6 Environmental Pathology Chemical Injury

The two leading causes of illness and death in the United States are tobacco and alcohol use.

Chemical Injury

The two leading causes of illness and death in the United States are tobacco and alcohol use.

Tobacco use

Table 6-1. Systemic Effects Associated with Tobacco UseSystem EffectsCardiovascular Acute myocardial infarction (AMI)

Sudden cardiac deathPeripheral vascular diseaseHypertension

Central nervous system Strokes: intracerebral bleed, subarachnoid hemorrhageGastrointestinal Oropharyngeal cancer: squamous cell carcinoma

Upper, midesophageal cancer: squamous cell carcinomaGastroesophageal reflux disease: decreases tone of lower esophageal sphincterDelayed healing of peptic ulcersPancreatic cancer: adenocarcinoma

General Low birth weight, fetal growth retardationNeutrophilic leukocytosis: decreased activation of neutrophil adhesion moleculesDecreased concentration of ascorbic acid and β-carotenes

Genitourinary Cervical cancer: squamous cell carcinomaDecreased testosterone in malesDecreased estrogen in femalesKidney cancer: renal cell carcinomaUrinary bladder cancer: transitional cell carcinoma

Integument Increased facial wrinklingMusculoskeletal Osteoporosis: due to decreased estrogen in females and decreased testosterone in malesRespiratory Laryngeal cancer: squamous cell carcinoma

Chronic obstructive pulmonary disease: chronic bronchitis, emphysemaLung cancer: squamous cell carcinoma, small cell carcinoma, some types of adenocarcinoma

Special senses Decreased sense of smell and tasteBlindness: macular degenerationCataracts

1. Tobacco is the leading cause of premature death in the United States. 2. The rate of cigarette smoking is increasing in females and decreasing in males. 3. Chemical components of tobacco

a. Nicotine i. Rapidly absorbed ii. Most addictive chemical in tobacco smoke iii. Cotinine is the most important metabolite of nicotine.

Screening test in blood or urine for detecting nicotine b. Polycyclic hydrocarbons are the primary carcinogens.

4. Smokeless tobacco (e.g., chewing tobacco)

o Can cause nicotine addiction and cancer 2. Passive (secondhand) smoke inhalation

a. Greatest impact on children i. Increased risk of respiratory and middle ear infections ii. Exacerbates asthma

b. Increased risk for lung cancer and coronary artery disease

5. Systemic effects associated with tobacco use 6. Beneficial effects of smoking cessation

c. Risk for cardiovascular disease

Approaches nonsmoker after 15 years .b Risk for lung cancer

Approaches nonsmoker after 15 years .c Risk for stroke

Approaches nonsmoker after 5 to 15 years .d Other benefits

i. Reduced risk for cancers of the mouth, larynx, esophagus, pancreas, and urinary bladder

ii. Improved pulmonary function regardless of severity of the disease

iii. Reduced risk for pneumonia, influenza, and bronchitis

Alcohol abuse page 109

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Table 6-2. Systemic Effects Associated with Alcohol AbuseSystem EffectsCardiovascular Congestive (dilated) cardiomyopathy: due to thiamine deficiency

Hypertension: vasopressor effects due to increase in catecholaminesCentral nervous system (CNS)

CNS depressant: particularly cerebral cortex and limbic systemWernicke's syndrome: confusion, ataxia, nystagmus due to thiamine deficiencyKorsakoff's psychosis: memory deficits due to thiamine deficiencyCerebellar atrophy: due to loss of Purkinje cellsCerebral atrophy: due to loss of neuronsCentral pontine myelinolysis: due to rapid intravenous fluid correction of hyponatremia in an alcoholic

Gastrointestinal Oropharyngeal and upper to midesophageal cancer: squamous cell carcinomaAcute hemorrhagic gastritisMallory-Weiss syndrome: tear of distal esophagus due to retchingBoerhaave's syndrome: rupture of distal esophagus due to retchingEsophageal varices: caused by portal vein hypertension in alcoholic cirrhosisAcute and chronic pancreatitis

General Fetal alcohol syndrome: mental retardation, microcephaly, atrial septal defectGenitourinary Testicular atrophy: decreased testosterone, decreased spermatogenesis

Increased risk for spontaneous abortionHematopoietic Folate deficiency: decreased reabsorption in jejunum; macrocytic anemia

Acquired sideroblastic anemia: microcytic anemia due to defect in heme synthesisAnemia chronic disease: most common anemia in alcoholics

Hepatobiliary Fatty liver, alcoholic hepatitis, cirrhosisHepatocellular carcinoma: preexisting cirrhosis

Integument Porphyria cutanea tarda: photosensitive bullous skin lesionsMusculoskeletal Rhabdomyolysis: direct alcohol effect on musclePeripheral nervous system Peripheral neuropathy: due to thiamine deficiency

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1. Alcohol metabolism a. Absorption occurs in the stomach (25%) b. Metabolism occurs in the stomach and liver

Alcohol dehydrogenase is the rate-limiting enzyme. c. Important products of alcohol metabolism

.i Reduced nicotinamide adenine dinucleotide (NADH) Causes conversion of pyruvate to lactate Causes conversion of acetoacetate to β-hydroxybutyrate Causes conversion of dihydroxyacetone phosphate to glycerol 3-

phosphate .ii Acetyl coenzyme A (acetyl CoA)

Used to synthesize fatty acids for triglyceride synthesis Used to synthesize ketoacids

b. Alcohol induction of the cytochrome P-450 enzyme system

Increases alcohol metabolism, which increases the tolerance for alcohol b. Legal blood alcohol limit for driving

Ranges from 80 to 100mg/dL .. Risk factors for alcohol-related disease

a. Amount b. Duration c. Female sex

.i Decreased gastric alcohol dehydrogenase levels Causes higher alcohol levels in women than in men, even after drinking

the same amount of alcohol .ii Genetic susceptibility

2. Systemic effects associated with alcohol abuse 3. Laboratory findings in alcohol abuse

a. Fasting hypoglycemia

Excess NADH causes pyruvate (substrate for gluconeogenesis) to convert to lactate.

d. Increased anion gap metabolic acidosis

.i Lactic acidosis

.ii β-Hydroxybutyric ketoacidosis Excess acetyl CoA is converted to β-hydroxybutyrate.

b. Other findings .i Hyperuricemia

Lactic acid and β-hydroxybutyric acid compete with uric acid for excretion

in the proximal tubules. .ii Hypertriglyceridemia

Increased production of glycerol 3-phosphate, the key substrate for triglyceride synthesis in the liver

.iii Serum aspartate aminotransferase (AST) greater than serum alanine aminotransferase (ALT) in liver disease

Alcohol is a mitochondrial toxin that causes release of AST, which is located in the mitochondria.

v.i Increased serum γ-glutamyltransferase (GGT)

Alcohol induces hyperplasia of the smooth endoplasmic reticulum causing increased synthesis of GGT.

Other drugs of abuse

Table 6-3. Selected Drugs of Abuse and Their EffectsDrug Description Toxic EffectsCocaine Stimulant Mydriasis, tachycardia, hypertension

Associated risk of AMI, CNS infarction, perforation of nasal septum (intranasal use)

Heroin Opiate Miotic pupils, noncardiogenic pulmonary edema (frothing from mouth), focal segmental glomerulosclerosis (nephrotic syndrome)Granulomatous reactions in skin and lungs from material used to "cut" (dilute) drug

Marijuana (Cannabis)*

THC-containing psychoactive stimulant

Red conjunctiva, euphoria, delayed reaction time

MPTP By-product of synthesis of meperidine

Irreversible Parkinson's disease: cytotoxic to neurons in nigrostriatal dopaminergic pathways

*Used medically to decrease nausea and vomiting associated with chemotherapy and to decrease intraocular pressure in glaucoma.AMI, myocardial infarction; CNS, central nervous system; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; THC, Δ9-tetrahydrocannabinol.

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Sedatives, stimulants, hallucinogens

1. CNS effects of long-term drug abuse a. Damage to neurotransmitter receptor sites b. Cerebral atrophy (e.g., alcohol)

2. Complications of intravenous drug use (IVDU) a. Hepatitis B b. Human immunodeficiency virus (HIV) c. Infective endocarditis

Caused by Staphylococcus aureus d. Tetanus

Complication of "skin popping

Adverse effects of therapeutic drug use

Table 6-4. Adverse Reactions Associated with Therapeutic Drug UseReaction Drug(s)Blood Dyscrasias  Aplastic anemia Chloramphenicol, alkylating agentsHemolytic anemia Penicillin, methyldopa, quinidineMacrocytic anemia Methotrexate (most common), phenytoin, oral contraceptives, 5-fluorouracilPlatelet dysfunction Aspirin, other NSAIDsThrombocytopenia Heparin (most common), quinidineCardiac  Congestive cardiomyopathy Doxorubicin, daunorubicinCentral Nervous System  Tinnitus, vertigo SalicylatesCutaneous  Angioedema ACE inhibitorsMaculopapular rash PenicillinPhotosensitive rash TetracyclineUrticaria PenicillinGastrointestinal  Hemorrhagic gastritis Iron, salicylatesHepatic  Cholestasis Oral contraceptives, estrogen, anabolic steroidsFatty change Amiodarone, tetracycline, methotrexateHepatic adenoma Oral contraceptivesLiver necrosis Acetaminophen (most common), isoniazid, salicylates, halothane, ironPulmonary  Asthma Aspirin, other NSAIDsInterstitial fibrosis Bleomycin, busulfan, nitrofurantoin, methotrexateSystemic  Drug-induced lupus Procainamide, hydralazine

ACE, angiotensin-converting enzyme; NSAID, nonsteroidal anti-inflammatory drug. page 113

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1. Acetaminophen a. Conversion to free radicals in the liver b. May result in damage to the liver (e.g., fulminant hepatitis) c. May result in damage to the kidneys (e.g., renal papillary necrosis)

2. Aspirin (acetylsalicylic acid) overdose a. General symptoms

Tinnitus, vertigo, change in mental status (confusion, seizures), tachypnea b. Acid-base disorders

.i Respiratory alkalosis may occur initially (within 12-24 hours) Due to direct stimulation of the respiratory center Respiratory acidosis may occur as a late finding.

.ii Shift to metabolic acidosis with an increased anion gap Occurs more often in children

.iii Mixed primary respiratory alkalosis and metabolic acidosis

Occurs more often in adults b. Hyperthermia

.i Salicylates damage the inner mitochondrial membrane.

.ii Oxidative energy is released as heat, not as adenosine triphosphate. c. Hemorrhagic gastritis, fulminant hepatitis

2. Disorders associated with exogenous estrogen without progestin a. Cancer (adenocarcinoma)

Endometrium, breast b. Venous thromboembolism

.i Estrogen decreases synthesis of antithrombin III (ATIII). ATIII normally neutralizes coagulation factors.

.ii Estrogen increases synthesis of factors I (fibrinogen), V, and VIII. b. Intrahepatic cholestasis with jaundice c. Cardiovascular effects

Myocardial infarction (MI), stroke .. Disorders associated with oral contraceptives

o Contain estrogen and progestin

a. Cancer

.i Breast (adenocarcinoma)

.ii Cervix (squamous cell carcinoma) b. Venous thromboembolism

.i Similar pathogenesis to estrogen without progestin c. Folate deficiency

.i Decreases jejunal reabsorption of folate d. Hypertension

.i Due to increased synthesis of angiotensinogen e. Hepatic adenoma

.i Risk of intraperitoneal hemorrhage f. Intrahepatic cholestasis with jaundice g. Cholesterol gallstones

.i Estrogen increases cholesterol excretion in bile.

Injuries caused by environmental chemicals

Table 6-5. Environmental Chemicals and Associated Toxic EffectsChemical Source Toxic EffectsArsenic Pesticides, animal dips Diarrhea, transverse bands in nails (Mee's lines),

convulsionsSquamous cell carcinoma of skin, liver angiosarcoma, lung cancer

Asbestos Insulation, roofing material Primary lung cancer, mesothelioma

Benzene Solvent Acute leukemia, aplastic anemiaCarbon monoxide Automobile exhaust, house

firesHeadache (first sign), cherry-red skin, comaDecreased oxygen saturation

Coral snake bite Neurotoxin: binds to presynaptic nerve terminals and acetylcholine

Snake has "red on yellow" bandsToxic effects: mydriasis, paralysis, and respiratory failure

Crotaline bite Venom cyto-hemo-neurotoxic Rattlesnake, copperhead, water moccasinToxic effects: local edema, shock, disseminated intravascular coagulation (DIC)

Cyanide House fires SeizuresEthylene glycol Antifreeze

End product: oxalic acidIncreased anion gap metabolic acidosisAcute renal failure

Isopropyl alcohol Rubbing alcoholEnd product: acetone

Deep coma

Latrodectus bite* (black widow spider)

Neurotoxin Painful biteMuscle cramps/spasms: occur in thighs and abdomen and simulate an acute abdomen

Lead Lead-based paint, batteries, metal casting

Microcytic anemia with coarse basophilic stippling, nephrotoxicity in proximal tubule

Loxosceles bite† (brown recluse spider)

Necrotoxin Painless to mildly painful bitePainful reddish blister with blue-white halo followed by extensive skin necrosis

Mercury Fish, insecticides Diarrhea, constricted visual fields, nephrotoxicity in proximal tubule

Methanol Window-washing fluidEnd product: formic acid

Increased anion gap metabolic acidosisBlindness due to optic atrophy

Organophosphates Pesticides Miotic pupils, paralysisDecreased serum and red blood cell cholinesterase levels

Polyvinyl chloride Plastics industry Liver angiosarcomaScorpion sting Neurotoxin Poisonous species in Southwestern deserts (Centruroides

sp.)Toxic effects: initially has painful sting followed by numbness, hypertension, ascending motor paralysis leading to death; may cause acute pancreatitis

Physical Injury Mechanical injury

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1. Types of skin wounds a. Contusion (bruise)

Blunt force injury to blood vessels with subsequent escape of blood into tissue b. Abrasion

Superficial excoriation of the epidermis c. Laceration

Jagged tear with intact bridging blood vessels, nerves, and connective tissue d. Incision

Wound with sharp margins with severed bridging blood vessels 2. Gunshot wounds

a. Contact wounds

.i Stellate-shaped

.ii Contain soot and gunpowder (fouling) b. Intermediate-range wounds

Powder tattooing (stippling) of the skin around the entrance site b. Long-range wounds

No powder tattooing c. Exit wounds

Typically larger and more irregular than entrance wounds .. Motor vehicle collisions

a. Frequently cause mechanical injury

b. Frequently alcohol-related

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1. Types of skin wounds a. Contusion (bruise)

Blunt force injury to blood vessels with subsequent escape of blood into tissue b. Abrasion

Superficial excoriation of the epidermis c. Laceration

Jagged tear with intact bridging blood vessels, nerves, and connective tissue d. Incision

Wound with sharp margins with severed bridging blood vessels 2. Gunshot wounds

a. Contact wounds

.i Stellate-shaped

.ii Contain soot and gunpowder (fouling) b. Intermediate-range wounds

Powder tattooing (stippling) of the skin around the entrance site b. Long-range wounds

No powder tattooing c. Exit wounds

Typically larger and more irregular than entrance wounds .. Motor vehicle collisions

a. Frequently cause mechanical injury

b. Frequently alcohol-related

Thermal injury

Table 6-6. Heat Injuries*Type of Injury Body Temperature Skin Mental StatusHeat cramps 37.0°C (98.6°F) Moist and cool NormalHeat exhaustion >37.8°C (>100°F) Sweating Minimally alteredHeat stroke >40°C (>104°F) Dry (anhidrosis) Impaired consciousness

*Heat injury is exacerbated by high humidity. page 117

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1. Burns a. First-degree

i. Painful partial-thickness burns (e.g., sunburn) ii. Heal without scarring

b. Second-degree i. Painful partial-thickness burns ii. Damage to entire epidermis iii. Blister formation iv. Usually heal without scarring

c. Third-degree i. Painless full-thickness burns ii. Extensive necrosis of epidermis and adnexa iii. Scarring is inevitable.

Keloids (exaggerated scars) commonly occur. Potential for developing squamous cell carcinoma

iv. Healing of epithelial surface Proliferation of residual epithelium located at burn margins and lining

adnexal structures d. Complications

i. Infection Sepsis due to Pseudomonas aeruginosa is the most common cause of

death. ii. Curling's ulcers (stomach)

2. Heat injuries 3. Frostbite

a. Pathogenesis i. Localized tissue injury caused by direct damage (e.g., ice crystallization in cells) ii. Indirect damage (e.g., vasodilation, thrombosis)

b. Clinical findings i. Loss of pain sensation

ii. Waxy appearance

Electrical injury 1. Produced by alternating current (AC) and direct current (DC)

a. AC is more dangerous than DC. b. AC produces tetanic contractions c. DC produces a single shock

2. Wet skin decreases resistance, which increases current. 3. Dry skin increases resistance, which decreases current.

4. Tissue damage increases with increased voltage and duration of exposure. 5. Current moving from the left arm to the right leg

a. Most dangerous route, because it affects the heart

b. Death results from cardiorespiratory arrest.

Drowning 1. Common cause of death in children from 1 to 14 years of age 2. Terms

a. Drowning refers to death by suffocation from immersion in liquid. b. Near drowning is defined as survival following asphyxia secondary to submersion. c. Wet drowning

i. 90% of cases ii. Initial laryngospasm on contact with water followed by relaxation and aspiration

of water d. Dry drowning is characterized by intense laryngospasm without aspiration.

3. Pathophysiology a. Hypoxemia with damage to central nervous system, heart, kidneys b. Lung aspiration (fresh or salt water)

i. Damages type II pneumocytes, which decreases surfactant production ii. Diffuse alveolar damage

c. Asphyxia in dry drowning d. Lung injury and hypoxemia in wet drowning

4. Cold water drowning a. Activates diving reflex

Shunts blood from the periphery to the central core

b. Hypothermia decreases metabolic demand.

High altitude injury 1. General

a. O2 concentration 21% b. Decreased barometric pressure c. Hypoxemic stimulus for respiratory alkalosis

Decrease in Paco2 causes a corresponding increase in Pao2. d. Respiratory alkalosis activates glycolysis

.i Increased synthesis of 2,3-bisphosphoglycerate

.ii Right-shifts O2-binding curve Increases release of O2 to tissue

2. Acute mountain sickness a. Usually occurs at above 8000 feet (2440m) elevation b. Risk factors

.i Increased rate of ascent

.ii Extreme altitude

c. Clinical findings .i Headache (most common) .ii Fatigue, dizziness, anorexia, insomnia .iii Acute pulmonary edema

Noncardiogenic (exudate) v.i Acute cerebral edema

Ataxia, stupor, coma d. Treatment

Immediate descent (if severe complications)

Radiation Injury Ionizing radiation injury

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Examples-x-rays, γ-rays

1. Pathophysiology a. Injury correlates with type of radiation, cumulative dose, and amount of surface area

exposed. b. Direct or indirect DNA injury occurs via formation of hydroxyl free radicals.

2. Tissue susceptibility a. Most radiosensitive tissues (highest mitotic activity)

i. Lymphoid tissue (most sensitive) ii. Bone marrow iii. Mucosa of gastrointestinal tract, germinal tissue

b. Least radiosensitive tissues i. Bone (least sensitive) ii. Brain, muscle, skin

3. Radiation effects in different tissues a. Hematopoietic

i. Lymphopenia (first change) ii. Thrombocytopenia iii. Bone marrow hypoplasia

b. Vascular i. Thrombosis (early), fibrosis (late) ii. Ischemic damage

c. Epidermal i. Acute effects are erythema, edema, blistering ii. Chronic effect is radiodermatitis

Potential for squamous cell carcinoma d. Gastrointestinal

i. Acute effect is diarrhea. ii. Chronic effects are adhesions with potential for bowel obstruction.

4. Cancers caused by radiation a. Acute leukemia (most common) b. Papillary carcinoma of the thyroid

c. Osteogenic sarcoma

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Examples-x-rays, γ-rays

1. Pathophysiology a. Injury correlates with type of radiation, cumulative dose, and amount of surface area

exposed. b. Direct or indirect DNA injury occurs via formation of hydroxyl free radicals.

2. Tissue susceptibility a. Most radiosensitive tissues (highest mitotic activity)

i. Lymphoid tissue (most sensitive) ii. Bone marrow iii. Mucosa of gastrointestinal tract, germinal tissue

b. Least radiosensitive tissues i. Bone (least sensitive) ii. Brain, muscle, skin

3. Radiation effects in different tissues a. Hematopoietic

i. Lymphopenia (first change) ii. Thrombocytopenia iii. Bone marrow hypoplasia

b. Vascular i. Thrombosis (early), fibrosis (late) ii. Ischemic damage

c. Epidermal i. Acute effects are erythema, edema, blistering ii. Chronic effect is radiodermatitis

Potential for squamous cell carcinoma d. Gastrointestinal

i. Acute effect is diarrhea. ii. Chronic effects are adhesions with potential for bowel obstruction.

4. Cancers caused by radiation a. Acute leukemia (most common) b. Papillary carcinoma of the thyroid

c. Osteogenic sarcoma

Nonionizing radiation 1. Ultraviolet light B (UVB) is most damaging

a. Pathogenesis i. Pyrimidine dimers distort the DNA helix ii. Inactivation of the TP53 suppressor gene iii. Activation of the RAS oncogene

b. General effects i. Sunburn ii. Actinic (solar) keratosis

Precursor of squamous cell carcinoma (2-5% of cases) iii. Corneal burns from skiing

c. Cancers i. Basal cell carcinoma (most common) ii. Squamous cell carcinoma, malignant melanoma

2. Effects of other types of radiation a. Laser radiation

Third-degree burns b. Microwave radiation

Skin burns, cataracts, sterility c. Infrared radiation

Skin burns, cataracts