Hesham M. Korashy
Assistant Professor of Molecular Toxicology
Department of Pharmacology, King Saud University
[email protected]
Objectives
 Understand the harmful effects of industrial hazards
 Define the relationship between hazard and risk
 Explore the routes of exposure to industrial hazards
 Shed lights on type of toxicity by industrial hazards
 Know the most toxic environmental hazardous
substances
 Examples.
 Mechanisms
Industrial Hazards
 Large exposures to chemicals can affect human health
directly or indirectly.
 disrupting ecological systems that exist in rivers, lakes,
oceans, streams, and wetlands
 The release of chemicals into the environment can
have global impacts
 Chemicals can be transported throughout the
atmosphere and are not bound by borders
Industrial Hazards
 All the changes that occur in the environment affect
people.
 Ultimately people can be exposed to any substance
that enters the environment
Industrial Hazard vs. Risk
 Hazard is the potential of a substance to cause
damage.
 Toxicity is the hazard of a substance which can cause
poisoning.
 Risk is a measure of the probability that harm will
occur under defined conditions of exposure to a
chemical
Risk
R=
function
f (H x E) = f (H x D xDose
t)
Hazard
Exposure
time
Industrial Hazard vs. Risk
R = f (H x E) = f (H x D x t)
Risk
function
Hazard
Exposure
Dose
time
 Thus, chemicals which pose only a small hazard but to
which there is frequent or excessive exposure may pose
as much risk as chemicals which have a high degree of
hazard but to which only limited exposure occurs
 Reducing risk is based on reducing exposure
Routes of Industrial hazards
Entry into the Body
There are three main routes by which hazardous
chemicals enter the body:
 absorption through the respiratory tract through
inhalation.
 absorption or injection through the skin or eyes.
 absorption through the digestive tract. This can
occur through eating or smoking with contaminated
hands or in contaminated work areas.
Types of Hazards Toxicity
 Acute poisoning is characterized by rapid absorption
of the substance and the exposure is sudden &
severe. Normally, a single large exposure is
involved. Examples: carbon monoxide or cyanide
poisoning.
 Chronic poisoning is characterized by prolonged or
repeated exposures of a duration measured in days,
months or years. Symptoms may not be immediately
apparent, but tend to build up in the body as a result of
chronic exposure. The effects are not seen until a critical
body burden is reached. Examples: lead or mercury
2007 Most Toxic Hazardous
Substances List (ATSDR)
2007
Ran
k
SUBSTANCE NAME
2005
RANK
1
ARSENIC
1
2
LEAD
2
3
MERCURY
3
4
VINYL CHLORIDE
4
5
POLYCHLORINATED BIPHENYLS
5
6
BENZENE
6
7
CADMIUM
8
8
POLYCYCLIC AROMATIC
HYDROCARBONS
7
9
BENZO(A)PYRENE
9
10
BENZO(B)FLUORANTHENE
10
Polycyclic Aromatic
Hydrocarbons (PAHs)
 Polycyclic aromatic hydrocarbons (PAHs) are a formed
in the nature as a result of incomplete combustion.
 These are large, flat molecules built of a collection of
fused benzene-like rings.
 These compounds show up whenever organic material
is burned: when smoking, at barbeques, and in the
slower geological combustion that formed oil and coal.
PAHs
 PAHs, since they are rich in carbon and are
hydrophobic, pass easily through cell membranes and
travel quickly into cells.
 Once inside, CYP450 enzymes detoxify and remove
them by adding oxygen atoms to the rings, making
them more water soluble.
 Unfortunately, some of the intermediate forms are
highly dangerous and cause genetic damage before
they can be removed.
PAHs
 As a pollutant, they are of concern because some
compounds have been identified as carcinogenic,
mutagenic ,and teratogenic.
 PAHs in the environment are found primarily in soil,
sediment and oily substances, as opposed to in water or
air. However, they are also a component of concern in
particulate matter suspended in air.
TCDD
 Dioxin is produced naturally in volcanoes and forest
fires and burning vegetation, such as wood, in
domestic stoves and fireplaces.
 TCDD is a ubiquitous trace byproduct of the
combustion of organic compounds and small amounts
of chloride.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)
Rare Cases of severe Dioxin
Exposure
 Cases of dioxin
poisoning are rare.
Rare cases of TCDD Toxicity
 Ukrainian presidential candidate, Viktor Yushchenko
has a blood level of dioxin of 100,000 units (parts per
trillion), the second highest level ever recorded in a
human.
 In 1998, two Austrian women unknowingly ingested
high levels of 2,3,7,8-TCDD. One of those two women
had the highest blood level of 2,3,7,8-TCDD ever
recorded in a human victim of dioxin poisoning
Mechanism of TCDD Toxicity
Mechanism of TCDD Toxicity
 CYP1A1
plays a major role in bio-activating
procarcinogens into carcinogenic intermediates.
 CYP1A1 is predominately expressed only after induction
by a group of highly toxic environmental chemicals
known as PAHs.
 CYP1A1 is considered to be a useful biomarker of
exposure to environmental PAHs and activation of the
AhR.
Benzo[a]pyrene (BaP)
 One of the best-studied examples of PAHs is
benzo[a]pyrene (BaP).
 It does not attack DNA itself, but reactive
intermediates are formed within cells, with a reactive
epoxide ring.
 This modified molecule is perfectly designed to be a
mutagen.
 The flat, planar ring looks just like a DNA base, so the
molecule slips into the stack of bases comfortably.
Then, the reactive epoxide attacks a neighboring
adenine or guanine nucleotide, forming a covalent
Benzo[a]pyrene
 Upon oxidation, PAHs
produce highly reactive
diol epoxide enantiomers.
 Upon binding chemically
to DNA, it gives rise to
DNA adducts with very
different structures and
biological activities.
 The DNA adducts is a
bulky aromatic ring
attached to the base of
DNA, block replication
Benzo[a]pyrene
Heavy Metals
 Metals comprise three-fourths of the elements in the
periodic table.
 A few of the metals are essential for life. Most of the
known metals are quite toxic to living organisms when
present in excess.
Biological Function
Metals Classification
Class A
(Fe)
Class C
(Zn, Cu)
Class B
(Sr)
Class D
(Hg, Pb)
Toxicity
Foulkes EC., Proc Soc Exp Biol Med. 223: 234-40, 2000.
Exposure to Heavy Metals
Dental Amalgam
Contaminated Solis
Industrial Activities & Waste
Breathing vapors
ATSDR (2005), www.atsdr.cdc.gov/cxcx3.html
CEPA (2006), www.ec.gc.ca/CEPARegistry/subs_list/Toxicupdate.cfm
Mechanisms of Heavy Metals
Toxicities
 Inhibition of heme biosynthesis, heme is the essential
structural component of hemoglobin, myoglobin and
cytochromes (Pb)
 Binds to sulfhydryl groups (-SH groups) of proteins
and enzymes.
 Inhalation: lung - local irritation and inhibition of
alpha1-antitrypsin associated with emphysema (Cd)
 Interfering with essential metals ions (Zn, Ca, Na) on
their channels
Mechanisms of Heavy Metals
Toxicities
 Induction of
oxidative stress
markers (ROS) and
its related genes
(NF-B, AP-1,
NQO1, and
MAPKs).
Factors affecting Metals Toxicities
 Interactions with essential metals
 Formation of metal-protein complex
 Age and stage of development
 Lifestyle factors
 Chemical forms
Factors affecting Metals Toxicities
Interactions with essential metals
 When the metabolism of a toxic metal is similar to
that of essential metals
 Vitamin C  Pb and Cd absorption and hence
toxicity because of  absorption of Fe.
Formation of metal-protein complex
 Several heavy metals form complex with
metallothioneine (MT), such as Cd, Cu, Zn, Hg
 This metal-MT complex has no enzymatic activity
Factors affecting Metals Toxicities
Age and stage of development
 Young children are more susceptible metal toxicity than
adults. Why:



Children consume more calories per pound BW than
adults
Children have higher GI absorption f metals than
adult
Milk diet, because of its high lipid content,  metal
absorption
Factors affecting Metals Toxicities
Lifestyle factors
 Smoking and cigarette smoke by itself contains heavy
metals Cd
 Alcohol may indirectly influence toxicity
Chemical Forms
 Dietary phosphate generally forms less soluble salt
with metals
 Alkyl compound such as MeHg are lipid soluble .
Treatment strategies
 Removal of the subject from the source(s) of
exposure.
 Treatment with chelating agents, such as EDTA,
Succimer, and Cysteine and N-Acetyl Cysteine
(NAC)
 Hemodialysis and/or chelating agent
 Dietary Zn to induce MT
 Administration of some antioxidants, Vitamin C, E
Formaldehyde
 Formaldehyde is also known as methanal, is a gas with
a strong pungent smell.
 Formaldehyde readily results from the incomplete
combustion of carbon-containing materials.
 Formaldehyde is produced industrially by the catalytic
oxidation of methanol. It may be found in the smoke
from forest fires, in automobile exhaust, and in
tobacco smoke.
 Formaldehyde is readily oxidized by atmospheric
oxygen to form formic acid
Formaldehyde
 Most formaldehyde is used in the production of
polymers and other chemicals, in many construction
materials, including carpet, and spray-on insulating
foams.
 formaldehyde is one of the more common indoor air
pollutants.
 Formaldehyde is classified as a probable human
carcinogen by the U.S. Environmental Protection
Agency. The International Agency for Research on
Cancer
Formaldehyde Toxicities
 Carcinogenicity: although the risk is small or
non-existent, the possibility that formaldehyde is a
human carcinogen cannot be excluded.
 Urinary Tract Disease: dysuria, suprapubic pain,
ureteric and bladder fibrosis, hydronephrosis,
vesicoureteral reflux
 Hypersensitivity : Hypersensitivity to formaldehyde
has had several manifestations
 acute exacerbation of eczema after injection of hepatitis
B vaccine containing formaldehyde
 Skin pruritus, burning, and redness
 Painful, enlarged, and haemorrhagic gingival margins
Treatment of Formaldehyde
Toxicities
 Treat signs and symptoms; no known antidote
 Contaminated skin should be washed with soap and
water
 After ingestion water, milk, and/or charcoal, should be
given
 Acidosis, resulting from metabolism of formaldehyde
to formic acid, may require IV NaHCO3 or Na lactate.
 Haemodialysis could be beneficial
 If seizure occurred, IV benzodiazepines or barbiturates
could be given.
Methanol
 Methyl alcohol is used as a pharmaceutical and
industrial solvent.
 It is also used as `wood naphtha' to denature ethanol
in the preparation of industrial methylated spirits.
 Methyl alcohol is also used as an extraction solvent in
food processing.
 Methyl alcohol is readily absorbed from the
gastrointestinal tract and distributed throughout the
body fluids.
Methanol Toxicity
 Characteristic symptoms of methyl alcohol poisoning
are caused by toxic metabolites and develop after a
latent period of about 12 to 24 hours, or longer
 metabolic acidosis with rapid, shallow breathing
 visual disturbances which often proceed to
irreversible blindness,
 severe abdominal pain, gastrointestinal
disturbances, pain in the back and extremities
 coma which in severe cases may terminate in death
due to respiratory failure or, rarely, to circulatory
collapse
Treatment of Methanol Toxicities
 Gastric lavage may be considered if the patient
presents within 1 hour of ingesting methyl alcohol
 Activated charcoal is probably of little use as it does
not absorb significant amounts of methyl alcohol
 Metabolic acidosis should be corrected immediately
with intravenous sodium bicarbonate.
 Haemodialysis may be indicated to increase the
removal of methyl alcohol and its toxic metabolites
Treatment of Methanol Toxicities
 Fomepizole, an inhibitor of alcohol dehydrogenase, is
also used; it inhibits the metabolism of methyl alcohol
to its toxic metabolites.
 Folinic acid and folic acid have been given in the
treatment of methyl alcohol toxicity because they may
enhance the metabolism of formic acid.
Ethylene Glycol
 Ethylene glycol is commonly encountered in antifreeze
solutions and has been used illicitly to sweeten some
wines
 Ethylene glycol is absorbed from the gastrointestinal
tract and is metabolised, chiefly in the liver, by alcohol
dehydrogenase
Ethylene Glycol Toxicities
 Toxic effects arising from ingestion of ethylene glycol
result from its major metabolites: aldehydes, glycolate,
lactate, and oxalate
 Clinical features may be divided into three stages
depending on the time elapsed since ingestion:
 0 -12 hours: the patient may show signs of drunkenness,
nausea, vomiting, convulsions and neurological defects.
 12 - 24 hours: tachycardia, mild hypertension,
pulmonary oedema, and heart failure.
 24 - 72 hours: flank pain, proteinuria, oxaluria,
haematuria, renal failure, respiratory failure,
cardiovascular collapse, and sometimes coma and death
Treatment of Ethylene Glycol
Toxicities
 The stomach should be emptied by lavage if ingestion
of ethylene glycol was within the preceding hour.
 metabolic acidosis should be corrected with sodium
bicarbonate intravenously and hypocalcaemia
corrected with calcium gluconate
 Haemodialysis or peritoneal dialysis may be of value
BENZENE
 Benzene occurs as a volatile, colorless, highly
flammable liquid that dissolves easily in water.
 Benzene is used as a constituent in motor fuels; as a
solvent for fats, waxes, resins, oils, inks, paints,
plastics, and rubber; in the extraction of oils from
seeds.
 It is also used as a chemical intermediate, in the
manufacture of detergents, explosives,
pharmaceuticals, and dyestuffs.
Environmental/Occupational
Exposure to Benzene
 Individuals employed in industries that manufacture
or use benzene may be exposed to the highest levels of
benzene.
 found in emissions from burning coal and oil, motor
vehicle exhaust, and evaporation from gasoline service
stations and in industrial solvents.
 Tobacco smoke contains benzene and accounts for
approximately 50 percent of the public's exposure to
benzene.
Benzene Toxicities
 Acute
 Coexposure to benzene with ethanol increase benzene
toxicity. How?
 Inhalation of benzene causes drowsiness, dizziness,
headaches, and unconsciousness in humans.
 Ingestion of large amounts of benzene may result in
vomiting, dizziness, convulsions, and death in humans.
 Exposure to liquid and vapor may irritate the skin (red
skin), eyes, and upper respiratory tract.
 Death may result from exposure to very high levels of
benzene.
Benzene Toxicities
 Chronic
 Long-term inhalation of benzene causes disorders in
the blood in humans. specifically affects bone marrow
causing aplastic anemia. What?
 Excessive bleeding. Why?
 Damage to the immune system. How?


changes in blood levels of antibodies
leukopenia.
Benzene Toxicities
 Chronic
 Structural and numerical chromosomal aberrations
in humans.
 Menstrual disorders and a decreased size of ovaries.
 Teratogenecity such as low birth weight, delayed
bone formation, and bone marrow damage.
 Leukemia has been observed in humans
occupationally exposed to benzene.
Nitrobenzene
 Nitrobenzene is an oily yellow liquid with an almond-
like or shoe-polish smell.
 The majority of nitrobenzene is used to manufacture
aniline, which is a chemical used in the manufacture of
polyurethane.
 Nitrobenzene is also used to produce lubricating oils
and in the manufacture of dyes, drugs, pesticides, and
synthetic rubber.
Environmental/Occupational
Exposure to Nitrobenzene
 Nitrobenzene has not been detected in ambient air or
in drinking water.
 Occupational exposure may occur in factories that
produce nitrobenzene or use nitrobenzene to produce
other products.
 Exposure may also occur for those persons who live
near a waste site where nitrobenzene has been found
or near a manufacturing or processing plant.
Detection of Exposure to
Nitrobenzene
 The levels of methemoglobin in the blood can be
measured to determine recent exposure to
nitrobenzene.
 However, this method is not specific for nitrobenzene,
as many toxic chemicals produce methemoglobin.
 For long-term exposure to nitrobenzene, the presence
of its breakdown products in the urine (p-nitro
phenol) can be used as an indication of nitrobenzene
exposure.
Nitrobenzene Toxicities
 Acute / Chronic
 Methemoglobinemia:



conversion of hemoglobin to methemoglobin in the
blood, which lowers the oxygen released to the
tissues of the body.
it is associated with fatigue, weakness, dyspnea,
headache, dizziness, bluish color skin, and you may
have nausea, vomiting.
Detected by measuring methemoglobin level.
 Respiratory failure, bluish-gray skin, disturbed
vision, coma, and ultimately death may occur.
Nitrobenzene Toxicities
 Acute / Chronic
 Reproductive toxicities such as a decrease in fertility,
reduced testicular weights, and decreased sperm
production have been noted in inhalation and oral animal
studies.
 Animal studies indicate that inhalation exposure to
nitrobenzene does not result in developmental effects,
such as birth defects or embryotoxic effects.
Treatment of Nitrobenzene
Toxicities
 Immediate removal from the exposure and transport
to medical facilities.
 Oxygen should be administered with assisted
ventilation of necessary. Why?
 Methylene blue given IV at 1-2 mg/kg as 1% solution to
reduce the methemoglobin half-life. HOW?
 Contaminated clothing should be removed and the
patient washed to remove skin contaminations.
Methylene blue Mechanism of
Action
 Methylene blue acts as a cofactor for (NADPH)
methemoglobin reductase.
 In patients with methemoglobinemia, this enzyme
remains inactive, but will be activated by methylene
blue when glucose-6-dehydrogenase (G6PD) is
normal.
 G6PD is a key enzyme in the formation of NADPH,
sufficient NADPH is generated to efficiently reduce
methylene blue to leucomethylene blue which then
donates an electron to methemoglobin reducing it to
Methemoglobin production and
action of methylene blue
Carbon Tetrachloride
 Carbon tetrachloride is a clear, nonflammable liquid
which is almost insoluble in water.
 Carbon tetrachloride is used as a solvent for oils, fats,
rubber waxes, and resins and as a starting material in
the manufacture of organic compounds.
 Carbon tetrachloride was formerly used as a dry
cleaning agent, and pesticide.
Environmental/Occupational
Exposure to CCL4
 Individuals may be exposed to carbon tetrachloride in
the air from accidental releases from production and
from its disposal waste site.
 Carbon tetrachloride is also a common contaminant of
indoor air:
 building materials or products, such as cleaning
agents, used in the home.
 Contaminated water
 Workers involved in the manufacture or use of carbon
tetrachloride are most likely exposed to CCL4.
Carbon Tetrachloride Toxicities
 Acute
 liver and kidneys damages.
 CNS depression: headache, weakness, lethargy,
nausea, and vomiting.
 Pulmonary edema.
 Chronic
 Chronic inhalation or oral exposure to carbon
tetrachloride produces liver and kidney damage in
humans and animals.
 Birth defects have not been observed in animals
exposed to carbon tetrachloride by inhalation or
ingestion.
Asbestos
 Asbestos are composed of minerals which are made
up of long, thin fibers that are somewhat similar to
fiberglass.
 Asbestos is neither volatile nor soluble; however,
small fibers may occur in suspension in both air and
water.
 The main uses of asbestos are in building materials,
paper products, asbestoscement products, textiles,
packings and asbestosreinforced plastics.
Environmental/Occupational
Exposure
 Airborne exposure to asbestos may occur through the erosion of




natural deposits from a variety of asbestos-related industries.
The concentrations in outdoor air are highly variable.
Asbestos has been detected in indoor air, where it is released
from a variety of building materials such as insulation and
ceiling and floor tiles.
Typical concentrations in indoor air range from 1 to 200 ng/m3.
Asbestos may be released to water from a number of sources,
including erosion of natural deposits, corrosion from asbestoscement pipes, asbestos roofing materials with subsequent
transport into sewers.
Asbestos Toxicities
 Chronic inhalation exposure to asbestos in humans can
lead to:
 Asbestosis: is a diffuse fibrous scarring of the lungs.
 Symptoms of asbestosis include shortness of breath,
difficulty in breathing, and coughing.
 Asbestosis is a progressive disease, i.e., the severity of
symptoms tends to increase with time, even after the
exposure has stopped.
 In severe cases, this disease can lead to death, due to
impairment of respiratory function.
 Pulmonary hypertension
 Immunological diseases.
Mechanisms of Asbestos-induced
Toxicities
Asbestos Toxicities
 Occupational studies have reported that exposure
to asbestos via inhalation can cause lung cancer
and Mesothelioma
 Mesothelioma is a asbestos-induced cancer develop
in the mesothelium, a protective lining that covers most
of the body's internal organs.
 No studies were located on the developmental or
reproductive effects of asbestos in animals or
humans via inhalation.
 Birth defects were not noted in the offspring of
animals exposed to asbestos in the diet during
pregnancy.