Environmental Pathology

ENVIRONMENTAL ENVIRONMENTAL PATHOLOGYPATHOLOGYFe A. Bartolome, MD, FPASMAP

Department of Pathology

Our Lady of Fatima University

Global Climate ChangeGlobal Climate Change

• Human activity a major contributorHuman activity a major contributor

• Increases of Increases of carbon dioxide, carbon dioxide, methane, and ozone methane, and ozone main main ingredients of the ingredients of the greenhouse effect greenhouse effect along with water vapor acts like a along with water vapor acts like a blanket blanket absorb energy radiated absorb energy radiated from the earth’s surfacefrom the earth’s surface

• Recent increases due to combustion Recent increases due to combustion of of hydrocarbonshydrocarbons in automobiles and in automobiles and energy plantsenergy plants


• Present concentration of Present concentration of atmospheric COatmospheric CO22 = 370 ppm = 370 ppm

Expected to increase to 500 – Expected to increase to 500 – 1200 ppm at the end of the 1200 ppm at the end of the centurycentury

Large scale deforestation a major Large scale deforestation a major contributor contributor decreased carbon decreased carbon sequestration by treessequestration by trees


• Effects of global warming:Effects of global warming:

1.1. Loss of reflective snow and ice Loss of reflective snow and ice increased heat absorptionincreased heat absorption

2.2. Greater evaporation from bodies Greater evaporation from bodies of water and transpiration from of water and transpiration from trees trees increased water vapor in increased water vapor in the atmospherethe atmosphere

3.3. Thawing of arctic tundra Thawing of arctic tundra large large releases of stored COreleases of stored CO2 2 and and methanemethane

4.4. Diminished growth of diatoms Diminished growth of diatoms decreased sequestration of COdecreased sequestration of CO22

Global Climate Change: Health ImpactsGlobal Climate Change: Health Impacts

Global Climate Change: Health ImpactsGlobal Climate Change: Health Impacts

Toxicity of Chemicals & Physical AgentsToxicity of Chemicals & Physical Agents

ToxicologyToxicology

• Science of poisonsScience of poisons

• Studies the distribution, effects, Studies the distribution, effects, and mechanisms of action of toxic and mechanisms of action of toxic agentsagents

• Includes the study of the effects of Includes the study of the effects of physical agents such as radiation physical agents such as radiation and heatand heat


Basic Principles:Basic Principles:

1.1. The definition of poison is not The definition of poison is not straightforward. It is a straightforward. It is a quantitative concept strictly quantitative concept strictly dependent on dosage.dependent on dosage.

2.2. Xenobiotics are exogenous Xenobiotics are exogenous chemicals in the environment (air, chemicals in the environment (air, water, food, and soil) that may be water, food, and soil) that may be absorbed into the body.absorbed into the body.

Xenobiotic MetabolismXenobiotic Metabolism

Xenobiotic Xenobiotic

Phase I reactionsHydrolysisReductionOxidation

Primary metabolite

Phase II reactions

GlucuronidationSulfation

MethylationConjugation

Secondary metabolite

Elimination in urine, bile, or feces

Non-toxic metabolite

Reactive metabolite

Effects on cellular molecules (enzymes,

receptors, membranes, DNA)

Molecular and cellular repair

Toxicity (short- and long-term effects)



3.3. Chemicals may be excreted in Chemicals may be excreted in urine, feces, or eliminated in urine, feces, or eliminated in expired air, or may accumulate in expired air, or may accumulate in tissues (e.g. Bone, fat, brain).tissues (e.g. Bone, fat, brain).

4.4. Chemicals may act at the site of Chemicals may act at the site of entry or at other sites following entry or at other sites following transport through blood.transport through blood.



5.5. Most solvents and drugs are Most solvents and drugs are lipophilic lipophilic facilitate transport facilitate transport through blood by lipoproteins and through blood by lipoproteins and entry into cells.entry into cells.

6.6. The most important catalyst in the The most important catalyst in the metabolism of xenobiotics is the metabolism of xenobiotics is the cytochrome P-450 enzyme system.cytochrome P-450 enzyme system.

Cytochrome P-450 enzyme systemCytochrome P-450 enzyme system

• Primarily in endoplasmic reticulum Primarily in endoplasmic reticulum of liver but also present in skin, of liver but also present in skin, lungs, GIT, and other organslungs, GIT, and other organs

• Catalyze reactions that either:Catalyze reactions that either:1.1. Detoxify xenobioticsDetoxify xenobiotics2.2. Activate xenobiotics into active Activate xenobiotics into active

compounds compounds cause cellular cause cellular injuryinjury

• Production of reactive oxygen Production of reactive oxygen species common to both reactions species common to both reactions cellular damage cellular damage


• Great variation in activity of CYPs Great variation in activity of CYPs among individuals due to:among individuals due to:1.1. Genetic polymorphism in Genetic polymorphism in

specific CYPsspecific CYPs2.2. Exposure to drugs or chemicals Exposure to drugs or chemicals

that induce or diminish activitythat induce or diminish activity Inducers: environmental Inducers: environmental

chemicals, drugs, smoking, chemicals, drugs, smoking, alcohol, hormonesalcohol, hormones

Decrease activity: fasting or Decrease activity: fasting or starvationstarvation


Inducers Bind to nuclear receptors (aryl hydrocarbon

receptor, PPAR, CAR, PXR)

Heterodimerize with retinoic

X receptor (RXR)

Form transcriptional

activation complex

Associates with promoter elements

on CYP genes

PPAR – peroxisome proliferator-activated receptors; CAR – constitutive androstane receptor; PXR – pregnane X receptor

Environmental Pollution: Air PollutionEnvironmental Pollution: Air Pollution

Outdoor Air PollutionOutdoor Air Pollution

• Six major pollutants: Six major pollutants: sulfur dioxide, sulfur dioxide, carbon monoxide, ozone, nitrogen carbon monoxide, ozone, nitrogen dioxide, lead, and particulate matter dioxide, lead, and particulate matter collectively produce SMOG (collectively produce SMOG (smsmoke oke and fand fogog))

• Lungs bear the brunt of adverse Lungs bear the brunt of adverse effects but other organs may be effects but other organs may be affected.affected.


Outdoor Air Pollution – Ozone Outdoor Air Pollution – Ozone

• UV radiation + O2 in stratosphere = UV radiation + O2 in stratosphere = ozone (O3)ozone (O3)

• Two types:Two types:1.1. Stratospheric ozone (ozone layer)Stratospheric ozone (ozone layer)

““good ozone” good ozone” absorbs the absorbs the most dangerous UV radiation most dangerous UV radiation from sunfrom sun

Decreased during last 30 years Decreased during last 30 years due to use of aerosolsdue to use of aerosols



• Two types:Two types:2.2. Ground-level ozoneGround-level ozone

Ozone that accumulates in the Ozone that accumulates in the lower atmospherelower atmosphere

Formed by reaction of nitrogen Formed by reaction of nitrogen oxides and volatile organic cpds oxides and volatile organic cpds in the presence of sunlightin the presence of sunlight

Due to industrial emissions and Due to industrial emissions and motor vehicle exhaustmotor vehicle exhaust

Effec

ts?



• Toxicity due to production of free Toxicity due to production of free radicals radicals injure epithelial cells injure epithelial cells release of inflammatory mediatorsrelease of inflammatory mediators

• Other agents (e.g. Sulfur dioxide from Other agents (e.g. Sulfur dioxide from power plants, copper smelters, paper power plants, copper smelters, paper mills) mills) released into the air released into the air combine with ozone to produce combine with ozone to produce sulfuric acidsulfuric acid Acid rainAcid rain Burning sensation in nose and Burning sensation in nose and

throat; respiratory symptomsthroat; respiratory symptoms


Outdoor Air Pollution – Particulate MatterOutdoor Air Pollution – Particulate Matter

• Known as sootKnown as soot• Emitted by:Emitted by:

1.1. coal- and oil-fired power plantscoal- and oil-fired power plants2.2. Industrial processed burning fuelsIndustrial processed burning fuels3.3. Diesel exhaustDiesel exhaust

• Fine or ultrafine particles < 10 um in Fine or ultrafine particles < 10 um in diameter the most harmful diameter the most harmful inhaled inhaled phagocytosed by macrophages & phagocytosed by macrophages & neutrophils neutrophils release inflammatory release inflammatory mediators (e.g. Macrophage mediators (e.g. Macrophage inflammatory protein 1inflammatory protein 1αα and and endothelins)endothelins)


Outdoor Air Pollution – Carbon Outdoor Air Pollution – Carbon MonoxideMonoxide

• Non-irritating, colorless, tasteless, Non-irritating, colorless, tasteless, odorless gasodorless gas

• Produced by incomplete oxidation of Produced by incomplete oxidation of carbonaceous materialscarbonaceous materials

• Low levels found in ambient air Low levels found in ambient air contribute to impaired respiratory contribute to impaired respiratory function but not life-threateningfunction but not life-threatening

• Important cause of accidental and Important cause of accidental and suicidal deathsuicidal death


Outdoor Air Pollution – Carbon MonoxideOutdoor Air Pollution – Carbon Monoxide

• Small, closed garage Small, closed garage lethal coma lethal coma within 5 minuteswithin 5 minutes

• If hemoglobin 20% - 30% saturated If hemoglobin 20% - 30% saturated with CO with CO systemic hypoxia systemic hypoxia

• If 60% - 70% saturated If 60% - 70% saturated unconsciousness and deathunconsciousness and death



• Acute poisoning:Acute poisoning:

Due to accidental exposure or Due to accidental exposure or suicide attemptsuicide attempt

Characteristic cherry-red color of Characteristic cherry-red color of skin and mucus membranes in light-skin and mucus membranes in light-skinned individuals skinned individuals due to high due to high levels of carboxyhemoglobinlevels of carboxyhemoglobin

Morphologic changes due to Morphologic changes due to systemic hypoxia; non-specificsystemic hypoxia; non-specific



• Chronic poisoning:Chronic poisoning:

Slowly developing hypoxia Slowly developing hypoxia ischemic changes in the CNS ischemic changes in the CNS (especially basal ganglia and (especially basal ganglia and lenticular nuclei)lenticular nuclei)

Cessation of exposure Cessation of exposure recovery recovery but with permanent neurologic but with permanent neurologic sequelae (impairment of memory, sequelae (impairment of memory, vision, hearing, and speech)vision, hearing, and speech)


Indoor Air PollutionIndoor Air Pollution

• Common pollutants:Common pollutants:1.1. Tobacco smoke – most commonTobacco smoke – most common2.2. Carbon monoxideCarbon monoxide3.3. Nitrogen dioxideNitrogen dioxide4.4. AsbestosAsbestos5.5. Volatile substances containing poly-Volatile substances containing poly-

cyclic aromatic hydrocarbons from cyclic aromatic hydrocarbons from cooking oils and coal burningcooking oils and coal burning

Environmental Pollution: MetalsEnvironmental Pollution: Metals

LeadLead

• Exposure occurs through Exposure occurs through contaminated air, food, and watercontaminated air, food, and water

• Major sources in the environment: Major sources in the environment: house paints, gasoline, mining, house paints, gasoline, mining, foundries, batteriesfoundries, batteries

• Other sources: toysOther sources: toys• Subclinical poisoning may occur in Subclinical poisoning may occur in

children exposed to levels < 10 ug/dLchildren exposed to levels < 10 ug/dL


LeadLead

• Majority of absorbed lead (80% - 85%) Majority of absorbed lead (80% - 85%) incorporated into bone and developing incorporated into bone and developing teeth teeth competes with calcium competes with calcium

• High levels High levels CNS disturbances in CNS disturbances in adults (peripheral neuropathies) and adults (peripheral neuropathies) and childrenchildren


Lead – Effects:Lead – Effects:

• Inhibition of neurotransmitters Inhibition of neurotransmitters due to disruption of calcium due to disruption of calcium homeostasishomeostasis

• Interference with normal Interference with normal remodelling of cartilage and remodelling of cartilage and primary bone trabeculae in primary bone trabeculae in epiphyses of children.epiphyses of children.



Blood and bone marrowBlood and bone marrow

• Inhibition of Inhibition of δδ-aminolevulinic acid -aminolevulinic acid dehydratase & ferrochelatase dehydratase & ferrochelatase inhibit heme synthesis inhibit heme synthesis microcytic, hypochromic anemia microcytic, hypochromic anemia with mild hemolysiswith mild hemolysis

• Characteristic; occurs early Characteristic; occurs early appearance of ringed sideroblastsappearance of ringed sideroblasts

• Basophilic stippling of red cellsBasophilic stippling of red cells


RBC with basophilic stipplings (arrow) RBC with basophilic stipplings (arrow) indicating clustering of ribosomes.indicating clustering of ribosomes.



Brain Brain

• Brain damage prone to occur in Brain damage prone to occur in children children sensory, motor, sensory, motor, intellectual, and psychologic intellectual, and psychologic impairmentsimpairments

• Adults Adults peripheral demyelinating peripheral demyelinating neuropathy involving motor nerves neuropathy involving motor nerves of the most commonly used muscles of the most commonly used muscles Extensor muscles of wrist & Extensor muscles of wrist &

fingers (wristdrop) fingers (wristdrop) peroneal peroneal muscles (footdrop)muscles (footdrop)



Gastrointestinal TractGastrointestinal Tract

• Extremely severe, poorly localized Extremely severe, poorly localized abdominal painabdominal pain

KidneysKidneys

• Proximal tubular damageProximal tubular damage• Chronic Chronic interstitial fibrosis interstitial fibrosis

renal failurerenal failure


Mercury Mercury

• Three forms of mercury:Three forms of mercury:1.1. Metallic mercury (elemental Metallic mercury (elemental

mercury)mercury)2.2. Inorganic mercury compounds Inorganic mercury compounds

(mercuric chloride)(mercuric chloride)3.3. Organic mercury (methyl mercury)Organic mercury (methyl mercury)

• Main sources at present:Main sources at present:1.1. Contaminated fish (methyl mercury)Contaminated fish (methyl mercury)2.2. Mercury vapors released from Mercury vapors released from

dental amalgamsdental amalgams


Mercury Mercury

• Minamata diseaseMinamata disease Cerebral palsy, deafness, blindness, Cerebral palsy, deafness, blindness,

mental retardation in children mental retardation in children exposed in uteroexposed in utero Methyl mercury metallic mercury Methyl mercury metallic mercury

lipid soluble lipid soluble facilitate brain facilitate brain accumulation accumulation impaired impaired cognitive, neuromotor, and cognitive, neuromotor, and behavioral functionbehavioral function


ArsenicArsenic

• ““poison of kings and the king of poison of kings and the king of poisons”poisons”

• Found naturally in soils and waterFound naturally in soils and water• Used in products such as wood Used in products such as wood

preservers, herbicides, and other preservers, herbicides, and other agricultural productsagricultural products

• Present in Chinese and Indian herbal Present in Chinese and Indian herbal medicinemedicine

• Arsenic trioxide – used in the Arsenic trioxide – used in the treatment of acute promyelocytic treatment of acute promyelocytic leukemialeukemia


Arsenic - Toxic EffectsArsenic - Toxic Effects

• Acute toxic effects due to interference Acute toxic effects due to interference with mitochondrial oxidative with mitochondrial oxidative phosphorylationphosphorylation Severe disturbances of GIT, cardio-Severe disturbances of GIT, cardio-

vascular system, and CNSvascular system, and CNS

• Most serious consequence of chronic Most serious consequence of chronic exposure is increased risk for exposure is increased risk for development of cancers (e.g. Basal and development of cancers (e.g. Basal and squamous cell Ca of skin)squamous cell Ca of skin)


CadmiumCadmium

• Relatively a modern problemRelatively a modern problem

• Can contaminate the soil and Can contaminate the soil and plants directly or through plants directly or through fertilizers and irrigation waterfertilizers and irrigation water

• Most important source for the Most important source for the general population is foodgeneral population is food

Occupational Health RisksOccupational Health Risks

Organic solventsOrganic solvents

• Sources:Sources:1.1. De-greasing & dry cleaning De-greasing & dry cleaning

agents, and paint removers agents, and paint removers chloroform and carbon chloroform and carbon tetrachloridetetrachloride Acute exposure: dizziness and Acute exposure: dizziness and

confusion confusion CNS depression CNS depression comacoma

Low levels toxic to liver and Low levels toxic to liver and kidneyskidneys


Organic solventsOrganic solvents

• Sources:Sources:2.2. Rubber workers Rubber workers benzene and 1,3- benzene and 1,3-

butadienebutadiene Increased risk of leukemiaIncreased risk of leukemia Benzene oxidized by hepatic Benzene oxidized by hepatic

CYP2E1 CYP2E1 disrupt differentiation disrupt differentiation of hematopoietic cells in bone of hematopoietic cells in bone marrow marrow marrow aplasia (dose- marrow aplasia (dose-dependent) dependent) increased risk of increased risk of acute myeloid leukemiaacute myeloid leukemia


Polycyclic hydrocarbonsPolycyclic hydrocarbons

• Released during combustion of fossil Released during combustion of fossil fuels, especially when coal and gas are fuels, especially when coal and gas are burned at high temperatures (steel burned at high temperatures (steel foundries)foundries); also present in tar and ; also present in tar and sootsoot

• Among the most potent carcinogensAmong the most potent carcinogens

• Lung, bladder, and scrotal cancerLung, bladder, and scrotal cancer


OrganochlorinesOrganochlorines

• Synthetic lipophilic substances that Synthetic lipophilic substances that resist degradationresist degradation

• Sources:Sources:1.1. Pesticides – DDTPesticides – DDT2.2. Non-pesticides – polychlorinated Non-pesticides – polychlorinated

biphenyls (PCBs) and dioxinbiphenyls (PCBs) and dioxin

• Endocrine disruptors Endocrine disruptors anti-estrogen anti-estrogen or anti-androgen activityor anti-androgen activity


OrganochlorinesOrganochlorines

• Dioxins and PCBsDioxins and PCBs FolliculitisFolliculitis Chloracne – dermatosis; acne, Chloracne – dermatosis; acne,

cyst formation, cyst formation, hyperpigmentation, and hyperpigmentation, and hyperkeratosis around face and hyperkeratosis around face and behind earsbehind ears

Liver and CNS abnormalitiesLiver and CNS abnormalities

Multiple cysts were present (A) on the face and (B) in the auricular areas, which normally are not affected in patients with common acne. Only a few cysts were present on the patient's back in summer 1998 (C), whereas 1 year later (D) the patient's back was covered with many severely inflamed cysts.


Mineral DustsMineral Dusts

• Cause chronic non-neoplastic lung Cause chronic non-neoplastic lung diseases called diseases called pneumoconiosespneumoconioses

• Sources:Sources:1.1. Mining of hard coal Mining of hard coal coal dust coal dust2.2. Sandblasting, stone cutting, etc. Sandblasting, stone cutting, etc.

silica silica3.3. Mining, fabrication, insulation Mining, fabrication, insulation

work work asbestos, beryllium asbestos, beryllium

Coal Worker’s Coal Worker’s PneumoconiosisPneumoconiosis

TobaccoTobacco

• Most common exogenous cause of Most common exogenous cause of human cancerhuman cancer Cigarette smoking – main culpritCigarette smoking – main culprit Smokeless tobacco (snuff, Smokeless tobacco (snuff,

chewing tobacco, etc.) chewing tobacco, etc.) oral oral cancercancer

Second-hand smoke Second-hand smoke lung lung cancer in non-smokerscancer in non-smokers

• Most preventable cause of human Most preventable cause of human death.death.

TobaccoTobacco

• Cessation of smoking –Cessation of smoking –

Significantly reduces within 5 Significantly reduces within 5 years the overall mortality and years the overall mortality and the risk of death from CV the risk of death from CV diseasesdiseases

Decreases lung cancer mortality Decreases lung cancer mortality by 21% within 5 yearsby 21% within 5 years

TobaccoTobacco

• Most common diseases caused by Most common diseases caused by cigarette smoking involve the lungs cigarette smoking involve the lungs and include:and include:1.1. EmphysemaEmphysema2.2. Chronic bronchitisChronic bronchitis3.3. Chronic obstructive pulmonary Chronic obstructive pulmonary

diseasedisease4.4. Lung cancerLung cancer

• Cigarette smoking increases risk for: Cigarette smoking increases risk for: atherosclerosis, MI, cancers (lips, atherosclerosis, MI, cancers (lips, mouth, pharynx, esophagus, mouth, pharynx, esophagus, pancreas, bladder, kidney, and cervix)pancreas, bladder, kidney, and cervix)

SMOKING

Direct irritant effect

Tracheo-bronchial mucosa

Bronchitis

Recruitment of leukocytes

to lungs

Increased local

elastase production

Injury to lung tissue

Emphysema

Cigarette smoke

Polycyclic hydrocarbons

& nitrosamines

CYPsIncrease

water solubility

of carcinogen

s

Excretion

Electrophilic intermediate

s of CYPs

Form DNA adducts

Mutations in K-ras and

p53

SMOKING

Increased platelet

aggregation

Decreased myocardial

oxygen supply

Decreased threshold for ventricular fibrillation

Significant lung diseaseHypoxia due to CO content of cigarette smoke

Increased oxygen demand

Atherosclerosis and M.I.

Atherosclerosis and M.I.

Maternal smoking Maternal smoking increases the risk of:increases the risk of:•Spontaneous abortionsSpontaneous abortions•Preterm birthsPreterm births•IUGRIUGR

Passive smoke inhalationPassive smoke inhalation

• Relative risk of lung cancer ~ 1.3x Relative risk of lung cancer ~ 1.3x higher than those not exposedhigher than those not exposed

• Increased risk of coronary AS and fatal Increased risk of coronary AS and fatal M.I.M.I.

ALCOHOLALCOHOL

AlcoholAlcohol

• Consumption in moderate amounts Consumption in moderate amounts generally not injuriousgenerally not injurious

• Ethanol absorbed unaltered in the Ethanol absorbed unaltered in the stomach and small intestines stomach and small intestines distributed to all tissues and fluids of distributed to all tissues and fluids of the body in direct proportion to the the body in direct proportion to the blood levelblood level < 10% excreted unchanged in urine, < 10% excreted unchanged in urine,

sweat, and breath sweat, and breath amount exhaled amount exhaled is proportional to blood levelis proportional to blood level 80 mg/dL in blood – legal definition 80 mg/dL in blood – legal definition

of DUI in the U.S.of DUI in the U.S.

AlcoholAlcohol

• Most of the alcohol in the blood is bio-Most of the alcohol in the blood is bio-transformed to acetaldehyde in the liver transformed to acetaldehyde in the liver by three enzyme systems:by three enzyme systems:

1.1. Alcohol dehydrogenase (ADH) – main; Alcohol dehydrogenase (ADH) – main; cytosol of hepatocytescytosol of hepatocytes

2.2. Microsomal ethanol-oxidizing system Microsomal ethanol-oxidizing system (MEOS) – participates if blood alcohol (MEOS) – participates if blood alcohol levels highlevels high

3.3. Catalase – use H2O2 as substrateCatalase – use H2O2 as substrate

AlcoholAlcohol

• Acetaldehyde Acetaldehyde many toxic effects many toxic effects responsible for some of the acute effects of responsible for some of the acute effects of alcohol and for the development of oral alcohol and for the development of oral cancers.cancers.

• Alcohol oxidation by ADH Alcohol oxidation by ADH reduction of reduction of NAD to NADH NAD to NADH accumulation of fat in the accumulation of fat in the liver and lactic acidosisliver and lactic acidosis

• Metabolism of ethanol in the liver by Metabolism of ethanol in the liver by CYP2E1 CYP2E1 reactive oxygen species reactive oxygen species lipid lipid peroxidation of cell membranesperoxidation of cell membranes

• Release of endotoxin by intestinal flora Release of endotoxin by intestinal flora release of TNF & cytokines from Kupffer release of TNF & cytokines from Kupffer cells cells hepatic injury hepatic injury

AlcoholAlcohol

Acute AlcoholismAcute Alcoholism

• Affects mainly CNS Affects mainly CNS depressant depressant (first affecting high brainstem (first affecting high brainstem reticular formation) reticular formation) stimulation stimulation and disordered cortical, motor, and and disordered cortical, motor, and intellectual behaviorintellectual behavior

• Moderate intake Moderate intake fatty change or fatty change or hepatic steatosishepatic steatosis

• Gastric changes: acute gastritis and Gastric changes: acute gastritis and ulcerationulceration

AlcoholAlcohol

Chronic AlcoholismChronic Alcoholism

• Affects not only liver and Affects not only liver and stomach, but virtually all other stomach, but virtually all other organs and tissues as wellorgans and tissues as well

• Significant morbidity with Significant morbidity with shortened life spanshortened life span

Areas of brain that can be damaged in utero by maternal alcohol consumption

Features of Fetal Alcohol Syndrome

Babies diagnosed with Fetal Alcohol Syndrome may have some but not all of the following physiological characteristics: •Small birth weight •Small head circumference •Small, widely spaced eyes •Flat midface •Short, upturned nose •Smooth, wide philtrum •Thin upper lip

Note: Facial characteristics may not be as apparent immediately after birth or during adolescence or adulthood as they are between the ages of two and ten. Facial characteristics may not be present at all if the mother did not drink during the brief period that the midface was forming - around the 20th day of pregnancy.

Injury by Therapeutic AgentsInjury by Therapeutic Agents

Hormonal Replacement TherapyHormonal Replacement Therapy

• Most common type: estrogen + Most common type: estrogen + progesteroneprogesterone Estrogen therapy alone used in Estrogen therapy alone used in

hysterectomized patients due to hysterectomized patients due to risk of uterine cancerrisk of uterine cancer

• Used in post-menopausal women to Used in post-menopausal women to prevent or slow the progression of prevent or slow the progression of osteoporosis and reduce likelihood osteoporosis and reduce likelihood of M.I.of M.I.



• Increased risk of breast cancer Increased risk of breast cancer (lobular and ductal-lobular (lobular and ductal-lobular carcinomas) after median time of 5 carcinomas) after median time of 5 to 8 yearsto 8 years

• Protective effect on development of Protective effect on development of AS and coronary disease in women < AS and coronary disease in women < 60 60 depends on response of depends on response of estrogen receptors that regulate estrogen receptors that regulate calcium homeostasis in blood calcium homeostasis in blood vesselsvessels



• Increased risk of venous thrombo-Increased risk of venous thrombo-embolism including embolism including deep vein deep vein thrombosis, pulmonary embolism, thrombosis, pulmonary embolism, and strokeand stroke More pronounced during first two More pronounced during first two

years of treatment and in women years of treatment and in women with risk factors (immobilization, with risk factors (immobilization, hypercoagulable states)hypercoagulable states)


Oral ContraceptivesOral Contraceptives

• Synthetic estradiol and variable Synthetic estradiol and variable amount of progestins amount of progestins inhibit inhibit ovulation or prevent implantationovulation or prevent implantation

• Present formulations with smaller Present formulations with smaller amounts of estrogen (~20 ug of amounts of estrogen (~20 ug of ethinyl estradiol) ethinyl estradiol) fewer side fewer side effectseffects



• Three-fold increased risk of venous Three-fold increased risk of venous thrombosis and pulmonary thrombo-thrombosis and pulmonary thrombo-embolism embolism due to acute phase due to acute phase response [inc. C-reactive protein response [inc. C-reactive protein and coagulation factors; decreased and coagulation factors; decreased anti-coagulants (protein S and anti-anti-coagulants (protein S and anti-thrombin III)]thrombin III)]



• Increased risk of myocardial Increased risk of myocardial infarction in smoking women of all infarction in smoking women of all ages and in non-smoking women > ages and in non-smoking women > 35 y/o35 y/o

• Reduced incidence of endometrial Reduced incidence of endometrial and ovarian cancersand ovarian cancers

• Increased risk of developing hepatic Increased risk of developing hepatic adenomaadenoma


Anabolic steroidsAnabolic steroids

• Synthetic versions of testosteroneSynthetic versions of testosterone

• 10 – 100 times higher than 10 – 100 times higher than therapeutic indications therapeutic indications inhibit inhibit production and release of LH and production and release of LH and FSH, and increases amount of FSH, and increases amount of estrogensestrogens


Acetaminophen Acetaminophen

• Most commonly used analgesic in Most commonly used analgesic in U.S.U.S. Cause of about 50% of cases of Cause of about 50% of cases of

acute liver failureacute liver failure

• Intentional overdosage (suicide) Intentional overdosage (suicide) the most common cause of toxicitythe most common cause of toxicity

• 5% metabolized through activity of 5% metabolized through activity of CYP2E to NAPQ1CYP2E to NAPQ1

Acetaminophen

Detoxification in liver by phase II

enzymes

Excreted in urine

~ 95%

< 5%

CYP2E1

NAPQ1

Covalent binding to hepatic proteins

Damage cellular membranes

Mitochondrial dysfunction

Depletion of glutathione

Increased hepatocyte

susceptibility to ROS-induced injury


Aspirin (Acetylsalicylic Acid)Aspirin (Acetylsalicylic Acid)

• In adults, overdose is usually In adults, overdose is usually suicidalsuicidal

• Source of salicylate poisoning is Source of salicylate poisoning is excessive use of ointments excessive use of ointments containing oil of wintergreen containing oil of wintergreen (methyl salicylate)(methyl salicylate)

• Ingestion of 2 – 4 gm by children or Ingestion of 2 – 4 gm by children or 10 – 30 gm by adults may be fatal10 – 30 gm by adults may be fatal

• Chronic toxicity: intake of 3 gm or Chronic toxicity: intake of 3 gm or more/day more/day salicylism salicylism

Drug AbuseDrug Abuse

Cocaine (Crack)Cocaine (Crack)

• Extracted from leaves of coca plant Extracted from leaves of coca plant prepared as water-soluble prepared as water-soluble powder (cocaine HCl)powder (cocaine HCl)

• Snorted or dissolved in water and Snorted or dissolved in water and injected SC or IVinjected SC or IV

Cocaine HCl is the final product exported from South America

Crack cocaine is made in the U.S. from several basic household products and cocaine HCl.



Cardiovascular Effects:Cardiovascular Effects:• Most serious physical effect due to Most serious physical effect due to

acute action on CVS: acute action on CVS: tachycardia, tachycardia, HPN, peripheral vasoconstrictionHPN, peripheral vasoconstriction

1.1. Sympathomimetic effect Sympathomimetic effect block block re-uptake of epinephrine and NE re-uptake of epinephrine and NE while stimulating pre-synaptic while stimulating pre-synaptic release of NE release of NE accumulation of accumulation of epinephrine & NE in synapses epinephrine & NE in synapses excess stimulationexcess stimulation



Cardiovascular Effects:Cardiovascular Effects:

2.2. Coronary artery vasoconstriction Coronary artery vasoconstriction myocardial ischemia myocardial ischemia M.I. M.I.

3.3. Enhanced platelet aggregation and Enhanced platelet aggregation and thrombus formationthrombus formation

4.4. Impaired ion transport in Impaired ion transport in myocardium myocardium lethal arrhythmia lethal arrhythmia



CNS Effects:CNS Effects:

1.1. Aberration of dopaminergic Aberration of dopaminergic pathways pathways hyperpyrexia hyperpyrexia

2.2. Seizures Seizures



Effects on pregnancyEffects on pregnancy

• Decreased blood flow to placenta Decreased blood flow to placenta fetal hypoxia and spontaneous fetal hypoxia and spontaneous abortionabortion

• Impaired fetal neurologic Impaired fetal neurologic developmentdevelopment


HeroinHeroin

• Opioid derived from poppy plantOpioid derived from poppy plant• Closely related to morphineClosely related to morphine• More harmful than cocaineMore harmful than cocaine• Physical effects related to:Physical effects related to:

1.1. Pharmacologic action of the agentPharmacologic action of the agent2.2. Reactions to the cutting agents or Reactions to the cutting agents or

contaminantscontaminants3.3. Hypersensitivity reactions to the Hypersensitivity reactions to the

drug or its adulterantsdrug or its adulterants4.4. Diseases contracted due to use of Diseases contracted due to use of

infected needlesinfected needles


HeroinHeroin

Sudden deathSudden death

• Related to overdoseRelated to overdose• Death due to:Death due to:

1.1. Respiratory depressionRespiratory depression2.2. Arrhythmia and cardiac Arrhythmia and cardiac

arrestarrest3.3. Severe pulmonary edemaSevere pulmonary edema


HeroinHeroin

Pulmonary injuryPulmonary injury

• Moderate to severe edemaModerate to severe edema• Septic embolism from Septic embolism from

endocarditisendocarditis• Lung abscessLung abscess• Opportunistic infectionsOpportunistic infections• Foreign body granuloma from Foreign body granuloma from

adulterantsadulterants


HeroinHeroin

Infections Infections

• Four sites most commonly Four sites most commonly infected: infected: skin and SC tissue, skin and SC tissue, heart valves, liver, and lungsheart valves, liver, and lungs

• S. aureus, S. aureus, viral hepatitis, fungi, viral hepatitis, fungi, HIVHIV


HeroinHeroin

SkinSkin

• Most frequent telltale sign of Most frequent telltale sign of addictionaddiction

• Acute changes: Acute changes: abscesses, abscesses, cellulitis, ulcerationcellulitis, ulceration

• Chronic use: Chronic use: hyperpigmentation hyperpigmentation over used veins, venous over used veins, venous thrombosisthrombosis


HeroinHeroin

Kidneys Kidneys

• Two forms most frequently Two forms most frequently encountered:encountered:1.1. Amyloidosis secondary to Amyloidosis secondary to

skin infectionsskin infections2.2. Focal glomerulosclerosisFocal glomerulosclerosis


Amphetamines – Metamphetamine Amphetamines – Metamphetamine

• ““speed” or “meth”speed” or “meth”• Closely related to amphetamine but Closely related to amphetamine but

with stronger CNS effectswith stronger CNS effects• Acts by releasing dopamine in the Acts by releasing dopamine in the

brain brain inhibit pre-synaptic inhibit pre-synaptic neurotransmission at corticostriatal neurotransmission at corticostriatal synapses synapses slow down glutamate slow down glutamate releaserelease


Amphetamines – MDMAAmphetamines – MDMA

• ““ecstasy”ecstasy”• 3,4 3,4

methylenedioxymethamphetaminemethylenedioxymethamphetamine• Increase serotonin release in the Increase serotonin release in the

CNS + impaired serotonin synthesisCNS + impaired serotonin synthesis• Decrease number of serotonergic Decrease number of serotonergic

axon terminals in the striatum and axon terminals in the striatum and the cortexthe cortex

• Increase peripheral effects of Increase peripheral effects of dopamine and adrenergic agentsdopamine and adrenergic agents


Marijuana (“pot”)Marijuana (“pot”)

• Made from the leaves of Made from the leaves of Cannabis Cannabis sativasativa tetrahydrocannabinol (THC) tetrahydrocannabinol (THC)

• Potential use to treat nausea Potential use to treat nausea secondary to cancer chemotherapy & secondary to cancer chemotherapy & pain reduction in cases of chronic pain reduction in cases of chronic painpain

• Endogenous cannabinoid system – Endogenous cannabinoid system – cannabinoid receptors CB1 and CB2 cannabinoid receptors CB1 and CB2 (endocannabinoids) (endocannabinoids) participate in participate in regulation of hypothalamic-pituitary regulation of hypothalamic-pituitary adrenal axis adrenal axis modulate control of modulate control of appetite, food intake, and energy appetite, food intake, and energy balance, including fertility and sexual balance, including fertility and sexual behaviorbehavior

Thermal InjuryThermal Injury

Thermal BurnsThermal Burns

• Clinical significance of burn injury Clinical significance of burn injury depends on the following factors:depends on the following factors:1.1. Depth of the burnsDepth of the burns2.2. Percentage of body surface Percentage of body surface

involvedinvolved3.3. Internal injuries due to inhalation of Internal injuries due to inhalation of

hot and toxic fumeshot and toxic fumes4.4. Promptness and efficacy of Promptness and efficacy of

treatmenttreatment


Superficial BurnsSuperficial Burns

• First-degree First-degree burns; confined burns; confined to epidermisto epidermis


Partial-thickness Partial-thickness BurnsBurns

• Second-degree Second-degree burns; burns; includes includes dermisdermis


Full-thickness Full-thickness BurnsBurns

• Third-degree Third-degree burns; extend to burns; extend to SC tissue and SC tissue and may involve may involve muscle tissue muscle tissue underneathunderneath


Thermal Burns: ComplicationsThermal Burns: Complications

1.1. Shock, sepsis, and respiratory Shock, sepsis, and respiratory insufficiencyinsufficiency

• Greatest threats; burns > 20% of Greatest threats; burns > 20% of body surface body surface rapid shift of body rapid shift of body fluids into interstitial compartments fluids into interstitial compartments hypovolemic shockhypovolemic shock

• Development of Development of hypermetabolic hypermetabolic statestate associated with excess heat associated with excess heat loss and increased need for loss and increased need for nutritional supportnutritional support



1.1. Shock, sepsis, and respiratory Shock, sepsis, and respiratory insufficiencyinsufficiency

• Burn site ideal for growth of Burn site ideal for growth of organisms organisms P. aeruginosa (most P. aeruginosa (most common), S. aureus, fungi, Candidacommon), S. aureus, fungi, Candida

• Most common serious sequelae: Most common serious sequelae: pneumonia or septic shock with pneumonia or septic shock with renal failure and/or ARDSrenal failure and/or ARDS



2.2. Injury to airways and lungsInjury to airways and lungs

• Develop within 24 to 48 hours after Develop within 24 to 48 hours after the burnthe burn

• May be the result of:May be the result of:1.1. Direct effect of heat on mouth, nose, Direct effect of heat on mouth, nose,

and upper airwaysand upper airways2.2. Inhalation of heated air and noxious Inhalation of heated air and noxious

gases in the smoke gases in the smoke inflammation inflammation and swelling and swelling partial or complete partial or complete airway obstructionairway obstruction



3.3. Development of hypertrophic scarsDevelopment of hypertrophic scars

• Both at site of original burn and at Both at site of original burn and at donor graft sitesdonor graft sites

• Injured nerve endings Injured nerve endings release of release of substance P substance P excess neuropeptides excess neuropeptides continuous angiogenesis continuous angiogenesis scar scar


Hyperthermia – Heat cramps Hyperthermia – Heat cramps

• Results from loss of electrolytes Results from loss of electrolytes via sweatingvia sweating

• Cramping of voluntary muscles in Cramping of voluntary muscles in association with vigorous exercise association with vigorous exercise HALLMARK HALLMARK


Hyperthermia – Heat exhaustionHyperthermia – Heat exhaustion

• Most common hyperthermic Most common hyperthermic syndromesyndrome

• Sudden onset with prostration Sudden onset with prostration and collapse and collapse due to failure of due to failure of CVS to compensate for CVS to compensate for hypovolemiahypovolemia

• Collapse brief and equilibrium Collapse brief and equilibrium spontaneously re-establishedspontaneously re-established


Hyperthermia – Heat strokeHyperthermia – Heat stroke

• Associated with high ambient Associated with high ambient temp., high humidity, and temp., high humidity, and exertionexertion

• Failure of thermoregulatory Failure of thermoregulatory mechanisms mechanisms no sweating, core no sweating, core body temp. > 40body temp. > 4000C C multi-organ multi-organ dysfunction dysfunction rapidly fatal rapidly fatal


HypothermiaHypothermia

• Prolonged exposure to low Prolonged exposure to low ambient temperaturesambient temperatures

• Body temperature of 90Body temperature of 9000F F loss loss of consciousness followed by of consciousness followed by bradycardia and atrial fibrillation bradycardia and atrial fibrillation at lower core temperaturesat lower core temperatures


Hypothermia - MechanismsHypothermia - Mechanisms

1.1. Direct effectsDirect effects• Crystallization of intra- and extra-Crystallization of intra- and extra-

cellular water cellular water high salt high salt concentrations concentrations physical physical disruptions within cellsdisruptions within cells

2.2. Indirect effectsIndirect effects• Result of circulatory changesResult of circulatory changes


Hypothermia – MechanismsHypothermia – Mechanisms

• Slowly developing chilling Slowly developing chilling vasoconstriction and increased vasoconstriction and increased vascular permeability vascular permeability edema and edema and hypoxia hypoxia gangrene of extremities gangrene of extremities (e.g. “trench foot”)(e.g. “trench foot”)

• Sudden, persistent chilling Sudden, persistent chilling vaso- vaso-constriction and increased blood constriction and increased blood viscosity viscosity ischemic injury and ischemic injury and degenerative changes of peripheral degenerative changes of peripheral nervesnerves

Radiation InjuryRadiation Injury

Non-Ionizing Radiation InjuryNon-Ionizing Radiation Injury

Non-ionizing radiationNon-ionizing radiation

• UV and infrared light, UV and infrared light, microwave and sound wavesmicrowave and sound waves

• Cause atoms in a molecule to Cause atoms in a molecule to move or vibrate move or vibrate not sufficient not sufficient to displace bound electrons to displace bound electrons from atomsfrom atoms

Non-Ionizing Radiation InjuryNon-Ionizing Radiation Injury

• UV rays derived from sun UV rays derived from sun increased incidence of SCCA, increased incidence of SCCA, basal cell carcinoma, and skin basal cell carcinoma, and skin melanomamelanoma

• Degree of risk depends on:Degree of risk depends on:1.1. Type of UV rayType of UV ray2.2. Intensity of exposureIntensity of exposure3.3. Quantity of light-absorbing Quantity of light-absorbing

protective coat of melaninprotective coat of melanin

UVB sunlight is directly absorbed by DNA resulting in single strand breaks and the formation of pyrimidine

dimers.

Ionizing Radiation InjuryIonizing Radiation Injury

Ionizing radiationIonizing radiation

• Main sources:Main sources:1.1. X-raysX-rays2.2. Gamma rays – Gamma rays –

electromagnetic waves of electromagnetic waves of very high frequencyvery high frequency

3.3. High-energy neutronsHigh-energy neutrons4.4. Alpha particles (2 protons Alpha particles (2 protons

and 2 neutrons)and 2 neutrons)5.5. Beta particles – electrons Beta particles – electrons


Ionizing radiationIonizing radiation

• Alpha particles Alpha particles induce heavy induce heavy damage in a restricted areadamage in a restricted area

• X-rays and gamma particles X-rays and gamma particles longer, deeper course with less longer, deeper course with less damage per unit of tissuedamage per unit of tissue

• With sufficient energy to remove With sufficient energy to remove tightly bound electrons tightly bound electrons Cause collision of electrons Cause collision of electrons

with other molecules with other molecules ionizationionization


Major Determinant of Biologic EffectsMajor Determinant of Biologic Effects

Rate of deliveryRate of delivery• Divided doses Divided doses allow cells to allow cells to

repair damage between repair damage between exposuresexposures

Field sizeField size• Small doses delivered to large Small doses delivered to large

fields fields lethal lethal• High doses delivered to small, High doses delivered to small,

shielded fields shielded fields tolerable tolerable



Cell proliferationCell proliferation• Rapidly dividing cells (gonads, Rapidly dividing cells (gonads,

bone marrow, lymphoid tissue, bone marrow, lymphoid tissue, mucosa of GIT) more vulnerable mucosa of GIT) more vulnerable due to DNA damage due to DNA damage mutations mutations and chromosomal abnormalitiesand chromosomal abnormalities

• DNA damage in quiescent cells DNA damage in quiescent cells compatible with survival if dose compatible with survival if dose not very highnot very high



Oxygen effects and hypoxiaOxygen effects and hypoxia• Production of reactive oxygen Production of reactive oxygen

species from radiolysis of water species from radiolysis of water main mechanism of DNA main mechanism of DNA damagedamage

• Poorly vascularized tissues with Poorly vascularized tissues with low oxygenation low oxygenation less sensitive less sensitive to radiation therapy than non-to radiation therapy than non-hypoxic tissueshypoxic tissues



Vascular damageVascular damage

• Damage to endothelial cells Damage to endothelial cells narrowing and occlusion of blood narrowing and occlusion of blood vessel vessel impaired healing, impaired healing, fibrosis, chronic ischemic atrophyfibrosis, chronic ischemic atrophy

Injury to arm of patient. Patient was draped for procedure and physicians did not realize that she had moved her arm so that it was resting on the port of the X-ray tube during the procedure.

Date post:	18-Jan-2015
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Environmental Pathology

Health & Medicine