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
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

 Environmental

Sources of Exposure

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 to Mining and Similar Occupations

Pneumoconiosis, characterized by cytokinemediated, 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 5

Normal Lung

Pulmonary Fibrosis

Inhalation Toxins Related to Farming

Organic dusts (hypersensitivity pneumonitis) moldy hay (Farmers 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 Risks Associated with Smoking

Lung Ca death Mouth Ca Larynx Ca Esophogus Ca CAD >35 yo Cerebro VD >35 yo COPD

Male 22 27 10 8 3 4 10

Female 12 6 18 10 2 5 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 g/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 Body

Alcoholic Cirrhosis

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

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 Most Sensitive

Cell Division Fastest

Least Sensitive

Slowest

Vitamin Deficiency
Vitamin Function A Vision Immune system Epithelium Deficiency State Diet, malabsorption Night blindness, xerophthalmia, keratomalacia, immune deficiency Blood calcium Diet, malabsorption, and phosphate inadequate sun, liver and renal disease Rickets, osteomalacia

Vitamin Deficiency
Vitamin Function Deficiency State E Antioxidant Diet, malabsorption tocopherols Free radical Neuromuscular scavenger deficits K Clotting Malabsorption, loss factors of gut flora, II, VII, IX, Coumadin therapy X bleeding

Vitamin Deficiency
Vitamin Thiamine (B1) TPP Function Deficiency State Diet, EtOH Polyneuropathy, cardiomyopathy, Wernicke-Korsakoff Diet, EtOH Cheilosis, glossitis, dermatitis (atrophy) Diet, EtOH Pellagra, dermitis, diarrhaea, dementia Enzyme cofactor, nerve conduction Riboflavine Enzyme co(B2) factor FMN, FAD Niacin Enzyme coNAD, factor NADP

Vitamin Deficiency
Vitamin Function Deficiency State Pyridoxine Enzyme co- Drugs (INH), EtOH (B6) factor Similar to riboflavin and niacin deficiency C HydroxylDiet, EtOH ation of Scurvey, weak proteins connective tissue Antioxidant Bleeding, fractures, gingival swelling, peridontal disease, poor wound healing