Transcript ENVIRONMENTAL PATHOLOGY

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
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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 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 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, 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 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 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
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fatty change (Tetracycline)
cholestasis (Chlorpromazine)
hepatitis (INH)
massive hepatic necrosis (Halothane)
Major Patterns of ADRs
• Renal reactions
– predictable (aminoglycosides)
– hypersensitivity (sulfa)
• Lung reactions
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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
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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
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Lymphocytes
Thrombocytes
Granulocytes
GI lining
Endothelial cells
Neural tissue
Sensitivity
Most Sensitive
Cell Division
Fastest
Least Sensitive
Slowest
Vitamin Deficiency
Vitamin Function
A
D
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
Enzyme cofactor,
nerve
conduction
Riboflavine Enzyme co(B2)
factor
FMN, FAD
Niacin
Enzyme coNAD,
factor
NADP
Deficiency State
Diet, EtOH
Polyneuropathy,
cardiomyopathy,
Wernicke-Korsakoff
Diet, EtOH
Cheilosis, glossitis,
dermatitis (atrophy)
Diet, EtOH
Pellagra, dermitis,
diarrhaea, dementia
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