ENVIRONMENTAL

& NUTRITIONAL PATHOLOGY

Environmental and Nutritional Pathology

Environment and Disease Common Exposures

Environmental Occupational

Nutrition and Disease

Reported Occupational Diseases

Disease Number Percentage

Repeated trauma Skin disorders Lung conditions due to toxic exposures Physical injury Poisoning Lung disease due to dusts All other illnesses Total

276,600 57,900 20,300

16,600 5,100 2,900 50,600 430,000

64 13 5
4 1 1 12 100

Mechanisms of Toxicity

Threshold effect Absorption at portals of entry

ingestion inhalation skin contact

Distribution within the body Metabolism and Excretion 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

Contents of Toxic Waste Dumps

Acetone Aldrin/Dieldrin Arsenic Barium DDT, DDE, DDD 1,1 and 1,2-Dichloroethane Lead Mercury

Benzene
2-Butanone Cadmium Carbon tetrachloride Chlordane

Methylene chloride
Nickel Pentachlorophenol Polychlorinated biphenyls Tri- and Tetrachloroethylene

Chloroform
Chromium

Toluene
Vinyl Chloride

Cyanide

Zinc

Dose-response Curve

Common Exposures
Personal Medications Outdoor Air Pollution Indoor Air Pollution Industrial Exposures Agricultural Hazards Natural Toxins Radiation Injury Physical Injury

Tobacco
440,000
cancer cardiovascular

premature deaths/year in USA

disease respiratory disease cerebrovascular disease

$150

billion in health related costs

By

far the most preventable cause

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
Lung, larynx

Carcinogen
Polycyclic aromatic hydrocarbons

4-(Methylnitrosoamino)-1-(3-pyridyl)-1-buta-none (NNK)
Polonium 210 Esophagus Pancreas Bladder Oral cavity (smoking) Oral cavity (snuff) N'-Nitrosonornicotine (NNN) NNK (?) 4-Aminobiphenyl, 2-naphthylamine Polycyclic aromatic hydrocarbons, NNK, NNN 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 Disease or Condition Males 2.8 1.5 Females 3.1 1.6

Coronary heart disease

Age 3564 Age 65 Cerebrovascular lesions Age 3564 Age 65 Aortic aneurysm Chronic airways obstruction Cancer Lip, oral cavity, pharynx 10.9 5.1

3.3
1.6 6.2 10.6

4
1.5 7.1

13.1

Esophagus
Stomach Pancreas Larynx Lung Cervix Kidney Bladder, other urinary organs

6.8
2 2.3 14.6

7.8
1.4 2.3 13 12.7 1.6

23.3
2.7 3.3

1.3 2.2

Cigarettes And The Workplace

Similar to asbestos exposure, 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

Alcohol
15 to 20 million alcoholics in the USA 100,000 deaths/year due to alcohol abuse Economic losses of $100 to $130 billion/year One to two drinks/day reduces incidence of coronary artery disease*

* What kind of
powerpoint?

person would put this kind of bullet on a

A) Drinker? B) Non-Drinker? C) Alcoholic in Denial?

Definition of Alcoholism

Effects of Blood Alcohol Levels in the Absence of Tolerance

Blood Level, mg/dL Usual Effect 20 80 200 Decreased inhibitions, a slight feeling of intoxication Decrease in complex cognitive 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

300 400

Metabolism Of Ethanol
20%

80%

ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase

LEGAL INTOXICATION

0.08%

Widmark Equation

C = A / (W * r)

C = concentration of EtOH in mg/dl A = mass of alcohol ingested in grams

density of ethanol = 0.8

W = body weight in grams r = Widmark distribution for ethanol

0.55 mL/ g body weight for females 0.68 mL / g body weight for males zero order kinetics

Elimination of ethanol = 0.015%/h (15mg/dl/h)

Medical measurements use mg/dl in plasma, whereas legal definitions use percentage (mass/volume) in whole blood

to estimate the alcohol level in whole blood using the alcohol level in blood plasma, divide by 1.16

Alcohol and the Liver

Fatty Change

present in over 90% of binge and chronic drinkers liver is enlarged but patient is asymptomatic changes are reversible with cessation of drinking macrosteatosis w/o inflammation or necrosis only between 10 - 15% of alcoholics will develop alcoholic hepatitis may have systemic symptoms and jaundice hepatocellular necrosis with Mallory bodies and PMNs (central hyaline sclerosis) thought to be a precursor of cirrhosis shrunken nodular liver with uniform small nodules (micronodular cirrhosis)

Alcohol hepatitis

Alcoholic cirrhosis

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

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 results from thiamine deficiency and direct toxicity

Mechanisms of Disease Caused by Ethanol Abuse

Organ System Liver Lesion Fatty change Mechanism Toxicity

Acute hepatitis
Alcoholic cirrhosis Nervous system Wernicke syndrome Korsakoff syndrome Thiamine deficiency Toxicity and thiamine deficiency

Cerebellar degeneration
Peripheral neuropathy Cardiovascular system Cardiomyopathy Hypertension

Nutritional deficiency
Thiamine deficiency Toxicity Vasopressor

Mechanisms of Disease Caused by Ethanol Abuse

Organ System
Gastrointestinal tract

Lesion
Gastritis Toxicity

Mechanism

Pancreatitis
Skeletal muscle Reproductive system Rhabdomyolysis Testicular atrophy Spontaneous abortion

Toxicity
Toxicity ? ?

Fetal alcohol syndrome

Growth retardation Mental retardation

Birth defects

Toxicity

Therapeutic Drugs (Medications)

Oral

Contraceptives (BCPs) Hormone Replacement Therapy (HRT) Acetaminophen Aspirin

Oral Contraceptives (BCPs)

Breast cancer and other cancers

no increase in breast cancer decrease endometrial and ovarian cancers increase in cervical cancer (?lifestyle induced) DVT and Pulmonary Embolism increased adds to other risk factors (e.g. Factor V Leiden) with current low estrogen pills, risk of MI and atherosclerosis not increased in non-smoking women < 45 y ischemic stroke increased regardless of age or smoking benign hepatic adenomas older women with prolonged use may rupture and cause intra-abdominal bleeding

Thromboembolic events

Cardiovascular disease

Liver tumors

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 for 5 years elevated approximated twofold in HRT users, especially within the first 2 years WHI reported 29% increased risk of myocardial infarction, especially during the first year of combined HRT use

Thromboembolic events

Cardiovascular disease

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 15 to 25 gm dose should be reduced in children with fever or dehydration

Aspirin

Overdose

respiratory alkalosis followed by metabolic acidosis that may be fatal headache, dizziness, ringing in the ears (tinnitus), mental confusion, drowsiness, nausea, vomiting, and diarrhea

Chronic aspirin toxicity (salicylism)

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

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

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

Carbon

Monoxide CO Nitrogen Dioxide NO2 Wood Smoke Formaldehyde

Radon
Manufactured Bioaerosols

Mineral Fibers

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

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

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

Effects of Lead

High affinity for sulfhydryl groups

inhibition of heme biosynthesis with hypochromic anemia and basophillic stippling of erythrocytes As a divalent cation, lead competes with calcium and is stored in bone. It also interferes with nerve transmission and brain development.

Competition with calcium ions

Inhibition of membrane-associated enzymes

Lead inhibits 5'-nucleotidase activity and sodiumpotassium ion pumps, leading to decreased survival of red blood cells (hemolysis), renal damage, and hypertension.

Consequences of lead exposure

T 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

RADIATION

This is the single most

RADIOSENSITIVE CELL
In your body

Radiation Dosimetry

Roentgen: unit of charge produced by x-rays or gamma

rays that ionize a specific volume of air

RAD (radiation absorbed dose): the dose of radiation

that will produce absorption of 100 ergs of energy per gram of tissue; 1 gm of tissue exposed to 1 roentgen of gamma rays is equal to 93 ergs Gray (Gy): the dose of radiation that will produce absorption of 1 joule of energy per kilogram of tissue; 1 Gy corresponds to 100 rad (SI unit for absorbed dose) REM (radiation equivalent man): the dose of radiation that causes a biologic effect equivalent to 1 rad of x-rays or gamma rays Sievert (Sv): the dose of radiation that causes a biologic effect equivalent to 1 Gy of x-rays or gamma rays; 1 Sv corresponds to 100 rem (SI unit)

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

Tumor-suppressor gene p53 activation

cell cycle arrest in presence of damaged DNA repair of DNA damage or apoptosis

Acute Whole Body Radiation

LD50 @ 6 wks 2.5 to 4.0 Gy (250 to 400 rad)

Hematopoietic

200600 REM Maximum neutrophil and platelet depression in 2 wk

6001000 REM Nausea, vomiting, diarrhea Hemorrhage and infection in 13 wk >1000 REM Intractable nausea and vomiting Confusion, somnolence, convulsions death in 1436 hr

Gastrointestinal

Central nervous system

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 AML but 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

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

Radiation effects on TISSUE

ACUTE (vasculitis, possibly fibrinoid necrosis) CHRONIC (fibrosis)

Physical Injury
Abrasion

basically a scrape superficial epidermis is torn off by friction or force regeneration without scarring usually occurs a laceration is an irregular tear in the skin produced by overstretching. The wound margins are frequently hemorrhagic and traumatized an incision is made by a sharp cutting object. The margins of the incision are usually relatively clean an injury caused by a blunt force that damages small blood vessels and causes interstitial bleeding, usually without disruption of the continuity of the tissue (cf ecchymosis)

Laceration vs. Incision

Contusion

Adult Mortality Rates in the United States, Ages 2544, in 1998

Rate per 100,000 population

Cause
Unintentional injuries
Cancer Homicide Human immunodeficiency virus Heart disease Suicide

Hispanic
33.4
16.8 13.1 12.1 10.3 7.8

Black
40.1
38.0

White
31.6
25.3

36.2 43.3
43.5

4.7 4.8
18.3 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

1st, 2nd, 3rd, 4th Degree FULL vs. PARTIAL Thickness Survival

BURNS

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>106, over 110 have been reported, high mortality.

HYPO-THERMIA
Often

in setting of homelessness or alcoholism or both

<

90 often fatal, assoc. w.

BRADYCARDIA ATRIAL FIBRILLATION

LIGHTNING/ELECTRICAL

ELECTRIC DISTURBANCES
NEURAL EKG

THERMAL INJURY, depends upon a particular tissues 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 & DISEASE

Food Safety
Additives Contaminants

Nutritional Deficiencies
Vitamins
Minerals

Obesity Diet and Disease Chemoprevention of Cancer

Vitamin Deficiency and Excess

Fat soluble vitamins

A, D, E, K readily stored in body fat poorly absorbed in digestive disorders involving malabsorbtion of fat

Water soluble vitamins

remaining vitamins readily excreted in urine

Vitamin stores
vitamins B-12 and A: stores sufficient for 1 year folate and thiamine may become depleted within weeks when eating a deficient diet

Vitamin D Metabolism

Absorption of vitamin D in the gut or synthesis from precursors in the skin Binding to a plasma 1 -globulin (Dbinding protein) and transport to liver Conversion to 25-hydroxyvitamin D, 25(OH)D (calcidol) by 25-hydroxylase in the liver Conversion of 25(OH)D to 1,25(OH)2 D (calcitrol, Vitamin D3) by 1-hydroxylase in the kidney; biologically this is the most active form of vitamin D.

Functions of Vitamin D

Stimulates intestinal absorption of calcium and phosphorus Collaborates with PTH in the mobilization of calcium from bone Stimulates the PTH-dependent reabsorption of calcium in the distal renal tubules 1,25(OH)2 D, the biologically active form of vitamin D, is best regarded as a steroid hormone which acts by binding to a highaffinity receptor

Vitamin D Deficiency

Holick et al (2005) reported the results of a large North American study that assessed the vitamin D status of postmenopausal women receiving therapy to treat or prevent osteoporosis 52% of 1536 women had inadequate [25(OH)D] levels (<30 ng/mL) 36% and 18% had levels less than 25 and 20 ng/mL, respectively.
Holick MF et al: J Clin Endocrinol Metab 90:3215, 2005

Vitamin D Deficiency

Childhood: Rickets
epiphyses

are open cartilage overgrowth

Adults: osteomalacia
bone

matrix is not calcified 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

Clotting factors VII, IX, and X and prothrombin (II) all require carboxylation of glutamate residues for functional activity

anticoagulant coumadin is a Vitamin K antagonist

Activation of anticoagulant proteins C and S also requires glutamate carboxylation Sources

endogenous intestinal bacterial flora diet

Vitamin K Deficiency

Causes
fat malabsorption reduced gut bacterial flora

administration of wide specturm antibiotics neonatal period before gut is colonized

liver disease with reduced recycling of vitamin K

Effects of vitamin K deficiency

bleeding diathesis estimated 3% prevalence of vitamin Kdependent bleeding diathesis among neonates warrants routine prophylactic vitamin K therapy for all newborns