environmental pathology chemical and physical agents nutrition david s. wilkinson, md, phd
TRANSCRIPT
ENVIRONMENTALPATHOLOGY
Chemical 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
Cyanide Poisoning
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
Normal Lung
Pulmonary Fibrosis
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, -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 10Ill 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
Lead Lines
Basophilic Stippling
Normal Kidney
Acute Tubular Necrosis
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)
Fatty Change in Liver
Normal Liver
Fatty Change in Liver
Alcoholic Hepatitis
Mallory Mallory BodyBody
Alcoholic Cirrhosis
Alcoholic Cirrhosis
RegeneratingNodules
Bands of Fibrosis
Adverse Drug Events
Adverse Drug Reactions
+
Therapeutic Misadventures
Adverse Drug Events
• 3-6% of all medical admissions
• 160,000 deaths/yrShapiro et al. JAMA 1971; 216: 467-472.
• Most common adverse event in hosp ptsLeape et al. NEJM 1991;324: 377-384.
• 6.5 ADE/100 admissions, 1% fatalBates 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
Contusion/22 hours
Laceration with Marginal Abrasion
Incision
Stab Wound
GSW/Contact
GSW/Close Range/Stippling
GSW/Distant and Contact
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
Radiation Injury
Radiation Sensitivity of Biological Tissue
• Lymphocytes• Thrombocytes• Granulocytes• GI lining• Endothelial cells• Neural tissue
Sensitivity Cell Division
Most Sensitive Fastest
Least SensitiveSlowest
Vitamin DeficiencyVitamin Function Deficiency State
A VisionImmunesystemEpithelium
Diet, malabsorptionNight blindness,xerophthalmia,keratomalacia,immune deficiency
D Blood calciumand phosphate
Diet, malabsorption,inadequate sun, liverand renal diseaseRickets,osteomalacia
Vitamin Function Deficiency State
Etocopherols
AntioxidantFree radicalscavenger
Diet, malabsorptionNeuromusculardeficits
K ClottingfactorsII, VII, IX,X
Malabsorption, lossof gut flora,Coumadin therapybleeding
Vitamin Deficiency
Vitamin DeficiencyVitamin Function Deficiency State
Thiamine(B1)TPP
Enzyme co-factor,nerveconduction
Diet, EtOHPolyneuropathy,cardiomyopathy,Wernicke-Korsakoff
Riboflavine(B2)FMN, FAD
Enzyme co-factor
Diet, EtOHCheilosis, glossitis,dermatitis (atrophy)
NiacinNAD,NADP
Enzyme co-factor
Diet, EtOHPellagra, dermitis,diarrhaea, dementia
Vitamin Deficiency
Vitamin Function Deficiency State
Pyridoxine(B6)
Enzyme co-factor
Drugs (INH), EtOHSimilar to riboflavinand niacin deficiency
C Hydroxyl-ation ofproteinsAntioxidant
Diet, EtOHScurvey, weakconnective tissueBleeding, fractures,gingival swelling,peridontal disease, poorwound healing