – Taiwan; same time with Japan
• Effects on fetus and on development of offspring of
poisoned women
• *Occupational – Workers exposed to PCBs develop
dermatologic problems that include:
– Chloracne, Folliculitis, Erythema, Dryness, Rash,
Hyperkeratosis, Hyperpigmentation
• *Other Effects – Hepatic abnormalities, and
Elevated plasma triglycerides
• Reproduction and Development is still studied
– The halogenated pesticides are potent endocrine
disrupters and there is widespread concern about
persistent estrogenic effect of these chemicals
– Adverse reproductive impacts found in many
animal studies
– Workers and general population exposed to
moderate to very high levels still not conclusive
– Adverse Behavioral effects in infants have been
reported
– Association to prenatal exposure to PCBs and
deficits in childhood intellectual function for
children born to mothers who had eaten large
quantities of contaminated fish
• Carcinogenic nature
– epidemiologic studies have established increase in
various cancers such as melanoma, breast,
pancreatic, and thyroid cancers
*POLYBROMINATED BIPHENYLS (PBBs) AND
THEIR ETHERS (PBDEs)
• Share many of the toxic and environmentally
damaging persistent qualities of PCBs
• Introduced as fire retardants in the 1950s and have
been used in massive quantities since that time
• Biphenyls are no longer produced and may no longer
be used
• Biphenyl ethers remain in use as fire retardants in
plastics for bedding and in automobile upholstery
• Carcinogenic
– PBBs are considered IARC class 2a: probable
human carcinogens
– PBDEs are not classified in IARC
*POLYCHLORINATED DIBENZO-p-DIOXINS
(PCDDs)
• Commonly called “dioxins”
• Large group of halogenated congeners of which
tetrachlorodibenzodioxin (TCDD) has been the most
carefully studied
– These chemicals are very stable and highly
lipophilic; poorly metabolized and very resistant to
environmental degradation
• *Similar compounds: there is a large group of
dioxin-like compounds, including the polychlorinated
dibenzofurans (PCDFs) and coplanar biphenyls
– Ex. PCBs which is in commercial use
– Ex. PCDDs and PCDFs that are unwanted byproducts
that appear in the environment and in manufactured
products as contaminants due to improperly controlled
combustion processes
– Ex. PCDDs and PCDFs are also produced when
unexpected heating to over 600°C occurs
o Ex. lightning strikes or Electrical fires in PCB-
containing transformers
• Several significant environmental contamination
involving dioxins and furans from industrial sites have
occurred
• In humans, recent publications have demonstrated an
elevated incidence of subsequent chronic diseases in
exposed persons
– Ex. diabetes, metabolic syndrome, and obesity
• 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
• Laboratory studies – of blood concentrations of TCDD
and its metabolites have provided insight into the
persistence and metabolism of the contaminants
• Laboratory Animals: TCDD produced variety of toxic
effects
– Wasting syndrome, Thymic atrophy, Epidermal
changes, Hepatotoxicity, Immunotoxicity, Effects on
reproduction and development, Teratogenicity,
Carcinogenicity
o Wasting syndrome is severe weight loss and
reduction of muscle mass and adipose tissue
• Occupational workers involved in manufacture of
2,4,5-T (thus presumably exposed to TCDD) consisted of
Contact dermatitis and Chloracne
– Severely TCCD-intoxicated patients: discrete
chloracne may be the only manifestation
• Presence of TCDD in 2,4,5-T [commercially known as
Silvex] was believed to be responsible for other human
toxicities associated with the herbicide
– There is epidemiologic evidence for association
between occupational exposure to phenoxy herbicides
and excess incidence of non-Hodgkin lymphoma
– TCDD contaminant seems to play a role in number of
cancers:
– Soft tissue sarcomas, Lung cancer, Hodgkin
lymphomas, and others
• TCDD is considered IARC Class 1, known human
carcinogen
• Other halogenated compounds of this type are not
currently classifiable as to carcinogenicity
• Appeared in the environment as unwanted byproducts of
the chemical industry
Oloteo, Perales, Qua, Rubio, Santos |18
• Chemically stable and highly resistant to
environmental degradation
PERFLUORINATED COMPOUNDS (PFCs)
• Coolant materials in air-conditioning systems
• Used as oxygen-carrying materials in clinical studies
• Used as heat-, stain-, and stick-resistant coatings for
cookware, fabrics and other materials (i.e. Teflon)
• Had deleterious effect in the ozone layer of the
atmosphere
• Persistent environmental chemical
– They are now banned because of impact to the
biosystems
– *Migration of lower molecular weight
fluorocarbons to the troposphere had a deleterious
effect on the protective ozone layer
o *They became banned from use
– *The higher molecular weight, more fluorinated
compounds, called Perfluorinated substance [e.g.,
Teflon] remained in broad use
o *Not banned from use
• Ingested and inhaled by humans
• Human half-life is 3 years (when absorbed)
– *perfluorooctanoic acid (PFOA) is estimated to be
about 3 years
• Potent endocrine disruptor
• Long-term adverse effect on reproductive function,
cellular proliferation and other cellular homeostatic
mechanisms
• Associated with proliferation of breast cancer cells;
renal, ovarian, prostate and Non-Hodgkin’s
lymphoma
• Associated with cholesterol and uric acid
abnormalities
• Polymer Fume Fever
– *an acute pulmonary disorder caused by pyrolysis
of PFOA
– When PFOA is heated above 350-400°C, toxic
fumes capable of causing polymer fume fever are
emitted
o Presented in overheated household cookware
or Burning of coated fabrics
– Cadmium vaporizes in welders and they develop
respiratory distress fever and malaise
– Usually self-limiting
– Animal studies have shown toxic effects on
immune, liver, and endocrine function and some
increase in tumors and neonatal deaths
• Perfluoro compounds are persistent environmental
chemicals
– Has a broad environmental impact
– PFA and related compounds are now found widely
in water, soil, and many terrestrial and avian
species
– Aquatic organisms have accumulated significant
loads of PFCs
ASBESTOS
• *group of naturally occurring long, flexible mineral fibers,
most commonly containing silicon
• *Because it is poorly metabolized and lipophilic, it is
highly persistent in the environment and accumulates in
the food chain
• Widely used in industry for over 100 years
• Synergistic effect with cigarette smoking and exposure
to radon daughters
• *All forms of asbestos have been shown to cause
progressive fibrotic lung disease (asbestosis), lung
cancer, and mesothelioma
– *Lung cancer occurs in people exposed at fiber
concentrations well below concentrations that produce
asbestosis
– *Recognition that all forms are dangerous and
carcinogenic led to many countries to ban all uses of
asbestos
– *All forms of asbestos cause mesothelioma of the
pleura or peritoneum at very low doses
– *Other cancers [colon, laryngeal, stomach, and
perhaps lymphoma] are increased in asbestos-
exposed patients
– *There are arguments and contradictions whether
chrysotile asbestos does not cause mesothelioma in
worker populations
• Mechanism for cancer is not well-defined
• Many countries has banned Asbestos
– Countries that still produce Asbestos include Canada,
Zimbabwe, Russia, Brazil, and others
– Argue that asbestos can be used safely with careful
workplace environmental controls
– Studies says that “safe use” is highly improbable
• *Effect: causes progressive fibrotic lung diseases
(asbestosis) characterized by shortness of breath. Also
associated with other cancers (lung cancer,
mesothelioma and cancers of the gastrointestinal tract)
ENDOCRINE DISRUPTORS
• Mimic, enhance or inhibit a hormonal action
• Usually have estrogen-like or antiandrogenic effects;
some affect thyroid functions
• Includes plant constituents like phytoestrogens,
mycoestrogens
• Synthetic forms are industrial chemicals, persistent
organochlorine agents (DDT), PCBs and brominated
flame retardants
• Increasing concerns mainly due to bioaccumulation,
toxicity and increasing contamination in the environment.
– Toxicity profile is very grim
• *Studies and their Importance
– *In vitro alone, are unreliable for regulatory
purposes
– *Animal studies are indispensable
o Modified endocrine responses in reptiles and
marine invertebrates have been observed
Oloteo, Perales, Qua, Rubio, Santos |19
 – *Humans, causal relation between exposure to a
specific environmental agent and an adverse
health effect due to endocrine modulation has not
been fully established
– *Populations, epidemiologic studies 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
*CYANOTOXINS
• Comprise a large family of cyclic peptides, alkaloids,
and lipopolysaccharides
• Products of blue-green algae that are widely
distributed in lakes and in salt water where they form
blooms at warm temperature
• Ingestion – if ingested in high concentrations,
cyanotoxins cause poisoning and rapid death by
respiratory failure
– Lower concentrations – may cause gastrointestinal
or skin conditions, and neurologic, hepatic, and
other organ system dysfunction
• *BMAA
– A cyanobacteria neurotoxin
– Implicated as a cause of neurodegenerative
disease
METALS
• Beryllium, Cadmium, Nanomaterials
• *Classic Metal poisons continue to be widely used
– E.g., Arsenic, Lead, Mercury
• *Occupational exposure due to Beryllium, Cadmium,
Manganese and Uranium are new
• Have posted major health problems in the industry,
home and environment
• Occupational exposure and poisoning due to these
are relatively new problems in medicine
• In 2016, we discovered that cobalt is also considered
as a human carcinogen
• NOT our heavy metals (this will be discussed
separately)
BERYLLIUM (Be)
• *PEL [8-hour]: 2 mcg/m3
• *PEL [30-day]: 0.01 mcg/m3
– This much still cannot prevent CBD
• Light alkaline metal
• Used in ceramics and alloys; computers; dental
equipment; devices that requires hardening like
missile ceramic nose cones and heat shield tiles in
space vehicles
• Inhalational route (most common route)
– *Highly toxic by inhalation
– Produces both acute beryllium disease and chronic
disease characterized by progressive pulmonary
fibrosis
• *Transdermal route
– Skin disease also develops in workers exposed to
beryllium
• Known human carcinogen (class 1)
• Acute Beryllium Disease and Chronic Beryllium Disease
• Characterized by progressive pulmonary fibrosis
– More so on the chronic phase
• *Chronic Beryllium Disease (CBD)
– *Prognosis: Poor
– Pulmonary disease
– Chronic granulomatous pulmonary fibrosis
– *In 5-15% of Population
o Immunologically sensitive to beryllium
o CBD is the result of activation of autoimmune
attack on the skin and lungs
o Is progressive and leads to severe disability, cancer
and death
– *Treatment: some show promise
• *Beryllium Disease (Occupational)
– beryllium in dental appliances; dentists and the
appliance makers are exposed to beryllium dust in
toxic concentrations
• *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 (Cd)
• *PEL: 5 mcg/m3
– Insufficiently protective for workers
• Transition metal
• Found in nickel cadmium batteries, pigments, low-
melting point eutectic materials; in solder; in television
phosphors; and in plating operations; semiconductors
and plastics
– *Cadmium smelting is done from residual dust from
lead smelting operations, and cadmium smelter
workers often face both lead and cadmium toxicity
• Inhaled and ingested
– Toxic by inhalation and by ingestion
• Cadmium Fume Fever
– Usually welders presenting chills, cough, fever, body
malaise
– *When metals plated with cadmium or welded with
cadmium-containing materials are vaporized by heat
of torches or cutting implements, the find dust and
fumes released cause this acute respiratory disorder
– *Common in welders
– *Characterized by Shaking chills, Cough, Fever,
Malaise
– *Produces transient pneumonia
• Chronic exposure may lead to progressive pulmonary
fibrosis, renal failure
– far more serious progressive pulmonary fibrosis
• Other observations include severe Kidney damage, Renal
failure
Oloteo, Perales, Qua, Rubio, Santos |20
• Human Carcinogen (Class 1)
INTERNATIONAL AGENCY FOR RESEARCH ON
NANOMATERIALS CANCER (IARC) CLASSIFICATION
• Any material, natural or manufactured, bearing a size Group Definition Includes
of at least one dimension that lies between 1 to 100 Group 1 - Carcinogenic to Smoking,
nm in size. Humans exposure to solar
• Play increasing roles in the industry - Sufficient evidence in radiation, alcoholic
humans. beverages and
– Pharmaceutical Industry, nanoparticles are being
- Causal relationship processed meats
tested and used to deliver cancer established
chemotherapeutic and other drugs Group 2A - Probably Carcinogenic Emissions from
• Gold, silver, cadmium, ceramic, aluminum oxide to Humans high temp, frying,
nanowears, carbon, silicon, and germanium - Limited evidence in steroids,
nanotubes, zinc oxide nanocrystal, gold nanowafers, humans exposures working
and copper oxide nanocubes - Sufficient evidence in in hairdressing,
• Toxicology profile is fairly novel animals red meat
• The increasing production led to environmental Group 2 - Possibly Carcinogenic Coffee, gasoline
contamination B to Humans and gasoline
- Limited evidence in engine exhaust,
• Inhalational, oral, dermal, parenteral are the routes
humans. welding fumes,
of exposure - Insufficient evidence in pickled vegetables
• Assumed that their toxicity may be both similar and animals
different from the larger, bulk materials Group 3 - Carcinogenicity not Tea, static
• Can cross cellular membranes, penetrate nuclear classifiable magnetic fields,
material and genetic information - Inadequate evidence in fluorescent
• Silica – kidney toxicity humans lighting,
• Zinc oxide – hepatocellular damage - Inadequate evidence in polyethene
• Multiwalled carbon nanotubes – cytotoxic in animals
Group 4 - Probably not ONLY 1 CHEMICAL
human (*lung cells) PLACED IN THIS
Carcinogenic
• Titanium dioxide – toxic to lungs (inhaled) and GROUP, OF ALL
- Evidence suggests no SUBSTANCES
other organs (ingested) carcinogenicity in ASSESSED
– Chemical found in sunscreens and sunblocks humans/animals Caprolactam,
• Nanomaterials can enter the environment at all which is used in
stages of their industrial life cycle the manufacture
– Ex. manufacturing, delivery, use, disposal of synthetic fibres
– When placed into waste streams, they may enter • Classification system used for an object/item/agent on
water systems whether they have direct carcinogenic effects to humans
– May be carried by wind or soils, and enter the food or not
chain
FOR FURTHER STUDIES
• Increasing production of nanomaterials and their
*High-Yield Terms to Learn
multiple uses have led to environmental
The increasing concentration of
contamination
a substance in the environment
– Many species, including bacteria, small mammals,
as the result of environmental
and fish and other aquatic organisms have been
Bioaccumulation persistence and physical
studied in laboratory assessments of nanomaterial properties (eg, lipid solubility)
toxicity that leads to accumulation in
– Ecotoxicology of nanomaterials remains an area of biologic tissues
deep concern and ongoing research Although the concentration of a
contaminant may be virtually
undetectable in water, it may be
Biomagnification magnified hundreds or
thousands of times as the
contaminant passes up the food
chain
Study of the toxic effects of
chemical and physical agents on
Ecotoxicology populations and communities of
living organisms within defined
ecosystems

Oloteo, Perales, Qua, Rubio, Santos |21

 Chemicals in the environment
that have estrogen-like or
antiandrogen activity or disrupt
thyroid function. There is
Endocrine
concern that exposure to
disruptors
endocrine disruptors may
increase reproductive cancers,
impair fertility, and have
teratogenic effects
The area of toxicology that deals
with the effects of agents found
in the environment (air, soil,
Environmental
water); regulated by the
toxicology
Environmental Protection Agency
(EPA) in the United States. The
FDA regulates exposure in food
The area of toxicology that deals
with the toxic effects of
chemicals found in the
Occupational
workplace; regulated by the
toxicology
Occupational Safety and Health
Administration (OSHA) in the
United States
The amount of exposure to a
given agent that is deemed safe
Threshold limit
for a stated time period. It is
value
higher for shorter periods than
for longer periods

Oloteo, Perales, Qua, Rubio, Santos |22

 MT6314: PHARMACOLOGY & TOXICOLOGY DMT 2023
CHAPTER 57: HEAVY METALS INTOXICATION & CHELATORS

OUTLINE CASE STUDY*

Introduction* • Some metals such as iron are essential for life, whereas
Case Study* others such as lead are present in all organisms but
Toxicology of Heavy Metals serve no useful biologic purpose. Some of the oldest
Lead diseases of humans can be traced to heavy metal
Arsenic poisoning associated with metal mining, refining, and
Mercury use.
Chelators • Even with the present recognition of the hazards of
Dimercaprol heavy metals, the incidence of intoxication remains
Succimer significant, and the need for preventive strategies and
Edetate Calcium Disodium effective therapy remains high.
Unithiol • Toxic heavy metals interfere with the function of
Penicillamine essential cations, cause enzyme inhibition, generate
Deferoxamine oxidative stress, alter gene expression, and perturb cell
Deferasirox and Deferiprone signaling. As a result, multisystem signs and symptoms
Prussian Blue are a hallmark of heavy metal intoxication.
Still Keepers Answers* • When intoxication occurs, chelator molecules
High-Yield Terms to Learn* (from chela “claw”), or their in vivo biotransformation
Important Characteristics of the Toxicology of Lead, products, may be used to bind the metal and facilitate
Arsenic, Mercury, and Iron* its excretion from the body. Chelator drugs are
Drug Summary Table: Heavy Metal Chelators* discussed in the second part of this chapter.
Toxicology of Selected Lead, Arsenic, and Mercury
Compounds* TOXICOLOGY OF HEAVY METALS
Prevention of Lead Poisoning: An Ongoing Effort* • Heavy metals are generally defined as metals with
Preparations Available* relatively high densities atomic weights or atomic
Iron Chelating Agents number.
• Some heavy metals are either essential nutrients like
Legend: Sources:
your iron, cobalt and zinc or relatively harmless like your
Purple – Lecturer • Doc Alferos – Lecturer
ruthenium, silver, and indium but can we toxic in larger
Asterisk* – Book • Katzung & Trevor’s
amounts or certain forms
Pharmacology 12e
• Other heavy metals such as cadmium, mercury and lead
• Katzung & Trevor’s
are highly poisonous.
Pharmacology 15e
• Potential sources of heavy metal poisoning include the
INTRODUCTION* mining, tailings, industrial wastes, agricultural runoff,
• The heavy metals discussed in this chapter—lead, occupational exposure, paints and treated timber.
arsenic, mercury, and iron—frequently cause • Chromium, arsenic, cadmium, mercury, and lead have
toxicity in humans. The toxicity profiles of metals the greatest potential to cause harm on account of their
differ, but most of their effects appear to result from extensive use, the toxicity of their combined form or
interaction with essential cations, sulfhydryl groups elemental form and their widespread distribution in the
of enzymes, and regulatory proteins. environment.
• Chelators are organic compounds with 2 or more
electronegative groups that form stable bonds with A. Lead
cationic metal atoms. These stable complexes lack • Lead is one of the oldest and most prevalent heavy
the toxicity of the free metals and often are excreted metal contaminants in the world. Once you
readily. Chelators, which function as chemical (unintelligible :<) but due to many public health
antagonists, are used as antidotes in the treatment measures and policies the news of this has declined
of heavy metal poisoning. significantly.
• Lead can be found in Storage batteries, ammunition,
metal allows, solder, glass, plastics, pigments and
ceramics
• As of today, there are No useful purpose in the human
body.

• *Lead poisoning is one of the oldest occupational and

environmental diseases in the world. Despite its
recognized hazards, lead continues to have widespread
commercial application, including production of storage

Balanquit, Bernardo, Broas, Capellan, Caringal |1

 batteries (nearly 90% of US consumption),
ammunition, metal alloys, solder, glass, plastics,
pigments, and ceramics.
• *Corrosion of lead plumbing in older buildings or
supply lines may increase the lead concentration of
tap water.
• *Environmental lead exposure, ubiquitous by virtue
of the anthropogenic distribution of lead to air,
water, and food, has declined considerably in the
last four decades as a result of the elimination of
lead as an additive in gasoline, as well as diminished
contact with lead-based paint and other lead-
containing consumer products, such as lead solder
in cans used as food containers.
• *Lead continues to be used in some formulations of
aviation gasoline for piston-engine aircraft.
• *The presence of lead in certain folk medicines (eg,
the Mexican remedies azarcon and greta, and
certain Ayurvedic preparations) and in cosmetics (eg,
kohl utilized around the eyes in certain African and
Asian communities) has contributed to lead
exposure to children and adults.
• *Although public health measures, together with
improved workplace conditions, have decreased the
incidence of serious overt lead poisoning, there
remains considerable concern over the effects of
low-level lead exposure.
• *Extensive evidence indicates that low levels of lead
exposure may have subtle subclinical adverse
effects on neurocognitive function in children and
may contribute to hypertension and cardiovascular
disease in adults.
• *Lead serves no useful purpose in the body and can
damage the hematopoietic tissues, liver, nervous
system, kidneys, gastrointestinal tract, and
reproductive system
• *In key target organs such as the developing central
nervous system, no level of lead exposure has been
shown to be without deleterious effects.
• *Lead is a major environmental hazard because it is
present in the air and water throughout the world.
Pharmacokinetics
• What is the important pharmacokinetic profile of
lead?
• Absorbed slowly but consistently via respiratory and
gastrointestinal tract
• Respiratory tract is the primary route of entry for
industrial exposure
• Intestinal tract is the primary route of entry for non-
industrial exposures (or at homes)
– Up to 50% absorbed in children
– Up to 10-15% in adults
– Low dietary calcium, iron deficiency and ingestion
on an empty stomach increases absorption
• Poor absorption in the skin
• Once it enters the bloodstream, 99% bound to
RBCs, 1% free in plasma
• The distribution starts from soft tissues to hard
tissues like bone.
• Distributed to bone marrow, brain, kidney, liver,
muscle and gonads; then to the heart and bones
• Crosses the placenta
• Half-life: 1-2 months
• Half-life in bones: years to decades
• This slow release response by the lead in the bone
may produce symptoms for years on some patients
who have been exposed to lead. For example:
patients who had a gunshot wound where the bullet
was not or never removed from the body. There
were reports that they developed lead intoxication
over a few years.
• 70% excreted in the urine
• 30% is excreted in bile, skin, hair, and nail
• *Inorganic lead is slowly but consistently absorbed
via the respiratory and gastrointestinal tracts.
• *It is poorly absorbed through the skin. Absorption
of lead dust via the respiratory tract is the most
common cause of industrial poisoning.
• *The intestinal tract is the primary route of entry in
nonindustrial exposure.
• *Absorption via the gastrointestinal tract varies with
the nature of the lead compound, but in general,
adults absorb about 10–15% of the ingested
amount, whereas young children absorb up to 50%.
• *Low dietary calcium, iron deficiency, and ingestion
on an empty stomach all have been associated with
increased lead absorption.
• *Once absorbed from the respiratory or
gastrointestinal tract, lead enters the bloodstream,
where approximately 99% is bound to erythrocytes
and 1% is present in the plasma.
• *Lead is subsequently distributed to soft tissues
such as the bone marrow, brain, kidney, liver,
muscle, and gonads; then to the subperiosteal
surface of bone; and later to bone matrix. Lead also
crosses the placenta and poses a potential hazard to
the fetus.
• *The kinetics of lead clearance from the body
follows a multicompartment model, composed
predominantly of the blood and soft tissues, with a
half-life of 1–2 months; and the skeleton, with a
half-life of years to decades.
• *Approximately 70% of the lead that is eliminated
appears in the urine, with lesser amounts excreted
through the bile, skin, hair, nails, sweat, and breast
milk. The fraction not undergoing prompt excretion,
approximately half of the absorbed lead, may be
incorporated into the skeleton, the repository of
more than 90% of the body lead burden in most
adults.
• *In patients with high bone lead burdens, slow
release from the skeleton may elevate blood lead
concentrations for years after exposure ceases, and
pathologic high bone turnover states such as
Balanquit, Bernardo, Broas, Capellan, Caringal |2
 hyperthyroidism or prolonged immobilization may
result in frank lead intoxication.
• *Migration of retained lead bullet fragments into a
joint space or adjacent to bone has been associated
with the development of lead poisoning signs and
symptoms years or decades after an initial gunshot
injury.
Pharmacodynamics
• Multiple mechanisms of actions
– Inhibition of enzymatic function
– Interference with action of essential cations
(calcium, zinc, iron)
– Produces free radicals or Oxidative stress
generation
– Gene expression changes
– Cell signaling alternation
– Disruption of membrane integrity
• *Lead exerts multisystemic toxic effects that are
mediated by multiple modes of action, including
inhibition of enzymatic function; interference with
the action of essential cations, particularly calcium,
iron, and zinc; generation of oxidative stress;
changes in gene expression; alterations in cell
signaling; and disruption of the integrity of
membranes in cells and intracellular organelles.
A. Nervous system*
– The developing central nervous system of the fetus
and young child is the most sensitive target organ
for lead’s toxic effect. Epidemiologic studies
suggest that blood lead concentrations <5 mcg/dL
may result in subclinical deficits in neurocognitive
function in lead-exposed young children, with no
demonstrable threshold or “no effect” level.
– The dose response between low blood lead
concentrations and cognitive function in young
children is nonlinear, such that the decrement in
intelligence associated with an increase in blood
lead from <1 to 10 mcg/dL (6.2 IQ points) exceeds
that associated with a change from 10 to 30
mcg/dL (3.0 IQ points).
– Adults are less sensitive to the central nervous
system (CNS) effects of lead, but long-term
exposure to blood lead concentrations in the range
of 10–30 mcg/dL may be associated with
subclinical effects on neurocognitive function.
– At blood lead concentrations higher than 30
mcg/dL, behavioral and neurocognitive signs or
symptoms may gradually emerge, including
irritability, fatigue, decreased libido, anorexia,
sleep disturbance, impaired visual-motor
coordination, and slowed reaction time. Headache,
arthralgias, and myalgias are also common
complaints. Tremor occurs but is less common.
– Lead encephalopathy, usually occurring at blood
lead concentrations higher than 100 mcg/dL, is
typically accompanied by increased intracranial
pressure and may cause ataxia, stupor, coma,
convulsions, and death.
– Recent epidemiological studies suggest that lead
may accentuate an age-related decline in cognitive
function in older adults.
– In experimental animals, developmental lead
exposure, possibly acting through epigenetic
mechanisms, has been associated with increased
expression of beta-amyloid, increased
phosphorylated tau protein, oxidative DNA
damage, and Alzheimer-type pathology in the
aging brain. There is wide interindividual variation
in the magnitude of lead exposure required to
cause overt lead-related signs and symptoms.
– Overt peripheral neuropathy may appear after
chronic high-dose lead exposure, usually following
months to years of blood lead concentrations
higher than 100 mcg/dL.
– Predominantly motor in character, the neuropathy
may present clinically with painless weakness of
the extensors, particularly in the upper extremity,
resulting in classic wrist-drop.
– Preclinical signs of lead-induced peripheral nerve
dysfunction may be detectable by
electrodiagnostic testing.
B. Blood*
– Lead can induce an anemia that may be either
normocytic or microcytic and hypochromic.
– Lead interferes with heme synthesis by blocking
the incorporation of iron into protoporphyrin IX
and by inhibiting the function of enzymes in the
heme synthesis pathway, including aminolaevulinic
acid dehydratase and ferrochelatase.
– Within 2–8 weeks after an elevation in blood lead
concentration (generally to 30–50 mcg/dL or
greater), increases in heme precursors, notably
free erythrocyte protoporphyrin or its zinc chelate,
zinc protoporphyrin, may be detectable in whole
blood.
– Lead also contributes to anemia by increasing
erythrocyte membrane fragility and decreasing red
cell survival time.
– Frank hemolysis may occur with high exposure.
Basophilic stippling on the peripheral blood smear,
thought to be a consequence of lead inhibition of
the enzyme 3′,5′-pyrimidine nucleotidase, is
sometimes a suggestive—albeit insensitive and
nonspecific—diagnostic clue to the presence of
lead intoxication.
C. Kidneys*
– Chronic high-dose lead exposure, usually
associated with months to years of blood lead
concentrations >80 mcg/dL, may result in renal
interstitial fibrosis and nephrosclerosis.
– Lead nephropathy may have a latency period of
years. Lead may alter uric acid excretion by the
Balanquit, Bernardo, Broas, Capellan, Caringal |3
 kidney, resulting in recurrent bouts of gouty
arthritis (“saturnine gout”).
– Acute high-dose lead exposure sometimes
produces transient azotemia, possibly as a
consequence of intrarenal vasoconstriction.
Studies conducted in general population samples
have documented an association between blood
lead concentration and measures of renal function,
including serum creatinine and creatinine
clearance.
– The presence of other risk factors for renal
insufficiency, including hypertension and diabetes,
may increase susceptibility to lead-induced renal
dysfunction.
D. Reproductive organs*
– High-dose lead exposure is a recognized risk factor
for stillbirth or spontaneous abortion.
– Epidemiologic studies of the impact of low-level
lead exposure on reproductive outcome such as
low birth weight, preterm delivery, or spontaneous
abortion have yielded mixed results. However, a
well-designed nested case-control study detected
an odds ratio for spontaneous abortion of 1.8
(95% CI 1.1–3.1) for every 5 mcg/dL increase in
maternal blood lead across an approximate range
of 5–20 mcg/dL.
– Recent studies have linked prenatal exposure to
low levels of lead (eg, maternal blood lead
concentrations of 5–15 mcg/dL) to decrements in
physical and cognitive development assessed
during the neonatal period and early childhood.
– In males, blood lead concentrations higher than 40
mcg/dL have been associated with diminished or
aberrant sperm production.
E. Gastrointestinal tract*
– Moderate lead poisoning may cause loss of
appetite, constipation, and, less commonly,
diarrhea.
– At high dosage, intermittent bouts of severe
colicky abdominal pain (“lead colic”) may occur.
– The mechanism of lead colic is unclear but is
believed to involve spasmodic contraction of the
smooth muscles of the intestinal wall, mediated by
alteration in synaptic transmission at the smooth
muscle-neuromuscular junction.
– In heavily exposed individuals with poor dental
hygiene, the reaction of circulating lead with sulfur
ions released by microbial action may produce dark
deposits of lead sulfide at the gingival margin
(“gingival lead lines”).
– Although frequently mentioned as a diagnostic
clue in the past, in recent times this has been a
relatively rare sign of lead exposure.
F. Cardiovascular system*
– Epidemiologic, experimental, and in vitro
mechanistic data indicate that lead exposure
elevates blood pressure in experimental animals
and in susceptible humans.
– The pressor effect of lead may be mediated by an
interaction with calcium-mediated contraction of
vascular smooth muscle, as well as generation of
oxidative stress and an associated interference
in nitric oxide signaling pathways.
– In populations with environmental or occupational
lead exposure, blood lead concentration is linked
with increases in systolic and diastolic blood
pressure.
– Studies of middle-aged and elderly men and
women have identified relatively low levels of lead
exposure sustained by the general population to
be an independent risk factor for hypertension.
– Lead exposure has also been associated with
prolongation of the QTc interval on the
electrocardiogram.
– Epidemiologic studies have linked chronic
environmental lead exposure associated with
population blood lead concentrations in the range
of 10–25 mcg/dL to a significantly increased risk of
cardiovascular mortality.
– This is of considerable public health concern
because these concentrations were prevalent in
the USA prior to the 1980s.
– Although general population blood lead
concentrations have since fallen considerably,
exposure associated with blood lead in this range
persists in occupational settings worldwide.
Lead Exposure
• Although often without obvious symptoms, lead
exposure can affect nearly every part of the human
body. No safe level of lead in the bloodstream has been
determined by the Federal Centers for Disease Control
and Prevention.
• What are the different effects of lead to the different
organs?
– In the CNS, the developing brain of a child and fetus
is the most sensitive organ for lead. It may include
behavioral problems, lower IQ, hearing loss, and
learning disabilities.
– In adults, the CNS is less sensitive but prolonged
exposure may have behavioral and neurocognitive
effects.
– In the blood, it may produce normocytic, microcytic or
hypochromic anemia that interferes with the heme
synthesis by blocking the incorporation of iron in front
of a pyrene 9 and by inhibiting enzymes in heme
synthesis.
– For the renal, the chronic high dose exposure may
lead to renal interstitial fibrosis and nephrosclerosis
– In the reproduction or reproductive organs, high dose
exposure may lead to stillbirths or spontaneous
abortion
– In the GI tract, patients may develop intermittent or
severe colicky abdominal pain also called lead colic.
Balanquit, Bernardo, Broas, Capellan, Caringal |4
 Other symptoms may include loss of appetite, • Before it is found in gas as tetraethyl and tetramethyl
constipation or diarrhea lead. In some areas though it’s still used as lead stearate
– In the cardiovascular, it has been linked with the and lead naphthenate.
increase in both systolic and diastolic blood
pressures in multiple studies also with QT interval A. Inorganic Lead Poisoning*
prolongation. At blood levels of 10-25 micrograms 1. Acute Lead Poisoning*
per deciliter significant cardiovascular mortality o Acute inorganic lead poisoning is uncommon today.
has been linked. Although prevalence in the US o It usually results from industrial inhalation of large
has since decreased, it’s still a major problem in quantities of lead oxide fumes or, in small children,
other parts of the globe. from ingestion of a large oral dose of lead in the
form of lead-based paint chips; small objects, eg,
toys coated or fabricated from lead; or
contaminated food or drink.
o The onset of severe symptoms usually requires
several days or weeks of recurrent exposure and
manifests as signs and symptoms of
encephalopathy or colic.
o Evidence of hemolytic anemia (or anemia with
basophilic stippling if exposure has been subacute)
and elevated hepatic aminotransferases may be
present.
o The diagnosis of acute inorganic lead poisoning
may be difficult, and depending on the presenting
symptoms, the condition has sometimes been
mistaken for appendicitis, peptic ulcer, biliary colic,
pancreatitis, or infectious meningitis.
o Subacute presentation, featuring headache,
fatigue, intermittent abdominal cramps, myalgias,
Major Forms of Lead Intoxication and arthralgias, has often been mistaken for a flu-
Forms Inorganic Organic like viral illness. When there has been recent
Major GI, Respiratory Skin, GI, ingestion of lead-containing paint chips, glazes,
Routes Respiratory pellets, or weights, radiopacities may be visible on
Distribution Soft tissues; Soft tissues abdominal radiographs.
redistributed to (especially liver and o It can occur rarely from industrial exposures
skeleton CNS) (usually via the inhalation of dust) and in children
who have ingested large quantities of chips or
Major CNS deficits; Encephalopathy
flakes from surfaces in older houses covered with
Clinical peripheral and sometimes
lead-containing paint.
Findings neuropathy; hepatotoxicity
o The primary signs of this syndrome are acute
anemia;
abdominal colic and central nervous system (CNS)
nephropathy;
changes, including, particularly in children, acute
hypertension;
encephalopathy.
reproductive
o The mortality rate is high in those with lead
toxicity
encephalopathy, and prompt chelation therapy is
Mechanism Inhibits Hepatic
mandatory.
of Action enzymes; dealkylation in the
interferes with liver (fast) →
2. Chronic Lead Poisoning*
essential trialkyl metabolites
o The patient with symptomatic chronic lead
cations; alters (slow) →
intoxication typically presents with multisystemic
membrane dissociation to lead
findings, including complaints of anorexia, fatigue,
structures
and malaise; neurologic complaints, including
Metabolism Renal or in the Urine and feces
headache, difficulty in concentrating, and
and kidney (major); sweat
irritability or depressed mood; weakness,
Elimination (major); feces (minor)
arthralgias, or myalgias; and gastrointestinal
and breast
symptoms.
milk (minor)
o Lead poisoning should be strongly suspected in any
• Organic lead poisoning is very rare now because of
patient presenting with headache, abdominal pain,
the public health measures we’ve undertaken to
and anemia; and less commonly with motor
prevent its use in the environment and in the
neuropathy, gout, and renal insufficiency.
occupation.

Balanquit, Bernardo, Broas, Capellan, Caringal |5

o Chronic lead intoxication should be considered
in any child with neurocognitive deficits, growth
retardation, or developmental delay.
o It is important to recognize that adverse effects
of lead that are of considerable public health
significance, such as subclinical decrements in
neurodevelopment in children and
hypertension in adults, are usually nonspecific
and may not come to medical attention.
o The diagnosis of lead intoxication is best
confirmed by measuring lead in whole blood.
Although this test reflects lead currently
circulating in blood and soft tissues and is not
a reliable marker of either recent or cumulative
lead exposure, most patients with lead-related
disease have blood lead concentrations higher
than the normal range.
o Though predominantly a research tool, the
concentration of lead in bone assessed by
noninvasive K X-ray fluorescence measurement
of lead has been correlated with long-term
cumulative lead exposure, and its relationship
to numerous lead-related disorders is the
subject of ongoing investigation.
o Measurement of lead excretion in the urine
after a single dose of a chelating agent
(sometimes called a “chelation challenge
test”) primarily reflects the lead content of soft
tissues and may not be a reliable marker of
long-term lead exposure, remote past exposure,
or skeletal lead burden.
o Accordingly, this test is rarely indicated in
clinical practice. Because of the lag time
associated with lead-induced elevations in
circulating heme precursors, the finding of a
blood lead concentration of 30 mcg/dL or more
with no concurrent increase in zinc
protoporphyrin suggests that the lead exposure
was of recent onset.
o Chronic inorganic lead poisoning (plumbism)
is much more common than the acute form.
o Signs include peripheral neuropathy (wrist-
drop is characteristic), anorexia, anemia,
tremor, weight loss, and gastrointestinal
symptoms.
o Treatment involves removal from the source of
exposure, and chelation therapy, usually with
oral succimer in outpatients and with
parenteral agents (eg, EDTA with or
without dimercaprol) in more severe cases.
o Chronic lead poisoning in children presents as
growth retardation, neurocognitive deficits,
and developmental delay.
o Succimer is generally used in such children.
Similarly, studies suggest that lead may
accentuate an age-related decline in cognitive
function in older adults.
o In workers exposed to lead, prophylaxis with
oral chelating agents is contraindicated
because some evidence suggests that lead
absorption may be enhanced by the presence of
chelators.
o In contrast, high dietary calcium is indicated
because it impedes lead absorption.
B. Organolead Poisoning*
1. Organic Lead Poisoning*
o Poisoning from organolead compounds is now very
rare, in large part because of the worldwide phase-
out of tetraethyl and tetra-methyl lead as antiknock
additives in gasoline.
o However, organolead compounds such as lead
stearate or lead naphthenate are still used in
certain commercial processes.
o Because of their volatility or lipid solubility,
organolead compounds tend to be well absorbed
through either the respiratory tract or the skin.
o Organolead compounds predominantly target the
CNS, producing dose-dependent effects that may
include neurocognitive deficits, insomnia, delirium,
hallucinations, tremor, convulsions, and death.
o Now rare, poisoning by organic lead was usually
due to tetraethyl lead or tetramethyl lead
contained in “antiknock” gasoline additives, which
are no longer used.
o This form of lead is readily absorbed through the
skin and lungs.
o The primary signs of intoxication include
hallucinations, headache, irritability, convulsions,
and coma.
o Treatment consists of decontamination and seizure
control.
Treatment
• We have to emphasize these heavy metals that we need
to reduce or prevent excessive exposure especially in
the homes, in the environment, and in the workplace.
• The cornerstone of treatment are three:
– Immediate termination of exposure - very important
– Supportive care whether they’re intensive or regular
supportive care
– Rational use of chelation therapy
• Immediate termination of exposure, supportive care
and rational use of chelation therapy
• Intravenous edetate calcium disodium (CaNa2EDTA) at
a dosage of 30-50mg/kg/d (milligram per kilogram per
day) by continuous infusion for up to 5 days only
• Oral Succimer (DMSA) after 5 days
– It would be followed by oral succimer (DMSA) after 5
days if the treatment remains to be incomplete
• Some patients like patients presenting with lead
encephalopathy may require intensive care as well
• Cerebral edema may be given with steroids, mannitol or
hypertonic saline, anticonvulsant if patients start
developing seizures.
• Retained lead objects like in the GI tract or some
gunshot wound require gastrointestinal
decontamination or removal
Balanquit, Bernardo, Broas, Capellan, Caringal |6
• Endpoint or objective of therapy is the resolution of
symptoms or return of blood lead concentration to
premorbid range
A. Treatment for Inorganic Lead Poisoning*
– Treatment of inorganic lead poisoning involves
immediate termination of exposure, supportive
care, and the judicious use of chelation therapy.
– Lead encephalopathy is a medical emergency that
requires intensive supportive care.
– Cerebral edema may improve with corticosteroids
and mannitol or hypertonic saline, and
anticonvulsants may be required to treat seizures.
– Radiopacities on abdominal radiographs may
suggest the presence of retained lead objects
requiring gastrointestinal decontamination.
– Adequate urine flow should be maintained, but
overhydration should be avoided.
Intravenous edetate calcium disodium
(CaNa2EDTA) is administered at a dosage of
1000–1500 mg/m2/d (approximately 30–50
mg/kg/d) by continuous infusion for up to 5 days.
– Some clinicians advocate that chelation treatment
for lead encephalopathy be initiated with an
intramuscular injection of dimercaprol, followed in
4 hours by concurrent administration of
dimercaprol and EDTA.
– Parenteral chelation is limited to 5 or fewer days,
at which time oral treatment with another
chelator, succimer (DMSA), may be instituted.
– In situations where CaNa2EDTA has been
unavailable, treatment of lead encephalopathy
with oral succimer has been successfully initiated
via a nasogastric tube.
– The end point for chelation is usually resolution of
symptoms or return of the blood lead
concentration to the premorbid range.
– In patients with chronic exposure, cessation of
chelation may be followed by an upward rebound
in blood lead concentration as the lead re-
equilibrates from bone lead stores.
– Although most clinicians support chelation for
symptomatic patients with elevated blood lead
concentrations, the decision to chelate
asymptomatic subjects is more controversial.
Since 1991, the Centers for Disease Control and
Prevention (CDC) has recommended chelation for
all children with blood lead concentrations of 45
mcg/dL or greater. However, a randomized,
double-blind, placebo-controlled clinical trial
of succimer in children with blood lead
concentrations between 25 and 44 mcg/dL found
no benefit on neurocognitive function or long-term
blood lead reduction.
– Prophylactic use of chelating agents in the
workplace should never be a substitute for
reduction or prevention of excessive exposure.
– Management of elevated blood lead levels in
children and adults should include a conscientious
effort to identify and reduce all potential sources of
future lead exposure.
B. Treatment for Organic Lead Poisoning*
– Initial treatment consists of decontaminating the skin
and preventing further exposure.
– Treatment of seizures requires appropriate use of
anticonvulsants.
– Empiric chelation may be attempted if high blood lead
concentrations are present.
B. Arsenic
• Found mainly in semiconductors and many other
products in the manufacturing industry
• *a naturally occurring element in the earth’s crust with
a long history of use
– as a constituent of commercial and industrial products
– as a component on some pharmaceuticals like Fowler’s
solution before
– as an agent of deliberate poisoning
• Semiconductors, wood preservatives, nonferrous alloys,
glass and turf herbicide monosodium methane arsonate
(MSMA)
– *Recent commercial applications of arsenic include its
use in the manufacture of semiconductors, wood
preservatives for industrial applications (eg, marine
timbers or utility poles), nonferrous alloys, glass, and
the turf herbicide known as monosodium methane
arsonate (MSMA).
• Groundwater may contain high amounts of arsenic
– *In some regions of the world, groundwater may
contain high levels of arsenic that has leached from
natural mineral deposits.
– Arsenic in drinking water in the Ganges delta of India
and Bangladesh is now recognized as one of the
world’s most pressing environmental and public health
problems today.
• Historically, used as a pharmaceutical agent but now
limited in use
– *It is of historical interest that Fowler’s solution, which
contains 1% potassium arsenite, was widely used as
a medicine for many conditions from the eighteenth
century through the mid-twentieth century.
– *Organic arsenicals were the first pharmaceutical
antibiotics or antimicrobials and were widely used for
the first half of the twentieth century until supplanted
by sulfonamides and other more effective and less
toxic agents.
– Fowler’s agent was invented by Thomas Fowler. He
used this to treat a variety of ailments including
asthma, chorea, eczema, pemphigus, psoriasis,
Hodgkin's lymphoma, and leukemia
– Because of its multiple side effects by the 20th century
including cirrhosis of the liver, idiopathic portal
hypertension blood, urinary bladder cancer and skin
cancers, the solution’s popularity diminished and now
it's bad for use
– However, in 2000 it was reintroduced as an orphan
drug for treatment of relapsed acute promyelocytic
Balanquit, Bernardo, Broas, Capellan, Caringal |7
 anemia in the form of arsenic trioxide injection so
that's the only accepted use, FDA-approved for
relapsed acute promyelocytic anemia
– *Melarsoprol, another trivalent arsenical or
another drug that has arsenic, is used in the
treatment of advanced African trypanosomiasis
• *Arsenic is widely used in industrial processes and
is also present in certain soils and released during
the burning of coal.
• *Arsenic is a naturally occurring element in the
earth’s crust with a long history of use as a
constituent of commercial and industrial products,
as a component in pharmaceuticals, and as an agent
of deliberate poisoning.
• *Recent commercial applications of arsenic include
its use in the manufacture of semiconductors, wood
preservatives for industrial applications (eg, marine
timbers or utility poles), nonferrous alloys, glass,
and the turf herbicide monosodium methane
arsonate (MSMA).
• *In some regions of the world, groundwater may
contain high levels of arsenic that has leached from
natural mineral deposits.
• *Arsenic in drinking water in the Ganges delta of
India and Bangladesh is now recognized as one of
the world’s most pressing environmental health
problems.
• *Environmental risk assessments have suggested
that arsenic migrating from coal combustion wastes
(eg, coal ash) deposited in unlined landfills may
contaminate underlying groundwater.
• *Arsine, an arsenous hydride (AsH3) gas with potent
hemolytic effects, is manufactured predominantly
for use in the semiconductor industry but may also
be generated accidentally when arsenic-containing
ores or scrap gallium arsenide semiconductors come
in contact with acidic solutions.
• *It is of historical interest that Fowler’s solution,
which contains 1% potassium arsenite, was widely
used as a medicine for many conditions from the
eighteenth century through the mid-twentieth
century.
• *Organic arsenicals were the first pharmaceutical
antimicrobials and were widely used for the first half
of the twentieth century until supplanted by
sulfonamides and other more effective and less toxic
agents.
• *Other organoarsenicals, most notably lewisite
(dichloro-[2-chlorovinyl] arsine), were developed in
the early 20th century as chemical warfare agents.
Pharmacokinetics
• Pharmacokinetic profile of arsenic is that it’s:
– Well-absorbed via respiratory and GI tract
– Percutaneous absorption is limited
o It has limited percutaneous or skin absorption
– Metabolized by the liver via methylation reactions
– Excreted in the Urine (major) sweat and feces
– Although the absorption in the skin is limited but
clinically significant effects are also observed
during heavy exposures
• *Soluble arsenic compounds are well absorbed
through the respiratory and gastrointestinal tracts.
• *Percutaneous absorption is limited but may be
clinically significant after heavy exposure to
concentrated arsenic reagents.
• *Most of the absorbed inorganic arsenic undergoes
methylation, mainly in the liver, to
monomethylarsonic acid and dimethylarsinic acid,
which are excreted, along with residual inorganic
arsenic, in the urine.
• *When chronic daily absorption is <1000 mcg of
soluble inorganic arsenic, approximately two thirds
of the absorbed dose is excreted in the urine within
2–3 days.
• *After massive ingestions, the elimination half-life is
prolonged.
• *Inhalation of arsenic compounds of low solubility
may result in prolonged retention in the lung and
may not be reflected by urinary arsenic excretion.
• *Arsenic binds to sulfhydryl groups present in
keratinized tissue, and following cessation of
exposure, hair, nails, and skin may contain elevated
levels after urine values have returned to normal.
However, arsenic in hair and nails as a result of
external deposition may be indistinguishable from
that incorporated after internal absorption.
Pharmacodynamics
• Multiple mechanisms of actions it shares multiple
mechanism of action like:
– Inhibition of enzyme functions
– Oxidative stress generation (oxidative stress or free
radical generation)
– Gene expression changes/ alteration
– Cell signaling alteration/ changes
• *Arsenic compounds are thought to exert their toxic
effects by several modes of action. Interference with
enzyme function may result from sulfhydryl group
binding by trivalent arsenic or by substitution for
phosphate.
• *Inorganic arsenic or its metabolites may induce
oxidative stress, alter gene expression, and interfere
with cell signal transduction.
• *Although on a molar basis, inorganic trivalent
arsenic (As3+, arsenite) is generally two to ten times
more acutely toxic than inorganic pentavalent
arsenic (As5+, arsenate), in vivo interconversion is
known to occur, and the full spectrum of arsenic
toxicity has occurred after sufficient exposure to
either form.
• *The trivalent form of the methylated metabolites
(eg, monomethylarsonous acid [MMAIII]) are more
toxic than the inorganic parent compounds.
Balanquit, Bernardo, Broas, Capellan, Caringal |8
 • *Reduced efficiency in the methylation of MMA to
dimethylarsonous acid (DMA), resulting in an
elevated percentage of MMA in the urine, has been
associated with an increased risk of chronic adverse
effects.
• *Arsenic methylation requires S-
adenosylmethionine, a universal methyl donor in the
body, and arsenic-associated perturbations in one-
carbon metabolism may underlie some arsenic-
induced epigenetic effects such as altered gene
expression.
• *Arsine gas is oxidized in vivo and exerts a potent
hemolytic effect associated with alteration of ion flux
across the erythrocyte membrane; it also disrupts
cellular respiration in other tissues.
• *Arsenic is a recognized human carcinogen and has
been associated with cancer of the lung, skin, and
bladder.
• *Marine organisms may contain large amounts of a
well-absorbed trimethylated organoarsenic,
arsenobetaine, as well as a variety of arsenosugars
and arsenolipids.
• *Arsenobetaine exerts no known toxic effects when
ingested by mammals and is excreted in the urine
unchanged; arsenosugars are partially metabolized
to dimethylarsinic acid.
• *Thioarsenite compounds that occur as minor
metabolites of inorganic arsenic and methylated
arsenic compounds in vivo may contribute to toxicity.
Arsenic Intoxication
Arsenic
Major Routes GI, Respiratory
Distribution Predominantly soft tissues
(highest in liver and kidney),
Tightly bound to skin, hair and
nails
Major Clinical Cardiovascular: shock,
Findings arrhythmias; CNS:
Encephalopathy, Peripheral
Neuropathy;
Others: Gastroenteritis,
Pancytopenias, Cancer
Mechanism of Multiple
Action
Metabolism Methylation; Excreted via Urine
and (major), Sweat and Feces (minor)
Elimination
• The major clinical findings that you can see in
arsenic intoxication are cardiovascular shock,
arrhythmias. CNS you have encephalopathy and
neuropathy as well. Others are gastroenteritis,
pancytopenia and multiple forms of cancer
Major Forms of Arsenic Intoxication*
1. Acute Inorganic Arsenic Poisoning*
o Within minutes to hours after exposure to high
doses (tens to hundreds of milligrams) of
soluble inorganic arsenic compounds, many
systems are affected.
o Initial gastrointestinal signs and symptoms include
nausea, vomiting, diarrhea, and abdominal pain.
o Diffuse capillary leak, combined with
gastrointestinal fluid loss, may result in
hypotension, shock, and death.
o Cardiopulmonary toxicity, including congestive
cardiomyopathy, cardiogenic or noncardiogenic
pulmonary edema, and ventricular arrhythmias
(particularly in association with QTc prolongation
on the electrocardiogram) may occur promptly or
after a delay of several days.
o Pancytopenia usually develops within 1 week, and
basophilic stippling of erythrocytes may be present
soon after.
o Central nervous system effects, including delirium,
encephalopathy, and coma, may occur within the
first few days of intoxication.
o An ascending sensorimotor peripheral neuropathy
may begin to develop after a delay of 2–6 weeks.
o This neuropathy may ultimately involve the
proximal musculature and result in neuromuscular
respiratory failure.
o Months after an acute poisoning, transverse white
striae (Aldrich-Mees lines) may be visible in the
nails.
o Acute inorganic arsenic poisoning should be
considered in an individual presenting with abrupt
onset of gastroenteritis in combination with
hypotension and metabolic acidosis.
o Suspicion should be further heightened when these
initial findings are followed by cardiac dysfunction,
pancytopenia, and peripheral neuropathy.
o The diagnosis may be confirmed by demonstration
of elevated amounts of inorganic arsenic and its
metabolites in the urine (typically in the range of
several thousand micrograms in the first 2–3 days
after acute symptomatic poisoning).
o Arsenic disappears rapidly from the blood, and
except in anuric patients, blood arsenic levels
should not be used for diagnostic purposes.
o Treatment is based on appropriate gut
decontamination, intensive supportive care, and
prompt chelation with unithiol, 3–5 mg/kg
intravenously every 4–6 hours,
or dimercaprol, 3–5 mg/kg intramuscularly every
4–6 hours.
o In animal studies, the efficacy of chelation has
been highest when it is administered within
minutes to hours after arsenic exposure; therefore,
if diagnostic suspicion is high, treatment should not
be withheld for the several days to weeks often
required to obtain laboratory confirmation.
o Succimer has also been effective in animal models
and has a higher therapeutic index
than dimercaprol.
o Acute arsenic poisoning results in severe
gastrointestinal discomfort, vomiting, “rice-water”
Balanquit, Bernardo, Broas, Capellan, Caringal |9
 stools, and capillary damage with dehydration
and shock.
o A sweet, garlicky odor may be detected in the
breath and the stools.
o Treatment consists of supportive therapy to
replace water and electrolytes, and chelation
therapy with dimercaprol.
2. Chronic arsenic poisoning*
o Chronic inorganic arsenic poisoning also results
in multisystemic signs and symptoms.
o Overt noncarcinogenic effects may be evident
after chronic absorption of more than 0.01
mg/kg/d (~500–1000 mcg/d in adults).
o The time to appearance of symptoms varies
with dose and interindividual tolerance.
o Constitutional symptoms of fatigue, weight loss,
and weakness may be present, along with
anemia, nonspecific gastrointestinal complaints,
and a sensorimotor peripheral neuropathy,
particularly featuring a stocking glove pattern
of dysesthesia.
o Skin changes—among the most characteristic
effects—typically develop after years of
exposure and include a “raindrop” pattern of
hyperpigmentation, and hyperkeratosis
involving the hands and feet.
o Peripheral vascular disease and noncirrhotic
portal hypertension may also occur.
o Epidemiologic studies suggest a possible link to
hypertension, cardiovascular disease mortality,
diabetes, chronic nonmalignant respiratory
disease, and adverse reproductive outcomes.
o Cancer of the lung, skin, bladder, and possibly
other sites, including the kidney and liver, may
appear years after exposure to doses of arsenic
that are not high enough to elicit other acute
or chronic effects.
o Some studies suggest that tobacco smoking
may interact synergistically with arsenic in
increasing the risk of certain adverse health
outcomes.
o Chronic arsenic intoxication causes skin
changes, hair loss, bone marrow depression
and anemia, and chronic nausea and
gastrointestinal disturbances.
o Dimercaprol therapy appears to be of value.
Arsenic is a known human carcinogen.
Dermatologic lesions associated with chronic
ingestion of arsenic in drinking water
o Administration of arsenite in cancer chemotherapy
regimens, often at a daily dose of 10–20 mg for
weeks to a few months, has been associated with
prolongation of the QT interval on the
electrocardiogram and occasionally has resulted in
malignant ventricular arrhythmias such as torsades
de pointes.
o The diagnosis of chronic arsenic poisoning involves
integration of the clinical findings with confirmation
of exposure.
o The urine concentration of the sum of inorganic
arsenic and its primary metabolites MMA and DMA
is <20 mcg/L in the general population.
o High urine levels associated with overt adverse
effects may return to normal within days to weeks
after exposure ceases. Because it may contain
large amounts of nontoxic organoarsenic such as
arsenobetaine, or arsenosugars that are
metabolized to DMA, all seafood should be avoided
for at least 3 days before submission of a urine
sample for diagnostic purposes.
o The arsenic content of hair and nails (normally <1
ppm) may sometimes reveal past elevated
exposure, but results should be interpreted
cautiously in view of the potential for external
contamination.
o Segmental analysis of hair or nails using sensitive
methods such as neutron activation analysis or
synchrotron radiation sources may sometimes
have forensic value for investigation of the
temporal pattern of arsenic poisoning.
o Management of chronic arsenic poisoning consists
primarily of termination of exposure and
nonspecific supportive care.
o Although empiric short-term oral chelation
with unithiol or succimer for symptomatic
individuals with elevated urine arsenic
concentrations may be considered, it has no
proven benefit beyond removal from exposure
alone.
o Preliminary studies suggest that dietary
supplementation of folate—thought to be a
cofactor in arsenic methylation—might be of value
in arsenic-exposed individuals, particularly men,
who are also deficient in folate.
3. Arsine gas*
o Arsine gas poisoning produces a distinctive pattern
of intoxication dominated by profound hemolytic
effects.
o After a latent period that may range from 2 to 24
hours post inhalation (depending on the magnitude
of exposure), massive intravascular hemolysis may
occur.
o Initial symptoms may include malaise, headache,
dyspnea, weakness, nausea, vomiting, abdominal
pain, jaundice, and hemoglobinuria.
Balanquit, Bernardo, Broas, Capellan, Caringal |10
 o Oliguric renal failure, a consequence of
hemoglobin deposition in the renal tubules,
often appears within 1–3 days.
o In massive exposures, lethal effects on cellular
respiration may occur before renal failure
develops.
o Urinary arsenic levels are elevated but are
seldom available to confirm the diagnosis
during the critical period of illness.
o Intensive supportive care—including exchange
transfusion, vigorous hydration, and, in the
case of acute renal failure, hemodialysis—is the
mainstay of therapy.
o Arsine gas (AsH3), an occupational hazard, is
formed during the refinement and processing
of certain metals and is used in the
semiconductor industry.
o Arsine causes a unique form of toxicity
characterized by massive hemolysis.
o Pigment overload from erythrocyte breakdown
can cause renal failure.
o Treatment is supportive. Currently available
chelating agents have not been demonstrated
to be of clinical value in arsine poisoning.
Raindrop Pattern
• Hyperpigmentation and hyperkeratosis involving
hands and feet
– Rain drop pattern as you can see in the pictures
are patterns of hyperpigmentation in keratosis
involving the hands and the feet
• Usually due to chronic inorganic arsenic poisoning
– One characteristic finding in chronic inorganic
arsenic poisoning is what we call a raindrop
pattern in the skin
– Skin changes is among the most characteristic
effect typically develops after years of exposure
Dermatologic lesions associated with chronic
ingestion of arsenic in drinking water.
Treatment for Arsenic
• Immediate termination of exposure, supportive care,
and chelation therapy
– The cornerstone of treatment in immediate
determination of exposure, supportive care
whether they're intensive or regular supportive
care and chelation therapy
• Gut decontamination if appropriate/needed
• Acute Poisoning (for acute poisoning the choice is):
Chelation with Unithiol 3-5mg/kg every 4-6 hours or
Dimercaprol every 4-6 hours
C. Mercury
• Now in the last is the most famous of them all probably
mercury, the liquid metal or also known as quicksilver
• You've probably heard of this in the news when DOH
closes down schools or facilities when there's mercury
spill
• Why is this done and why is it important?
• Minamata Disease (1950s)
– In 1950s, there was this incident called Minamata
disease, secondary to mercury poisoning.
– In the early 1950s, residents of Minamata, a small
coastal city in southern Japan, began observing some
startling animal behavior.
– First, cats and dogs would suddenly foam in the mouth,
birds would crash land, fish would explicitly go belly-
up. Before long, humans too were suffering from what
became known as Minamata disease.
– Patients developed slurring of speech, stumbled about
and had trouble with simple tasks such as buttoning
buttons.
– The culprit finally emerged in 1959 when it was
determined that the chemical company Chisso
Corporation, one of Minamata’s biggest employers
was dumping mercury in the sea as part of its
manufacturing process and that this toxin was
poisoning people and animals as well for a local who
ate local seafood.
– Chisso continued releasing mercury tainted
wastewater until 1968 reportedly causing at least two
thousand more deaths as well as birth defects,
paralysis and other maladies
– In commemoration of the Minamata disease in 2013
under the International Minamata Convention, 128
countries committed to the worldwide phase-out of by
2020 of mercury
– Philippines is one country who signed this into law as
well
• Quicksilver or liquid metal
– Mercury is also known as your Quicksilver or liquid
metal because it is the only metal that is liquid in
ordinary conditions or temperature
• Today it has been largely removed in the instruments
like BP apparatuses and thermometers, but we still
encounter them in some folk medicine, antiseptics, and
cosmetic skin lightening products, the unregulated ones.
• Mined predominantly as HgS in cinnabar ores
• Also found in electrolytic production of chlorine and
caustic soda, electrical equipment, thermometers,
instruments, fluorescent lamps, dental amalgams,
artisanal gold production.
• Environmental release of mercury from burning of fossil
fuels contributes to bioaccumulation in fishes.
– Again in 2013, under Minamata Convention, 128
countries committed to the worldwide phase-out of
numerous products like thermometers, pesticides, and
Balanquit, Bernardo, Broas, Capellan, Caringal |11
 batteries by 2020. By 2025, manufacturing
processes like chloralkaline production will be
banned. The Philippines is one of the countries
that signed [in the Convention].
• *Metallic mercury as “quicksilver”—the only metal
that is liquid under ordinary conditions—has
attracted scholarly and scientific interest from
antiquity.
• *The mining of mercury was early recognized as
being hazardous to health.
• *As industrial use of mercury became common
during the last 200 years, new forms of toxicity were
recognized that were found to be associated with
various transformations of the metal.
• *In the early 1950s, a mysterious epidemic of birth
defects and neurologic disease occurred in the
Japanese fishing village of Minamata.
• *The causative agent was determined to be
methylmercury in contaminated seafood, traced to
industrial discharges into the bay from a nearby
factory.
• *In addition to elemental mercury and alkylmercury
(including methylmercury), other key mercurial
include inorganic mercury salts and aryl mercury
compounds, each of which exerts a relatively unique
pattern of clinical toxicity.
• *Mercury is mined predominantly as HgS in cinnabar
ore and is then converted commercially to a variety
of chemical forms.
• *Key industrial and commercial applications of
mercury are found in the electrolytic production of
chlorine and caustic soda; the manufacture of
electrical equipment, thermometers, and other
instruments; fluorescent lamps; and dental
amalgam.
• *The widespread use of elemental mercury in
artisanal gold production is a problem in many
developing countries.
• *Mercury use in pharmaceuticals and in biocides has
declined substantially in recent years, but occasional
use in antiseptics, folk medicines, and cosmetic skin-
lightening creams is still encountered.
• *Thimerosal, an organomercurial preservative that
is metabolized in part to ethyl mercury, has been
removed from almost all the vaccines in which it was
formerly present.
• *Environmental releases of mercury from the
burning of fossil fuels, which contributes to the
bioaccumulation of methylmercury in fish, remains a
concern in some regions of the world.
• *Low-level exposure to mercury released from
dental amalgam fillings occurs, but systemic toxicity
from this source has not been established.
• *The main source of inorganic mercury as a toxic
hazard is through the use of mercury-containing
materials in dental laboratories and in the
manufacture of wood preservatives, insecticides,
and batteries.
• *Organic mercury compounds are used as seed
dressings (treatments to prevent fungal and bacterial
infection of seed and to improve the seed’s dispersion
and adhesiveness) and fungicides.
Pharmacokinetics
• Inhalation is one of the major common occupational
sources of chemical poisoning
• Absorption varies depending on the chemical form
• Usually absorbed from the lungs, GI tract, and
percutaneous tissues route
• Distributed well in the tissues (most concentrated in
the kidneys)
– therefore, a fraction of this is retained in the
kidneys and the brain as well for months to years
• Excreted via urine and feces
• *The absorption of mercury varies considerably
depending on the chemical form of the metal.
• *Elemental mercury is quite volatile and can be
absorbed from the lungs.
• *It is poorly absorbed from the intact gastrointestinal
tract.
• *Inhaled mercury is the primary source of
occupational exposure.
• *Organic short chain alkylmercury compounds are
volatile and potentially harmful by inhalation as well
as by ingestion.
• *Percutaneous absorption of metallic mercury and
inorganic mercury can be of clinical concern following
massive acute or long-term chronic exposure.
• *Alkylmercury compounds appear to be well
absorbed through the skin, and acute contact with a
few drops of dimethylmercury has resulted in severe,
delayed toxicity.
• *After absorption, mercury is distributed to the
tissues within a few hours, with the highest
concentration occurring in the kidney.
• *Inorganic mercury is excreted through the urine and
feces. Excretion of inorganic mercury follows a
multicompartment model: most is excreted within
weeks to months, but a fraction may be retained in
the kidneys and brain for years.
• *After inhalation of elemental mercury vapor, urinary
mercury levels decline with a half-life of
approximately 1–3 months.
• *Urine mercury concentration is <1.5 mcg/L in most
individuals without occupational exposure, and the
median general population urine mercury
concentration in the 2015–2016 NHANES study was
less than the limit of detection of 0.13 mcg/L.
• *Methylmercury, which has a blood and whole-body
half-life of approximately 50 days, undergoes biliary
excretion and enterohepatic circulation, with more
than two thirds eventually excreted in the feces.
• *The geometric mean total blood mercury
concentration in the US population in the 2015–2016
NHANES was 0.678 mcg/L; the 95th percentile was
4.25 mcg/L (~90% present as methylmercury).
Balanquit, Bernardo, Broas, Capellan, Caringal |12
 • *Mercury binds to sulfhydryl groups in keratinized o Acute ingestion of inorganic mercury salts, such as
tissue, and as with lead and arsenic, traces appear in mercuric chloride, can result in a corrosive,
the hair and nails. potentially life-threatening hemorrhagic
• *Mercury in hair has served as a valid biomarker of gastroenteritis followed within hours to days by
methylmercury exposure over an interval of weeks to acute tubular necrosis and oliguric renal failure.
months in epidemiologic studies. o Acute mercury poisoning usually occurs through
inhalation of inorganic elemental mercury.
Mercury Intoxication o It causes chest pain, shortness of breath, nausea
Elemental Inorganic Organic and vomiting, kidney damage, gastroenteritis, and
Mercury Mercury Mercury CNS damage.
Major Respiratory GI, skin GI, skin, o In addition to intensive supportive care, prompt
Routes Tract (minor) resp. tract chelation with oral succimer or with
(minor) intramuscular dimercaprol is essential.
Distributi Soft tissues, Soft tissues Soft o Acute ingestion of mercuric chloride causes a
on esp. kidneys esp. kidneys tissues
severe, life-threatening hemorrhagic
and CNS
Major CNS: Tremor, Acute Renal CNS
gastroenteritis followed within hours to days by
Clinical behavioral Tubular effects; acute tubular necrosis and oliguric renal failure.
Findings (erethism); Necrosis; birth
gingivostomat gastroenteri defects 2. Chronic Mercury Poisoning*
itis, peripheral tis, CNS o Chronic poisoning from inhalation of mercury vapor
neuropathy; effects results in a classic triad of tremor, neuropsychiatric
acrodynia; (rare) disturbance, and gingivostomatitis.
pneumonitis o The tremor usually begins as a fine intention
Mechanis Inhibits Inhibits Inhibits
tremor of the hands, but the face may also be
m of enzymes; enzymes; enzymes,
involved, and progression to choreiform
Action alters alters alter
membranes membranes microtubul movements of the limbs may occur.
es, o Neuropsychiatric manifestations, including memory
neuronal loss, fatigue, insomnia, and anorexia, are common.
defects o There may be an insidious change in mood to
Metabolis Urine (major), Urine Deacylatio shyness, withdrawal, and depression along with
m and feces (minor) n+ explosive anger or blushing (a behavioral pattern
Eliminati Fecal referred to as erethism).
on (alkyl, o Recent studies suggest that low-dose exposure
major),
may produce subclinical neurologic effects.
urine
(after o Gingivostomatitis, sometimes accompanied by
diacylation loosening of the teeth, may be reported after high-
, minor) dose exposure.
• Erethism muscularis or what you call the “Mad o Evidence of peripheral nerve damage may be
Hatter’s Disease” a neurological disorder that is detected on electrodiagnostic testing, but overt
characterized by irritability, low self-confidence, peripheral neuropathy is rare.
depression, apathy, shyness, and in some cases and o Acrodynia is an uncommon idiosyncratic reaction to
long exposure can cause delirium, personality subacute or chronic mercury exposure and occurs
changes and memory loss. mainly in children.
• +Deacylation in the liver o It is characterized by painful erythema of the
extremities and may be associated with
Major Forms of Mercury Intoxication* hypertension, diaphoresis, anorexia, insomnia,
• Mercury interacts with sulfhydryl groups in vivo, irritability or apathy, and a miliary rash.
inhibiting enzymes and altering cell membranes. o Chronic exposure to inorganic mercury salts,
• The pattern of clinical intoxication from mercury sometimes via topical application in cosmetic skin-
depends to a great extent on the chemical form of lightening creams, has been associated with
the metal and the route and severity of exposure. neurological symptoms and renal toxicity in case
reports and case series.
1. Acute Mercury Poisoning* o Severe methylmercury intoxication from illicitly
o Acute inhalation of elemental mercury vapors produced skin-lightening creams has been
may cause chemical pneumonitis and reported.
noncardiogenic pulmonary edema. o Methylmercury intoxication affects mainly the CNS
o Acute gingivostomatitis may occur, and and results in facial and peripheral paresthesias,
neurologic sequelae (see following text) may ataxia, hearing impairment, dysarthria,
also ensue.

Balanquit, Bernardo, Broas, Capellan, Caringal |13

 neuropsychiatric disturbance, and progressive
constriction of the visual fields.
o Signs and symptoms of methylmercury
intoxication may first appear several weeks or
months after exposure begins.
o Methylmercury is a reproductive toxin. High-
dose prenatal exposure to methylmercury may
produce severe intellectual disability and a
cerebral palsy-like syndrome in the offspring.
o Low-level prenatal exposures to methylmercury
have been associated with a risk of subclinical
neurodevelopmental deficits.
o Dimethylmercury is a rarely encountered but
extremely neurotoxic form of organomercury
that may result in delayed lethality following
exposure to minute quantities.
o Chronic mercury poisoning may occur with
inorganic or organic mercury.
o Poisoning from inhalation of mercury vapor
presents as a diffuse set of symptoms involving
the gums and teeth, gastrointestinal
disturbances, and neurologic and behavioral
changes (erethism).
o Chronic mercury intoxication has been treated
with succimer and unithiol, but their efficacy
has not been established.
o Dimercaprol may redistribute mercury to the
CNS and should not be used in chronic
exposure to elemental mercury.
3. Organic Mercury Poisoning*
o Intoxication with organic mercury compounds
was first recognized in connection with an
epidemic of neurologic and psychiatric disease
in the village of Minamata, Japan, which was
first noticed in the 1950s.
o The outbreak was a result of consumption of
fish containing a high content of
methylmercury, which was produced by
bacteria in seawater from mercury in the
effluent of a nearby vinyl plastics-
manufacturing plant.
o Similar epidemics have resulted from the
consumption of grain that was intended for use
as seed and treated with fungicidal organic
mercury compounds.
o Treatment with chelators has been tried, but
the benefits are uncertain.
Treatment
• Cornerstone of treatment is the same with two
previous heavy metals:
• Immediate removal from the source, supportive
care, and chelation therapy
• Acute: unithiol, dimecaprol, succimer
• Dimecaprol should never be used for the elemental
or organic mercury intoxication (due to
redistribution)
A. Acute Exposure*
– In addition to intensive supportive care, prompt
chelation with oral or intravenous unithiol, oral
intramuscular dimercaprol, or oral succimer may be of
value in diminishing nephrotoxicity after acute
overexposure to inorganic mercury salts.
– Vigorous hydration may help to maintain urine output,
but if acute renal failure ensues, days to weeks of
hemodialysis or hemodiafiltration in conjunction with
chelation may be necessary.
– Because the efficacy of chelation declines with time
since exposure, treatment should not be delayed until
the onset of oliguria or other major systemic effects.
B. Chronic Exposure*
– Unithiol and succimer increase urine mercury
excretion following acute or chronic elemental
mercury inhalation, but the impact of such treatment
on clinical outcome is unknown.
– Dimercaprol has been shown to redistribute mercury
to the central nervous system from other tissue sites,
and since the brain is a key target
organ, dimercaprol should not be used in treatment of
chronic exposure to elemental or organic mercury.
– Limited data suggest that succimer, unithiol, and N-
acetyl-L-cysteine (NAC) may enhance body clearance
of methylmercury.
D. Iron*
• Acute poisoning from the ingestion of ferrous
sulfate tablets occurs frequently in small children,
although the incidence of poisonings dropped
dramatically in the United States after iron supplements
were required to be packed in unit-dose packaging.
• The initial symptoms of iron poisoning include vomiting,
gastrointestinal bleeding, lethargy, and gray cyanosis.
• These can be followed by signs of severe
gastrointestinal necrosis, pneumonitis, jaundice,
seizures, and coma.
• Deferoxamine is the chelating agent of choice. Chronic
excessive intake of iron can lead to hemosiderosis or
hemochromatosis
PHARMACOLOGY OF CHELATORS
• Drugs used to prevent or reverse the toxic effect of
heavy metals on an enzyme of other cellular target, or
to accelerate the elimination of metal from the body
• The ones that we used have treatment or antidote for
metal poisoning
• The basic principle of chelators is that they bind to
metallic ions tightly and render them water-soluble and
ready for excretion
• Chelators come from a Greek word “chela” meaning
“crab’s claw”
• By forming a complex with a heavy metal, it renders the
metal unavailable for toxic interaction with functional
groups of enzyme or other proteins, coenzymes, cellular
nucleophiles, and membranes.
Balanquit, Bernardo, Broas, Capellan, Caringal |14
• Chelating agents contain one or more coordinating
atoms, usually oxygen, sulfur, or nitrogen which
donates a pair electron to a cationic metal to form
one or more covalent bonds, making them water-
soluble and ready for elimination.
• However, there are many limitations to chelating
agents:
• The metal-mobilizing effects of a therapeutic
chelating agent may also redistribute some of the
metal to vital organs
– Like dimercaprol, it has the ability to redistribute
mercury and arsenic to the CNS or brain and at the
same time enhancing urinary excretion
• They may also enhance the excretion of essential
cations (Zinc, Copper)
– Zinc for EDTA
– Zinc and Copper for succimer
• The longer the half-life of a metal in a particular
organ, the less effectively they can be removed by
chelation
– Therefore, it is best given at the acute phase of
toxicity
• *Chelating agents are drugs used to prevent or
reverse the toxic effects of a heavy metal on an
enzyme or other cellular target, or to accelerate the
elimination of the metal from the body.
• *By forming a complex with the heavy metal, the
chelating agent renders the metal unavailable for
toxic interactions with functional groups of enzymes
or other proteins, coenzymes, cellular nucleophiles,
and membranes.
• *Chelating agents contain one or more coordinating
atoms, usually oxygen, sulfur, or nitrogen, which
donate a pair of electrons to a cationic metal ion to
form one or more coordinate-covalent bonds.
• *Depending on the number of metal-ligand bonds,
the complex may be referred to as mono-, bi-, or
polydentate.
• *Chelators used clinically include dimercaprol (BAL),
succimer, unithiol, penicillamine, edetate (EDTA),
deferoxamine, and deferasirox.
• *Variations among these agents in their affinities for
specific metals govern their clinical applications
Salt and chelate formation with edetate
(ethylenediaminetetraacetate, EDTA). (A) In a solution
of the disodium salt of EDTA, the sodium and hydrogen
ions are chemically and biologically available. (B) In
solutions of calcium disodium edetate, calcium is bound
by coordinate-covalent bonds with nitrogens as well as
by the usual ionic bonds. (C) In the lead–edetate
chelate, lead is incorporated into five heterocyclic rings.
• *In some cases, the metal-mobilizing effect of a
therapeutic chelating agent may not only enhance that
metal’s excretion—a desired effect—but may also
redistribute some of the metal to other vital organs.
• *This has been demonstrated for dimercaprol, which
redistributes mercury and arsenic to the brain while also
enhancing urinary mercury and arsenic excretion.
• *Although several chelating agents have the capacity to
mobilize cadmium, their tendency to redistribute
cadmium to the kidney and increase nephrotoxicity has
negated their therapeutic value in cadmium intoxication.
• *In addition to removing the target metal that is
exerting toxic effects on the body, some chelating
agents may enhance excretion of essential cations, such
as zinc in the case of calcium EDTA and
diethylenetriaminepentaacetic acid (DTPA), and zinc
and copper in the case of succimer.
• *No clinical significance of this effect has been
demonstrated, although some animal data suggest the
possibility of adverse developmental impact.
• *If prolonged chelation during the prenatal period or
early childhood period is necessary, judicious
supplementation of the diet with zinc might be
considered.
• *The longer the half-life of a metal in a particular organ,
the less effectively it will be removed by chelation. For
example, in the case of lead chelation with calcium
EDTA or succimer, or of plutonium chelation with DTPA,
the metal is more effectively removed from soft tissues
than from bone, where incorporation into bone matrix
results in prolonged retention.
• *In most cases, the capacity of chelating agents to
prevent or reduce the adverse effects of toxic metals
appears to be greatest when such agents are
administered very soon after an acute metal exposure.
• *Use of chelating agents days to weeks after an acute
metal exposure ends—or their use in the treatment of
chronic metal intoxication—may still be associated with
increased metal excretion.
Balanquit, Bernardo, Broas, Capellan, Caringal |15
• *However, at that point, the capacity of such
enhanced excretion to mitigate the pathologic effect
of the metal exposure may be reduced.
CHELATOR BENEFITS VS DRAWBACKS
• Benefits:
1. Effective against acute poisoning
2. Form non-toxic complexes
o water-soluble complexes
3. Remove metal from soft tissues
4. Oral therapy is available
• Drawbacks:
1. Redistribution of toxic metal
o to other organs of the body
2. Essential metal loss
3. No removal of metal from intracellular sites
4. Hepatoxicity and nephrotoxicity
o glaring side effects
5. Poor clinical recovery
o depending on the phase of the treatment
6. Pro-oxidant effects (DTPA)
o more oxidative stress in produced
7. Headache, nausea, increased blood pressure
CHELATORS OR CHELATING AGENTS
• Dimercaprol
• Succimer
• Edetate Calcium Disodium (EDTA)
• Unithiol
• Penicillamine
– a derivative of penicillin
• Deferoxamine
• Deferasirox
• Deferiprone
• Prussian blue
A. Dimercaprol
• 2,3-Dimercaptopropanolol, BAL
– British Anti-Lewisite
– used as an antidote for a warfare agent known as
lewisite in World War II
• As single-agent treatment of acute poisoning by
arsenic and inorganic mercury
• It prevents the reverses metal-induced inhibition of
sulfhydryl-containing enzyme
• Increases rate of excretion of arsenic and lead
• Given via IM, excreted via kidneys
• Adverse effects: hypertension, tachycardia, nausea,
vomiting, lacrimation, salivation, fever, pain at
injection site, thrombocytopenia, increase in
Prothrombin time.
• Redistributes arsenic and mercury to CNS
• Also used as conjunction therapy with EDTA for
severe lead poisoning.
• *Dimercaprol (2,3-dimercaptopropanol; BAL [British
antilewisite]) is a bidentate chelator; that is, a
chelator that forms 2 bonds with the metal ion,
preventing the metal’s binding to tissue proteins and
permitting its rapid excretion.
• *Dimercaprol, an oily, colorless liquid with a strong
mercaptan-like odor, was developed in Great Britain
during World War II as a therapeutic antidote against
poisoning by the arsenic-containing warfare agent
lewisite.
• *It thus became known as British anti-lewisite, or BAL.
• *Because aqueous solutions of dimercaprol are
unstable and oxidize readily, it is dispensed in 10%
solution in peanut oil and must be administered by
intramuscular injection, which is often painful.
Chemical structures of several chelators. Ferroxamine
(ferrioxamine) without the chelated iron is deferoxamine.
It is represented here to show the functional groups; the
iron is actually held in a caged system. The structures of
the in vivo metal-chelator complexes
for dimercaprol, succimer, penicillamine, and unithiol
(see text) are not known and may involve the formation
of mixed disulfides with amino acids.
• *In animal models, dimercaprol prevents and reverses
arsenic-induced inhibition of sulfhydryl-containing
enzymes and, if given soon after exposure, may protect
against the lethal effects of inorganic and organic
arsenicals.
• *Human data indicate that it can increase the rate of
excretion of arsenic and lead and may offer therapeutic
benefit in the treatment of acute intoxication by arsenic,
lead, and mercury.
1. Clinical use*
o Dimercaprol is used in acute arsenic and mercury
poisoning and, in combination with EDTA, for lead
poisoning.
o It is an oily liquid that must be given parenterally.
2. Indications and Toxicity*
o Dimercaprol is FDA approved as single-agent
treatment of acute poisoning by arsenic and
inorganic mercury and for the treatment of severe
lead poisoning when used in conjunction
with edetate calcium disodium.
Balanquit, Bernardo, Broas, Capellan, Caringal |16
 o Although studies of its metabolism in humans
are limited, intramuscularly administered
dimercaprol appears to be readily absorbed,
metabolized, and excreted by the kidney within
4–8 hours.
o Animal models indicate that it may also
undergo biliary excretion, but the role of this
excretory route in humans and other details of
its biotransformation are uncertain.
o When used in therapeutic doses, dimercaprol is
associated with a high incidence of adverse
effects, including hypertension, tachycardia,
nausea, vomiting, lacrimation, salivation, fever
(particularly in children), and pain at the
injection site.
o Its use has also been associated with
thrombocytopenia and increased prothrombin
time—factors that may limit intramuscular
injection because of the risk of hematoma
formation at the injection site.
o Despite its protective effects in acutely
intoxicated animals, dimercaprol may
redistribute arsenic and mercury to the central
nervous system, and it is not advocated for
treatment of chronic poisoning.
o Water-soluble analogs of dimercaprol—unithiol
and succimer—have higher therapeutic indices
and have replaced dimercaprol in many
settings.
o Dimercaprol causes a high incidence of adverse
effects, possibly because it is highly lipophilic
and readily enters cells.
o Its toxicity includes transient hypertension,
tachycardia, headache, nausea and vomiting,
paresthesias, and fever (especially in children).
o It may cause pain and hematomas at the
injection site.
o Long-term use is associated with
thrombocytopenia and increased prothrombin
time.
B. Succimer
• Succimer (Dimercaptosuccinic Acid DMSA)-
• Water soluble analog of dimercaprol
• Treatment of children with blood lead concentration
of >45 mcg/dL
• It prevents and reverses metal-induced inhibition of
sulfhydryl-containing enzyme
• Increase rate of excretion of lead
• It decreases mercury content in kidney
• Has positive effect against arsenic as well
• Given oral, IV
• Adverse effects: Gi disturbances are the most
common
• Associated with increase in ALT, AST, mild
neutropenia
• *Succimer is a water-soluble analog of dimercaprol,
and like that agent it has been shown in animal
studies to prevent and reverse metal-induced inhibition
of sulfhydryl-containing enzymes and to protect against
the acute lethal effects of arsenic.
• *In humans, treatment with succimer is associated with
an increase in urinary lead excretion and a decrease in
blood lead concentration.
• *It may also decrease the mercury content of the kidney,
a key target organ of inorganic mercury salts.
• *It is absorbed rapidly but somewhat variably after oral
administration. Peak blood levels of succimer occur at
approximately 3 hours. The drug binds in vivo to the
amino acid cysteine to form 1:1 and 1:2 mixed
disulfides, possibly in the kidney, and it may be these
complexes that are the active chelating moieties.
• *Experimental data suggest that multidrug-resistance
protein 2 (Mrp2), one of a group of transporter proteins
involved in the cellular excretion of xenobiotics,
facilitates the renal excretion of mercury compounds
that are bound to the transformed succimer and to
unithiol.
• *The elimination half-time of transformed succimer is
approximately 2–4 hours.
• *Succimer (2,3-dimercaptosuccinic acid; DMSA) is a
water-soluble bidentate congener of dimercaprol.
1. Clinical use*
o Succimer is used for the oral treatment of lead
toxicity in children and adults. It is as effective as
parenteral EDTA in reducing blood lead
concentration.
o Succimer is also effective in arsenic and mercury
poisoning, if given within a few hours of exposure.
2. Indications and Toxicity*
o Succimer is currently FDA approved for the
treatment of children with blood lead
concentrations >45 mcg/dL, but it is also
commonly used in adults.
o The typical dosage is 10 mg/kg orally three times
a day.
o Oral administration of succimer is comparable to
parenteral EDTA in reducing blood lead
concentration and has supplanted EDTA in
outpatient treatment of patients who are capable
of absorbing the oral drug.
o However, despite the demonstrated capacity of
both succimer and EDTA to enhance lead
elimination, their value in reversing established
lead toxicity or in otherwise improving therapeutic
outcome has yet to be established by a placebo-
controlled clinical trial.
o In a recent study in lead-exposed juvenile rats,
high-dose succimer did reduce lead-induced
neurocognitive impairment when administered to
animals with moderate- and high-dose lead
exposure.
o Conversely, when administered to the control
group that was not lead exposed, succimer was
Balanquit, Bernardo, Broas, Capellan, Caringal |17
 associated with a decrement in neurocognitive • *Unithiol exhibits protective effects against the toxic
performance. action of mercury and arsenic in animal models, and it
o Based on its protective effects against arsenic increases the excretion of mercury, arsenic, and lead in
in animals and its ability to mobilize mercury humans.
from the kidney, succimer has also been used • *Animal studies and a few case reports suggest that
in the treatment of arsenic and mercury unithiol may also have usefulness in the treatment of
poisoning. poisoning by bismuth compounds.
o In limited clinical trials, succimer has been well • *A water-soluble derivative of dimercaprol, unithiol can
tolerated. It has a negligible impact on body be administered orally or intravenously.
stores of calcium, iron, and magnesium.
o It induces a mild increase in urinary excretion
of zinc and, less consistently, copper.
o This effect on trace metal balance has not been
associated with overt adverse effects, but its
long-term impact on neurodevelopment is
uncertain.
o Gastrointestinal disturbances, including
1. Clinical use*
anorexia, nausea, vomiting, and diarrhea, are
o Intravenous unithiol is used in the initial treatment
the most common side effects, occurring in
of severe acute poisoning by inorganic mercury or
<10% of patients.
arsenic. Oral unithiol is an alternative
o Rashes, sometimes requiring discontinuation of
to succimer in the treatment of lead intoxication.
the medication, have been reported in <5% of
patients.
2. Indications and Toxicity*
o Mild, reversible increases in liver
o Unithiol has no FDA-approved indications, but
aminotransferases have been noted in <5% of
experimental studies and its pharmacologic and
patients, and isolated cases of mild to
pharmacodynamic profile suggest that intravenous
moderate neutropenia have been reported.
unithiol offers advantages over
o Although succimer appears to be less toxic
intramuscular dimercaprol or oral succimer in the
than dimercaprol, gastrointestinal distress,
initial treatment of severe acute poisoning by
CNS effects, skin rash, and elevation of liver
inorganic mercury or arsenic.
enzymes may occur.
o Aqueous preparations of unithiol (usually 50
mg/mL in sterile water) can be administered at a
C. Unithiol
dosage of 3–5 mg/kg every 4 hours by slow
• Unithiol (Dimercaptopropane Sulfonic Acid, DMPS)
intravenous infusion over 20 minutes.
• Water soluble analog of dimercaprol
o If a few days of treatment are accompanied by
• No FDA-approved indications
stabilization of the patient’s cardiovascular and
• Protective effects against mercury and arsenic
gastrointestinal status, it may be possible to
• Increase urinary excretion of mercury, arsenic and
change to oral administration of 4–8 mg/kg every
lead
6–8 hours.
• Given Orally and IV (slow infusion)
o Oral unithiol may also be considered as an
• Excreted via kidneys
alternative to oral succimer in the treatment of
• Adverse effects: Dermatologic reactions are the
lead intoxication.
most common (urticaria, exanthems, isolated cases
o Intravenous unithiol in conjunction with high-flux
of SJS, erythema multiforme)
hemodialysis or hemodiafiltration may be useful in
the treatment of patients with anuric renal failure
• *Dimercaptopropanesulfonic acid, DMPS
caused by mercury salts and bismuth.
• *Unithiol, a dimercapto chelating agent that is a
o Unithiol has been reported to have a low overall
water-soluble analog of dimercaprol.
incidence of adverse effects (<4%).
• *Unithiol can be administered orally and
o Self-limited dermatologic reactions (drug
intravenously.
exanthems or urticaria) are the most commonly
• *Bioavailability by the oral route is approximately
reported adverse effects, although isolated cases
50%, with peak blood levels occurring in
of major allergic reactions, including erythema
approximately 4 hours.
multiforme and Stevens-Johnson syndrome, have
• *Over 80% of an intravenous dose is excreted in the
been reported.
urine, mainly as cyclic DMPS sulfides.
o Because rapid intravenous infusion may cause
• *The elimination half-time of total unithiol (parent
vasodilation and hypotension, unithiol should be
drug and its transformation products) is
infused slowly over 15–20 minutes.
approximately 20 hours.
o Unithiol causes a low incidence of dermatological
reactions, usually mild.

Balanquit, Bernardo, Broas, Capellan, Caringal |18

 o Vasodilation and hypotension may occur with
rapid intravenous infusion.
D. Penicillamine
• Penicillamine (D-Dimethylcysteine)
• White Crystalline, derivative of Penicillin
• D-Penicillamine is less toxic than the L-isomer form
• Used primarily to treat or prevent Copper poisoning
(i.e. Wilson’s Disease)
• Also used in Severe Rheumatoid Arthritis
• Absorbed via oral route
• Adverse effects: Hypersensitivity, nephrotoxicity
with proteinuria, pancytopenia, pyridoxine and
insufficiency
• *D-Dimethylcysteine
• *Penicillamine is a white, crystalline, water-soluble
derivative of penicillin. D-Penicillamine is less toxic
than the L-isomer and consequently is the preferred
therapeutic form.
• *Penicillamine is readily absorbed from the gut and
is resistant to metabolic degradation.
• *Penicillamine, a derivative of penicillin, is another
bidentate chelator.
1. Clinical use*
o The major uses of penicillamine are in the
treatment of copper poisoning and Wilson’s
disease.
o It is sometimes used as adjunctive therapy in
gold, arsenic, and lead intoxication and in
rheumatoid arthritis.
o The agent is water-soluble, well absorbed from
the gastrointestinal tract, and excreted
unchanged.
2. Indications and Toxicity*
o Penicillamine is used chiefly for treatment of
poisoning with copper or to prevent copper
accumulation, as in Wilson disease
(hepatolenticular degeneration).
o It is also used occasionally in the treatment of
severe rheumatoid arthritis. Its ability to
increase urinary excretion of lead and mercury
had occasioned its use in outpatient treatment
for intoxication with these metals, but succimer,
with its stronger metal-mobilizing capacity and
lower adverse-effect profile, has generally
replaced penicillamine for these purposes.
o Adverse effects have been seen in up to one
third of patients receiving penicillamine.
o Hypersensitivity reactions include rash, pruritus,
and drug fever, and the drug should be used
with extreme caution, if at all, in patients with
a history of penicillin allergy.
o Nephrotoxicity with proteinuria has also been
reported, and protracted use of the drug may
result in renal insufficiency.
o Pancytopenia has been associated with prolonged
drug intake.
o Pyridoxine deficiency is a frequent toxic effect of
other forms of the drug but is rarely seen with
the D isomer.
o An acetylated derivative, N-acetylpenicillamine,
has been used experimentally in mercury poisoning
and may have superior metal-mobilizing capacity,
but it is not commercially available.
o Adverse effects are common and may be severe.
They include nephrotoxicity with proteinuria,
pancytopenia, and autoimmune dysfunction,
including lupus erythematosus and hemolytic
anemia.
E. Ethylenediaminetetraacetic acid or Edetate
calcium disodium
• Edetate Calcium Disodium (Ethylenediaminetetraacetic
acid, EDTA)
• Calcium disodium salt form of EDTA
• Indicated mainly for chelation of lead
• Chelator of zinc, manganese and certain heavy
radionucleotide poisoning
• Chelates extracellular metals ions much more effectively
compared to intracellular metal ions
• Limited oral absorption
• Given IV infusion; Excreted via the kidney
• This one is very famous. It’s used in your purple-top to
prevent coagulation blood. In the case of heavy metals,
the sodium salt form of the EDTA is used because a
calcium form reduces the potential depletion of calcium
stores in the body which is life-threatening and is
indicated mainly for creation of lead chelator zinc, as
well as manganese and heavy radionucleotide poisoning.
It has a propensity to clip extracellular metal ions much
more effectively compared to intracellular metal ions
because it penetrates poorly to the cell membrane. It
has a limited oral absorption because it is polar, and it
may increase absorption of lead if it’s in the gut as well.
• *Ethylenediaminetetraacetic acid is an efficient chelator
of many divalent and trivalent metals in vitro.
• *To prevent potentially life-threatening depletion of
calcium, treatment of metal intoxication should only be
performed with the calcium disodium salt form of EDTA
(edetate calcium disodium).
• *EDTA penetrates cell membranes relatively poorly and
therefore chelates extracellular metal ions much more
effectively than intracellular ions.
• *The highly polar ionic character of EDTA limits its oral
absorption. Moreover, oral administration may increase
lead absorption from the gut.
• *Consequently, EDTA should be administered by
intravenous infusion.
• *In patients with normal renal function, EDTA is rapidly
excreted by glomerular filtration, with 50% of an
injected dose appearing in the urine within 1 hour.
Balanquit, Bernardo, Broas, Capellan, Caringal |19
• *EDTA mobilizes lead from soft tissues, causing a
marked increase in urinary lead excretion and a
corresponding decline in blood lead concentration.
• *In patients with renal insufficiency, excretion of the
drug—and its metal-mobilizing effects—may be
delayed.
• *Ethylenediaminetetraacetic acid (EDTA; edetate) is
an efficient polydentate chelator of many divalent
cations, including calcium, and trivalent cations.
1. Clinical use*
o The primary use of EDTA is in the treatment of
lead poisoning. Because the agent is highly
polar, it is given parenterally.
o To prevent dangerous hypocalcemia, EDTA is
given as the calcium disodium salt.
2. Indications and Toxicity*
o Edetate calcium disodium is indicated chiefly
for the chelation of lead, but it may also have
usefulness in poisoning by zinc, manganese,
and certain heavy radionuclides.
o A randomized, double-blind, placebo-controlled
prospective trial of edetate
disodium (not edetate calcium disodium)
observed a significant decrease in
cardiovascular events in a subgroup consisting
of diabetic patients with a prior history of
myocardial infarction.
o A follow-up randomized, placebo-controlled
trial of edetate disodium chelation in a larger
cohort of post-MI diabetic subjects is underway.
o Because the drug and the mobilized metals are
excreted via the urine, the drug is relatively
contraindicated in anuric patients.
o In such instances, the use of low doses of EDTA
in combination with high-flux hemodialysis or
hemofiltration has been described.
o Nephrotoxicity from EDTA has been reported,
but in most cases can be prevented by
maintenance of adequate urine flow, avoidance
of excessive doses, and limitation of a
treatment course to 5 or fewer consecutive
days.
o EDTA may result in temporary zinc depletion
that is of uncertain clinical significance.
o Analogs of EDTA, the calcium and zinc
disodium salts of DTPA,
diethylenetriaminepentaacetate, have been
used for removal (“decorporation”) of certain
transuranic, rare earth, and transition metal
radioisotopes, and in 2004 were approved by
the FDA for treatment of contamination with
plutonium, americium, and curium.
o The most important adverse effect of the agent
is nephrotoxicity, including renal tubular
necrosis.
o This risk can be reduced by adequate hydration
and restricting treatment with EDTA to 5 days or
less.
o Electrocardiographic changes can occur at high
doses.
F. Deferoxamine*
• Deferoxamine is isolated from Streptomyces pilosus.
• It binds iron avidly but binds essential trace metals
poorly. Furthermore, though competing for loosely
bound iron in iron-carrying proteins (hemosiderin and
ferritin), it fails to compete for biologically chelated iron,
as in microsomal and mitochondrial cytochromes and
hemoproteins.
• Consequently, it is the parenteral chelator of choice for
iron poisoning.
• Deferoxamine has recently been investigated as a
potential means to reduce secondary neuronal injury by
iron released from hematomas after spontaneous
cerebral hemorrhage.
• Deferoxamine plus hemodialysis may also be useful in
the treatment of aluminum toxicity in renal failure.
• Deferoxamine is poorly absorbed when administered
orally and may increase iron absorption when given by
this route.
• It should therefore be administered intramuscularly or,
preferably, intravenously.
• It is believed to be metabolized, but the pathways are
unknown.
• The iron-chelator complex is excreted in the urine, often
turning the urine an orange-red color.
• Rapid intravenous administration may result in
hypotension.
• Adverse idiosyncratic responses such as flushing,
abdominal discomfort, and rash have also been
observed.
• Pulmonary complications (eg, acute respiratory distress
syndrome) have been reported in some patients
undergoing deferoxamine infusions lasting longer than
24 hours, and neurotoxicity and increased susceptibility
to certain infections (eg, with Yersinia enterocolitica)
have been described after long-term therapy of iron
overload conditions (eg, thalassemia major).
• Deferoxamine is a polydentate bacterial product with
an extremely high and selective affinity for iron and a
much lower affinity for aluminum. Fortunately, the drug
competes poorly for heme iron in hemoglobin and
cytochromes.
1. Clinical use
o Deferoxamine is used parenterally in the
treatment of acute iron intoxication and in the
treatment of iron overload caused by blood
transfusions in patients with diseases such as
thalassemia or myelodysplastic syndrome.
2. Toxicity
o Skin reactions (blushing, erythema, urticaria) may
occur. With long-term use, neurotoxicity (eg,
Balanquit, Bernardo, Broas, Capellan, Caringal |20
 retinal degeneration), hepatic and renal
dysfunction, and severe coagulopathies have
been reported.
o Rapid intravenous administration of
deferoxamine can cause histamine release and
hypotensive shock.
G. Deferasirox and Deferipone*
• Deferasirox is a newer tridentate chelator with
selectively high affinity for iron.
• Deferasirox is an oral drug approved for treatment
of iron overload.
• Deferasirox is a tridentate chelator with a high
affinity for iron and low affinity for other metals, eg,
zinc and copper. It is orally active and well absorbed.
• In the circulation, it binds iron, and the complex is
excreted in the bile.
• Deferasirox was approved by the FDA in 2005 for
the oral treatment of iron overload caused by blood
transfusions, a problem in the treatment of
thalassemia and myelodysplastic syndrome.
• More than 5 years of clinical experience suggest that
daily long-term usage is generally well tolerated,
with the most common adverse effects consisting of
mild to moderate gastrointestinal disturbances and
skin rash.
• Monitoring of liver and renal function has been
advised because renal and liver impairment and
failure associated with deferasirox have been
reported during treatment of older adults with
myelodysplastic syndromes.
• Deferiprone, a bidentate iron chelator cleared
predominantly via the kidney, was approved by the
FDA in 2011 as a second-line oral chelator for
patients with transfusional iron overload due to
thalassemia.
• Compared to deferasirox, deferiprone appears to be
relatively more efficient in decreasing cardiac iron
but less efficient in decreasing hepatic iron.
• Because neutropenia has occurred in 5–10% of
patients, with agranulocytosis in approximately 1%,
regular hematologic monitoring is recommended.
• Magnetic resonance imaging has been increasingly
used to evaluate cardiac and hepatic iron burden
and to guide iron chelation therapy.
• Regimens that combine iron-chelating agents have
been used in cases when monotherapy has yielded
suboptimal results.
H. Prussian Blue
• Prussian Blue (Ferric Hexacyanoferrate)
• Indicated for treatment of contamination with
radioactive Cesium and intoxication with thallium
salts
• Ion exchange and mechanical trapping or
absorption
• Given orally, minimal GI absorption (<1%), excreted
via feces
• Adverse Effects: Constipation
• *Ferric Hexacyanoferrate
• *Ferric hexacyanoferrate (insoluble Prussian blue)
is a hydrated crystalline compound in which Fe2+ and
Fe3+ atoms are coordinated with cyanide groups in a
cubic lattice structure.
• *Although used as a dark blue commercial pigment for
nearly 300 years, it was only three decades ago that its
potential usefulness as a pharmaceutical chelator was
recognized.
• *Primarily by ion exchange, and secondarily by
mechanical trapping or adsorption, the compound has
high affinity for certain univalent cations, particularly
cesium and thallium.
• *Used as an oral drug, insoluble Prussian blue
undergoes minimal gastrointestinal absorption (<1%).
Because the complexes it forms with cesium or thallium
are nonabsorbable, oral administration of the chelator
diminishes intestinal absorption or interrupts
enterohepatic and enteroenteric circulation of these
cations, thereby accelerating their elimination in the
feces.
• *In clinical case series, the use of Prussian blue has
been associated with a decline in the biologic half-life
(ie, in vivo retention) of radioactive cesium and thallium.
• *Prussian blue is a hydrated crystalline compound in
which Fe2+ and Fe3+ atoms are coordinated with
cyanide groups in a cubic lattice structure.
• *Prussian blue is approved for the treatment of
contamination with radioactive cesium (137Cs) and
intoxication with thallium salts.
1. Indications and Toxicity*
o Prussian blue has not been associated with
significant adverse effects. Constipation, which
may occur in some cases, should be treated with
laxatives or increased dietary fiber.
SKILL KEEPER ANSWERS: IRON DEFICIENCY*
• Iron is the essential metallic element of heme, the
molecule responsible for the bulk of oxygen transport in
the blood.
• How is the iron content of the body regulated?
– Regulation of total body iron occurs through a tightly
regulated system of intestinal absorption. Iron is
absorbed and either stored in mucosal cells as ferritin
or transported into blood and distributed throughout
the body bound to transferrin. Most of the iron in the
body is present in hemoglobin. Small quantities of iron
are eliminated in sweat, saliva, and the exfoliation of
skin and mucosal cells.
• How is the iron deficiency diagnosed and
treated?
– Iron deficiency can be diagnosed from red blood cell
changes, including microcytic size and decreased
hemoglobin content, and from measurement of serum
Balanquit, Bernardo, Broas, Capellan, Caringal |21
 and bone marrow iron stores. Iron deficiency
anemia is treated by dietary oral ferrous iron
supplements or, in severe cases, parenteral
administration of a colloid containing a core of iron
oxyhydroxide surrounded by a shell of
carbohydrate.

HIGH-YIELD TERMS TO LEARN*

Chelating A molecule with 2 or more
agent electronegative groups that can
form stable coordinate complexes
with multivalent cationic metal
atoms
Erethism Syndrome resulting from mercury
poisoning characterized by
insomnia, memory loss, excitability,
and delirium
Plumbism A range of toxic syndromes due to
chronic lead poisoning that may
vary as a function of blood or tissue
levels and patient age

Balanquit, Bernardo, Broas, Capellan, Caringal |22

 MT6314: PHARMACOLOGY & TOXICOLOGY DMT 2023
CHAPTER 57: HEAVY METALS INTOXICATION & CHELATORS

IMPORTANT CHARACTERISTICS OF THE TOXICOLOGY OF LEAD, ARSENIC, MERCURY, AND IRON*

Route of Target Organs for
Metal Form Entering Body Treatment
Absorption Toxicity
Lead Inorganic lead oxides and salts Gastrointestinal, Hematopoietic Dimercaprol, EDTA,
respiratory, skin system, CNS, kidneys succimer, unithiol
Tetraethyl lead (minor) CNS Seizure control
Arsenic Inorganic arsenic salts All mucous surfaces Capillaries, Dimercaprol, unithiol,
gastrointestinal tract, succimer,
hematopoietic system penicillamine
Arsine gas Inhalation Erythrocytes Supportive
Mercury Elemental Inhalation CNS, kidneys Succimer, unithiol
Inorganic salts Gastrointestinal Kidneys, Succimer, unithiol,
gastrointestinal tract penicillamine,
dimercaprol
Organic mercurials Gastrointestinal CNS Supportive
Iron Ferrous sulfate Gastrointestinal Gastrointestinal, CNS, Deferoxamine,
blood deferasirox

DRUG SUMMARY TABLE: HEAVY METAL CHELATORS*

Mechanism Clinical
Drugs Pharmacokinetics Toxicities, Interactions
of Action Applications
EDTA Chelator of Lead poisoning – Parenteral Administered as calcium disodium
(ethylenediamine- many divalent poisoning by zinc, salt to avoid calcium depletion –
tetraacetic acid; and trivalent manganese, and nephrotoxicity, ECG changes
edetate) metals certain heavy
radionuclides
Deferoxamine Chelates Acute iron Preferred route of Rapid IV administration may cause
excess iron poisoning – administration: hypotension – neurotoxicity and
inherited or intramuscular or increased susceptibility to certain
acquired subcutaneous infections have occurred with long
hemochromatosis term use
Deferasirox Oral iron chelator for treatment of hemochromatosis
Dimercaprol Bidentate Arsenic and Parenteral Transient hypertension,
chelator forms inorganic mercury tachycardia, headache, nausea,
2 bonds with poisoning – vomiting, paresthesias, fever –
metal ions combined with thrombocytopenia and increased
EDTA for lead prothrombin time with long term
poisoning use
Succimer Water-soluble congener of dimercaprol used for oral treatment of lead poisoning
Unithiol Water-soluble congener of dimercaprol used intravenously for initial treatment of severe
mercury or arsenic poisoning and used orally for lead poisoning
Penicillamine Bidentate Copper poisoning Oral Nephrotoxicity, pancytopenia,
chelator and Wilson’s autoimmune dysfunction, including
disease lupus erythematosus and hemolytic
anemia

TOXICOLOGY OF SELECTED ARSENIC, LEAD, AND MERCURY COMPOUNDS*

Form Metabolism
Major Route Major Clinical Key Aspects of
Entering Distribution and
of Absorption Effects Mechanism
Body Elimination
Arsenic Inorganic Gastrointestinal, Predominantly Cardiovascular: Inhibits Methylation.
arsenic respiratory (all soft tissues shock, arrythmias. enzymes; Renal
salts mucosal (highest in CNS: encephalopathy, interferes with (major);
surfaces) liver, kidney). peripheral oxidative sweat and
Avidly bound neuropathy. phosphorylation; feces (minor)
Gastroenteritis; alters cell

Balanquit, Bernardo, Broas, Capellan, Caringal |23

 in skin, hair, pancytopenia; cancer signaling, gene
nails (many sites) expression
Lead Inorganic Gastrointestinal, Soft tissues; CNS deficits; Inhibits Renal
lead respiratory redistributed peripheral enzymes; (major);
oxides and to skeleton neuropathy; anemia; interferes with feces and
salts (>90% of nephropathy; essential cations; breast milk
adult body hypertension; alters membrane (minor)
burden) reproductive toxicity structure
Organic Skin, Soft tissues, Encephalopathy Hepatic Urine and
(tetraethyl gastrointestinal, especially dealkylation feces
lead) respiratory liver, CNS (fast) → trialkyl (major);
metabolites sweat (minor)
(slow) →
dissociation to
lead
Mercury Elemental Respiratory tract Soft tissues, CNS: tremor, Inhibits Elemental Hg
mercury especially behavioral enzymes; alters converted to
kidney, CNS (erethism); membranes Hg 2+. Urine
gingivostomatitis, (major);
peripheral feces (minor)
neuropathy;
acrodynia;
pneumonitis (high
dose)
Inorganic Gastrointestinal, Soft tissues, Acute renal tubular Inhibits Urine
Hg+ (less skin (minor) especially necrosis; enzymes; alters
toxic); Hg kidney gastroenteritis; CNS membranes
2+ (more effects (rare)
toxic)
Organic: Gastrointestinal, Soft tissues CNS effects, birth Inhibits Diacylation.
alkyl, aryl skin, respiratory defects enzymes; alters Fecal (alkyl
(minor) microtubules, major); urine
neuronal (Hg 2+ after
structure diacylation,
minor)

PREVENTION OF LEAD POISONING: AN ONGOING EFFORT*

Exposure Sources Examples of Preventive Measures
Home Exposure The US Environmental Protection Agency’s (EPA) Lead
• The US Consumer Product Safety Commission adopted Renovation, Repair, and Painting Rule requires that
major restrictions on the use of lead in residential house companies performing renovation, repair, and painting
paint in 1977. Prior to then, thousands of tons of lead projects that disturb lead-based paint in homes, child care
pigments were applied in millions of homes. The American facilities, and preschools built before 1978 have their firm
Healthy Homes Survey (2005-2006) estimated that 35% certified by EPA (or an EPA-authorized state), use certified
of homes had some lead-based paint and 22% had one renovators who are trained by EPA-approved training
or more lead-based paint hazards. providers, and follow lead-safe work practices.
Workplace Exposure Present OSHA rules regarding workplace lead exposure and
• The US Occupational Health and Safety Administration medical removal protection date from the late 1970s and
(OSHA) estimates that more than 1.6 million workers are no longer offer adequate protection. The Occupational Lead
potentially exposed to lead. State and federal OSHA Poisoning Prevention Program of the California Department
programs have established permissible exposure levels of Public Health offers up-to-date, health protective
for lead in workplace air, as well as medical surveillance guidance.
requirements for workers that may mandate periodic
blood lead monitoring.
Water If more than 10% of tap water samples at sites likely to
• Lead may enter drinking water when service pipes or have lead plumbing exceed the lead action level of 15 parts
interior plumbing, fittings, or faucets contain lead, per billion, water systems are required to institute corrosion
especially when the water has high acidity or low mineral control and other measures. The Safe Drinking Water Act,
content that corrodes pipes and plumbing fixtures. amended by the Reduction of Lead in Drinking Water Act

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Children
• Because of normal mouthing behavior, children are at
special risk of exposure to lead present in toys, jewelry,
printed material, and other consumer products.
of 2011, sets limits on the lead content of new plumbing
materials for potable water.
The US Consumer Product Safety Commission has
promulgated rules that limit the amount of lead that can be
present in children’s products.

PREPARATIONS AVAILABLE*
Generic Name Available as
Deferasirox Exjade, Jadenu
Deferiprone Ferripox
Deferoxamine Generic, Desferal
Dimercaprol BAL in oil
Edetate calcium [calcium EDTA] Calcium Disodium Versenate
Penicillamine Cuprimine, Depen
Pentetate Calcium Trisodium [calcium DTPA] and Generic
Pentetate Zinc Trisodium [zinc DTPA]
Prussian Blue Radiogardase
Succimer Chemet, Succicaptal (in Europe)
Unithiol Dimaval

IRON CHELATING AGENTS

Deferoxamine Deferasirox Deferiprone
Chemistry Isolated from Streptomyces pilosus Tridentate iron chelator Bidentate iron chelator
Main Use Parenteral chelator of choice for iron Oral treatment of iron Second-line oral chelator
poisoning overload due to blood for iron overload due to
transfusion (especially seen blood transfusion in
in patients with thalassemia thalassemia major
major and myelodysplastic Relatively, more efficient in
syndrome) decreasing cardiac iron
Relatively, more efficient in
decreasing hepatic iron
Other Uses Combined with hemodialysis for
aluminum poisoning
Absorption, Given IM or IV; excreted via urine Given orally; excreted in Given orally; excreted via
Metabolism and bile urine
Elimination
Adverse Effects Hypotension, flushing, abdominal Mild to moderate GI Neutropenia, agranulocytes
discomfort, rashes, pulmonary disturbances and skin
complications rashes; liver profile
abnormalities

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