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ENVIRONMENTAL
ENVIRONMENTAL
&
&
NUTRITIONAL
NUTRITIONAL
PATHOLOGY
PATHOLOGY
Environmental and
Environmental and
Nutritional Pathology
Nutritional Pathology
 Environment and Disease
Environment and Disease
 Common Exposures
Common Exposures
 Environmental
Environmental
 Occupational
Occupational
 Nutrition
Nutrition and Disease
and Disease
Reported Occupational Diseases
Reported Occupational Diseases
Disease
Disease Number
Number Percentage
Percentage
Repeated trauma
Repeated trauma 276,600
276,600 64
64
Skin disorders
Skin disorders 57,900
57,900 13
13
Lung conditions due to
Lung conditions due to
toxic exposures
toxic exposures
20,300
20,300 5
5
Physical injury
Physical injury 16,600
16,600 4
4
Poisoning
Poisoning 5,100
5,100 1
1
Lung disease due to
Lung disease due to
dusts
dusts
2,900
2,900 1
1
All other illnesses
All other illnesses 50,600
50,600 12
12
Total
Total 430,000
430,000 100
100
Mechanisms of Toxicity
Mechanisms of Toxicity
 Threshold effect
Threshold effect
 Absorption at portals of entry
Absorption at portals of entry
 ingestion
ingestion
 inhalation
inhalation
 skin contact
skin contact
 Distribution within the body
Distribution within the body
 Metabolism and Excretion
Metabolism and Excretion
 Toxic effects
Toxic effects
Xenobiotic Mechanisms
 Phase I Reactions (Smooth ER), makes them
less lipophilic by adding a direct polar group
 Cytochrome P-450-dependent monooxygenase
system
 Flavin-containing monooxygenase system
 Peroxidase-dependent cooxidation
 Phase II Reactions, combines them with other
polar substances
 Glucuronidation
 Biomethylation
 Glutathione conjugation
pathology-environmentalnutritionaldisease-101201075746-phpapp02.pdf
Contents of Toxic Waste Dumps
Acetone DDT, DDE, DDD
Aldrin/Dieldrin 1,1 and 1,2-Dichloroethane
Arsenic Lead
Barium Mercury
Benzene Methylene chloride
2-Butanone Nickel
Cadmium Pentachlorophenol
Carbon tetrachloride Polychlorinated biphenyls
Chlordane Tri- and Tetrachloroethylene
Chloroform Toluene
Chromium Vinyl Chloride
Cyanide Zinc
Dose-response Curve
Dose-response Curve
Common
Common Exposures
Exposures
 Personal
Personal
 Medications
Medications
 Outdoor Air Pollution
Outdoor Air Pollution
 Indoor Air Pollution
Indoor Air Pollution
 Industrial Exposures
Industrial Exposures
 Agricultural Hazards
Agricultural Hazards
 Natural Toxins
Natural Toxins
 Radiation Injury
Radiation Injury
 Physical Injury
Physical Injury
Tobacco
Tobacco
 440,000 premature deaths/year in USA
440,000 premature deaths/year in USA
 cancer
cancer
 cardiovascular disease
cardiovascular disease
 respiratory disease
respiratory disease
 cerebrovascular disease
cerebrovascular disease
 $150 billion in health related costs
$150 billion in health related costs
By far
By far the most preventable cause
the most preventable cause
of death in the United States
of death in the United States
Tobacco and Cancer
70% of all lung cancers
30% of all cancers
Organ-Specific Carcinogens in Tobacco Smoke
Organ Carcinogen
Lung, larynx Polycyclic aromatic hydrocarbons
4-(Methylnitrosoamino)-1-(3-pyridyl)-1-buta-none
(NNK)
Polonium 210
Esophagus N'-Nitrosonornicotine (NNN)
Pancreas NNK (?)
Bladder 4-Aminobiphenyl, 2-naphthylamine
Oral cavity (smoking) Polycyclic aromatic hydrocarbons, NNK, NNN
Oral cavity (snuff) NNK, NNN, polonium 210
Data from Szczesny LB, Holbrook JH: Cigarette smoking. In Rom WH (ed): Environmental
and Occupational Medicine, 2nd ed. Boston, Little, Brown, 1992, p. 1211.
Relative Risks for Current Smokers of Cigarettes
Relative Risks for Current Smokers of Cigarettes
Disease or Condition Males
Males Females
Females
Coronary heart disease
Coronary heart disease
Age 35–64
Age 35–64 2.8
2.8 3.1
3.1
Age ≥ 65
Age ≥ 65 1.5
1.5 1.6
1.6
Cerebrovascular lesions
Cerebrovascular lesions
Age 35–64
Age 35–64 3.3
3.3 4
4
Age ≥ 65
Age ≥ 65 1.6
1.6 1.5
1.5
Aortic aneurysm
Aortic aneurysm 6.2
6.2 7.1
7.1
Chronic airways obstruction
Chronic airways obstruction 10.6
10.6 13.1
13.1
Cancer
Cancer
Lip, oral cavity, pharynx
Lip, oral cavity, pharynx 10.9
10.9 5.1
5.1
Esophagus
Esophagus 6.8
6.8 7.8
7.8
Stomach
Stomach 2
2 1.4
1.4
Pancreas
Pancreas 2.3
2.3 2.3
2.3
Larynx
Larynx 14.6
14.6 13
13
Lung
Lung 23.3
23.3 12.7
12.7
Cervix
Cervix 1.6
1.6
Kidney
Kidney 2.7
2.7 1.3
1.3
Bladder, other urinary organs
Bladder, other urinary organs 3.3
3.3 2.2
2.2
Cigarettes And The Workplace
Cigarettes And The Workplace
 Similar to asbestos exposure, cigarette smoke is
Similar to asbestos exposure, cigarette smoke is
synergistic with radon decay products in causing
synergistic with radon decay products in causing
lung cancer
lung cancer
 Cigarette smoke exacerbates bronchitis, asthma,
Cigarette smoke exacerbates bronchitis, asthma,
and pneumoconiosis associated with exposure
and pneumoconiosis associated with exposure
to silica, coal dust, grain dust, cotton dust, and
to silica, coal dust, grain dust, cotton dust, and
welding fumes
welding fumes
Alcohol
Alcohol
 15 to 20 million alcoholics in the USA
15 to 20 million alcoholics in the USA
 100,000 deaths/year due to alcohol
100,000 deaths/year due to alcohol
abuse
abuse
 Economic losses of $100 to $130
Economic losses of $100 to $130
billion/year
billion/year
 One to two drinks/day reduces
One to two drinks/day reduces
incidence of coronary artery disease*
incidence of coronary artery disease*
* What kind of person would put this kind of bullet on a
powerpoint?
A. Drinker? B) Non-Drinker?
Definition of Alcoholism
?
Effects of Blood Alcohol Levels in the Absence of Tolerance
Effects of Blood Alcohol Levels in the Absence of Tolerance
Blood Level, mg/dL
Blood Level, mg/dL Usual Effect
Usual Effect
20
20 Decreased inhibitions, a slight
Decreased inhibitions, a slight
feeling of intoxication
feeling of intoxication
80
80 Decrease in complex cognitive
Decrease in complex cognitive
functions and motor performance
functions and motor performance
200
200 Obvious slurred speech, motor
Obvious slurred speech, motor
incoordination, irritability, and
incoordination, irritability, and
poor judgment
poor judgment
300
300 Light coma and depressed vital
Light coma and depressed vital
signs
signs
400
400 Death
Death
Harrison Internal Med, 16th
Ed
Metabolism Of Ethanol
Metabolism Of Ethanol
ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase
20%
80%
pathology-environmentalnutritionaldisease-101201075746-phpapp02.pdf
LEGAL INTOXICATION
0.08%
Widmark Equation
Widmark Equation
 C = A / (W * r)
C = A / (W * r)
 C = concentration of EtOH in mg/dl
C = concentration of EtOH in mg/dl
 A = mass of alcohol ingested in grams
A = mass of alcohol ingested in grams
 density of ethanol = 0.8
density of ethanol = 0.8
 W = body weight in grams
W = body weight in grams
 r = Widmark distribution for ethanol
r = Widmark distribution for ethanol
 0.55 mL/ g body weight for females
0.55 mL/ g body weight for females
 0.68 mL / g body weight for males
0.68 mL / g body weight for males
 Elimination of ethanol = 0.015%/h (15mg/dl/h)
Elimination of ethanol = 0.015%/h (15mg/dl/h)
 zero order kinetics
zero order kinetics
 Medical measurements use mg/dl in plasma, whereas
Medical measurements use mg/dl in plasma, whereas
legal definitions use percentage (mass/volume) in whole
legal definitions use percentage (mass/volume) in whole
blood
blood
 to estimate the alcohol level in whole blood using the alcohol
to estimate the alcohol level in whole blood using the alcohol
level in blood plasma, divide by 1.16
level in blood plasma, divide by 1.16
Alcohol and the Liver
Alcohol and the Liver
 Fatty Change
Fatty Change
 present in over 90% of binge and chronic drinkers
present in over 90% of binge and chronic drinkers
 liver is enlarged but patient is asymptomatic
liver is enlarged but patient is asymptomatic
 changes are reversible with cessation of drinking
changes are reversible with cessation of drinking
 macrosteatosis w/o inflammation or necrosis
macrosteatosis w/o inflammation or necrosis
 Alcohol hepatitis
Alcohol hepatitis
 only between 10 - 15% of alcoholics will develop
only between 10 - 15% of alcoholics will develop
alcoholic hepatitis
alcoholic hepatitis
 may have systemic symptoms and jaundice
may have systemic symptoms and jaundice
 hepatocellular necrosis with Mallory bodies and PMNs
hepatocellular necrosis with Mallory bodies and PMNs
(central hyaline sclerosis)
(central hyaline sclerosis)
 thought to be a precursor of cirrhosis
thought to be a precursor of cirrhosis
 Alcoholic cirrhosis
Alcoholic cirrhosis
 shrunken nodular liver with uniform small nodules
shrunken nodular liver with uniform small nodules
(micronodular cirrhosis)
(micronodular cirrhosis)
Fatty Change Biochemistry
Fatty Change Biochemistry
 Catabolism of fat by peripheral tissues is
Catabolism of fat by peripheral tissues is
increased, and there is increased delivery of
increased, and there is increased delivery of
free fatty acids to the liver
free fatty acids to the liver
 An excess of NADH over NAD stimulates
An excess of NADH over NAD stimulates
lipid biosynthesis
lipid biosynthesis
 Oxidation of fatty acids by mitochondria is
Oxidation of fatty acids by mitochondria is
decreased
decreased
 Acetaldehyde forms adducts with tubulin and
Acetaldehyde forms adducts with tubulin and
impairs function of microtubules, resulting in
impairs function of microtubules, resulting in
decreased transport of lipoproteins from the
decreased transport of lipoproteins from the
liver
liver
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pathology-environmentalnutritionaldisease-101201075746-phpapp02.pdf
pathology-environmentalnutritionaldisease-101201075746-phpapp02.pdf
pathology-environmentalnutritionaldisease-101201075746-phpapp02.pdf
Neurologic Manifestations of Alcoholism
Neurologic Manifestations of Alcoholism
 Wernicke syndrome
Wernicke syndrome
 confusion, ataxia, and diplopia from
confusion, ataxia, and diplopia from
ophthalmoplegia
ophthalmoplegia
 damage to mammillary bodies, cerebellum and
damage to mammillary bodies, cerebellum and
periaqueductal gray matter
periaqueductal gray matter of the midbrain
of the midbrain
 due to thiamine deficiency
due to thiamine deficiency
 may respond to prompt thiamine replacement
may respond to prompt thiamine replacement
 Korsakov syndrome
Korsakov syndrome
 memory loss and confabulation
memory loss and confabulation
 results from thiamine deficiency and direct
results from thiamine deficiency and direct
toxicity
toxicity
pathology-environmentalnutritionaldisease-101201075746-phpapp02.pdf
Mechanisms of Disease Caused by Ethanol Abuse
Organ System Lesion Mechanism
Liver Fatty change Toxicity
Acute hepatitis
Alcoholic cirrhosis
Nervous system Wernicke syndrome Thiamine deficiency
Korsakoff syndrome Toxicity and thiamine
deficiency
Cerebellar degeneration Nutritional deficiency
Peripheral neuropathy Thiamine deficiency
Cardiovascular
system
Cardiomyopathy Toxicity
Hypertension Vasopressor
Mechanisms of Disease Caused by Ethanol Abuse
Organ System Lesion Mechanism
Gastrointestinal
tract
Gastritis Toxicity
Pancreatitis Toxicity
Skeletal muscle Rhabdomyolysis Toxicity
Reproductive
system
Testicular atrophy ?
Spontaneous
abortion
?
Fetal alcohol
syndrome
Growth retardation Toxicity
Mental retardation
Birth defects
Therapeutic Drugs
Therapeutic Drugs
(Medications)
(Medications)
 Oral Contraceptives (BCPs)
Oral Contraceptives (BCPs)
 Hormone Replacement Therapy (HRT)
Hormone Replacement Therapy (HRT)
 Acetaminophen
Acetaminophen
 Aspirin
Aspirin
Oral Contraceptives (BCPs)
Oral Contraceptives (BCPs)
 Breast cancer and other cancers
Breast cancer and other cancers
 no increase in breast cancer
no increase in breast cancer
 decrease endometrial and ovarian cancers
decrease endometrial and ovarian cancers
 increase in cervical cancer (?lifestyle induced)
increase in cervical cancer (?lifestyle induced)
 Thromboembolic events
Thromboembolic events
 DVT and Pulmonary Embolism increased
DVT and Pulmonary Embolism increased
 adds to other risk factors (e.g. Factor V Leiden)
adds to other risk factors (e.g. Factor V Leiden)
 Cardiovascular disease
Cardiovascular disease
 with current low estrogen pills, risk of MI and
with current low estrogen pills, risk of MI and
atherosclerosis not increased in non-smoking women < 45 y
atherosclerosis not increased in non-smoking women < 45 y
 ischemic stroke increased regardless of age or smoking
ischemic stroke increased regardless of age or smoking
 Liver tumors
Liver tumors
 benign hepatic adenomas
benign hepatic adenomas
 older women with prolonged use
older women with prolonged use
 may rupture and cause intra-abdominal bleeding
may rupture and cause intra-abdominal bleeding
Hormone Replacement Therapy (HRT)
Hormone Replacement Therapy (HRT)
 Cancer
Cancer
 in women with a uterus combined estrogen and
in women with a uterus combined estrogen and
progestin Rx necessary to reduce endometrial cancer
progestin Rx necessary to reduce endometrial cancer
 WHI showed increased risk of breast cancer in women
WHI showed increased risk of breast cancer in women
who used HRT combined therapy for 5 years
who used HRT combined therapy for 5 years
 Thromboembolic events
Thromboembolic events
 elevated approximated twofold in HRT users, especially
elevated approximated twofold in HRT users, especially
within the first 2 years
within the first 2 years
 Cardiovascular disease
Cardiovascular disease
 WHI reported 29% increased risk of myocardial
WHI reported 29% increased risk of myocardial
infarction, especially during the first year of combined
infarction, especially during the first year of combined
HRT use
HRT use
Acetaminophen (Tylenol)
Acetaminophen (Tylenol)
 Does not affect cyclooxygenase so bleeding
Does not affect cyclooxygenase so bleeding
associated with aspirin does not occur
associated with aspirin does not occur
 Has analgesic and antipyretic actions but no
Has analgesic and antipyretic actions but no
anti-inflammatory action
anti-inflammatory action
 Large doses may produce hepatic necrosis
Large doses may produce hepatic necrosis
 patients should not exceed recommended dose
patients should not exceed recommended dose
(4 grams/day)
(4 grams/day)
 toxic dose in adults is 15 to 25 gm
toxic dose in adults is 15 to 25 gm
 dose should be reduced in children with fever or
dose should be reduced in children with fever or
dehydration
dehydration
Aspirin
Aspirin
 Overdose
Overdose
 respiratory alkalosis followed by metabolic acidosis that
respiratory alkalosis followed by metabolic acidosis that
may be fatal
may be fatal
 Chronic aspirin toxicity (salicylism)
Chronic aspirin toxicity (salicylism)
 headache, dizziness, ringing in the ears (tinnitus),
headache, dizziness, ringing in the ears (tinnitus),
mental confusion, drowsiness, nausea, vomiting, and
mental confusion, drowsiness, nausea, vomiting, and
diarrhea
diarrhea
 Inhibits cyclooxygenase (COX 1 & 2)
Inhibits cyclooxygenase (COX 1 & 2)
 Erosive gastritis is a major cause of GI bleeding
Erosive gastritis is a major cause of GI bleeding
 May be implicated in Reye syndrome (fatty liver
May be implicated in Reye syndrome (fatty liver
with encephalopathy) in children < 15 years old,
with encephalopathy) in children < 15 years old,
especially with influenza and chicken pox
especially with influenza and chicken pox
Cox-1 and Cox-2 Inhibitors
Cox-1 and Cox-2 Inhibitors
 Cyclooxygenase 1
Cyclooxygenase 1
 constitutively expressed and active in the
constitutively expressed and active in the
normal platelet (thromboxane A2)
normal platelet (thromboxane A2)
 involved in synthesis of gastro-protective
involved in synthesis of gastro-protective
prostaglandins
prostaglandins
 Cyclooxygenase 2
Cyclooxygenase 2
 induced, especially in inflamed tissue
induced, especially in inflamed tissue
 in vessel wall produces prostacyclin (PGI
in vessel wall produces prostacyclin (PGI2
2)
)
 Aspirin and other nonselective NSAIDS
Aspirin and other nonselective NSAIDS
inhibit both COX-1 and COX-2
inhibit both COX-1 and COX-2
Figure 2-16 Generation of arachidonic acid metabolites and their roles in inflammation. The molecular
targets of action of some anti-inflammatory drugs are indicated by a red X. COX, cyclooxygenase; HETE,
hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 15 August 2005 06:35 PM)
© 2005 Elsevier
Indoor Air Pollution
Indoor Air Pollution
 Carbon Monoxide CO
Carbon Monoxide CO
 Nitrogen Dioxide NO
Nitrogen Dioxide NO2
2
 Wood Smoke
Wood Smoke
 Formaldehyde
Formaldehyde
Radon
Radon
 Manufactured Mineral Fibers
Manufactured Mineral Fibers
 Bioaerosols
Bioaerosols
Radon
Radon
 Radon is a radioactive gas and a decay
Radon is a radioactive gas and a decay
product of uranium
product of uranium
 It is widely distributed in the soil and is
It is widely distributed in the soil and is
prevalent in homes (especially in basements)
prevalent in homes (especially in basements)
 Radon decay products are alpha emitters
Radon decay products are alpha emitters
 10% of US homes have levels associated with
10% of US homes have levels associated with
an increased risk of lung cancer and an
an increased risk of lung cancer and an
estimated 10,000 lung cancers per year in the
estimated 10,000 lung cancers per year in the
United States are due to radon. Smoking
United States are due to radon. Smoking
elevates risk.
elevates risk.
 Proper venting reduces the exposure
Proper venting reduces the exposure
Lead
Lead
 lead is classified as a heavy metal (others
lead is classified as a heavy metal (others
include mercury, arsenic, and cadmium)
include mercury, arsenic, and cadmium)
 Source of exposure
Source of exposure
 lead paint
lead paint
 lead solder in plumbing (older houses)
lead solder in plumbing (older houses)
 lead-glazed ceramics
lead-glazed ceramics
 industrial exposure
industrial exposure
 Route of exposure
Route of exposure
 inhalation with industrial exposure
inhalation with industrial exposure
 ingestion with household exposure
ingestion with household exposure
Lead Distribution and Excretion
Lead Distribution and Excretion
 Lead is a divalent cation that is taken up by
Lead is a divalent cation that is taken up by
bone and developing teeth in children (80%
bone and developing teeth in children (80%
to 85%)
to 85%)
 Half-life of lead in bone is 30 years
Half-life of lead in bone is 30 years
 Blood accumulates 5% to 10% of lead, but
Blood accumulates 5% to 10% of lead, but
lead is rapidly cleared from the blood
lead is rapidly cleared from the blood
 lead in blood indicates recent exposure
lead in blood indicates recent exposure
 blood level does not allow the determination of
blood level does not allow the determination of
total body burden
total body burden
 Remainder is distributed in the soft tissues
Remainder is distributed in the soft tissues
 Excretion is via the kidneys
Excretion is via the kidneys
Effects of Lead
Effects of Lead
 High affinity for sulfhydryl groups
High affinity for sulfhydryl groups
 inhibition of heme biosynthesis with hypochromic
inhibition of heme biosynthesis with hypochromic
anemia and basophillic stippling of erythrocytes
anemia and basophillic stippling of erythrocytes
 Competition with calcium ions
Competition with calcium ions
 As a divalent cation, lead competes with calcium and is
As a divalent cation, lead competes with calcium and is
stored in bone.
stored in bone.
 It also interferes with nerve transmission and brain
It also interferes with nerve transmission and brain
development.
development.
 Inhibition of membrane-associated enzymes
Inhibition of membrane-associated enzymes
 Lead inhibits 5'-nucleotidase activity and sodium-
Lead inhibits 5'-nucleotidase activity and sodium-
potassium ion pumps, leading to decreased survival of
potassium ion pumps, leading to decreased survival of
red blood cells (hemolysis), renal damage, and
red blood cells (hemolysis), renal damage, and
hypertension.
hypertension.
Consequences
of lead
exposure
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pathology-environmentalnutritionaldisease-101201075746-phpapp02.pdf
“RADIATION”
 T ½
 Curie vs. Becqerel
 IONIZING vs. NON-IONIZING
 PARTICULATE vs. NON-PARTICULATE
(Photons)
 ENERGY: Kev, Mev (~Wavelength)
 Linear Energy Transfer (LET), Relative
Biologic Effect (RBE)
 LD50@60d
This is the single most
RADIOSENSITIVE CELL
In your body
Radiation Dosimetry
Radiation Dosimetry
 Roentgen:
Roentgen: unit of charge produced by x-rays or gamma
unit of charge produced by x-rays or gamma
rays that ionize a specific volume of air
rays that ionize a specific volume of air
 RAD
RAD (radiation absorbed dose):
(radiation absorbed dose): the dose of radiation
the dose of radiation
that will produce absorption of 100 ergs of energy per gram
that will produce absorption of 100 ergs of energy per gram
of tissue; 1 gm of tissue exposed to 1 roentgen of gamma
of tissue; 1 gm of tissue exposed to 1 roentgen of gamma
rays is equal to 93 ergs
rays is equal to 93 ergs
 Gray
Gray (Gy): the dose of radiation that will produce
(Gy): the dose of radiation that will produce
absorption of 1 joule of energy per kilogram of tissue; 1 Gy
absorption of 1 joule of energy per kilogram of tissue; 1 Gy
corresponds to 100 rad (SI unit for absorbed dose)
corresponds to 100 rad (SI unit for absorbed dose)
 REM
REM (radiation equivalent man):
(radiation equivalent man): the dose of radiation that
the dose of radiation that
causes a biologic effect equivalent to 1 rad of x-rays or
causes a biologic effect equivalent to 1 rad of x-rays or
gamma rays
gamma rays
 Sievert
Sievert (Sv): the dose of radiation that causes a biologic
(Sv): the dose of radiation that causes a biologic
effect equivalent to 1 Gy of x-rays or gamma rays; 1 Sv
effect equivalent to 1 Gy of x-rays or gamma rays; 1 Sv
corresponds to 100 rem (SI unit)
corresponds to 100 rem (SI unit)
Acute Effects of Ionizing Radiation
Acute Effects of Ionizing Radiation
 Free radical generation
Free radical generation
 Ionizing radiation + H
Ionizing radiation + H2
20 → H
0 → H3
30
0+
+
+ OH·
+ OH·
 DNA Damage
DNA Damage
 double-stranded DNA breaks needed to kill cell
double-stranded DNA breaks needed to kill cell
(mammalian cells can repair single stranded
(mammalian cells can repair single stranded
breaks)
breaks)
 cross-linking of DNA strands, cleavage of sugar-
cross-linking of DNA strands, cleavage of sugar-
phosphate bonds
phosphate bonds
 Tumor-suppressor gene
Tumor-suppressor gene p53
p53 activation
activation
 cell cycle arrest in presence of damaged DNA
cell cycle arrest in presence of damaged DNA
 repair of DNA damage or apoptosis
repair of DNA damage or apoptosis
Acute Whole Body Radiation
Acute Whole Body Radiation
 LD50 @ 6 wks 2.5 to 4.0 Gy (250 to 400 rad)
LD50 @ 6 wks 2.5 to 4.0 Gy (250 to 400 rad)
 Hematopoietic
Hematopoietic
 200–600 REM
200–600 REM
 Maximum neutrophil and platelet depression in 2 wk
Maximum neutrophil and platelet depression in 2 wk
 Gastrointestinal
Gastrointestinal
 600–1000 REM
600–1000 REM
 Nausea, vomiting, diarrhea
Nausea, vomiting, diarrhea
 Hemorrhage and infection in 1–3 wk
Hemorrhage and infection in 1–3 wk
 Central nervous system
Central nervous system
 >1000 REM
>1000 REM
 Intractable nausea and vomiting
Intractable nausea and vomiting
 Confusion, somnolence, convulsions
Confusion, somnolence, convulsions
 death in 14–36 hr
death in 14–36 hr
Therapeutic Radiation
Therapeutic Radiation
 External radiation is delivered to malignant
External radiation is delivered to malignant
neoplasms at fractionated doses up to 40 to
neoplasms at fractionated doses up to 40 to
70 Gy (4000 to 7000 rad), with shielding of
70 Gy (4000 to 7000 rad), with shielding of
adjacent normal tissues
adjacent normal tissues
 Therapeutic radiation alone seems to add
Therapeutic radiation alone seems to add
little risk of AML but can increase the risk in
little risk of AML but can increase the risk in
people exposed to alkylating agents
people exposed to alkylating agents
 Fatigue, nausea and vomiting frequent
Fatigue, nausea and vomiting frequent
 Bone marrow suppression may occur
Bone marrow suppression may occur
especially with chest or abdominal radiation
especially with chest or abdominal radiation
Delayed Radiation Injury
Delayed Radiation Injury
 Carcinogenesis (atom bomb survivors)
Carcinogenesis (atom bomb survivors)
 myeloid leukemias peak 5 to 7 years after exposure
myeloid leukemias peak 5 to 7 years after exposure
 breast and thyroid cancers may show greater latency
breast and thyroid cancers may show greater latency
 no germline mutations noted in progeny of survivors
no germline mutations noted in progeny of survivors
 Vascular effects
Vascular effects
 endothelial necrosis followed by intimal and medial
endothelial necrosis followed by intimal and medial
fibrosis
fibrosis
 capillaries may become thrombosed and obliterated or
capillaries may become thrombosed and obliterated or
ectatic
ectatic
 Parenchymal atrophy and fibrosis
Parenchymal atrophy and fibrosis
Radiation effects on TISSUE
 ACUTE (vasculitis, possibly “fibrinoid” necrosis)
 CHRONIC (fibrosis)
Physical Injury
Physical Injury
 Abrasion
Abrasion
 basically a scrape
basically a scrape
 superficial epidermis is torn off by friction or force
superficial epidermis is torn off by friction or force
 regeneration without scarring usually occurs
regeneration without scarring usually occurs

Laceration vs. Incision
Laceration vs. Incision
 a laceration is an irregular tear in the skin produced by
a laceration is an irregular tear in the skin produced by
overstretching. The wound margins are frequently hemorrhagic
overstretching. The wound margins are frequently hemorrhagic
and traumatized
and traumatized
 an incision is made by a sharp cutting object. The margins of
an incision is made by a sharp cutting object. The margins of
the incision are usually relatively clean
the incision are usually relatively clean
 Contusion
Contusion
 an injury caused by a blunt force that damages small blood
an injury caused by a blunt force that damages small blood
vessels and causes interstitial bleeding, usually without
vessels and causes interstitial bleeding, usually without
disruption of the continuity of the tissue (
disruption of the continuity of the tissue (cf
cf ecchymosis)
ecchymosis)
pathology-environmentalnutritionaldisease-101201075746-phpapp02.pdf
Adult Mortality Rates in the United States, Ages 25–44, in 1998
Rate per 100,000 population
Cause Hispanic Black White
Unintentional injuries 33.4 40.1 31.6
Cancer 16.8 38.0 25.3
Homicide 13.1 36.2 4.7
Human immunodeficiency virus 12.1 43.3 4.8
Heart disease 10.3 43.5 18.3
Suicide 7.8 — 17.0
Total 130.2 303.7 139.4
Data from CDC Fact Book, 2000/2001, Department of Health and Human Services,
Centers for Disease Control and Prevention.
GUNSHOT WOUND
 Entrance Vs. Exit
 Far range Vs. Close range
BURNS
 1st
, 2nd
, 3rd
, 4th
“Degree”
 FULL vs. PARTIAL Thickness
 Survival
 PERCENT of body using the rule of NINES
 DEGREE (i.e., Depth)
 Respiratory Tract Involvement
 AGE
 Speed of access to Burn Unit
 Immune System (Pseudomonas, S. aureus,
Candida)
HYPER-THERMIA
 HEAT
 CRAMPS: Electrolyte loss via sweat
 EXHAUSTION: Water depletion and lack
of cardiovascular compensation
 “STROKE”: Extensive peripheral
vasodilatation, i.e., “shocky”, very serious,
T>106º, over 110º have been reported, high
mortality.
HYPO-THERMIA
Often in setting of
homelessness or alcoholism
or both
< 90º often fatal, assoc. w.
 BRADYCARDIA
 ATRIAL FIBRILLATION
LIGHTNING/ELECTRICAL
 ELECTRIC DISTURBANCES
 NEURAL
 EKG
 THERMAL INJURY, depends upon a particular
tissue’s RESISTANCE to electrical flow
 “LIGHTNING” MARKS
ATMOSPHERIC PRESSURE
Altitude Illness
Blast Injuries
Decompression Injuries
ALTITUDE ILLNESS
 Caused by LOW Oxygen Tension
 HIGH ALTITUDES (>4000 m)
 OBTUNDATION
 INCREASED CAPILLARY PERMEABILITY
 ACUTE PULMONARY EDEMA (HAPE)
Q: What is the name of the base camp at Mt. Everest
A: Pulmonary Edema
BLAST INJURIES
 RELATED TO RAPID ATMOSPHERIC
PRESSURE CHANGES
 LUNGS
 VISCERA, especially GAS filled viscera
 Rupture, Hemorrhage, etc.
 IMMERSION BLAST also possible,
causing more of a total body compression
syndrome
DECOMPRESSION
 Related to GAS SOLUBILITY in divers
ascending rapidly, especially the more
NON-SOLUBLE gasses, like NITROGEN,
and, to a lesser extent, XENON
 AIR EMBOLISM is the common pathology
 ACUTE:
 “BENDS” (peri-articular), acute
 “CHOKES” (lungs), acute
 “STAGGERS” (inner ear), acute
 CHRONIC:
 ASEPTIC NECROSIS: humeri, femurs
NUTRITION
NUTRITION & DISEASE
& DISEASE
 Food Safety
Food Safety
 Additives
Additives
 Contaminants
Contaminants
 Nutritional Deficiencies
Nutritional Deficiencies
 Vitamins
Vitamins
 Minerals
Minerals
 Obesity
Obesity
 Diet and Disease
Diet and Disease
 Chemoprevention of Cancer
Chemoprevention of Cancer
Vitamin Deficiency and Excess
Vitamin Deficiency and Excess
 Fat soluble vitamins
Fat soluble vitamins
 A, D, E, K
A, D, E, K
 readily stored in body fat
readily stored in body fat
 poorly absorbed in digestive disorders involving
poorly absorbed in digestive disorders involving
malabsorbtion of fat
malabsorbtion of fat
 Water soluble vitamins
Water soluble vitamins
 remaining vitamins
remaining vitamins
 readily excreted in urine
readily excreted in urine
 Vitamin stores
Vitamin stores
 vitamins B-12 and A: stores sufficient for 1 year
vitamins B-12 and A: stores sufficient for 1 year
 folate and thiamine may become depleted
folate and thiamine may become depleted
within weeks when eating a deficient diet
within weeks when eating a deficient diet
Vitamin D Metabolism
Vitamin D Metabolism
 Absorption of vitamin D in the gut or
Absorption of vitamin D in the gut or
synthesis from precursors in the skin
synthesis from precursors in the skin
 Binding to a plasma α1 -globulin (D-
Binding to a plasma α1 -globulin (D-
binding protein) and transport to liver
binding protein) and transport to liver
 Conversion to 25-hydroxyvitamin D,
Conversion to 25-hydroxyvitamin D,
25(OH)D (calcidol) by 25-hydroxylase in
25(OH)D (calcidol) by 25-hydroxylase in
the liver
the liver
 Conversion of 25(OH)D to 1,25(OH)
Conversion of 25(OH)D to 1,25(OH)2
2 D
D
(calcitrol, Vitamin D3) by α1-hydroxylase
(calcitrol, Vitamin D3) by α1-hydroxylase
in the kidney;
in the kidney; biologically this is the most
biologically this is the most
active form of vitamin D
active form of vitamin D.
.
Functions of Vitamin D
Functions of Vitamin D
 Stimulates intestinal absorption of calcium
Stimulates intestinal absorption of calcium
and phosphorus
and phosphorus
 Collaborates with PTH in the mobilization
Collaborates with PTH in the mobilization
of calcium from bone
of calcium from bone
 Stimulates the PTH-dependent reabsorption
Stimulates the PTH-dependent reabsorption
of calcium in the distal renal tubules
of calcium in the distal renal tubules
 1,25(OH)
1,25(OH)2
2 D, the biologically active form of
D, the biologically active form of
vitamin D, is best regarded as a steroid
vitamin D, is best regarded as a steroid
hormone which acts by binding to a high-
hormone which acts by binding to a high-
affinity receptor
affinity receptor
pathology-environmentalnutritionaldisease-101201075746-phpapp02.pdf
Vitamin D Deficiency
Vitamin D Deficiency
 Holick et al (2005) reported the results of a
Holick et al (2005) reported the results of a
large North American study that assessed
large North American study that assessed
the vitamin D status of postmenopausal
the vitamin D status of postmenopausal
women receiving therapy to treat or prevent
women receiving therapy to treat or prevent
osteoporosis
osteoporosis
 52% of 1536 women had inadequate
52% of 1536 women had inadequate
[25(OH)D] levels (<30 ng/mL)
[25(OH)D] levels (<30 ng/mL)
 36% and 18% had levels less than 25 and 20
36% and 18% had levels less than 25 and 20
ng/mL, respectively.
ng/mL, respectively.
Holick MF et al: J Clin Endocrinol Metab 90:3215, 2005
pathology-environmentalnutritionaldisease-101201075746-phpapp02.pdf
Vitamin D Deficiency
Vitamin D Deficiency
 Childhood: Rickets
Childhood: Rickets
 epiphyses are open
epiphyses are open
 cartilage overgrowth
cartilage overgrowth
 Adults:
Adults: osteomalacia
osteomalacia
 bone matrix is not calcified
bone matrix is not calcified
 vs osteoporosis (matrix reduced)
vs osteoporosis (matrix reduced)
ADULTS
CHILDREN
(RICKETS)
OSTEOMALACIA
1) Bone fractures that happen
with very little injury
2) Muscle weakness
3) Widespread bone pain,
especially in the hips
Vitamin K
Vitamin K
 Clotting factors VII, IX, and X and
Clotting factors VII, IX, and X and
prothrombin (II) all require carboxylation of
prothrombin (II) all require carboxylation of
glutamate residues for functional activity
glutamate residues for functional activity
 anticoagulant coumadin is a Vitamin K
anticoagulant coumadin is a Vitamin K
antagonist
antagonist
 Activation of anticoagulant proteins C and S
Activation of anticoagulant proteins C and S
also requires glutamate carboxylation
also requires glutamate carboxylation
 Sources
Sources
 endogenous intestinal bacterial flora
endogenous intestinal bacterial flora
 diet
diet
Vitamin K Deficiency
Vitamin K Deficiency
 Causes
Causes
 fat malabsorption
fat malabsorption
 reduced gut bacterial flora
reduced gut bacterial flora
 administration of wide specturm antibiotics
administration of wide specturm antibiotics
 neonatal period before gut is colonized
neonatal period before gut is colonized
 liver disease with reduced recycling of vitamin K
liver disease with reduced recycling of vitamin K
 Effects of vitamin K deficiency
Effects of vitamin K deficiency
 bleeding diathesis
bleeding diathesis
 estimated 3% prevalence of vitamin K-
estimated 3% prevalence of vitamin K-
dependent bleeding diathesis among neonates
dependent bleeding diathesis among neonates
warrants routine prophylactic vitamin K therapy
warrants routine prophylactic vitamin K therapy
for all newborns
for all newborns

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pathology-environmentalnutritionaldisease-101201075746-phpapp02.pdf

  • 2. Environmental and Environmental and Nutritional Pathology Nutritional Pathology  Environment and Disease Environment and Disease  Common Exposures Common Exposures  Environmental Environmental  Occupational Occupational  Nutrition Nutrition and Disease and Disease
  • 3. Reported Occupational Diseases Reported Occupational Diseases Disease Disease Number Number Percentage Percentage Repeated trauma Repeated trauma 276,600 276,600 64 64 Skin disorders Skin disorders 57,900 57,900 13 13 Lung conditions due to Lung conditions due to toxic exposures toxic exposures 20,300 20,300 5 5 Physical injury Physical injury 16,600 16,600 4 4 Poisoning Poisoning 5,100 5,100 1 1 Lung disease due to Lung disease due to dusts dusts 2,900 2,900 1 1 All other illnesses All other illnesses 50,600 50,600 12 12 Total Total 430,000 430,000 100 100
  • 4. Mechanisms of Toxicity Mechanisms of Toxicity  Threshold effect Threshold effect  Absorption at portals of entry Absorption at portals of entry  ingestion ingestion  inhalation inhalation  skin contact skin contact  Distribution within the body Distribution within the body  Metabolism and Excretion Metabolism and Excretion  Toxic effects Toxic effects
  • 5. Xenobiotic Mechanisms  Phase I Reactions (Smooth ER), makes them less lipophilic by adding a direct polar group  Cytochrome P-450-dependent monooxygenase system  Flavin-containing monooxygenase system  Peroxidase-dependent cooxidation  Phase II Reactions, combines them with other polar substances  Glucuronidation  Biomethylation  Glutathione conjugation
  • 7. Contents of Toxic Waste Dumps Acetone DDT, DDE, DDD Aldrin/Dieldrin 1,1 and 1,2-Dichloroethane Arsenic Lead Barium Mercury Benzene Methylene chloride 2-Butanone Nickel Cadmium Pentachlorophenol Carbon tetrachloride Polychlorinated biphenyls Chlordane Tri- and Tetrachloroethylene Chloroform Toluene Chromium Vinyl Chloride Cyanide Zinc
  • 9. Common Common Exposures Exposures  Personal Personal  Medications Medications  Outdoor Air Pollution Outdoor Air Pollution  Indoor Air Pollution Indoor Air Pollution  Industrial Exposures Industrial Exposures  Agricultural Hazards Agricultural Hazards  Natural Toxins Natural Toxins  Radiation Injury Radiation Injury  Physical Injury Physical Injury
  • 10. Tobacco Tobacco  440,000 premature deaths/year in USA 440,000 premature deaths/year in USA  cancer cancer  cardiovascular disease cardiovascular disease  respiratory disease respiratory disease  cerebrovascular disease cerebrovascular disease  $150 billion in health related costs $150 billion in health related costs By far By far the most preventable cause the most preventable cause of death in the United States of death in the United States
  • 11. Tobacco and Cancer 70% of all lung cancers 30% of all cancers
  • 12. Organ-Specific Carcinogens in Tobacco Smoke Organ Carcinogen Lung, larynx Polycyclic aromatic hydrocarbons 4-(Methylnitrosoamino)-1-(3-pyridyl)-1-buta-none (NNK) Polonium 210 Esophagus N'-Nitrosonornicotine (NNN) Pancreas NNK (?) Bladder 4-Aminobiphenyl, 2-naphthylamine Oral cavity (smoking) Polycyclic aromatic hydrocarbons, NNK, NNN Oral cavity (snuff) NNK, NNN, polonium 210 Data from Szczesny LB, Holbrook JH: Cigarette smoking. In Rom WH (ed): Environmental and Occupational Medicine, 2nd ed. Boston, Little, Brown, 1992, p. 1211.
  • 13. Relative Risks for Current Smokers of Cigarettes Relative Risks for Current Smokers of Cigarettes Disease or Condition Males Males Females Females Coronary heart disease Coronary heart disease Age 35–64 Age 35–64 2.8 2.8 3.1 3.1 Age ≥ 65 Age ≥ 65 1.5 1.5 1.6 1.6 Cerebrovascular lesions Cerebrovascular lesions Age 35–64 Age 35–64 3.3 3.3 4 4 Age ≥ 65 Age ≥ 65 1.6 1.6 1.5 1.5 Aortic aneurysm Aortic aneurysm 6.2 6.2 7.1 7.1 Chronic airways obstruction Chronic airways obstruction 10.6 10.6 13.1 13.1 Cancer Cancer Lip, oral cavity, pharynx Lip, oral cavity, pharynx 10.9 10.9 5.1 5.1 Esophagus Esophagus 6.8 6.8 7.8 7.8 Stomach Stomach 2 2 1.4 1.4 Pancreas Pancreas 2.3 2.3 2.3 2.3 Larynx Larynx 14.6 14.6 13 13 Lung Lung 23.3 23.3 12.7 12.7 Cervix Cervix 1.6 1.6 Kidney Kidney 2.7 2.7 1.3 1.3 Bladder, other urinary organs Bladder, other urinary organs 3.3 3.3 2.2 2.2
  • 14. Cigarettes And The Workplace Cigarettes And The Workplace  Similar to asbestos exposure, cigarette smoke is Similar to asbestos exposure, cigarette smoke is synergistic with radon decay products in causing synergistic with radon decay products in causing lung cancer lung cancer  Cigarette smoke exacerbates bronchitis, asthma, Cigarette smoke exacerbates bronchitis, asthma, and pneumoconiosis associated with exposure and pneumoconiosis associated with exposure to silica, coal dust, grain dust, cotton dust, and to silica, coal dust, grain dust, cotton dust, and welding fumes welding fumes
  • 15. Alcohol Alcohol  15 to 20 million alcoholics in the USA 15 to 20 million alcoholics in the USA  100,000 deaths/year due to alcohol 100,000 deaths/year due to alcohol abuse abuse  Economic losses of $100 to $130 Economic losses of $100 to $130 billion/year billion/year  One to two drinks/day reduces One to two drinks/day reduces incidence of coronary artery disease* incidence of coronary artery disease* * What kind of person would put this kind of bullet on a powerpoint? A. Drinker? B) Non-Drinker?
  • 17. Effects of Blood Alcohol Levels in the Absence of Tolerance Effects of Blood Alcohol Levels in the Absence of Tolerance Blood Level, mg/dL Blood Level, mg/dL Usual Effect Usual Effect 20 20 Decreased inhibitions, a slight Decreased inhibitions, a slight feeling of intoxication feeling of intoxication 80 80 Decrease in complex cognitive Decrease in complex cognitive functions and motor performance functions and motor performance 200 200 Obvious slurred speech, motor Obvious slurred speech, motor incoordination, irritability, and incoordination, irritability, and poor judgment poor judgment 300 300 Light coma and depressed vital Light coma and depressed vital signs signs 400 400 Death Death Harrison Internal Med, 16th Ed
  • 18. Metabolism Of Ethanol Metabolism Of Ethanol ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase 20% 80%
  • 21. Widmark Equation Widmark Equation  C = A / (W * r) C = A / (W * r)  C = concentration of EtOH in mg/dl C = concentration of EtOH in mg/dl  A = mass of alcohol ingested in grams A = mass of alcohol ingested in grams  density of ethanol = 0.8 density of ethanol = 0.8  W = body weight in grams W = body weight in grams  r = Widmark distribution for ethanol r = Widmark distribution for ethanol  0.55 mL/ g body weight for females 0.55 mL/ g body weight for females  0.68 mL / g body weight for males 0.68 mL / g body weight for males  Elimination of ethanol = 0.015%/h (15mg/dl/h) Elimination of ethanol = 0.015%/h (15mg/dl/h)  zero order kinetics zero order kinetics  Medical measurements use mg/dl in plasma, whereas Medical measurements use mg/dl in plasma, whereas legal definitions use percentage (mass/volume) in whole legal definitions use percentage (mass/volume) in whole blood blood  to estimate the alcohol level in whole blood using the alcohol to estimate the alcohol level in whole blood using the alcohol level in blood plasma, divide by 1.16 level in blood plasma, divide by 1.16
  • 22. Alcohol and the Liver Alcohol and the Liver  Fatty Change Fatty Change  present in over 90% of binge and chronic drinkers present in over 90% of binge and chronic drinkers  liver is enlarged but patient is asymptomatic liver is enlarged but patient is asymptomatic  changes are reversible with cessation of drinking changes are reversible with cessation of drinking  macrosteatosis w/o inflammation or necrosis macrosteatosis w/o inflammation or necrosis  Alcohol hepatitis Alcohol hepatitis  only between 10 - 15% of alcoholics will develop only between 10 - 15% of alcoholics will develop alcoholic hepatitis alcoholic hepatitis  may have systemic symptoms and jaundice may have systemic symptoms and jaundice  hepatocellular necrosis with Mallory bodies and PMNs hepatocellular necrosis with Mallory bodies and PMNs (central hyaline sclerosis) (central hyaline sclerosis)  thought to be a precursor of cirrhosis thought to be a precursor of cirrhosis  Alcoholic cirrhosis Alcoholic cirrhosis  shrunken nodular liver with uniform small nodules shrunken nodular liver with uniform small nodules (micronodular cirrhosis) (micronodular cirrhosis)
  • 23. Fatty Change Biochemistry Fatty Change Biochemistry  Catabolism of fat by peripheral tissues is Catabolism of fat by peripheral tissues is increased, and there is increased delivery of increased, and there is increased delivery of free fatty acids to the liver free fatty acids to the liver  An excess of NADH over NAD stimulates An excess of NADH over NAD stimulates lipid biosynthesis lipid biosynthesis  Oxidation of fatty acids by mitochondria is Oxidation of fatty acids by mitochondria is decreased decreased  Acetaldehyde forms adducts with tubulin and Acetaldehyde forms adducts with tubulin and impairs function of microtubules, resulting in impairs function of microtubules, resulting in decreased transport of lipoproteins from the decreased transport of lipoproteins from the liver liver
  • 28. Neurologic Manifestations of Alcoholism Neurologic Manifestations of Alcoholism  Wernicke syndrome Wernicke syndrome  confusion, ataxia, and diplopia from confusion, ataxia, and diplopia from ophthalmoplegia ophthalmoplegia  damage to mammillary bodies, cerebellum and damage to mammillary bodies, cerebellum and periaqueductal gray matter periaqueductal gray matter of the midbrain of the midbrain  due to thiamine deficiency due to thiamine deficiency  may respond to prompt thiamine replacement may respond to prompt thiamine replacement  Korsakov syndrome Korsakov syndrome  memory loss and confabulation memory loss and confabulation  results from thiamine deficiency and direct results from thiamine deficiency and direct toxicity toxicity
  • 30. Mechanisms of Disease Caused by Ethanol Abuse Organ System Lesion Mechanism Liver Fatty change Toxicity Acute hepatitis Alcoholic cirrhosis Nervous system Wernicke syndrome Thiamine deficiency Korsakoff syndrome Toxicity and thiamine deficiency Cerebellar degeneration Nutritional deficiency Peripheral neuropathy Thiamine deficiency Cardiovascular system Cardiomyopathy Toxicity Hypertension Vasopressor
  • 31. Mechanisms of Disease Caused by Ethanol Abuse Organ System Lesion Mechanism Gastrointestinal tract Gastritis Toxicity Pancreatitis Toxicity Skeletal muscle Rhabdomyolysis Toxicity Reproductive system Testicular atrophy ? Spontaneous abortion ? Fetal alcohol syndrome Growth retardation Toxicity Mental retardation Birth defects
  • 32. Therapeutic Drugs Therapeutic Drugs (Medications) (Medications)  Oral Contraceptives (BCPs) Oral Contraceptives (BCPs)  Hormone Replacement Therapy (HRT) Hormone Replacement Therapy (HRT)  Acetaminophen Acetaminophen  Aspirin Aspirin
  • 33. Oral Contraceptives (BCPs) Oral Contraceptives (BCPs)  Breast cancer and other cancers Breast cancer and other cancers  no increase in breast cancer no increase in breast cancer  decrease endometrial and ovarian cancers decrease endometrial and ovarian cancers  increase in cervical cancer (?lifestyle induced) increase in cervical cancer (?lifestyle induced)  Thromboembolic events Thromboembolic events  DVT and Pulmonary Embolism increased DVT and Pulmonary Embolism increased  adds to other risk factors (e.g. Factor V Leiden) adds to other risk factors (e.g. Factor V Leiden)  Cardiovascular disease Cardiovascular disease  with current low estrogen pills, risk of MI and with current low estrogen pills, risk of MI and atherosclerosis not increased in non-smoking women < 45 y atherosclerosis not increased in non-smoking women < 45 y  ischemic stroke increased regardless of age or smoking ischemic stroke increased regardless of age or smoking  Liver tumors Liver tumors  benign hepatic adenomas benign hepatic adenomas  older women with prolonged use older women with prolonged use  may rupture and cause intra-abdominal bleeding may rupture and cause intra-abdominal bleeding
  • 34. Hormone Replacement Therapy (HRT) Hormone Replacement Therapy (HRT)  Cancer Cancer  in women with a uterus combined estrogen and in women with a uterus combined estrogen and progestin Rx necessary to reduce endometrial cancer progestin Rx necessary to reduce endometrial cancer  WHI showed increased risk of breast cancer in women WHI showed increased risk of breast cancer in women who used HRT combined therapy for 5 years who used HRT combined therapy for 5 years  Thromboembolic events Thromboembolic events  elevated approximated twofold in HRT users, especially elevated approximated twofold in HRT users, especially within the first 2 years within the first 2 years  Cardiovascular disease Cardiovascular disease  WHI reported 29% increased risk of myocardial WHI reported 29% increased risk of myocardial infarction, especially during the first year of combined infarction, especially during the first year of combined HRT use HRT use
  • 35. Acetaminophen (Tylenol) Acetaminophen (Tylenol)  Does not affect cyclooxygenase so bleeding Does not affect cyclooxygenase so bleeding associated with aspirin does not occur associated with aspirin does not occur  Has analgesic and antipyretic actions but no Has analgesic and antipyretic actions but no anti-inflammatory action anti-inflammatory action  Large doses may produce hepatic necrosis Large doses may produce hepatic necrosis  patients should not exceed recommended dose patients should not exceed recommended dose (4 grams/day) (4 grams/day)  toxic dose in adults is 15 to 25 gm toxic dose in adults is 15 to 25 gm  dose should be reduced in children with fever or dose should be reduced in children with fever or dehydration dehydration
  • 36. Aspirin Aspirin  Overdose Overdose  respiratory alkalosis followed by metabolic acidosis that respiratory alkalosis followed by metabolic acidosis that may be fatal may be fatal  Chronic aspirin toxicity (salicylism) Chronic aspirin toxicity (salicylism)  headache, dizziness, ringing in the ears (tinnitus), headache, dizziness, ringing in the ears (tinnitus), mental confusion, drowsiness, nausea, vomiting, and mental confusion, drowsiness, nausea, vomiting, and diarrhea diarrhea  Inhibits cyclooxygenase (COX 1 & 2) Inhibits cyclooxygenase (COX 1 & 2)  Erosive gastritis is a major cause of GI bleeding Erosive gastritis is a major cause of GI bleeding  May be implicated in Reye syndrome (fatty liver May be implicated in Reye syndrome (fatty liver with encephalopathy) in children < 15 years old, with encephalopathy) in children < 15 years old, especially with influenza and chicken pox especially with influenza and chicken pox
  • 37. Cox-1 and Cox-2 Inhibitors Cox-1 and Cox-2 Inhibitors  Cyclooxygenase 1 Cyclooxygenase 1  constitutively expressed and active in the constitutively expressed and active in the normal platelet (thromboxane A2) normal platelet (thromboxane A2)  involved in synthesis of gastro-protective involved in synthesis of gastro-protective prostaglandins prostaglandins  Cyclooxygenase 2 Cyclooxygenase 2  induced, especially in inflamed tissue induced, especially in inflamed tissue  in vessel wall produces prostacyclin (PGI in vessel wall produces prostacyclin (PGI2 2) )  Aspirin and other nonselective NSAIDS Aspirin and other nonselective NSAIDS inhibit both COX-1 and COX-2 inhibit both COX-1 and COX-2
  • 38. Figure 2-16 Generation of arachidonic acid metabolites and their roles in inflammation. The molecular targets of action of some anti-inflammatory drugs are indicated by a red X. COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 15 August 2005 06:35 PM) © 2005 Elsevier
  • 39. Indoor Air Pollution Indoor Air Pollution  Carbon Monoxide CO Carbon Monoxide CO  Nitrogen Dioxide NO Nitrogen Dioxide NO2 2  Wood Smoke Wood Smoke  Formaldehyde Formaldehyde Radon Radon  Manufactured Mineral Fibers Manufactured Mineral Fibers  Bioaerosols Bioaerosols
  • 40. Radon Radon  Radon is a radioactive gas and a decay Radon is a radioactive gas and a decay product of uranium product of uranium  It is widely distributed in the soil and is It is widely distributed in the soil and is prevalent in homes (especially in basements) prevalent in homes (especially in basements)  Radon decay products are alpha emitters Radon decay products are alpha emitters  10% of US homes have levels associated with 10% of US homes have levels associated with an increased risk of lung cancer and an an increased risk of lung cancer and an estimated 10,000 lung cancers per year in the estimated 10,000 lung cancers per year in the United States are due to radon. Smoking United States are due to radon. Smoking elevates risk. elevates risk.  Proper venting reduces the exposure Proper venting reduces the exposure
  • 41. Lead Lead  lead is classified as a heavy metal (others lead is classified as a heavy metal (others include mercury, arsenic, and cadmium) include mercury, arsenic, and cadmium)  Source of exposure Source of exposure  lead paint lead paint  lead solder in plumbing (older houses) lead solder in plumbing (older houses)  lead-glazed ceramics lead-glazed ceramics  industrial exposure industrial exposure  Route of exposure Route of exposure  inhalation with industrial exposure inhalation with industrial exposure  ingestion with household exposure ingestion with household exposure
  • 42. Lead Distribution and Excretion Lead Distribution and Excretion  Lead is a divalent cation that is taken up by Lead is a divalent cation that is taken up by bone and developing teeth in children (80% bone and developing teeth in children (80% to 85%) to 85%)  Half-life of lead in bone is 30 years Half-life of lead in bone is 30 years  Blood accumulates 5% to 10% of lead, but Blood accumulates 5% to 10% of lead, but lead is rapidly cleared from the blood lead is rapidly cleared from the blood  lead in blood indicates recent exposure lead in blood indicates recent exposure  blood level does not allow the determination of blood level does not allow the determination of total body burden total body burden  Remainder is distributed in the soft tissues Remainder is distributed in the soft tissues  Excretion is via the kidneys Excretion is via the kidneys
  • 43. Effects of Lead Effects of Lead  High affinity for sulfhydryl groups High affinity for sulfhydryl groups  inhibition of heme biosynthesis with hypochromic inhibition of heme biosynthesis with hypochromic anemia and basophillic stippling of erythrocytes anemia and basophillic stippling of erythrocytes  Competition with calcium ions Competition with calcium ions  As a divalent cation, lead competes with calcium and is As a divalent cation, lead competes with calcium and is stored in bone. stored in bone.  It also interferes with nerve transmission and brain It also interferes with nerve transmission and brain development. development.  Inhibition of membrane-associated enzymes Inhibition of membrane-associated enzymes  Lead inhibits 5'-nucleotidase activity and sodium- Lead inhibits 5'-nucleotidase activity and sodium- potassium ion pumps, leading to decreased survival of potassium ion pumps, leading to decreased survival of red blood cells (hemolysis), renal damage, and red blood cells (hemolysis), renal damage, and hypertension. hypertension.
  • 47. “RADIATION”  T ½  Curie vs. Becqerel  IONIZING vs. NON-IONIZING  PARTICULATE vs. NON-PARTICULATE (Photons)  ENERGY: Kev, Mev (~Wavelength)  Linear Energy Transfer (LET), Relative Biologic Effect (RBE)  LD50@60d
  • 48. This is the single most RADIOSENSITIVE CELL In your body
  • 49. Radiation Dosimetry Radiation Dosimetry  Roentgen: Roentgen: unit of charge produced by x-rays or gamma unit of charge produced by x-rays or gamma rays that ionize a specific volume of air rays that ionize a specific volume of air  RAD RAD (radiation absorbed dose): (radiation absorbed dose): the dose of radiation the dose of radiation that will produce absorption of 100 ergs of energy per gram that will produce absorption of 100 ergs of energy per gram of tissue; 1 gm of tissue exposed to 1 roentgen of gamma of tissue; 1 gm of tissue exposed to 1 roentgen of gamma rays is equal to 93 ergs rays is equal to 93 ergs  Gray Gray (Gy): the dose of radiation that will produce (Gy): the dose of radiation that will produce absorption of 1 joule of energy per kilogram of tissue; 1 Gy absorption of 1 joule of energy per kilogram of tissue; 1 Gy corresponds to 100 rad (SI unit for absorbed dose) corresponds to 100 rad (SI unit for absorbed dose)  REM REM (radiation equivalent man): (radiation equivalent man): the dose of radiation that the dose of radiation that causes a biologic effect equivalent to 1 rad of x-rays or causes a biologic effect equivalent to 1 rad of x-rays or gamma rays gamma rays  Sievert Sievert (Sv): the dose of radiation that causes a biologic (Sv): the dose of radiation that causes a biologic effect equivalent to 1 Gy of x-rays or gamma rays; 1 Sv effect equivalent to 1 Gy of x-rays or gamma rays; 1 Sv corresponds to 100 rem (SI unit) corresponds to 100 rem (SI unit)
  • 50. Acute Effects of Ionizing Radiation Acute Effects of Ionizing Radiation  Free radical generation Free radical generation  Ionizing radiation + H Ionizing radiation + H2 20 → H 0 → H3 30 0+ + + OH· + OH·  DNA Damage DNA Damage  double-stranded DNA breaks needed to kill cell double-stranded DNA breaks needed to kill cell (mammalian cells can repair single stranded (mammalian cells can repair single stranded breaks) breaks)  cross-linking of DNA strands, cleavage of sugar- cross-linking of DNA strands, cleavage of sugar- phosphate bonds phosphate bonds  Tumor-suppressor gene Tumor-suppressor gene p53 p53 activation activation  cell cycle arrest in presence of damaged DNA cell cycle arrest in presence of damaged DNA  repair of DNA damage or apoptosis repair of DNA damage or apoptosis
  • 51. Acute Whole Body Radiation Acute Whole Body Radiation  LD50 @ 6 wks 2.5 to 4.0 Gy (250 to 400 rad) LD50 @ 6 wks 2.5 to 4.0 Gy (250 to 400 rad)  Hematopoietic Hematopoietic  200–600 REM 200–600 REM  Maximum neutrophil and platelet depression in 2 wk Maximum neutrophil and platelet depression in 2 wk  Gastrointestinal Gastrointestinal  600–1000 REM 600–1000 REM  Nausea, vomiting, diarrhea Nausea, vomiting, diarrhea  Hemorrhage and infection in 1–3 wk Hemorrhage and infection in 1–3 wk  Central nervous system Central nervous system  >1000 REM >1000 REM  Intractable nausea and vomiting Intractable nausea and vomiting  Confusion, somnolence, convulsions Confusion, somnolence, convulsions  death in 14–36 hr death in 14–36 hr
  • 52. Therapeutic Radiation Therapeutic Radiation  External radiation is delivered to malignant External radiation is delivered to malignant neoplasms at fractionated doses up to 40 to neoplasms at fractionated doses up to 40 to 70 Gy (4000 to 7000 rad), with shielding of 70 Gy (4000 to 7000 rad), with shielding of adjacent normal tissues adjacent normal tissues  Therapeutic radiation alone seems to add Therapeutic radiation alone seems to add little risk of AML but can increase the risk in little risk of AML but can increase the risk in people exposed to alkylating agents people exposed to alkylating agents  Fatigue, nausea and vomiting frequent Fatigue, nausea and vomiting frequent  Bone marrow suppression may occur Bone marrow suppression may occur especially with chest or abdominal radiation especially with chest or abdominal radiation
  • 53. Delayed Radiation Injury Delayed Radiation Injury  Carcinogenesis (atom bomb survivors) Carcinogenesis (atom bomb survivors)  myeloid leukemias peak 5 to 7 years after exposure myeloid leukemias peak 5 to 7 years after exposure  breast and thyroid cancers may show greater latency breast and thyroid cancers may show greater latency  no germline mutations noted in progeny of survivors no germline mutations noted in progeny of survivors  Vascular effects Vascular effects  endothelial necrosis followed by intimal and medial endothelial necrosis followed by intimal and medial fibrosis fibrosis  capillaries may become thrombosed and obliterated or capillaries may become thrombosed and obliterated or ectatic ectatic  Parenchymal atrophy and fibrosis Parenchymal atrophy and fibrosis
  • 54. Radiation effects on TISSUE  ACUTE (vasculitis, possibly “fibrinoid” necrosis)  CHRONIC (fibrosis)
  • 55. Physical Injury Physical Injury  Abrasion Abrasion  basically a scrape basically a scrape  superficial epidermis is torn off by friction or force superficial epidermis is torn off by friction or force  regeneration without scarring usually occurs regeneration without scarring usually occurs  Laceration vs. Incision Laceration vs. Incision  a laceration is an irregular tear in the skin produced by a laceration is an irregular tear in the skin produced by overstretching. The wound margins are frequently hemorrhagic overstretching. The wound margins are frequently hemorrhagic and traumatized and traumatized  an incision is made by a sharp cutting object. The margins of an incision is made by a sharp cutting object. The margins of the incision are usually relatively clean the incision are usually relatively clean  Contusion Contusion  an injury caused by a blunt force that damages small blood an injury caused by a blunt force that damages small blood vessels and causes interstitial bleeding, usually without vessels and causes interstitial bleeding, usually without disruption of the continuity of the tissue ( disruption of the continuity of the tissue (cf cf ecchymosis) ecchymosis)
  • 57. Adult Mortality Rates in the United States, Ages 25–44, in 1998 Rate per 100,000 population Cause Hispanic Black White Unintentional injuries 33.4 40.1 31.6 Cancer 16.8 38.0 25.3 Homicide 13.1 36.2 4.7 Human immunodeficiency virus 12.1 43.3 4.8 Heart disease 10.3 43.5 18.3 Suicide 7.8 — 17.0 Total 130.2 303.7 139.4 Data from CDC Fact Book, 2000/2001, Department of Health and Human Services, Centers for Disease Control and Prevention.
  • 58. GUNSHOT WOUND  Entrance Vs. Exit  Far range Vs. Close range
  • 59. BURNS  1st , 2nd , 3rd , 4th “Degree”  FULL vs. PARTIAL Thickness  Survival  PERCENT of body using the rule of NINES  DEGREE (i.e., Depth)  Respiratory Tract Involvement  AGE  Speed of access to Burn Unit  Immune System (Pseudomonas, S. aureus, Candida)
  • 60. HYPER-THERMIA  HEAT  CRAMPS: Electrolyte loss via sweat  EXHAUSTION: Water depletion and lack of cardiovascular compensation  “STROKE”: Extensive peripheral vasodilatation, i.e., “shocky”, very serious, T>106º, over 110º have been reported, high mortality.
  • 61. HYPO-THERMIA Often in setting of homelessness or alcoholism or both < 90º often fatal, assoc. w.  BRADYCARDIA  ATRIAL FIBRILLATION
  • 62. LIGHTNING/ELECTRICAL  ELECTRIC DISTURBANCES  NEURAL  EKG  THERMAL INJURY, depends upon a particular tissue’s RESISTANCE to electrical flow  “LIGHTNING” MARKS
  • 63. ATMOSPHERIC PRESSURE Altitude Illness Blast Injuries Decompression Injuries
  • 64. ALTITUDE ILLNESS  Caused by LOW Oxygen Tension  HIGH ALTITUDES (>4000 m)  OBTUNDATION  INCREASED CAPILLARY PERMEABILITY  ACUTE PULMONARY EDEMA (HAPE) Q: What is the name of the base camp at Mt. Everest A: Pulmonary Edema
  • 65. BLAST INJURIES  RELATED TO RAPID ATMOSPHERIC PRESSURE CHANGES  LUNGS  VISCERA, especially GAS filled viscera  Rupture, Hemorrhage, etc.  IMMERSION BLAST also possible, causing more of a total body compression syndrome
  • 66. DECOMPRESSION  Related to GAS SOLUBILITY in divers ascending rapidly, especially the more NON-SOLUBLE gasses, like NITROGEN, and, to a lesser extent, XENON  AIR EMBOLISM is the common pathology  ACUTE:  “BENDS” (peri-articular), acute  “CHOKES” (lungs), acute  “STAGGERS” (inner ear), acute  CHRONIC:  ASEPTIC NECROSIS: humeri, femurs
  • 67. NUTRITION NUTRITION & DISEASE & DISEASE  Food Safety Food Safety  Additives Additives  Contaminants Contaminants  Nutritional Deficiencies Nutritional Deficiencies  Vitamins Vitamins  Minerals Minerals  Obesity Obesity  Diet and Disease Diet and Disease  Chemoprevention of Cancer Chemoprevention of Cancer
  • 68. Vitamin Deficiency and Excess Vitamin Deficiency and Excess  Fat soluble vitamins Fat soluble vitamins  A, D, E, K A, D, E, K  readily stored in body fat readily stored in body fat  poorly absorbed in digestive disorders involving poorly absorbed in digestive disorders involving malabsorbtion of fat malabsorbtion of fat  Water soluble vitamins Water soluble vitamins  remaining vitamins remaining vitamins  readily excreted in urine readily excreted in urine  Vitamin stores Vitamin stores  vitamins B-12 and A: stores sufficient for 1 year vitamins B-12 and A: stores sufficient for 1 year  folate and thiamine may become depleted folate and thiamine may become depleted within weeks when eating a deficient diet within weeks when eating a deficient diet
  • 69. Vitamin D Metabolism Vitamin D Metabolism  Absorption of vitamin D in the gut or Absorption of vitamin D in the gut or synthesis from precursors in the skin synthesis from precursors in the skin  Binding to a plasma α1 -globulin (D- Binding to a plasma α1 -globulin (D- binding protein) and transport to liver binding protein) and transport to liver  Conversion to 25-hydroxyvitamin D, Conversion to 25-hydroxyvitamin D, 25(OH)D (calcidol) by 25-hydroxylase in 25(OH)D (calcidol) by 25-hydroxylase in the liver the liver  Conversion of 25(OH)D to 1,25(OH) Conversion of 25(OH)D to 1,25(OH)2 2 D D (calcitrol, Vitamin D3) by α1-hydroxylase (calcitrol, Vitamin D3) by α1-hydroxylase in the kidney; in the kidney; biologically this is the most biologically this is the most active form of vitamin D active form of vitamin D. .
  • 70. Functions of Vitamin D Functions of Vitamin D  Stimulates intestinal absorption of calcium Stimulates intestinal absorption of calcium and phosphorus and phosphorus  Collaborates with PTH in the mobilization Collaborates with PTH in the mobilization of calcium from bone of calcium from bone  Stimulates the PTH-dependent reabsorption Stimulates the PTH-dependent reabsorption of calcium in the distal renal tubules of calcium in the distal renal tubules  1,25(OH) 1,25(OH)2 2 D, the biologically active form of D, the biologically active form of vitamin D, is best regarded as a steroid vitamin D, is best regarded as a steroid hormone which acts by binding to a high- hormone which acts by binding to a high- affinity receptor affinity receptor
  • 72. Vitamin D Deficiency Vitamin D Deficiency  Holick et al (2005) reported the results of a Holick et al (2005) reported the results of a large North American study that assessed large North American study that assessed the vitamin D status of postmenopausal the vitamin D status of postmenopausal women receiving therapy to treat or prevent women receiving therapy to treat or prevent osteoporosis osteoporosis  52% of 1536 women had inadequate 52% of 1536 women had inadequate [25(OH)D] levels (<30 ng/mL) [25(OH)D] levels (<30 ng/mL)  36% and 18% had levels less than 25 and 20 36% and 18% had levels less than 25 and 20 ng/mL, respectively. ng/mL, respectively. Holick MF et al: J Clin Endocrinol Metab 90:3215, 2005
  • 74. Vitamin D Deficiency Vitamin D Deficiency  Childhood: Rickets Childhood: Rickets  epiphyses are open epiphyses are open  cartilage overgrowth cartilage overgrowth  Adults: Adults: osteomalacia osteomalacia  bone matrix is not calcified bone matrix is not calcified  vs osteoporosis (matrix reduced) vs osteoporosis (matrix reduced) ADULTS CHILDREN (RICKETS) OSTEOMALACIA 1) Bone fractures that happen with very little injury 2) Muscle weakness 3) Widespread bone pain, especially in the hips
  • 75. Vitamin K Vitamin K  Clotting factors VII, IX, and X and Clotting factors VII, IX, and X and prothrombin (II) all require carboxylation of prothrombin (II) all require carboxylation of glutamate residues for functional activity glutamate residues for functional activity  anticoagulant coumadin is a Vitamin K anticoagulant coumadin is a Vitamin K antagonist antagonist  Activation of anticoagulant proteins C and S Activation of anticoagulant proteins C and S also requires glutamate carboxylation also requires glutamate carboxylation  Sources Sources  endogenous intestinal bacterial flora endogenous intestinal bacterial flora  diet diet
  • 76. Vitamin K Deficiency Vitamin K Deficiency  Causes Causes  fat malabsorption fat malabsorption  reduced gut bacterial flora reduced gut bacterial flora  administration of wide specturm antibiotics administration of wide specturm antibiotics  neonatal period before gut is colonized neonatal period before gut is colonized  liver disease with reduced recycling of vitamin K liver disease with reduced recycling of vitamin K  Effects of vitamin K deficiency Effects of vitamin K deficiency  bleeding diathesis bleeding diathesis  estimated 3% prevalence of vitamin K- estimated 3% prevalence of vitamin K- dependent bleeding diathesis among neonates dependent bleeding diathesis among neonates warrants routine prophylactic vitamin K therapy warrants routine prophylactic vitamin K therapy for all newborns for all newborns