ENVIRONMENTAL PATHOLOGY Chemical and Physical Agents

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ENVIRONMENTALPATHOLOGYChemical and Physical
Agents

• David S. Wilkinson, MD, PhD

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Environmental PathologyMagnitude of the Problem

• 600,000 cancer cases/year related to chemical
  carcinogens (est)
• 400,000 deaths related to smoking
• 1990 Reported Chemical Exposures
• 1.7 million reported chemical exp/yr
• 80 accidental
• Children lt6 yo account for 50
• 612 fatalities, 50 suicides

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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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Important Characteristics of Toxic Substances

• Physical properties
• Chemical properties
• Absorption
• Distribution
• Metabolism
• Excretion

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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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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
• Signs
• Clinicopathologic correlation
• related to mechanism and tissue localization
• Acute vs chronic

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Laboratory DiagnosisStrategy is Agent Dependent

• Analyte to measure
• Pb RBC protoporphyrin, blood Pb)
• Preferred specimen
• source (blood, urine, gastric fluid, feces)
• container (preservative, anticoagulant)
• timing (acetaminophen 4 hrs, 2 levels)
• temperature control

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Laboratory DiagnosisDecision Levels

• Reference interval
• Indicative of exposure
• Correlates with symptoms, prognosis
• Requires therapy
• acetaminophen N-acetylcysteine

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Lung InjuryRelated 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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Indoor Air Pollutants

• All of the outdoor pollutants
• Radon (rooms with poor air exchange)
• lung cancer (synergistic with cigarette smoke)
• Organic dusts
• allergic reactions, infections
• Formaldehyde (foam insulation)
• allergic reactions

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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)

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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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Other Inhalation Toxins

• Hydrocarbons, ethers, ketones
• paint thinners, glue, solvents
• benzene, toluene, xylene, acetone
• substance abuse
• Halogenated hydrocarbons
• CHCl3 (anesthetic)
• CCl4 (cleaner)
• trichloroethane (solvent)
• Chlorine (hypochlorite acid)
• pool workers

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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)
• Lead ( inhibits heme synthesis)
• Arsenic
• Iron

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Organic Alcohols

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

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Adverse Drug Reactions

• Any response to a drug that is noxious and
  unintended and that occurs at doses used in
  humans for prophylaxis, diagnosis, or therapy,
  excluding failure to accomplish the intended
  purpose.
• (Calculated risk)

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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
• hypersensitivity
• 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

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Syndromes Related to Drugs of Abuse

• Pulmonary complications
• Granulomas
• 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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Physical Injuries

• High-altitude sickness (CNS and pulmonary edema)
• Blast injury
• Gas embolism
• Decompression (Caisson) disease
• Electrical injury
• neural pathway disruption
• thermal effects

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Thermal Injuries

• burns (depth and area determine prognosis)
• partial vs full-thickness
• shock and sepsis
• heat stroke (temp gt 40o C)
• exertional
• febrile
• frostbite
• hypothermia

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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
• Differential radiosensitivity
• Oxygen effect
• Whole body radiation