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