Environmental Pathology


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Environmental Pathology

  1. 1. ENVIRONMENTAL PATHOLOGY Fe A. Bartolome, MD, FPASMAP Department of Pathology Our Lady of Fatima University
  2. 2. Global Climate Change <ul><li>Human activity a major contributor </li></ul><ul><li>Increases of carbon dioxide, methane, and ozone  main ingredients of the greenhouse effect  along with water vapor acts like a blanket  absorb energy radiated from the earth’s surface </li></ul><ul><li>Recent increases due to combustion of hydrocarbons in automobiles and energy plants </li></ul>
  3. 3. Global Climate Change <ul><li>Present concentration of atmospheric CO 2 = 370 ppm </li></ul><ul><ul><li>Expected to increase to 500 – 1200 ppm at the end of the century </li></ul></ul><ul><ul><li>Large scale deforestation a major contributor  decreased carbon sequestration by trees </li></ul></ul>
  4. 4. Global Climate Change <ul><li>Effects of global warming: </li></ul><ul><ul><li>Loss of reflective snow and ice  increased heat absorption </li></ul></ul><ul><ul><li>Greater evaporation from bodies of water and transpiration from trees  increased water vapor in the atmosphere </li></ul></ul><ul><ul><li>Thawing of arctic tundra  large releases of stored CO 2 and methane </li></ul></ul><ul><ul><li>Diminished growth of diatoms  decreased sequestration of CO 2 </li></ul></ul>
  5. 5. Global Climate Change: Health Impacts
  6. 6. Global Climate Change: Health Impacts
  7. 7. Toxicity of Chemicals & Physical Agents <ul><li>Toxicology </li></ul><ul><ul><li>Science of poisons </li></ul></ul><ul><ul><li>Studies the distribution, effects, and mechanisms of action of toxic agents </li></ul></ul><ul><ul><li>Includes the study of the effects of physical agents such as radiation and heat </li></ul></ul>
  8. 8. Toxicity of Chemicals & Physical Agents <ul><li>Basic Principles: </li></ul><ul><ul><li>The definition of poison is not straightforward. It is a quantitative concept strictly dependent on dosage. </li></ul></ul><ul><ul><li>Xenobiotics are exogenous chemicals in the environment (air, water, food, and soil) that may be absorbed into the body. </li></ul></ul>
  9. 9. Xenobiotic Metabolism Xenobiotic Xenobiotic Phase I reactions Hydrolysis Reduction Oxidation Primary metabolite Phase II reactions Glucuronidation Sulfation Methylation Conjugation 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)
  10. 10. Toxicity of Chemicals & Physical Agents <ul><li>Basic Principles: </li></ul><ul><ul><li>Chemicals may be excreted in urine, feces, or eliminated in expired air, or may accumulate in tissues (e.g. Bone, fat, brain). </li></ul></ul><ul><ul><li>Chemicals may act at the site of entry or at other sites following transport through blood. </li></ul></ul>
  11. 11. Toxicity of Chemicals & Physical Agents <ul><li>Basic Principles: </li></ul><ul><ul><li>Most solvents and drugs are lipophilic  facilitate transport through blood by lipoproteins and entry into cells. </li></ul></ul><ul><ul><li>The most important catalyst in the metabolism of xenobiotics is the cytochrome P-450 enzyme system. </li></ul></ul>
  12. 12. Cytochrome P-450 enzyme system <ul><ul><li>Primarily in endoplasmic reticulum of liver but also present in skin, lungs, GIT, and other organs </li></ul></ul><ul><ul><li>Catalyze reactions that either: </li></ul></ul><ul><ul><ul><li>Detoxify xenobiotics </li></ul></ul></ul><ul><ul><ul><li>Activate xenobiotics into active compounds  cause cellular injury </li></ul></ul></ul><ul><ul><li>Production of reactive oxygen species common to both reactions  cellular damage </li></ul></ul>
  13. 13. Cytochrome P-450 enzyme system <ul><ul><li>Great variation in activity of CYPs among individuals due to: </li></ul></ul><ul><ul><ul><li>Genetic polymorphism in specific CYPs </li></ul></ul></ul><ul><ul><ul><li>Exposure to drugs or chemicals that induce or diminish activity </li></ul></ul></ul><ul><ul><ul><ul><li>Inducers: environmental chemicals, drugs, smoking, alcohol, hormones </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Decrease activity: fasting or starvation </li></ul></ul></ul></ul>
  14. 14. Cytochrome P-450 enzyme system 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
  15. 15. Environmental Pollution: Air Pollution <ul><li>Outdoor Air Pollution </li></ul><ul><li>Six major pollutants: sulfur dioxide, carbon monoxide, ozone, nitrogen dioxide, lead, and particulate matter  collectively produce SMOG ( sm oke and f og ) </li></ul><ul><li>Lungs bear the brunt of adverse effects but other organs may be affected. </li></ul>
  16. 17. Environmental Pollution: Air Pollution <ul><li>Outdoor Air Pollution – Ozone </li></ul><ul><li>UV radiation + O2 in stratosphere = ozone (O3) </li></ul><ul><li>Two types: </li></ul><ul><ul><li>Stratospheric ozone (ozone layer) </li></ul></ul><ul><ul><ul><li>“ good ozone”  absorbs the most dangerous UV radiation from sun </li></ul></ul></ul><ul><ul><ul><li>Decreased during last 30 years due to use of aerosols </li></ul></ul></ul>
  17. 18. Environmental Pollution: Air Pollution <ul><li>Outdoor Air Pollution – Ozone </li></ul><ul><li>Two types: </li></ul><ul><ul><li>Ground-level ozone </li></ul></ul><ul><ul><ul><li>Ozone that accumulates in the lower atmosphere </li></ul></ul></ul><ul><ul><ul><li>Formed by reaction of nitrogen oxides and volatile organic cpds in the presence of sunlight </li></ul></ul></ul><ul><ul><ul><li>Due to industrial emissions and motor vehicle exhaust </li></ul></ul></ul>
  18. 21. Effects?
  19. 26. Environmental Pollution: Air Pollution <ul><li>Outdoor Air Pollution – Ozone </li></ul><ul><li>Toxicity due to production of free radicals  injure epithelial cells  release of inflammatory mediators </li></ul><ul><li>Other agents (e.g. Sulfur dioxide from power plants, copper smelters, paper mills)  released into the air  combine with ozone to produce sulfuric acid </li></ul><ul><ul><li>Acid rain </li></ul></ul><ul><ul><li>Burning sensation in nose and throat; respiratory symptoms </li></ul></ul>
  20. 28. Environmental Pollution: Air Pollution <ul><li>Outdoor Air Pollution – Particulate Matter </li></ul><ul><li>Known as soot </li></ul><ul><li>Emitted by: </li></ul><ul><ul><li>coal- and oil-fired power plants </li></ul></ul><ul><ul><li>Industrial processed burning fuels </li></ul></ul><ul><ul><li>Diesel exhaust </li></ul></ul><ul><li>Fine or ultrafine particles < 10 um in diameter the most harmful  inhaled  phagocytosed by macrophages & neutrophils  release inflammatory mediators (e.g. Macrophage inflammatory protein 1 α and endothelins) </li></ul>
  21. 31. Environmental Pollution: Air Pollution <ul><li>Outdoor Air Pollution – Carbon Monoxide </li></ul><ul><li>Non-irritating, colorless, tasteless, odorless gas </li></ul><ul><li>Produced by incomplete oxidation of carbonaceous materials </li></ul><ul><li>Low levels found in ambient air  contribute to impaired respiratory function but not life-threatening </li></ul><ul><li>Important cause of accidental and suicidal death </li></ul>
  22. 34. Environmental Pollution: Air Pollution <ul><li>Outdoor Air Pollution – Carbon Monoxide </li></ul><ul><li>Small, closed garage  lethal coma within 5 minutes </li></ul><ul><li>If hemoglobin 20% - 30% saturated with CO  systemic hypoxia </li></ul><ul><li>If 60% - 70% saturated  unconsciousness and death </li></ul>
  23. 35. Environmental Pollution: Air Pollution <ul><li>Outdoor Air Pollution – Carbon Monoxide </li></ul><ul><li>Acute poisoning: </li></ul><ul><ul><li>Due to accidental exposure or suicide attempt </li></ul></ul><ul><ul><li>Characteristic cherry-red color of skin and mucus membranes in light-skinned individuals  due to high levels of carboxyhemoglobin </li></ul></ul><ul><ul><li>Morphologic changes due to systemic hypoxia; non-specific </li></ul></ul>
  24. 37. Environmental Pollution: Air Pollution <ul><li>Outdoor Air Pollution – Carbon Monoxide </li></ul><ul><li>Chronic poisoning: </li></ul><ul><ul><li>Slowly developing hypoxia  ischemic changes in the CNS (especially basal ganglia and lenticular nuclei) </li></ul></ul><ul><ul><li>Cessation of exposure  recovery but with permanent neurologic sequelae (impairment of memory, vision, hearing, and speech) </li></ul></ul>
  25. 39. Environmental Pollution: Air Pollution <ul><li>Indoor Air Pollution </li></ul><ul><li>Common pollutants: </li></ul><ul><ul><li>Tobacco smoke – most common </li></ul></ul><ul><ul><li>Carbon monoxide </li></ul></ul><ul><ul><li>Nitrogen dioxide </li></ul></ul><ul><ul><li>Asbestos </li></ul></ul><ul><ul><li>Volatile substances containing poly-cyclic aromatic hydrocarbons from cooking oils and coal burning </li></ul></ul>
  26. 42. Environmental Pollution: Metals <ul><li>Lead </li></ul><ul><li>Exposure occurs through contaminated air, food, and water </li></ul><ul><li>Major sources in the environment: house paints, gasoline, mining, foundries, batteries </li></ul><ul><li>Other sources: toys </li></ul><ul><li>Subclinical poisoning may occur in children exposed to levels < 10 ug/dL </li></ul>
  27. 46. Environmental Pollution: Metals <ul><li>Lead </li></ul><ul><li>Majority of absorbed lead (80% - 85%) incorporated into bone and developing teeth  competes with calcium </li></ul><ul><li>High levels  CNS disturbances in adults (peripheral neuropathies) and children </li></ul>
  28. 48. Environmental Pollution: Metals <ul><li>Lead – Effects: </li></ul><ul><ul><li>Inhibition of neurotransmitters due to disruption of calcium homeostasis </li></ul></ul><ul><ul><li>Interference with normal remodelling of cartilage and primary bone trabeculae in epiphyses of children. </li></ul></ul>
  29. 49. Environmental Pollution: Metals <ul><li>Lead – Effects: </li></ul><ul><li>Blood and bone marrow </li></ul><ul><ul><li>Inhibition of δ -aminolevulinic acid dehydratase & ferrochelatase  inhibit heme synthesis  microcytic, hypochromic anemia with mild hemolysis </li></ul></ul><ul><ul><li>Characteristic; occurs early  appearance of ringed sideroblasts </li></ul></ul><ul><ul><li>Basophilic stippling of red cells </li></ul></ul>
  30. 50. Environmental Pollution: Metals RBC with basophilic stipplings (arrow) indicating clustering of ribosomes.
  31. 51. Environmental Pollution: Metals <ul><li>Lead – Effects: </li></ul><ul><li>Brain </li></ul><ul><ul><li>Brain damage prone to occur in children  sensory, motor, intellectual, and psychologic impairments </li></ul></ul><ul><ul><li>Adults  peripheral demyelinating neuropathy involving motor nerves of the most commonly used muscles </li></ul></ul><ul><ul><ul><li>Extensor muscles of wrist & fingers (wristdrop)  peroneal muscles (footdrop) </li></ul></ul></ul>
  32. 52. Environmental Pollution: Metals <ul><li>Lead – Effects: </li></ul><ul><li>Gastrointestinal Tract </li></ul><ul><ul><li>Extremely severe, poorly localized abdominal pain </li></ul></ul><ul><li>Kidneys </li></ul><ul><ul><li>Proximal tubular damage </li></ul></ul><ul><ul><li>Chronic  interstitial fibrosis  renal failure </li></ul></ul>
  33. 58. Environmental Pollution: Metals <ul><li>Mercury </li></ul><ul><li>Three forms of mercury: </li></ul><ul><ul><li>Metallic mercury (elemental mercury) </li></ul></ul><ul><ul><li>Inorganic mercury compounds (mercuric chloride) </li></ul></ul><ul><ul><li>Organic mercury (methyl mercury) </li></ul></ul><ul><li>Main sources at present: </li></ul><ul><ul><li>Contaminated fish (methyl mercury) </li></ul></ul><ul><ul><li>Mercury vapors released from dental amalgams </li></ul></ul>
  34. 62. Environmental Pollution: Metals <ul><li>Mercury </li></ul><ul><li>Minamata disease </li></ul><ul><ul><li>Cerebral palsy, deafness, blindness, mental retardation in children exposed in utero </li></ul></ul><ul><ul><ul><li>Methyl mercury metallic mercury lipid soluble  facilitate brain accumulation  impaired cognitive, neuromotor, and behavioral function </li></ul></ul></ul>
  35. 64. Environmental Pollution: Metals <ul><li>Arsenic </li></ul><ul><li>“ poison of kings and the king of poisons” </li></ul><ul><li>Found naturally in soils and water </li></ul><ul><li>Used in products such as wood preservers, herbicides, and other agricultural products </li></ul><ul><li>Present in Chinese and Indian herbal medicine </li></ul><ul><li>Arsenic trioxide – used in the treatment of acute promyelocytic leukemia </li></ul>
  36. 67. Environmental Pollution: Metals <ul><li>Arsenic - Toxic Effects </li></ul><ul><li>Acute toxic effects due to interference with mitochondrial oxidative phosphorylation </li></ul><ul><ul><li>Severe disturbances of GIT, cardio-vascular system, and CNS </li></ul></ul><ul><li>Most serious consequence of chronic exposure is increased risk for development of cancers (e.g. Basal and squamous cell Ca of skin) </li></ul>
  37. 71. Environmental Pollution: Metals <ul><li>Cadmium </li></ul><ul><li>Relatively a modern problem </li></ul><ul><li>Can contaminate the soil and plants directly or through fertilizers and irrigation water </li></ul><ul><li>Most important source for the general population is food </li></ul>
  38. 75. Occupational Health Risks <ul><li>Organic solvents </li></ul><ul><li>Sources: </li></ul><ul><ul><li>De-greasing & dry cleaning agents, and paint removers  chloroform and carbon tetrachloride </li></ul></ul><ul><ul><ul><li>Acute exposure: dizziness and confusion  CNS depression  coma </li></ul></ul></ul><ul><ul><ul><li>Low levels toxic to liver and kidneys </li></ul></ul></ul>
  39. 76. Occupational Health Risks <ul><li>Organic solvents </li></ul><ul><li>Sources: </li></ul><ul><ul><li>Rubber workers  benzene and 1,3-butadiene </li></ul></ul><ul><ul><ul><li>Increased risk of leukemia </li></ul></ul></ul><ul><ul><ul><li>Benzene oxidized by hepatic CYP2E1  disrupt differentiation of hematopoietic cells in bone marrow  marrow aplasia (dose-dependent)  increased risk of acute myeloid leukemia </li></ul></ul></ul>
  40. 78. Occupational Health Risks <ul><li>Polycyclic hydrocarbons </li></ul><ul><li>Released during combustion of fossil fuels, especially when coal and gas are burned at high temperatures (steel foundries) ; also present in tar and soot </li></ul><ul><li>Among the most potent carcinogens </li></ul><ul><li>Lung, bladder, and scrotal cancer </li></ul>
  41. 79. Occupational Health Risks <ul><li>Organochlorines </li></ul><ul><li>Synthetic lipophilic substances that resist degradation </li></ul><ul><li>Sources: </li></ul><ul><ul><li>Pesticides – DDT </li></ul></ul><ul><ul><li>Non-pesticides – polychlorinated biphenyls (PCBs) and dioxin </li></ul></ul><ul><li>Endocrine disruptors  anti-estrogen or anti-androgen activity </li></ul>
  42. 80. Occupational Health Risks <ul><li>Organochlorines </li></ul><ul><li>Dioxins and PCBs </li></ul><ul><ul><li>Folliculitis </li></ul></ul><ul><ul><li>Chloracne – dermatosis; acne, cyst formation, hyperpigmentation, and hyperkeratosis around face and behind ears </li></ul></ul><ul><ul><li>Liver and CNS abnormalities </li></ul></ul>
  43. 81. 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.
  44. 82. Occupational Health Risks <ul><li>Mineral Dusts </li></ul><ul><li>Cause chronic non-neoplastic lung diseases called pneumoconioses </li></ul><ul><li>Sources: </li></ul><ul><ul><li>Mining of hard coal  coal dust </li></ul></ul><ul><ul><li>Sandblasting, stone cutting, etc.  silica </li></ul></ul><ul><ul><li>Mining, fabrication, insulation work  asbestos, beryllium </li></ul></ul>
  45. 84. Coal Worker’s Pneumoconiosis
  46. 86. Tobacco <ul><li>Most common exogenous cause of human cancer </li></ul><ul><ul><li>Cigarette smoking – main culprit </li></ul></ul><ul><ul><li>Smokeless tobacco (snuff, chewing tobacco, etc.)  oral cancer </li></ul></ul><ul><ul><li>Second-hand smoke  lung cancer in non-smokers </li></ul></ul><ul><li>Most preventable cause of human death. </li></ul>
  47. 87. Tobacco <ul><li>Cessation of smoking – </li></ul><ul><ul><li>Significantly reduces within 5 years the overall mortality and the risk of death from CV diseases </li></ul></ul><ul><ul><li>Decreases lung cancer mortality by 21% within 5 years </li></ul></ul>
  48. 88. Tobacco <ul><li>Most common diseases caused by cigarette smoking involve the lungs and include: </li></ul><ul><ul><li>Emphysema </li></ul></ul><ul><ul><li>Chronic bronchitis </li></ul></ul><ul><ul><li>Chronic obstructive pulmonary disease </li></ul></ul><ul><ul><li>Lung cancer </li></ul></ul><ul><li>Cigarette smoking increases risk for: atherosclerosis, MI, cancers (lips, mouth, pharynx, esophagus, pancreas, bladder, kidney, and cervix) </li></ul>
  49. 93. 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 CYPs Increase water solubility of carcinogens Excretion Electrophilic intermediates of CYPs Form DNA adducts Mutations in K-ras and p53
  50. 94. SMOKING Increased platelet aggregation Decreased myocardial oxygen supply Decreased threshold for ventricular fibrillation Significant lung disease Hypoxia due to CO content of cigarette smoke Increased oxygen demand Atherosclerosis and M.I.
  51. 95. <ul><li>Maternal smoking increases the risk of: </li></ul><ul><li>Spontaneous abortions </li></ul><ul><li>Preterm births </li></ul><ul><li>IUGR </li></ul>
  52. 96. <ul><li>Passive smoke inhalation </li></ul><ul><ul><li>Relative risk of lung cancer ~ 1.3x higher than those not exposed </li></ul></ul><ul><ul><li>Increased risk of coronary AS and fatal M.I. </li></ul></ul>
  53. 97. ALCOHOL
  54. 98. Alcohol <ul><li>Consumption in moderate amounts generally not injurious </li></ul><ul><li>Ethanol absorbed unaltered in the stomach and small intestines  distributed to all tissues and fluids of the body in direct proportion to the blood level </li></ul><ul><ul><li>< 10% excreted unchanged in urine, sweat, and breath  amount exhaled is proportional to blood level </li></ul></ul><ul><ul><ul><li>80 mg/dL in blood – legal definition of DUI in the U.S. </li></ul></ul></ul>
  55. 100. Alcohol <ul><li>Most of the alcohol in the blood is bio-transformed to acetaldehyde in the liver by three enzyme systems: </li></ul><ul><ul><li>Alcohol dehydrogenase (ADH) – main; cytosol of hepatocytes </li></ul></ul><ul><ul><li>Microsomal ethanol-oxidizing system (MEOS) – participates if blood alcohol levels high </li></ul></ul><ul><ul><li>Catalase – use H2O2 as substrate </li></ul></ul>
  56. 102. Alcohol <ul><li>Acetaldehyde  many toxic effects  responsible for some of the acute effects of alcohol and for the development of oral cancers. </li></ul><ul><li>Alcohol oxidation by ADH  reduction of NAD to NADH  accumulation of fat in the liver and lactic acidosis </li></ul><ul><li>Metabolism of ethanol in the liver by CYP2E1  reactive oxygen species  lipid peroxidation of cell membranes </li></ul><ul><li>Release of endotoxin by intestinal flora  release of TNF & cytokines from Kupffer cells  hepatic injury </li></ul>
  57. 104. Alcohol <ul><li>Acute Alcoholism </li></ul><ul><ul><li>Affects mainly CNS  depressant (first affecting high brainstem reticular formation)  stimulation and disordered cortical, motor, and intellectual behavior </li></ul></ul><ul><ul><li>Moderate intake  fatty change or hepatic steatosis </li></ul></ul><ul><ul><li>Gastric changes: acute gastritis and ulceration </li></ul></ul>
  58. 105. Alcohol <ul><li>Chronic Alcoholism </li></ul><ul><ul><li>Affects not only liver and stomach, but virtually all other organs and tissues as well </li></ul></ul><ul><ul><li>Significant morbidity with shortened life span </li></ul></ul>
  59. 109. Areas of brain that can be damaged in utero by maternal alcohol consumption
  60. 110. Features of Fetal Alcohol Syndrome
  61. 111. <ul><li>Babies diagnosed with Fetal Alcohol Syndrome may have some but not all of the following physiological characteristics: </li></ul><ul><li>  </li></ul><ul><li>Small birth weight </li></ul><ul><li>Small head circumference </li></ul><ul><li>Small, widely spaced eyes </li></ul><ul><li>Flat midface </li></ul><ul><li>Short, upturned nose </li></ul><ul><li>Smooth, wide philtrum </li></ul><ul><li>Thin upper lip </li></ul><ul><li>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. </li></ul>
  62. 113. Injury by Therapeutic Agents <ul><li>Hormonal Replacement Therapy </li></ul><ul><ul><li>Most common type: estrogen + progesterone </li></ul></ul><ul><ul><ul><li>Estrogen therapy alone used in hysterectomized patients due to risk of uterine cancer </li></ul></ul></ul><ul><ul><li>Used in post-menopausal women to prevent or slow the progression of osteoporosis and reduce likelihood of M.I. </li></ul></ul>
  63. 115. Injury by Therapeutic Agents <ul><li>Hormonal Replacement Therapy </li></ul><ul><ul><li>Increased risk of breast cancer (lobular and ductal-lobular carcinomas) after median time of 5 to 8 years </li></ul></ul><ul><ul><li>Protective effect on development of AS and coronary disease in women < 60  depends on response of estrogen receptors that regulate calcium homeostasis in blood vessels </li></ul></ul>
  64. 116. Injury by Therapeutic Agents <ul><li>Hormonal Replacement Therapy </li></ul><ul><ul><li>Increased risk of venous thrombo-embolism including deep vein thrombosis, pulmonary embolism, and stroke </li></ul></ul><ul><ul><ul><li>More pronounced during first two years of treatment and in women with risk factors (immobilization, hypercoagulable states) </li></ul></ul></ul>
  65. 117. Injury by Therapeutic Agents <ul><li>Oral Contraceptives </li></ul><ul><ul><li>Synthetic estradiol and variable amount of progestins  inhibit ovulation or prevent implantation </li></ul></ul><ul><ul><li>Present formulations with smaller amounts of estrogen (~20 ug of ethinyl estradiol)  fewer side effects </li></ul></ul>
  66. 118. Injury by Therapeutic Agents <ul><li>Oral Contraceptives </li></ul><ul><ul><li>Three-fold increased risk of venous thrombosis and pulmonary thrombo-embolism  due to acute phase response [inc. C-reactive protein and coagulation factors; decreased anti-coagulants (protein S and anti-thrombin III)] </li></ul></ul>
  67. 119. Injury by Therapeutic Agents <ul><li>Oral Contraceptives </li></ul><ul><ul><li>Increased risk of myocardial infarction in smoking women of all ages and in non-smoking women > 35 y/o </li></ul></ul><ul><ul><li>Reduced incidence of endometrial and ovarian cancers </li></ul></ul><ul><ul><li>Increased risk of developing hepatic adenoma </li></ul></ul>
  68. 120. Injury by Therapeutic Agents <ul><li>Anabolic steroids </li></ul><ul><ul><li>Synthetic versions of testosterone </li></ul></ul><ul><ul><li>10 – 100 times higher than therapeutic indications  inhibit production and release of LH and FSH, and increases amount of estrogens </li></ul></ul>
  69. 122. Injury by Therapeutic Agents <ul><li>Acetaminophen </li></ul><ul><ul><li>Most commonly used analgesic in U.S. </li></ul></ul><ul><ul><ul><li>Cause of about 50% of cases of acute liver failure </li></ul></ul></ul><ul><ul><li>Intentional overdosage (suicide) the most common cause of toxicity </li></ul></ul><ul><ul><li>5% metabolized through activity of CYP2E to NAPQ1 </li></ul></ul>
  70. 123. 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
  71. 125. Injury by Therapeutic Agents <ul><li>Aspirin (Acetylsalicylic Acid) </li></ul><ul><ul><li>In adults, overdose is usually suicidal </li></ul></ul><ul><ul><li>Source of salicylate poisoning is excessive use of ointments containing oil of wintergreen (methyl salicylate) </li></ul></ul><ul><ul><li>Ingestion of 2 – 4 gm by children or 10 – 30 gm by adults may be fatal </li></ul></ul><ul><ul><li>Chronic toxicity: intake of 3 gm or more/day  salicylism </li></ul></ul>
  72. 127. Drug Abuse <ul><li>Cocaine (Crack) </li></ul><ul><ul><li>Extracted from leaves of coca plant  prepared as water-soluble powder (cocaine HCl) </li></ul></ul><ul><ul><li>Snorted or dissolved in water and injected SC or IV </li></ul></ul>
  73. 128. 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. 
  74. 130. Drug Abuse <ul><li>Cocaine (Crack) </li></ul><ul><li>Cardiovascular Effects: </li></ul><ul><ul><li>Most serious physical effect due to acute action on CVS: tachycardia, HPN, peripheral vasoconstriction </li></ul></ul><ul><ul><li>Sympathomimetic effect  block re-uptake of epinephrine and NE while stimulating pre-synaptic release of NE  accumulation of epinephrine & NE in synapses  excess stimulation </li></ul></ul>
  75. 132. Drug Abuse <ul><li>Cocaine (Crack) </li></ul><ul><li>Cardiovascular Effects: </li></ul><ul><ul><li>Coronary artery vasoconstriction  myocardial ischemia  M.I. </li></ul></ul><ul><ul><li>Enhanced platelet aggregation and thrombus formation </li></ul></ul><ul><ul><li>Impaired ion transport in myocardium  lethal arrhythmia </li></ul></ul>
  76. 133. Drug Abuse <ul><li>Cocaine (Crack) </li></ul><ul><li>CNS Effects: </li></ul><ul><ul><li>Aberration of dopaminergic pathways  hyperpyrexia </li></ul></ul><ul><ul><li>Seizures </li></ul></ul>
  77. 134. Drug Abuse <ul><li>Cocaine (Crack) </li></ul><ul><li>Effects on pregnancy </li></ul><ul><ul><li>Decreased blood flow to placenta  fetal hypoxia and spontaneous abortion </li></ul></ul><ul><ul><li>Impaired fetal neurologic development </li></ul></ul>
  78. 137. Drug Abuse <ul><li>Heroin </li></ul><ul><ul><li>Opioid derived from poppy plant </li></ul></ul><ul><ul><li>Closely related to morphine </li></ul></ul><ul><ul><li>More harmful than cocaine </li></ul></ul><ul><ul><li>Physical effects related to: </li></ul></ul><ul><ul><ul><li>Pharmacologic action of the agent </li></ul></ul></ul><ul><ul><ul><li>Reactions to the cutting agents or contaminants </li></ul></ul></ul><ul><ul><ul><li>Hypersensitivity reactions to the drug or its adulterants </li></ul></ul></ul><ul><ul><ul><li>Diseases contracted due to use of infected needles </li></ul></ul></ul>
  79. 139. Drug Abuse <ul><li>Heroin </li></ul><ul><li>Sudden death </li></ul><ul><ul><li>Related to overdose </li></ul></ul><ul><ul><li>Death due to: </li></ul></ul><ul><ul><ul><li>Respiratory depression </li></ul></ul></ul><ul><ul><ul><li>Arrhythmia and cardiac arrest </li></ul></ul></ul><ul><ul><ul><li>Severe pulmonary edema </li></ul></ul></ul>
  80. 140. Drug Abuse <ul><li>Heroin </li></ul><ul><li>Pulmonary injury </li></ul><ul><ul><li>Moderate to severe edema </li></ul></ul><ul><ul><li>Septic embolism from endocarditis </li></ul></ul><ul><ul><li>Lung abscess </li></ul></ul><ul><ul><li>Opportunistic infections </li></ul></ul><ul><ul><li>Foreign body granuloma from adulterants </li></ul></ul>
  81. 141. Drug Abuse <ul><li>Heroin </li></ul><ul><li>Infections </li></ul><ul><ul><li>Four sites most commonly infected: skin and SC tissue, heart valves, liver, and lungs </li></ul></ul><ul><ul><li>S. aureus, viral hepatitis, fungi, HIV </li></ul></ul>
  82. 142. Drug Abuse <ul><li>Heroin </li></ul><ul><li>Skin </li></ul><ul><ul><li>Most frequent telltale sign of addiction </li></ul></ul><ul><ul><li>Acute changes: abscesses, cellulitis, ulceration </li></ul></ul><ul><ul><li>Chronic use: hyperpigmentation over used veins, venous thrombosis </li></ul></ul>
  83. 144. Drug Abuse <ul><li>Heroin </li></ul><ul><li>Kidneys </li></ul><ul><ul><li>Two forms most frequently encountered: </li></ul></ul><ul><ul><ul><li>Amyloidosis secondary to skin infections </li></ul></ul></ul><ul><ul><ul><li>Focal glomerulosclerosis </li></ul></ul></ul>
  84. 146. Drug Abuse <ul><li>Amphetamines – Metamphetamine </li></ul><ul><ul><li>“ speed” or “meth” </li></ul></ul><ul><ul><li>Closely related to amphetamine but with stronger CNS effects </li></ul></ul><ul><ul><li>Acts by releasing dopamine in the brain  inhibit pre-synaptic neurotransmission at corticostriatal synapses  slow down glutamate release </li></ul></ul>
  85. 149. Drug Abuse <ul><li>Amphetamines – MDMA </li></ul><ul><ul><li>“ ecstasy” </li></ul></ul><ul><ul><li>3,4 methylenedioxymethamphetamine </li></ul></ul><ul><ul><li>Increase serotonin release in the CNS + impaired serotonin synthesis </li></ul></ul><ul><ul><li>Decrease number of serotonergic axon terminals in the striatum and the cortex </li></ul></ul><ul><ul><li>Increase peripheral effects of dopamine and adrenergic agents </li></ul></ul>
  86. 153. Drug Abuse <ul><li>Marijuana (“pot”) </li></ul><ul><ul><li>Made from the leaves of Cannabis sativa  tetrahydrocannabinol (THC) </li></ul></ul><ul><ul><li>Potential use to treat nausea secondary to cancer chemotherapy & pain reduction in cases of chronic pain </li></ul></ul><ul><ul><li>Endogenous cannabinoid system – cannabinoid receptors CB1 and CB2 (endocannabinoids)  participate in regulation of hypothalamic-pituitary adrenal axis  modulate control of appetite, food intake, and energy balance, including fertility and sexual behavior </li></ul></ul>
  87. 157. Thermal Injury <ul><li>Thermal Burns </li></ul><ul><li>Clinical significance of burn injury depends on the following factors: </li></ul><ul><ul><li>Depth of the burns </li></ul></ul><ul><ul><li>Percentage of body surface involved </li></ul></ul><ul><ul><li>Internal injuries due to inhalation of hot and toxic fumes </li></ul></ul><ul><ul><li>Promptness and efficacy of treatment </li></ul></ul>
  88. 159. Thermal Injury <ul><li>Superficial Burns </li></ul><ul><li>First-degree burns; confined to epidermis </li></ul>
  89. 160. Thermal Injury <ul><li>Partial-thickness Burns </li></ul><ul><li>Second-degree burns; includes dermis </li></ul>
  90. 161. Thermal Injury <ul><li>Full-thickness Burns </li></ul><ul><li>Third-degree burns; extend to SC tissue and may involve muscle tissue underneath </li></ul>
  91. 163. Thermal Injury <ul><li>Thermal Burns: Complications </li></ul><ul><li>Shock, sepsis, and respiratory insufficiency </li></ul><ul><ul><li>Greatest threats; burns > 20% of body surface  rapid shift of body fluids into interstitial compartments  hypovolemic shock </li></ul></ul><ul><ul><li>Development of hypermetabolic state associated with excess heat loss and increased need for nutritional support </li></ul></ul>
  92. 164. Thermal Injury <ul><li>Thermal Burns: Complications </li></ul><ul><li>Shock, sepsis, and respiratory insufficiency </li></ul><ul><ul><li>Burn site ideal for growth of organisms  P. aeruginosa (most common), S. aureus, fungi, Candida </li></ul></ul><ul><ul><li>Most common serious sequelae: pneumonia or septic shock with renal failure and/or ARDS </li></ul></ul>
  93. 165. Thermal Injury <ul><li>Thermal Burns: Complications </li></ul><ul><li>Injury to airways and lungs </li></ul><ul><ul><li>Develop within 24 to 48 hours after the burn </li></ul></ul><ul><ul><li>May be the result of: </li></ul></ul><ul><ul><ul><li>Direct effect of heat on mouth, nose, and upper airways </li></ul></ul></ul><ul><ul><ul><li>Inhalation of heated air and noxious gases in the smoke  inflammation and swelling  partial or complete airway obstruction </li></ul></ul></ul>
  94. 166. Thermal Injury <ul><li>Thermal Burns: Complications </li></ul><ul><li>Development of hypertrophic scars </li></ul><ul><ul><li>Both at site of original burn and at donor graft sites </li></ul></ul><ul><ul><li>Injured nerve endings  release of substance P  excess neuropeptides  continuous angiogenesis  scar </li></ul></ul>
  95. 169. Thermal Injury <ul><li>Hyperthermia – Heat cramps </li></ul><ul><ul><li>Results from loss of electrolytes via sweating </li></ul></ul><ul><ul><li>Cramping of voluntary muscles in association with vigorous exercise  HALLMARK </li></ul></ul>
  96. 170. Thermal Injury <ul><li>Hyperthermia – Heat exhaustion </li></ul><ul><ul><li>Most common hyperthermic syndrome </li></ul></ul><ul><ul><li>Sudden onset with prostration and collapse  due to failure of CVS to compensate for hypovolemia </li></ul></ul><ul><ul><li>Collapse brief and equilibrium spontaneously re-established </li></ul></ul>
  97. 171. Thermal Injury <ul><li>Hyperthermia – Heat stroke </li></ul><ul><ul><li>Associated with high ambient temp., high humidity, and exertion </li></ul></ul><ul><ul><li>Failure of thermoregulatory mechanisms  no sweating, core body temp. > 40 0 C  multi-organ dysfunction  rapidly fatal </li></ul></ul>
  98. 173. Thermal Injury <ul><li>Hypothermia </li></ul><ul><ul><li>Prolonged exposure to low ambient temperatures </li></ul></ul><ul><ul><li>Body temperature of 90 0 F  loss of consciousness followed by bradycardia and atrial fibrillation at lower core temperatures </li></ul></ul>
  99. 174. Thermal Injury <ul><li>Hypothermia - Mechanisms </li></ul><ul><ul><li>Direct effects </li></ul></ul><ul><ul><ul><li>Crystallization of intra- and extra-cellular water  high salt concentrations  physical disruptions within cells </li></ul></ul></ul><ul><ul><li>Indirect effects </li></ul></ul><ul><ul><ul><li>Result of circulatory changes </li></ul></ul></ul>
  100. 175. Thermal Injury <ul><li>Hypothermia – Mechanisms </li></ul><ul><li>Slowly developing chilling  vasoconstriction and increased vascular permeability  edema and hypoxia  gangrene of extremities (e.g. “trench foot”) </li></ul><ul><li>Sudden, persistent chilling  vaso-constriction and increased blood viscosity  ischemic injury and degenerative changes of peripheral nerves </li></ul>
  101. 177. Radiation Injury
  102. 178. Non-Ionizing Radiation Injury <ul><li>Non-ionizing radiation </li></ul><ul><ul><li>UV and infrared light, microwave and sound waves </li></ul></ul><ul><ul><li>Cause atoms in a molecule to move or vibrate  not sufficient to displace bound electrons from atoms </li></ul></ul>
  103. 179. Non-Ionizing Radiation Injury <ul><ul><li>UV rays derived from sun  increased incidence of SCCA, basal cell carcinoma, and skin melanoma </li></ul></ul><ul><ul><li>Degree of risk depends on: </li></ul></ul><ul><ul><ul><li>Type of UV ray </li></ul></ul></ul><ul><ul><ul><li>Intensity of exposure </li></ul></ul></ul><ul><ul><ul><li>Quantity of light-absorbing protective coat of melanin </li></ul></ul></ul>
  104. 181. UVB sunlight is directly absorbed by DNA resulting in single strand breaks and the formation of pyrimidine dimers.
  105. 182. Ionizing Radiation Injury <ul><li>Ionizing radiation </li></ul><ul><ul><li>Main sources: </li></ul></ul><ul><ul><ul><li>X-rays </li></ul></ul></ul><ul><ul><ul><li>Gamma rays – electromagnetic waves of very high frequency </li></ul></ul></ul><ul><ul><ul><li>High-energy neutrons </li></ul></ul></ul><ul><ul><ul><li>Alpha particles (2 protons and 2 neutrons) </li></ul></ul></ul><ul><ul><ul><li>Beta particles – electrons </li></ul></ul></ul>
  106. 184. Ionizing Radiation Injury <ul><li>Ionizing radiation </li></ul><ul><ul><li>Alpha particles  induce heavy damage in a restricted area </li></ul></ul><ul><ul><li>X-rays and gamma particles  longer, deeper course with less damage per unit of tissue </li></ul></ul><ul><ul><li>With sufficient energy to remove tightly bound electrons </li></ul></ul><ul><ul><ul><li>Cause collision of electrons with other molecules  ionization </li></ul></ul></ul>
  107. 185. Ionizing Radiation Injury <ul><li>Major Determinant of Biologic Effects </li></ul><ul><li>Rate of delivery </li></ul><ul><ul><li>Divided doses  allow cells to repair damage between exposures </li></ul></ul><ul><li>Field size </li></ul><ul><ul><li>Small doses delivered to large fields  lethal </li></ul></ul><ul><ul><li>High doses delivered to small, shielded fields  tolerable </li></ul></ul>
  108. 186. Ionizing Radiation Injury <ul><li>Major Determinant of Biologic Effects </li></ul><ul><li>Cell proliferation </li></ul><ul><ul><li>Rapidly dividing cells (gonads, bone marrow, lymphoid tissue, mucosa of GIT) more vulnerable due to DNA damage  mutations and chromosomal abnormalities </li></ul></ul><ul><ul><li>DNA damage in quiescent cells compatible with survival if dose not very high </li></ul></ul>
  109. 187. Ionizing Radiation Injury <ul><li>Major Determinant of Biologic Effects </li></ul><ul><li>Oxygen effects and hypoxia </li></ul><ul><ul><li>Production of reactive oxygen species from radiolysis of water  main mechanism of DNA damage </li></ul></ul><ul><ul><li>Poorly vascularized tissues with low oxygenation  less sensitive to radiation therapy than non-hypoxic tissues </li></ul></ul>
  110. 188. Ionizing Radiation Injury <ul><li>Major Determinant of Biologic Effects </li></ul><ul><li>Vascular damage </li></ul><ul><ul><li>Damage to endothelial cells  narrowing and occlusion of blood vessel  impaired healing, fibrosis, chronic ischemic atrophy </li></ul></ul>
  111. 191. 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.