ENVIRONMENTAL PATHOLOGY Chemical and Physical Agents Nutrition

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ENVIRONMENTALPATHOLOGYChemical and Physical
AgentsNutrition

• David S. Wilkinson, MD, PhD

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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 lt6 yo account for 50
• 1261 fatalities, 50 suicides

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US Government Agencies Regulate Environmental
Hazards

• Environmental Protection Agency
• Food and Drug Administration
• Occupational Safety and Health Administration
• Consumer Products Safety Commission

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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)

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Mechanisms of Toxicity

• Corrosive, tissue destruction (acids, alkali)
• desiccation
• protein destruction
• denaturation
• hydrolysis
• fat saponification
• Inhibition of enzyme activity
• cyanide cytochrome oxidase

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Cyanide Poisoning
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Mechanisms of Toxicity

• Alternate metabolic pathways
• ethanol NAD/NADH
• Disturbances of homeostasis
• steroids immune system
• aspirin acidosis
• Mutagenesis
• Carcinogenesis

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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

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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

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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

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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

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Normal Lung
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Pulmonary Fibrosis
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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)

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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

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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 gt35 yo 3 2
• Cerebro VD gt35 yo 4 5
• COPD 10 10
• Ill health effects of smoking partially reversible

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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

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Lead Lines
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Basophilic Stippling
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Normal Kidney
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Acute Tubular Necrosis
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Organic Alcohols

• Ethanol
• 1/3 of Americans characterized as heavy drinkers
• CNS depressant
• legally intoxicated gt100 mg/dL
• Nearly 50 of fatal MVA
• Methanol (toxic metabolites inhibit hexokinase,
  may cause blindness)
• Ethylene glycol (antifreeze, ATN)

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Fatty Change in Liver
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Normal Liver
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Fatty Change in Liver
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Alcoholic Hepatitis
Mallory Body
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Alcoholic Cirrhosis
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Alcoholic Cirrhosis
Bands of Fibrosis
Regenerating Nodules
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Adverse Drug Events

• Adverse Drug Reactions
• Therapeutic Misadventures

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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 1991324 377-384.
• 6.5 ADE/100 admissions, 1 fatal
• Bates et al. JAMA 1995 274 29-34.

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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)

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Major Patterns of ADRs

• Renal reactions
• predictable (aminoglycosides)
• hypersensitivity (sulfa)
• Lung reactions
• congestion
• edema
• hemorrhage
• interstitial fibrosis

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Major Patterns of ADRs

• Cardiac reactions
• arrhythmias
• cardiomyopathy
• CNS reactions
• respiratory depression
• Systemic reactions
• anaphylaxis
• vasculitis
• hormonal effects (HRT, OC)

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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

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Physical Injuries

• Mechanical force
• abrasion
• laceration
• incision
• contusion
• Gunshot wounds
• entry wound
• exit wound

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Contusion/22 hours
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Laceration with Marginal Abrasion
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Incision
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Stab Wound
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GSW/Contact
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GSW/Close Range/Stippling
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GSW/Distant and Contact
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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

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Radiation Injury
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Radiation Sensitivity of Biological Tissue

• Sensitivity Cell Division
• Most Sensitive Fastest
• Least Sensitive Slowest

• Lymphocytes
• Thrombocytes
• Granulocytes
• GI lining
• Endothelial cells
• Neural tissue

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Vitamin Deficiency
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Vitamin Deficiency
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Vitamin Deficiency
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Vitamin Deficiency