2. ENVIRONMENTAL AND NUTRITIONAL PATHOLOGY
• Environment and Disease
• Common Exposures
• Environmental
• Occupational
• Nutrition and Disease
3. Disease Number Percentage
Repeated trauma 276,600 64
Skin disorders 57,900 13
Lung conditions due to
toxic exposures
20,300 5
Physical injury 16,600 4
Poisoning 5,100 1
Lung disease due to
dusts
2,900 1
All other illnesses 50,600 12
Total 430,000 100
REPORTED OCCUPATIONAL DISEASES
4. RVRS Medical College, Bhilwara
MECHANISMS OF TOXICITY
Threshold effect
Absorption at portals of entry
ingestion
inhalation
skin contact
Distribution within the body
Metabolism and Excretion
Toxic effects
5. XENOBIOTIC METABOLISM
• TOXINS CAN BE METABOLISED TO NONTOXIC
METABOLITES AND ELIMINATED FROM THE BODY
KNOWN AS DETOXIFICATION
• THEY CAN BE TURNED INTO REACTIVE
METABOLITES THAT ARE TOXIC TO CELLULAR
COMPONENTS
• IF CELLULAR REPAIR IS NOT EFFECTIVE SHORT
TERM AND LONG TERM EFFECTS DEVELOP
6. XENOBIOTIC MECHANISMS
• Phase I Reactions (Smooth ER), makes them less lipophilic by adding a direct
polar group
• Cytochrome P-450-dependent monooxygenase system OR CYPs are
primarily expressed in hepatocytes in which they are localized to ER.
CAN ALSO FOUND IN SKIN LUNGS AND GI MUCOSA
• Flavin-containing monooxygenase system
• Peroxidase-dependent cooxidation
• Phase II Reactions, combines them with other polar substances
• Glucuronidation
• Biomethylation
• Glutathione conjugation
7. • BOTH PHASE 1 AND 2 REACTIONS MAY PRODUCE REACTIVE
OXYGEN SPECIES (ROS) AS A BYPRODUCT WHICH CAN CAUSE
CELLULAR INJURY.
• Example are
• PRODUCTION OF TRICHLOROMETHYL FREE RADICALS FROM CARBON
TETRACHLORID,IN LIVER
• DNA BINDING METABOLITE FROM BENZOPYRENE WHICH IS CARCINOGEN PRESENT
IN CIGARETTE SMOKE, IN LUNG
• CYP PARTICIPATE IN METABOLISM OF ALCOHOL AND DRUGS LIKE
• ACETAMINOPHEN,BARBITURATES,WARFARIN
• AND ANTICONVULSANTS
8. • THERE IS GREAT VARIATION IN THE ACTIVITY OF CYPs AMONG
INDIVIDUALS
• FACTORS AFFECTING CYP ACTIVITIES ARE GENETIC
POLYMORPHISM,DRUGS AND CHEMICALS
• CYP INDUCERS ARE CHEMICALS ,DRUGS,SMOKING,ALCOHOL
AND HORMONES
• FASTING AND STARVATION CAN DECREASE CYP ACTIVITY
9.
10. CONTENTS OF TOXIC WASTE DUMPS
Acetone
Aldrin/Dieldrin
Arsenic Barium
Benzene
2-Butanone
Cadmium
Carbon tetrachloride
Chlordane
Chloroform
Chromium
Cyanide
DDT, DDE, DDD
1,1 and 1,2-Dichloroethane
Lead
Mercury Methylene
chloride Nickel
Pentachlorophenol
Polychlorinated biphenyls Tri-
and Tetrachloroethylene
Toluene
Vinyl Chloride
Zinc
13. TOBACCO
• 440,000premature deaths/year in USA
• cancer
• cardiovascular disease
• respiratory disease
• cerebrovascular disease
• $150billion in health related costs
• Byfarthe most preventable cause of death in the United
States
16. Relative Risks for Current Smokers of Cigarettes
Males Females
2.8
1.5
3.1
1.6
Disease or Condition
Coronary heart disease
Age 35–64
Age ≥ 65
Cerebrovascular lesions
Age 35–64
Age ≥ 65
Aortic aneurysm
3.3
1.6
6.2
4
1.5
7.1
10.6 13.1
Chronic airwaysobstruction
Cancer
Lip, oral cavity, pharynx 10.9 5.1
Esophagus 6.8 7.8
Stomach 2 1.4
Pancreas 2.3 2.3
Larynx 14.6 13
23.3
Lung
Cervix
Kidney
Bladder, other urinary organs
2.7
3.3
12.7
1.6
1.3
2.2
17. CIGARETTES AND THE WORKPLACE
• cigarette smoke is synergistic with radon decay products in causing
lung cancer
• Cigarette smoke exacerbates bronchitis, asthma, and
pneumoconiosis associated with exposure to silica, coal dust, grain
dust, cotton dust, and welding fumes
18. ALCOHOL
• 15to 20 million alcoholics in theUSA
• 100,000 deaths/year due to alcohol abuse
• Economic losses of $100to $130 billion/year
• One to two drinks/day reduces incidence of coronary
artery disease*
19. Definition of Alcoholism
A CONCENTRATION OF 80MG/DL IN BLOOD CONTITUTES THE LEGAL
DEFINITION OF DRUNK DRIVING IN MOST STATES.
DROWSINESS OCCURS AT 200MG/DL
STUPOR AT 300MG/DL
COMA WITH POSSIBLE RESPIRATORY ARREST AT HIGHER LEVEL
MOST OF THE ALCOHOL IS METABOLISED TO ACETALDEHYDE IN IN THE
LIVER BY THREE ENZYME SYSTEMS
• ALCOHOL DEHYDROGENASE
• CYTOCROME P-450 ISOENZYMES
• CATALASE
AT HIGH BLOOD ALCOHOL LEVELS ETHANOL OXIDIZING SYSTEM PLAY A
ROLE
20. EFFECTS OF BLOOD ALCOHOL LEVELS IN THE ABSENCE OF TOLERANCE
Blood Level, mg/dL Usual Effect
20
80
Decreased inhibitions, a slight feeling of
intoxication
Decrease in complex cognitive
200
300
400
functions and motor performance
Obvious slurred speech, motor
incoordination, irritability, and poor
judgment
Light coma and depressed vital signs
Death
Harrison Internal Med, 16th Ed
22. • OXIDATION TAKES PLACE IN THE CYTOSL
• P450 SYSTEM AND ITS CYP2E ARE LOCATED IN THE ER
• CATALASE ARE LOCATED IN THE PEROXISOMES
• SEVERAL TOXIC EFFECTS RESULTS FROM ETHANOL METABOLISM LIKE
• ACETALDEHYDEIS THE DIDECT PRODUCT OF ALCOHOL OXIDATION RESPONSIBLE FOR
ACUTE EFFECTS
• ALCOHOL OXIDATION BY ALCOHOL DEHYDROGENASE CAUSES DECRESE IN NAD AND
INCREASE IN NADH WHICH CAN CAUSE LACTIC ACIDOSIS
• ROS GENERATION
METABOLISM OF ETHANOL OXIDATION TO ACETALDEHYDE
TAKE PLACE BY THREE DIFFERENT ROUTES
25. ADVERSE EFFECTS OF ALCOHOL
• ACUTE ALCOHOLISM MAINLY EFFECTS CNS BUT ALSO INDUCE HEPATIC AND GASTRIC
CHAGES WHICH ARE REVERSIBLE IF CONSUMPTION IS DISCONTINUED
• CHRONIC ALCOHOLISM AFFECTS LIVER BY PRODUCING FATTY LIVER, ALCOHOLIC
HEPATITIS AND CIRRHOSIS WHICH LEAD TO PORTAL HYPERTENSION AND INCRESES THE
RISK 0F DEVELOPMENT OF HEPATOCELLULAR CARCINOMA
• CHRONIC ALCOHOLISM CAN CAUSE BLEEDING FROM GASTRITIS AND GASTRIC ULCERS
, PERIPHERAL NEUROPATHY, ALCOHOLIC CARDIOMYOPATHY AND PANCREATITIS
• CHRONIC ALCOHOLISM IS MAJOR RISK FACTORS FOR CANCER OF ORAL CAVITY,
LARYNX AND ESOPHAGUS
26. ALCOHOLAND THE LIVER
o Fatty Change
o present in over 90%of binge and chronic drinkers
o liver is enlarged but patient is asymptomatic
o changes are reversible with cessation of drinking
o macrosteatosis w/o inflammation ornecrosis
o Alcohol hepatitis
o only between 10- 15%of alcoholics will develop alcoholic hepatitis
o may have systemic symptoms and jaundice
o hepatocellular necrosis with Mallory bodies and PMNs (central hyaline
sclerosis)
o thought to be a precursor of cirrhosis
o Alcoholic cirrhosis
o shrunken nodular liver with uniform small nodules (micronodular
cirrhosis)
27. FATTY CHANGE BIOCHEMISTRY
• Catabolism of fat by peripheral tissues is increased, and there is
increased delivery of free fatty acids to the liver
• An excess of NADH over NAD stimulates lipid biosynthesis
• Oxidation of fatty acids by mitochondria is decreased
• Acetaldehyde forms adducts with tubulin and impairs function of
microtubules, resulting in decreased transport of lipoproteins from the
liver
28.
29.
30.
31.
32. NEUROLOGIC MANIFESTATIONS OF ALCOHOLISM
• Wernicke syndrome
• confusion, ataxia, and diplopia from ophthalmoplegia
• damage to mammillary bodies, cerebellum and periaqueductal gray matter of
the midbrain
• due to thiamine deficiency
• may respond to prompt thiamine replacement
• Korsakov syndrome
• memory loss and confabulation ( HONESTLY LYING)
• results from thiamine deficiency and direct toxicity
33. MECHANISMS OF DISEASE CAUSED BY ETHANOLABUSE
Organ System
Liver
Mechanism
Toxicity
Lesion
Fatty change
Acute hepatitis
Alcoholic cirrhosis
Nervous system Wernicke syndrome
Korsakoff syndrome
Cardiovascular
system
Cerebellar degeneration
Peripheral neuropathy
Cardiomyopathy
Thiamine deficiency
Toxicity and thiamine
deficiency
Nutritional deficiency
Thiamine deficiency
Toxicity
Hypertension Vasopressor
36. ORAL CONTRACEPTIVES (BCPS)
• Breast cancer and other cancers
• no increase in breast cancer
• decrease endometrial and ovarian cancers
• increase in cervical cancer (?lifestyle induced)
• Thromboembolic events
• DVT and Pulmonary Embolism increased
• adds to other risk factors (e.g. Factor V Leiden)
• Cardiovascular disease
• with current low estrogen pills, risk of MI and atherosclerosis not increased in non-smoking
women < 45y
• ischemic stroke increased regardless of age or smoking
• Liver tumors
• benign hepatic adenomas
• older women with prolonged use
• may rupture and cause intra-abdominal bleeding
37. HORMONE REPLACEMENT THERAPY (HRT)
Cancer
in women with a uterus combined estrogen and progestin Rx necessary to reduce
endometrial cancer
WHI showed increased risk of breast cancer in women who used HRT combined
therapy for5 years
Thromboembolic events
elevated approximated twofold in HRT users, especially within the first 2 years
Cardiovascular disease
WHI reported 29%increased risk of myocardial infarction, especially during the first year
of combined HRT use
38. ACETAMINOPHEN (TYLENOL)
Does not affect cyclooxygenase so bleeding associated
with aspirin does not occur
Has analgesic and antipyretic actions but no anti-
inflammatory action
Large doses may produce hepatic necrosis
patients should not exceed recommended dose (4 grams/day)
toxic dose in adults is 15to 25gm
dose should be reduced in children with fever or dehydration
39. ASPIRIN
Overdose
respiratory alkalosis followed by metabolic acidosis that may be fatal
Chronic aspirin toxicity (salicylism)
headache, dizziness, ringing in the ears (tinnitus), mental confusion,
drowsiness, nausea, vomiting, and diarrhea
Inhibits cyclooxygenase (COX 1& 2)
Erosive gastritis is a major cause of GI bleeding
May be implicated in Reye syndrome (fatty liver with
encephalopathy) in children < 15 years old, especially with
influenza and chicken pox
40. COX-1 AND COX-2 INHIBITORS
Cyclooxygenase 1
constitutively expressed and active in the normal platelet
(thromboxane A2)
involved in synthesis of gastro-protective prostaglandins
Cyclooxygenase 2
induced, especially in inflamed tissue
in vessel wall produces prostacyclin (PGI2)
Aspirin and other nonselective NSAIDS inhibit both COX-1
and COX-2
41.
42. INDOOR AIR POLLUTION
o Carbon Monoxide CO
o Nitrogen Dioxide NO2
o Wood Smoke
o Formaldehyde
o Radon
o Manufactured Mineral Fibers
o Bioaerosols
43. RADON
Radon is a radioactive gas and a decay product of
uranium
It is widely distributed in the soil and is prevalent in homes
(especially in basements)
Radon decay products are alpha emitters
10%of US homes have levels associated with an increased risk
of lung cancer and an estimated 10,000 lung cancers per year in
the United States are due to radon. Smoking elevates risk.
Proper venting reduces the exposure
44. LEAD
lead is classified as a heavy metal (others include
mercury, arsenic, and cadmium)
Source of exposure
lead paint
lead solder in plumbing (older houses)
lead-glazed ceramics
industrial exposure
Route of exposure
inhalation with industrial exposure
ingestion with household exposure
45. LEAD DISTRIBUTION AND EXCRETION
Lead is a divalent cation that is taken up by bone and
developing teeth in children (80% to 85%)
Half-life of lead in bone is 30 years
Blood accumulates 5% to 10% of lead, but lead is rapidly
cleared from the blood
lead in blood indicates recent exposure
blood level does not allow the determination of total body burden
Remainder is distributed in the soft tissues
Excretion is via the kidneys
46. EFFECTS OF LEAD
High affinity for sulfhydryl groups
inhibition of heme biosynthesis with hypochromic anemia and
basophillic stippling of erythrocytes
Competition with calcium ions
As a divalent cation, lead competes with calcium and is stored in bone.
It also interferes with nerve transmission and brain development.
Inhibition of membrane-associated enzymes
Lead inhibits 5'-nucleotidase activity and sodium- potassium ion pumps,
leading to decreased survival of red blood cells (hemolysis), renal damage,
and hypertension.
49. “RADIATION”
Linear Energy Transfer (LET), Relative T ½ - 1010
Curie vs. Becqerel: ONE CURIE IS DEFINED AS 3.7x 1010 radioactive decay per
second
ONE BECQUERAL IS DEFINED AS THE ACTIVITY OF ONE RADIOACTIVE
DECAY PER SECOND
IONIZING vs. NON-IONIZING
PARTICULATE vs. NON-PARTICULATE
(Photons)
ENERGY: Kev, Mev (~Wavelength)
Biologic Effect (RBE relative biological effectiveness). RBE is defined as
the ratio of doses required by the two radiation to cause the same level of
effect
50. RADIATION DOSIMETRY
o Roentgen: unit of charge produced by x-rays orgamma rays that ionize a
specific volume of air
o RAD(radiation absorbed dose): the dose of radiation that will produce
absorption of 100ergs of energy per gram of tissue; 1gm of tissue exposed to 1
roentgen ofgamma rays in equal to 93 ergs
o Gray (Gy): the dose of radiation that will produce absorption of 1joule of energy
per kilogram of tissue; 1Gy corresponds to 100rad (SI unit forabsorbed dose)
o REM (radiation equivalent man): the dose of radiation that causes a biologic effect
equivalent to 1rad of x-rays or gamma rays
o Sievert (Sv): the dose of radiation that causes a biologic effect equivalent to 1Gy
of x-rays orgamma rays; 1Sv corresponds to 100rem (SI unit)
51. ACUTE EFFECTS OF IONIZING RADIATION
Free radical generation
Ionizing radiation + H20 → H30++ OH·
DNA Damage
double-stranded DNA breaks needed to kill cell
(mammalian cells can repair single stranded breaks)
cross-linking of DNA strands, cleavage of sugar-
phosphate bonds
cell cycle arrest in presence of damaged DNA
repairof DNA damage or apoptosis
Tumor-suppressor gene p53 activation
52. RVRS Medical College, Bhilwara
ACUTE WHOLE BODY RADIATION
LD50 @ 6 wks 2.5 to 4.0 Gy (250 to 400 rad)
Hematopoietic
200–600 REM
Maximum neutrophil and platelet depression in 2 wk
Gastrointestinal
600–1000 REM
Nausea, vomiting, diarrhea
Hemorrhage and infection in 1–3 wk
Central nervous system
>1000 REM
Intractable nausea and vomiting
Confusion, somnolence, convulsions
death in 14–36 hr
53. THERAPEUTIC RADIATION
External radiation is delivered to malignant neoplasms at fractionated
doses up to 40 to 70 Gy (4000 to 7000 rad), with shielding of adjacent
normal tissues
Therapeutic radiation alone seems to add little risk of AMLbut can
increase the risk in people exposed to alkylating agents
Fatigue, nausea and vomiting frequent
Bone marrow suppression may occur especially with chest or
abdominal radiation
54. DELAYED RADIATION INJURY
Carcinogenesis (atom bomb survivors)
myeloid leukemias peak 5 to 7 years after exposure
breast and thyroid cancers may show greater latency
no germline mutations noted in progeny of survivors
Vascular effects
endothelial necrosis followed by intimal and medial fibrosis
capillaries may become thrombosed and obliterated or ectatic
Parenchymal atrophy and fibrosis
55. RVRS Medical College, Bhilwara
RADIATION EFFECTS ON TISSUE
ACUTE (vasculitis, possibly “fibrinoid” necrosis)
CHRONIC (fibrosis)
