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ENVIRONMENTAL PATHOLOGY Chemical and Physical Agents Nutrition. David S. Wilkinson, MD, PhD. Environmental Pathology Magnitude of the Problem in US. 600,000 cancer cases/year related to chemical carcinogens (est) 400,000 deaths related to smoking Reported Chemical Exposures
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ENVIRONMENTALPATHOLOGYChemical and Physical AgentsNutrition David S. Wilkinson, MD, PhD
Environmental PathologyMagnitude of the Problem in US • 600,000 cancer cases/year related to chemical carcinogens (est) • 400,000 deaths related to smoking • Reported Chemical Exposures • 2.4 million reported chemical exp/yr (2005) • 80% accidental • Children <6 yo account for 50% • 1261 fatalities, 50% suicides
US Government Agencies Regulate Environmental Hazards • Environmental Protection Agency • Food and Drug Administration • Occupational Safety and Health Administration • Consumer Products Safety Commission
Sources of Exposure • Environmental • Man-made • Intentional (Hg, Minimata, Japan) • Accidental • methyl isocyanate, Bhopal, India • radiation, Chernobyl • Natural (H2S/CO/CO2, Cameroon) • Occupational (mining, dye, chemical) • Iatrogenic (drugs) • Self-administered (substance abuse, suicide)
Mechanisms of Toxicity • Corrosive, tissue destruction (acids, alkali) • desiccation • protein destruction • denaturation • hydrolysis • fat saponification • Inhibition of enzyme activity cyanide: cytochrome oxidase
Mechanisms of Toxicity • Alternate metabolic pathways • ethanol: NAD/NADH • Disturbances of homeostasis • steroids: immune system • aspirin: acidosis • Mutagenesis • Carcinogenesis
Clinical Findings • Symptoms-patient complaints • Signs-what you observe • Clinicopathologic correlation • related to mechanism and tissue localization • Acute vs chronic-the signs and symptoms may differ
Lung Injury Related to Air Pollution • Acute and chronic inflammation • direct cell injury • Emphysema-enhanced proteolysis • Asthma-allergic or irritant effect • Hypersensitivity pneumonitis • immunologic injury related to organic dusts • Pneumoconiosis-cytokines • Neoplasia • mutagenic/promoting effects
Main Constituents of Smog • SO2 respiratory irritant (acid rain) • NO2*, NO respiratory irritant (xs O2) • CO carboxyhemoglobin ( O2) • O3* respiratory irritant • Pb binds sulfhydryl groups *Oxidant pollutants Mostly produced by combustion of fossil fuels
Inhalation Toxins Related toMining and Similar Occupations Pneumoconiosis, characterized by cytokine-mediated, progressive fibrotic scarring • coal dust (anthracosis) • silica (silicosis) • asbestos (asbestosis), Ca/Mg silicate • pleural plaques, mesothelioma, bronchogenic ca • beryllium (berylliosis) Macrophages produce cytokines Size matters-0.5 to 5μ
Inhalation Toxins Related to Farming • Organic dusts (hypersensitivity pneumonitis) • moldy hay (Farmer’s Lung) • bird droppings (bird breeders lung) • Pesticides • organophosphate (acetycholine esterase inhibitors) • organochlorine (DDT, chlordane) • Herbicides (paraquat, diquat, dioxin) • Fertilizer (ammonia)
Tobacco Smoking • 400,000 deaths/yr (21% of all deaths in US) • 50 Million smokers in US • Smoke composition • carcinogens (polycyclic HC, b-naphthylamine, nitrosamines) • Irritants and toxins • ammonia, formaldehyde, oxides of nitrogen • CO • Nicotine
Relative Disease RisksAssociated with Smoking Male Female Lung Ca death 22 12 Mouth Ca 27 6 Larynx Ca 10 18 Esophogus Ca 8 10 CAD >35 yo 3 2 Cerebro VD >35 yo 4 5 COPD 10 10 Ill health effects of smoking partially reversible
Heavy Metal Toxic Agents • Mercury (HgCl2 , ATN; org Hg, CNS function) • Lead ( inhibits heme synthesis, CNS function, kidneys, GI) • 2-11% of children in US exceed 10 μg/dL • Arsenic • Iron
Organic Alcohols • Ethanol • 1/3 of Americans characterized as heavy drinkers • CNS depressant • legally intoxicated >100 mg/dL • Nearly 50% of fatal MVA • Methanol (toxic metabolites inhibit hexokinase, may cause blindness) • Ethylene glycol (antifreeze, ATN)
Alcoholic Hepatitis Mallory Body
Alcoholic Cirrhosis Bands of Fibrosis Regenerating Nodules
Adverse Drug Events Adverse Drug Reactions + Therapeutic Misadventures
Adverse Drug Events • 3-6% of all medical admissions • 160,000 deaths/yr Shapiro et al. JAMA 1971; 216: 467-472. • Most common adverse event in hosp pts Leape et al. NEJM 1991;324: 377-384. • 6.5 ADE/100 admissions, 1% fatal Bates et al. JAMA 1995; 274: 29-34.
Major Patterns of ADRs • Blood dyscrasias (Chloramphenicol) • dose related or idiosyncratic • pan or line specific • Skin eruptions (Penicillin) • Hepatic reactions • fatty change (Tetracycline) • cholestasis (Chlorpromazine) • hepatitis (INH) • massive hepatic necrosis (Halothane)
Major Patterns of ADRs • Renal reactions • predictable (aminoglycosides) • hypersensitivity (sulfa) • Lung reactions • congestion • edema • hemorrhage • interstitial fibrosis
Major Patterns of ADRs • Cardiac reactions • arrhythmias • cardiomyopathy • CNS reactions • respiratory depression • Systemic reactions • anaphylaxis • vasculitis • hormonal effects (HRT, OC)
Syndromes Related to Drugs of Abuse • Pulmonary complications (edema, septic emboli, absess, opportunistic infections) • Granulomas (adulterants) • Infectious complications • Kidney disease Often related to diluents, cutting agents, and needle sharing
Physical Injuries • Mechanical force • abrasion • laceration • incision • contusion • Gunshot wounds • entry wound • exit wound
Radiation Injury • Direct (target) effect-radiation acts directly on target molecules, such as DNA • Indirect effect-free radical intermediary • Cell death, mutations, developmental abnormalities • Tissues have differential radiosensitivity • Oxygen effect • Whole body radiation
Lymphocytes Thrombocytes Granulocytes GI lining Endothelial cells Neural tissue Sensitivity Cell Division Most Sensitive Fastest Least Sensitive Slowest Radiation Sensitivity of Biological Tissue