Pathology Ch9 - Environmental and Nutritional Diseases - pp403-432
Environmental Effects on Global Disease Burden
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Dramatic increase in mortality due to HIV/AIDS and associated infections
o 11.2% decrease in deaths from infectious disease, maternal, neonatal, and nutritional disorders
o 39.2% increase in deaths from noncommunicable diseases (cancer, diabetes, CV disease)
o 9.2% increase in deaths from injuries
o All attributable to aging of world population (average 26.1 years > 29.5 years)
Undernutrition is the single leading global cause of health loss
o Due to poor general nutrition
o Due to deficiencies in specific nutrients that inc. risk of infections
Ischemic heart disease and cerebrovascular disease remain leading cause of death in developed countries
o Risk factors: smoking, HTN, obesity, high cholesterol, and alcohol abuse
In developing countries, five of the 10 leading causes of death are infectious diseases
o Respiratory infections
o HIV/AIDS
o Diarrheal diseases
o Tuberculosis
o Malaria
In the postnatal period, 50% of deaths in children <5yo are attributed to pneumonia, diarrheal disease, and malaria
o Has decreased from 11.5 million in 1990 > 7 million in 2010
Emerging infectious diseases
o Diseases caused by newly evolved strains or organisms (ex. MRSA, resistant tuberculosis, resistant malaria)
o Diseases caused by pathogens endemic in other species that jumped to human populations (ex. HIV)
o Diseases caused by pathogens that have been present in humans, but show a recent inc. in incidence
Health Effects of Climate Change
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Without immediate action, climate change will become the preeminent global cause of environmental disease
Principal cause are greenhouse gases, particularly CO2, ozone, and methane
Negative impact on human health:
o CV, cerebrovascular, and respiratory disease (worsened by heat waves and air pollution)
o Gastroenteritis, cholera, and other foodborne/waterborne diseases (due to contamination as a consequence of
floods and disruption of clean water supplies and sewer treatment after heavy rains/disasters)
o Vector-borne infectious diseases (due to changes in vector numbers related to inc. temperatures, crop failures,
and more extreme weather variation)
o Malnutrition (due to changes in local climate that disrupt crop production)
Melting of the western Antarctic ice shelf > raise ocean levels 5m > displace 10% of global population
Toxicity of Chemical and Physical Agents
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Definition of a poison is not straight forward (dosage differentiates a poison from a remedy)
Xenobiotics = exogenous chemicals in the environment that may be absorbed into the body
Chemicals may be excreted in urine/feces, eliminated in expired air, or may accumulate in bone/fat/brain/etc.
Chemicals may act at site of entry or at other sites after transported through blood
Most solvents/drugs are lipophilic > facilitates transport in blood via lipoproteins and penetration into plasma membranes
Most solvents/drugs/xenobiotics are metabolized (detoxified) or activated to form toxic metabolites
o Phase I reaction
 Chemicals undergo hydrolysis, oxidation, or reduction
 Most important enzyme = cytochrome P450 (CYP) in ER of liver
 CYP can either detoxify xenobiotics, or rarely convert them into active compounds that cause damage
o Phase II reaction
 Products of phase I metabolized into water-soluble compounds via glucuronidation, sulfation,
methylation, and conjucation w/ glutathione
o CYP can be induced by environmental chemicals, drugs, smoking, alcohol, and hormones
 Inducers bind nuclear receptors > heterodimerize w/ retinoic X receptor (RXR) > promoter elements
 Nuclear receptors = aryl hydrocarbon receptor, PPAR, CAR, PXR
o CYP can be inhibited by fasting, or starvation
Environmental Pollution
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Air Pollution
o Outdoor Air Pollution
 EPA sets limit for: sulfur dioxide, carbon monoxide, ozone, nitrogen dioxide, lead, and particulate matter
 Collectively, these agents produce smog
 Ozone (O3)
 Produced by UV radiation interacting w/ O2 that normally accumulates in the "ozone" layer
 The ozone layer, which normally absorbs dangerous UV from the sun, is thinning due to use of
chlorofluorocarbon gases in air conditioners/refrigerators/aerosols over the last 35 years
o Due to air currents, the depletion has been most profound in polar regions
o Ground-level ozone is formed by reaction of nitrogen oxides w/ volatile organic
compounds in the presence of sunlight > accumulates below "good" ozone in the
stratosphere
 Damage due to production of free radicals > injure epithelial cells along respiratory tract and
type I alveolar cells > inflammatory mediators
o Result in upper respiratory tract inflammation and mild symptoms
o Can be more severe in pts w/ asthma or emphysema
 Sulfur dioxide
 Produced by coal and oil burning plants, copper smelting, and byproduct of paper mills
 Converted into sulfuric acid and sulfuric trioxide in air
 Results in burning sensation in nose/throat, difficulty breathing, and asthma attacks
 Particulates (soot)
 Morbidity and mortality related to pulmonary inflammation and secondary CV effects
 Produced by coal and oil burning plants, and diesel exhaust
 Fine or ultrafine particles (<10μm) enter the alveoli > phagocytosed by macrophages/neutrophils
> release of inflammatory mediators
 Carbon monoxide
 Systemic asphyxiant that can cause accidental and suicidal death
 CO is a nonirritating, colorless, tasteless, odorless gas
 Produced from incomplete oxidation of hydrocarbons (automotive engines, furnaces, cigarettes)
 Normally rapidly oxidized to O2 in the atmosphere > accumulates only at the source
 Greater concern to acute toxicity due
o Binds hemoglobin with high affinity
o Leads to CNS depression and systemic hypoxia
o Characterized by cherry-red color of skin and mucous membranes
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Indoor Air Pollution
 Tobacco smoke = most common
 Wood smoke
 Contains various oxides of nitrogen and carbon
 Irritant that may predispose to lung infections
 May contain polycyclic hydrocarbons (carcinogens)
 Bioaerosols
 Microbiologic agents causing Legionnaires disease, viral pneumonia, and common cold
 Allergens (dander, dust mites, fungi, and molds) causing rhinitis, eye irritation, and asthma
 Radon
 Radioactive gas from uranium present in soil and in homes
 Can cause lung cancer in uranium miners
 Low level exposure in the home doesn't seem to be linked to cancer risk
 Formaldehyde
 Used in manufacture of building materials
 Concentrations 0.1ppm or higher > burning eyes/throat and can trigger asthma attacks
 Classified as a carcinogen
 Sick building syndrome
 May be a consequence of exposure to one or more indoor pollutants
 Possibly due to poor ventilation
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Metals as Environmental Pollutants
o Lead
 Readily absorbed metal that binds to sulfhydryl groups in proteins > interferes w/ calcium metabolism
 Leads to hematologic, skeletal, neurologic, GI, and renal toxicities
 Low blood levels (under 10 ug/mL) > dec. IQ/hearing/growth, impaired peripheral nerve fxn
 20 ug/mL > dec. nerve conduction, altered vitamin D metabolism and Ca++ homeostasis
 40 ug/mL > dec. hemoglobin synthesis
 100 ug/mL > encephalopathy, nephropathy, frank anemia, colic
 150 ug/mL > death
 Exposure through contaminated air, food and water
 Sources = mining, foundries, batteries, spray painting, and flaking lead paint in older houses
 Children absorb more ingested lead than adults
 Neurotoxic effects due to disruption of Ca++ homeostasis
 Interferes w/ remodeling of cartilage and primary bone trabeculae in epiphyses in children
 Causes inc. bone density detected as radiodense "lead lines"
 Inhibits healing of fractures by increasing chondrogenesis and delaying cartilage mineralization
 Inhibits activity of δ-aminolevulinic acid dehydratase and ferrochelatase (heme synthesis)
 Most obvious sign is microcytic hypochromic anemia
o Mercury
 Binds to sulfhydryl groups in certain proteins > damage in CNS and kidneys
 Inhalation of mercury > tremor, gingivitis, and bizarre behavior
 Main source = contaminated fish (methyl mercury) and vapors released from dental amalgams
 Inorganic mercury from degassing of earth's crust > converted to methyl mercury by bacteria >
enters food chain > concentrates in carnivorous fish (swordfish, shark, bluefish)
 Minamata disease = cerebral palsy, deafness, blidness, mental retardation, and major CNS defects in
children exposed in utero
 Lipid solubility facilitates their accumulation in the brain
 Pregnant women should avoid fish known to contain high levels of mercury
o Arsenic
 Interferes with cellular metabolism > toxicities of GI tract, nervous system, skin, and heart
 Found naturally in soils and water, used in wood preservers and herbicides
 Most toxic forms = arsenic trioxide, sodium arsenite, and arsenic trichloride
 Ingested in large quantities > acute GI, CV, and CNS toxicities (often fatal)
 Attributed to interference w/ mitochondiral oxidative phosphorylation
 Neurologic effects (2-8 weeks after exposure) > sensorimotor neuropathy > paresthesias, numbness, pain
 Chronic exposure > skin changes (hyperpigmentation and hyperkeratosis), carcinogenic
o Cadmium
 Preferentially toxic to the kidneys and lungs due to inc. production of ROS
 Sources = mining, electroplating, and production of nickel-cadmium batteries
 Can contaminate soil and plants > food is most important source of exposure in general population
Occupational Health Risks: Industrial and Agricultural Exposures
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Organic solvents
o Chloroform and carbon tetrachloride found in degreasing and dry cleaning agents and paint removers
o Acute exposure > dizziness and confusion > CNS depression > coma
o Lower levels are toxic for liver and kidneys
o Exposure of rubber workers to benzene and 1,3-butadiene > inc. risk of leukemia
Polycyclic hydrocarbons
o Released during combustion of fossil fuels (coal and gas)
o Present in tar and soot
o Exposure of chimney sweeps > scrotal cancers
o Implicated in lung and bladder cancers
Organochlorides
o Synthetic lipophilic products that resist degradation
o Used in pesticides = DDT, lindane, aldrin, and dieldrin
o Nonpesticide = polychlorinated biphenyls (PCBs) and dioxin
o Most disrupt hormonal balance due to antiestrogenic or antiandrogenic activity
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Dioxins and PCBs
o Can cause skin disorders (folliculitis and dermatitis)
o Chloracne = acne, cyst formation, hyperpigmentation, and hyperkeratosis around face and ears
o Can also cause abnormalities in liver and CNS
Inhalation of mineral dusts
o Cause chronic, nonneoplastic lung disease (pneumoconioses)
o Most common = coat dust, silica, asbestos, and beryllium
Vinyl chloride
o Used in synthesis of polyvinyl resins
o Leads to angiosarcoma of the liver
Bisphenol A (BPA)
o Used in synthesis of polycarbonate food and water containers, and of epoxy resins lining food bottles/cans
o Potential endocrine disruptor and heart disease
Effects of Tobacco
o Most readily preventable cause of death in humans
o Contains 2000-4000 substances, 60 of which are carcinogenic
o Cause death mostly from cardiovascular disease, various cancers, and chronic respiratory problems
o Cessation of smoking reduces overall mortality and risk of CV disease within 5 years of stopping
o Smoking and Lung Cancer
 Direct irritant effect on tracheobronchial mucosa > inflammation and inc. mucus production (bronchitis)
 Also recruits leukocytes to lung > inc. elastase production > injury to lung tissue (emphysema)
 Polycyclic hydrocarbons and nitrosamine are potent carcinogens
 Smoking 1 cigarette/day = 5x risk of cancer; Smoking 20/day = 12x risk of cancer
 Increases risk of other carcinogenic influences (ex. asbestos and uranium)
o Smoking and Other Diseases
 Associated w/ cancers of the esophagus, pancreas, bladder, kidney, cervix, and bone marrow
 Lung diseases = emphysema, chronic bronchitis, COPD
 Strongly linked to atherosclerosis and MI (due to inc. platelet aggregation, dec. myocardial O2 supply, inc.
O2 demand, and dec. threshold for ventricular fibrillation)
 Harmful to fetus > spontaneous abortions and preterm births, intrauterine growth retardation
 Second hand smoke associated w/ same health consequences
Effects of Alcohol
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Moderate amounts are not detrimental, and may actually protect against some disorders
o 20-30 g/day > inc. HDL levels, inhibit platelet aggregation, and lower fibrinogen levels (protect from CHD)
Legal limit = 80 mg/dL (3x 12oz beers, 15oz wine, 4-5oz of liquor)
o 200 mg/dL > drowsiness
o 300 mg/dL > stupor
o Higher levels > coma, respiratory arrest
o Chronic alcoholics can tolerate up to 700 mg/dL
Most alcohol in blood is oxidized to acetaldehyde in the liver
o Alcohol dehydrogenase handles most of the work
o Higher levels processed by microsomal ethanol-oxidizing system (CYP2E1)
 May interfere w/ other substrates and delay drug catabolism
o Small amount metabolized by catalase
Acetaldehyde is converted to acetate by acetaldehyde dehydrogenase > used in mitochondrial respiratory chain
Toxic metabolites produced by metabolism of ethanol
o Acetaldehyde responsible for acute effects of alcohol and development of oral cancers
 Acetaldehyde dehydrogenase has very low activity in 50% of Asians (heterozygotes for normal ALDH2*1
w/ ALDH2*2)
 Homozygotes for ALDH2*2 variant have NO tolerance for alcohol > nausea, flushing, tachycardia,
hyperventilation
o Alcohol oxidation by alcohol dehydrogenase causes reduction of NAD to NADH
 NAD required for fatty acid oxidation in the liver and conversion of lactate to pyruvate
 Deficiency > accumulation of fat in liver of alcoholics
o Metabolism by CYP2E1 produces ROS > lipid peroxidation of hepatocyte cell membranes
Acute alcoholism
o Affects mainly the CNS, but may induce reversible hepatic and gastric changes
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o Even w/ moderate intake > fat droplets accumulate in cytoplasm of hepatocytes (hepatic steatosis)
o Gastric changes include acute gastritis and ulceration
Chronic alcoholism
o Liver = alcoholic hepatitis and cirrhosis, associated w/ portal HTN, and hepatocellular carcinoma
o GI tract = massive bleeding from gastritis, gastric ulcer, or esophageal varices
o Thiamine (B1) deficiency = peripheral neuropathies and Wernicke-Karsakoff syndrome
o Heart = dilated congestive cardiomyopathy (alcoholic cardiomyopathy), HTN, coronary heart disease
o Pregnancy = fetal alcohol syndrome (microcephaly, growth retardation, facial abnormalities, reduced mental fxn)
o Cancers = oral cavity, esophagus, liver, breast (in women) due to acetaldehyde
Injury by Therapeutic Drugs and Drugs of Abuse
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Injury by Therapeutic Drugs (Adverse Drug Reactions)
o Anticoagulants
 Warfarin = antagonist of vitamin K (food rich in vitamin K interfere w/ its metabolism)
 Dabigatran = direct inhibitor of thrombin
 Results in bleeding which can be fatal, and thrombotic complication stemming from undertreatment
o Menopausal Hormone Therapy (MHT)
 Estrogens + progestogen, normally used to treat postmenopausal hot flashes and osteoporosis
 After prolonged use (5 years) may inc. risk of breast cancer
 First 2 years of Tx associated w/ inc. risk of stroke, and venous thromboembolism (DVT and PE)
 Protects against atherosclerosis only if initiated <60 yo
 Estrogen alone can cause uterine cancer (only used alone in hysterectomized women)
 Estrogen alone slightly reduces risk of breast cancer
o Oral Contraceptives (OCs)
 May inc. risk of cervical carcinomas in women infected w/ HPV
 3-6x increase in risk of thromboembolism (still 2-6x lower than risk associated w/ pregnancy)
 2x increase in risk of atherosclerosis and MI in >35yo smokers
 Associated w/ hepatic adenoma in older women that have been on OCs for prolonged periods
o Anabolic Steroids
 Used in doses 10-100x higher than therapeutic indications > inhibit LH/FSH production and results in
excess production of estrogens
 Results in stunted growth in adolescents, acne, gynecomastia, and testicular atrophy
 Females show growth of facial hair and menstrual changes
 Also associated w/ psychiatric disturbances and inc. risk of MI
o Acetaminophen
 Responsible for 50% of acute liver failure in the US, w/ 30% mortality
 Normally 95% is detoxified in liver and excreted in urine
 5% metabolized by CYPs to NAPQI (highly reactive metabolite) > conjugated w/ glutathione (GSH)
 Taken in high doses > NAPQI accumulates > hepatocellular damage (centrilobular necrosis)
 Normal dose = 0.5g; Toxic dose = 15-25g
 Toxicity begins w/ nausea, vomiting, diarrhea, and sometimes shock > followed by jaundice
 Can be treated in early stages w/ N-acetylcysteine > restores GSH levels
o Aspirin (Acetylsalicylic Acid)
 Causes alkalosis due to stimulation of respiratory center in the medulla
 Followed by metabolic acidosis and accumulation of pyruvate and lactate > enhances formation of nonionized forms of salicylates > diffuse into brain > effects varying from nausea to coma
 Fatal dose = 10-30g (adults) and 2-4g (children)
 Chronic use of >3g/day may result in chronic aspirin toxicity (salicylism)
 Results in headaches, dizziness, tinnitus, hearing impairment, mental confusion, drowsiness,
nausea, vomiting, and diarrhea
 CNS changes may progress to convulsions and coma
 Often there is acute erosive gastritis > bleeding and ulceration
 When taken in analgesic mixtures w/ phenacetin/acetaminophen > tubulointerstitial nephritis and renal
papillary necrosis (analgesic nephropathy)
Injury by Nontherapeutic Agents (Drug Abuse)
o Cocaine (and crack)
 Physical dependence generally doesn't occur, but psychologic withdrawal is profound
 Acts by blocking reuptake of dopamine in CNS, and blocking reuptake of epi/norepinephrine in synapses
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CV = acute sympathomimetic effect > tachycardia, HTN, peripheral vasoconstriction. May induce
myocardial ischemia via coronary artery vasoconstriction and enhancing platelet aggregation and
thrombus formation (potentiated in cigarette smokers). Can also precipitate lethal arrhythmias by
disrupting normal ion transport in the myocardium.
 CNS = hyperpyrexia (due to aberrations of dopaminergic pathways that control body temp) and seizures
 Pregnancy = acute decrease in blood flow to placenta > fetal hypoxia and spontaneous abortion.
Neurologic impairment of the fetus may result due to chronic drug use.
 Other = perforation of nasal septum, dec. lung diffusing capacity (smokers), dilated cardiomyopathy
Opiates (oxycodone, heroin)
 Sudden death = related to overdose, b/c purity is generally unknown > respiratory depression, arrhythmia
and cardiac arrest, and severe pulmonary edema
 Pulmonary injury = moderate/severe edema, septic embolism from endocarditis, lung abscess,
opportunistic infections, and foreign-body granulomas from talc or other adulterants
 Infections = most commonly skin and subcutaneous tissue, heart valves, liver, and lungs due to S. aureus,
viral hepatitis, and HIV
 Skin = abscesses, cellulitis, and ulcerations due to subcutaneous injection
 Kidneys = amyloidosis (secondary to skin infections) and glomerulosclerosis > proteinuria and nephrotic
syndrome
Amphetamines and Related Drugs
 Methamphetamine (speed aka meth)
 Related to amphetamine, but with stronger CNS effects
 Releases dopamine in the brain > inhibits presynaptic neurotransmission at corticostriatal
synapses > slows glutamate release
 Long-term use leads to violent behaviors, confusion, and paranoia/hallucinations
 MDMA (ecstasy)
 Increase serotonin release in CNS
 Reduces number of sertonergic axon terminals in striatum and cortex
 May increase peripheral effects of dopamine and adrenergic agents
Marijuana
 Beneficial effects = treating nausea secondary to cancer chemo, analgesia in some chronic conditions
 Use distorts sensory perception and impairs motor coordination for 4-5 hours
 W/ continued use > progress to cognitive and psychomotor impairment (inability to judge time,
speed, and distance)
 CV = Increases heart rate and sometimes blood pressure > may cause angina in people w/ CAD
 Respiratory system = laryngitis, pharyngitis, bronchitis, cough/hoarseness, asthma-like symptoms
 3x tar inhaled compared to normal cigarettes
Other Drugs
 Chronic inhalation of vapors (huffing) > cognitive abnormalities and MRI-detectable brain damage
 Bath salts (4-methyl-meth-cathinone and methylenedioxypyrovalerone) > amphetamine-like effects
Injury by Physical Agents
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Mechanical Trauma
o Abrasions, contusions, lacerations, incision wounds, and puncture wounds
Thermal Injury
o Thermal Burns
 Classified depending on depth
 Superficial burns (first-degree burns) confined to epidermis
 Partial thickness burns (second-degree) involve injury to dermis
 Full-thickness burns (third-degree) extend to subcutaneous tissue, may involve damage to
muscle tissue (previously known as fourth-degree)
 Shock, sepsis, and respiratory insufficiency are the greatest threats to life
 Burns >20% of body surface> Rapid shift of body fluids into interstitial compartments due to
"systemic inflammatory response syndrome" > shock
 Widespread vascular leakiness > edema (including pulmonary edema)
 Development of hypermetabolic state associated w/ excess heat loss
 Burn site is ideal for growth of microorganisms due to serum and debris (providing nutrients) and
injury compromising blood flow (blocks inflammatory response)
o Most commonly psuedomonas aeruginosa, but also MRSA, and Candida species
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Organ system failures have dropped over the last 30 years due to earlier excision and grafting
Injury to airways/lungs may result from direct effect of heat or from inhalation of heated air/noxious gas
 Water-soluble gases (chlorine, sulfur oxide, ammonia) > form acids or alkalis in upper airway
 Lipid-soluble gases (nitrous oxide and products of plastics) > reach deeper airways > pneumonitis
 Long term sequelae of hypertrophic scarring and itching
o Hyperthermia
 Heat cramps =
 Result from loss of electrolytes via sweating > cramping of voluntary muscles, usually associated
w/ vigorous exercise
 Normal core body temp is maintained via heat-dissipating mechanisms
 Heat exhaustion =
 Sudden prostration and collapse resulting from failure of CV system to compensate for
hypovolemia caused by dehydration
 Equilibrium is re-established if pt is able to rehydrate
 Heat stroke =
 Associated w/ high ambient temps, high humidity, and exertion
 Thermoregulatory mechanisms fail, sweating ceases, and core body temp rises to >40C >
multiorgan dysfunction that can be rapidly fatal
 Hyperthemia accompanied by generalized vasodilation > peripheral blood pooling > dec.
effective circulation volume
 Hyperkalamia, tachycardia, arrhythmias, and other systemic effects are common
 Sustained contractions of skeletal muscle can exacerbate hyperthermia and lead to muscle
necrosis (rhabdomyolysis), stemming from nitrosylation of ryanodine receptor 1 (RYR1)
(regulates Ca++ release from SR)
 Malignant hyperthermia =
 Inherited mutations in RYR1 > heat-stroke-like rise in core body temp and muscle contractions
following exposure to common anesthetics
o Hypothermia
 Associated w/ low ambient temp, high humidity, wet clothing, and dilation of superficial vasculature (due
to alcohol ingestion)
 Loss of consciousness occurs at body temps <90F, followed by bradycardia and atrial fibrillation
 Direct effects =
 Mediated by physical disruption within cells by high salt concentrations caused by crystallization
of intra- and extra-cellular water
 Indirect effects =
 Result from circulatory changes
 Slow chilling > vasoconstriction and inc. vascular permeability > edema and hypoxia
o Ex. "trench foot" in WWI soldiers > gangrene
 Sudden chilling > vasoconstriction and inc. viscosity of blood > ischemic injury (possibly
gangrene) and degenerative changes in peripheral nerves. Vascular injury and edema occur after
temperature begins to return to normal.
Electrical Injury
o Low-voltage currents (home/office) 120-220V
 Alternating current induces tetanic muscle spasm > irreversible clutching likely to occur
 Sufficient current can pass through the body to cause ventricular fibrillation
 If current is sustained, it can cause burns at sites of entry/exit and internal organs
o High-voltage currents (power lines, lightning)
 Damage is similar to low-voltage current, but is more likely to produce paralysis of medullary centers and
extensive burns
Injury Produced by Ionizing Radiation
o Radiation = energy that travels in form of waves or high-speed particles
o Nonionizing radiation = UV and IR light, microwave, and sound waves > can cause molecules to vibrate, but not
sufficient to displace bound electrons from atoms
o Ionizing radiation = xrays and gamma rays, high-energy neutrons, alpha/beta particles > sufficient energy to
remove tightly bound electrons
o Radiation units
 Curie (Ci) = disintegrations per second of a radioisotop
 Gray (Gy) = energy absorbed by target tissue per unit mass (1 centigray cGy = 100 erg/g tissue)
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 Sievert (Sv) = equivalent dose that depends on biologic rather than physical effects of radiation
Main Determinant of the Biologic Effects of Ionizing Radiation
 Rate of delivery = damage is cumulative, but divided doses allow cells to repair some damage
 Field size = large doses to one field generally OK, but small dose over whole body can be fatal
 Cell proliferation = rapidly dividing cells are more vulnerable to injury, since radiation damages DNA
 Oxygen effects and hypoxia = DNA damaged by ROS generated by radiolysis of water > poorly vascularized
areas w/ low oxygenation (ex. center of a tumor) are less sensitive to radiation than nonhypoxic tissue
 Vascular damage = damage to endothelial cells > narrowing/occlusion of vasculature > impaired healing,
fibrosis, and chronic ischemic atrophy. Usually appears months/years after exposure.
Morphology
 Changes in chromosomes = dsDNA breaks, deletions, translocations, fragmentation
 Mitotic spindle often becomes disorderly > polyploidy and aneuploidy
 Nuclear swelling and condensation and clumping of chromatin may appear
 Giant cells w/ pleomorphic nuclei may appear and persist for years after exposure
 Cytoplasmic changes = swelling, mitochondrial distortion, degeneration of ER
Total-Body Irradiation
 Doses <1 Sv produce minimal symptoms, if any
 Higher doses > acute radiation syndromes
 1-2 Sv = Lymphocytes > moderate granulocytopenia, lymphocytopenia
 2-10 Sv = Bone marrow > leukopenia, hemorrhage, hair loss, vomiting
 10-20 Sv = Small bowel > diarrhea, fever, electrolyte imbalance, vomiting
 >50 Sv = Brain > ataxia, coma, convulsions, vomiting
Acute Effects of Hematopoietic and Lymphoid Systems
 Extremely susceptible to radiation injury
 High dose > severe lymphocytopenia, shrinkage of lymph nodes, and spleen may appear within hours
 Sublethal dose > regeneration is prompt > restore normal lymphocytes within weeks/months
 Dose dependent marrow aplasia > neutropenia, thrombocytopenia > anemia
 Very high doses > kill marrow stem cells > permanent aplasia (aplastic anemia)
Fibrosis
 May occur weeks/months after irradiation due to replacement of dead parenchymal cells by CT
 Vascular damage, death of tissue stem cells, and release of cytokines/chemokines > inflammation and
fibroblast activation > fibrosis
 Common sites = lungs, salivary glands, colorectal and pelvic areas
DNA Damage and Carcinogenesis
 Single-base damage, single- and double-strand breaks, and DNA-protein cross-links
 Most serious damage = double-stranded breaks (DSBs)
 Repaired by homologous recombination and nonhomologous end joining (NHEJ)
 DNA repaired through NHEJ produces the most mutations
 If replication of cells containing DSBs isn't stopped > cells with chromosome damage persists >
carcinogenesis
Cancer Risks from Exposures to Radiation
 Acute or prolonged exposures that result in doses > 100 mSv cause serious consequences
 Significant increase in risk associated w/ > 50 mSv
 "Reasonable" evidence associated w/ > 5 mSv
 NOTE: AP chest xray (0.01 mSv), lateral chest xray (0.15 mSv), and CT of chest (10 mSv)
 Risk of cancers is greatest in children