Hesham M. KorashyAssistant Professor of Molecular Toxicology

Department of Pharmacology, King Saud Universityhkorashy@ksu.edu.sa

ObjectivesUnderstand the harmful effects of industrial

hazardsDefine the relationship between hazard and riskExplore the routes of exposure to industrial

hazardsShed lights on type of toxicity by industrial

hazardsKnow the most toxic environmental hazardous

substancesExamples.Mechanisms

Industrial HazardsLarge 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 HazardsAll the changes that occur in the environment

affect people.

Ultimately people can be exposed to any substance that enters the environment

Industrial Hazard vs. RiskHazard 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

R = f (H x E) = f (H x D x t)Riskfunction

Hazard ExposureDose time

Industrial Hazard vs. Risk R = f (H x E) = f (H x D x t)

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

Riskfunction

Hazard ExposureDose time

Routes of Industrial hazards Entry into the BodyThere 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 ToxicityAcute 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 poisoning or pesticide exposure. 

2007Rank

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

2007 Most Toxic HazardousSubstances List (ATSDR)

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, 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

PAHsAs 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.

TCDDDioxin 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 ToxicityUkrainian 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 ToxicityCYP1A1 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 bond.

Benzo[a]pyreneUpon 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 and transcription.

Benzo[a]pyrene

Heavy MetalsMetals 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.

Metals Classification

Class B(Sr)

Class C(Zn, Cu)

Class D(Hg, Pb)

Class A(Fe)

Toxicity

Bio

log

ical Fu

ncti

on

Foulkes EC., Proc Soc Exp Biol Med. 223: 234-40, 2000.

Exposure to Heavy Metals

Breathing vapors

ATSDR (2005), www.atsdr.cdc.gov/cxcx3.htmlCEPA (2006), www.ec.gc.ca/CEPARegistry/subs_list/Toxicupdate.cfm

Industrial Activities & Waste

Dental Amalgam Contaminated Solis

Mechanisms of Heavy Metals ToxicitiesInhibition 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 ToxicitiesInteractions 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 complexSeveral heavy metals form complex with

metallothioneine (MT), such as Cd, Cu, Zn, HgThis metal-MT complex has no enzymatic

activity

Factors affecting Metals ToxicitiesAge 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 ToxicitiesLifestyle factors

Smoking and cigarette smoke by itself contains heavy metals Cd

Alcohol may indirectly influence toxicity

Chemical FormsDietary 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

FormaldehydeFormaldehyde 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

FormaldehydeMost 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 ToxicitiesCarcinogenicity: 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 manifestationsacute 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.

MethanolMethyl 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 ToxicityCharacteristic 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 ToxicitiesGastric 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 ToxicitiesFomepizole, 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 GlycolEthylene 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 ToxicitiesToxic 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 ToxicitiesThe 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

BENZENEBenzene 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.

contaminated water.

Benzene ToxicitiesAcute

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 ToxicitiesChronic

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 antibodiesleukopenia.

Benzene ToxicitiesChronic

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.

NitrobenzeneNitrobenzene 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 NitrobenzeneNitrobenzene 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 NitrobenzeneThe 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 ToxicitiesAcute / 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 ToxicitiesAcute / 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 ToxicitiesImmediate 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 hemoglobin

Methemoglobin production and action of methylene blue

Carbon TetrachlorideCarbon 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 CCL4Individuals 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 ToxicitiesAcute

liver and kidneys damages. CNS depression: headache, weakness,

lethargy, nausea, and vomiting.Pulmonary edema.

ChronicChronic 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.

AsbestosAsbestos 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.

Asbestos use is currently decreasing.

Environmental/Occupational ExposureAirborne 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 asbestos-cement pipes, asbestos roofing materials with subsequent transport into sewers.

Asbestos ToxicitiesChronic 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 ToxicitiesOccupational studies have reported that

exposure to asbestos via inhalation can cause lung cancer and MesotheliomaMesothelioma 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.