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Home , Acute radiation syndrome

Pathology week 11: Environmental pathology ver.2

Chemicals found at sites Metals, volatile organic compounds, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, ester plasticizers, , dioxins

Dose-response curve for acute chemical toxicity

Ceiling effect

% cum. response

Threshold dose

Subthreshold dose dose

- threshold dose = dose at which measurable response occurs - left of this dose, no measurable response = subthreshold levels = permissible exposure level - ceiling effect = plateau reached at higher doses

Principles of xenobiotic metabolism - xenobiotic = any foreign compound not produced by an organism's metabolism - most lipophilic (facilitates in blood by lipoproteins and penetration thru lipid membranes) - metabolised to hydrophilic metabolites in 2 steps: o phase I rxns (polar functional group added to parent compound – freq. oxidation reactions producing reactive, electrophilic intermediates) o phase II rxns (conjugation with endogenous substrates more water soluble, more readily excreted) - genetic variations in level of activity of these enzymes eg. CYP 1A1 induced by polycyclic aromatic hydrocarbons in tobacco smoke – smokers with certain alleles in this gene higher risk lung - multiple pathways in metabolism – depend on age, sex etc - exogenous factors (nutritional/hormonal alter enzyme activity) - exogenous factors(chemical, drugs, EtOH, stress) induce/inhibit enzymes - other repair pathways may modify interaction - ↑/↓ sensitivity to toxicity/carcinogenetic effects of xenobiotic

1 Phase I reactions 1. cytochrome P-450-dependent mono-oxygenase system a. in smooth endoplasmic reticulum (SER), composed of haem protein CYp P-450 b. NADPH transfers electrons to CYP P-450 via NADPH P-450 reductase c. Metabolite from this reaction can bind to DNA – carcinogenesis 2. Flavin-containing mono-oxygenase system: in SER of liver a. oxidises nicotine and other amines 3. Peroxidase-dependent co-oxidation a. catalysed by prostaglandin-H synthase (enzyme in arachidonic acid metabolism) b. located in SER, high activity in seminal vesicles/kidneys/bladder c. metabolises 2-naphthylamine (synthetic dyes) – risk bladder cancer All generate oxygen free radicals as byproducts. May lead to depletion of glutathione if: - cysteine or selenium deficiency (co-factors) - excessive redox cycling chemicals such as paraquat

Phase II reactions 1. glucuronidation a. alternative pathway metabolism naphthylamine is oxidation then glucuronidation. Metabolite excreted in urine. If urine acidic carcinogenic. 2. biomethylation a. inorganic causes kidneys. Methylated by aquatic bugs, eaten by fish, eaten by humans, easily taken up in GIT – crosses BBB and placenta. 3. glutathione conjugation a. common pathway for detoxification primary metabolites. Vinyl chloride metabolised then conjugated to reduced glutathione and excreted.

Organ system effects/complications of tobacco smoke Inhaled smoke – particulate phase of tar and gas phase. 43 known chemical carcinogens, carcinogenic metals (arsenic, nickel, cadmium, chromium), acetaldehyde, phenol, irritants (nitrogen dioxide, formaldehyde), hydrogen cyanide, carbon monoxide.

1. Lung cancer (multiple carcinogens: polycyclic aromatic hydrocarbons, NNK, , acetaldehyde, phenol) a. preneoplastic changes in tracheobronchial lining smokers b. dose-related, cessation reduces risk, synergistic with asbestos 2. Inhaled carcinogens causes mucosal injury: laryngeal, oral, lip, pharynx 3. Inhaled carcinogens swallowed in saliva: oesophageal, stomach cancer 4. Haematogenous spread: pancreatic, bladder, cervical cancer 5. IHD: multiplicative risk factor with HTN/lipids for CAD/AS 6. Risk cardiac arrest: ↑ plt adhesion/aggregation, arrhythmias, imbalance O2 supply/demand 7. Cerebrovascular : multiplicative risk factor for AMI/CVA esp women on OCP/HRT 8. Increased morbidity due to LRTIs: cilia toxins impair clearance, irritate respiratory epithelium 9. COPD: increased risk chronic bronchitis/emphysema 10. Peptic ulcers: ↑ risk, ↓ healing, ↑ reflux, ↓ bicarb secretion from pancreas 11. Fetal : COHb levels high than mothers – LBW, prematurity, abortion, PROM, placenta, previa 12. SIDS: ↑ risk due to maternal smoking 13. Accidental injuries (esp fires) increased risk 14. Exacerbated bronchitis, asthma, pneumoconiosis 15. ?Vector for transport other agents to lungs – radon gas in miners – lung cancer

Metabolism of alcohol - metabolised to acetaldehyde by alcohol dehydrogenase in gastric mucosa/liver, by CYP2E1 + catalase in liver. - Converted to acetic acid by aldehyde dehydrogenase. - Polymorphisms aldehyde dehydrogenase (50% Asian – ↓ activity due to point mutation – facial flushing.) - Women lower levels gastric alcohol dehydrogenase than men – higher blood alcohol levels.

Organ effects of alcohol abuse 1. Liver a. Fatty change - acute, reversible. If chronic causes hepatomegaly. Due to: i. ↑ catabolism fat by peripheral tissues, increased delivery FFAs to liver ii. Excess NADH (involved in metabolism EtOH) stimulates lipid biosyntesis iii. Oxidation fatty acids in mitochondria decreased iv. Acetaldehyde impairs function microtubules and causes ↓ transport of lipoproteins from liver 2 b. Acute alcoholic hepatitis i. Potentially reversible – , liver tenderness, jaundice ii. Due to direct toxic effects EtOH – mitochondrial injury, depletion glutathione, ↑ generation iii. Histology: focal areas hepatocyte necrosis and injury – fat accum, alcoholic hyaline or Mallory bodies, neutrophils accum around area of necrosis c. Cirrhosis i. In 10-15% chronic alcohol abuse ii. Hard, shrunken liver with micronodules of regenerating hepatocytes surrounded by dense bands of collagen iii. , muscle wasting, ascites, GI haemorrhage, coma iv. Histology: perisinusoidal , deposition collagen by perisinusoidal stellate cells (Ito cells) in spaces of Disse 2. CNS a. Acute depressive effects (?fluidisation membrane phospholipids and altered signal transduction) b. Occas drinkers: BAL 200mg/dL – inebriation; BAL 300-400mg/dL – coma, resp arrest, death c. Thiamine deficiency common in chronic alcoholics: degen nerve cells, reactive gliosis, cerebellum + peripheral nerves. , altered cognition, ophthalmoplegia, nystagmus – Wernicke syndrome. Severe dementia – Korsakoffs 3. CVS a. Chronic: dilated cardiomyopathy due to direct toxicity b. Alcoholics: HTN due to vasopressor effects of alcohol triggered by release catecholamines c. Moderate use: protective effect (↑ HDL, ↓ plt aggregation) 4. GIT a. Acute gastritis – direct toxic effect b. Acute and chronic pancreatitis – acinar destruction – impaired absorption 5. Skeletal muscle a. Direct toxicity, muscle weakness, pain, breakdown myoglobin 6. Reproductive a. Chronic use: testicular atrophy, decreased fertility b. Women: ↑ risk spontaneous abortion 7. Fetal alcohol syndrome a. 1 drink/day. Growth, develop defects (microcephaly, facial dysmorph, malformation brain/CVS/GU) b. ?due to acetaldehyde crossing placenta 8. Cancers a. Oral cavity, pharynx, oesophagus, liver, ?breast b. ?acetaldehyde tumour promoter, induction CYP enzymes may activate other carcinogens c. Cheap substitutes for EtOH i. Methanol – metabolized to formaldehyde + formic acid – metabolic acidosis, dizzy, N/V, blurred vision/blindness, resp depression ii. Ethylene glycol – lethal dose 1.4ml/kg – metabolised to aldehydes, glycolate, oxalate, lactate. If survive toxicity –ARF due to obstruction tubules from calcium oxalate crystals

Common drugs of abuse CNS depressants, CNS stimulants, narcotics, hallucinogens. Nicotine: - nicotine acetylcholine receptor agonist CNS depressants: - ethanol - barbiturates (downers, chronic use induces P450) - benzos o high dose drowsy, dizzy, coma o GABA A receptor agonist CNS stimulants: - cocaine o rapid high euphoria, ↑ energy. Chronic – insomnia, anxiety, paranoia, hallucinations o OD: , arrhythmias, resp arrest o Crosses BBB: Dopamine transport antagonist, 5HT receptor toxicity o In periphery blocks reuptake N/NA – xs catecholamine stimulation – vasoconstriction, HTN/CVA/coronary artery spasm o Decreased flow to placenta, risk abortion, abruption, haemmorhages - amphetamines o OD: sweating, , restless, confusion, delirium, seizures, arrhythmias, coma 3 o Fetal malformations and withdrawal symptoms Narcotics: - opiates o Mu opioid receptor agonist o iv heroin: suppression of anxiety, sedation, mood changes, , resp depression o OD: seizures, resp depression, arrest, death o IVDU: esp staph endocarditis; hepatitis, AIDS Hallucinogens: - mescaline, psilocybin, LSD (lysergic acid diethylamide) o NMDA glutamate receptor channel antagonists - marijuana o from hemp plant = Cannabis sativa, active ingredient ∆-THC (tetahydrocannabinol) o CBI cannabinoid receptor agonist

Adverse drug reactions 1. blood dyscrasias – ganulocytopenia, aplastic anaemia, pancytopenia, haemolytic anaemia 2. cutaneous – urticaria, dermatitis, fixed drug eruptions 3. cardiac – arrhythmias, cardiomyopathy 4. renal – GN, ATN 5. pulmonary – asthma (NSAIDs), acute pneumonitis, interstitial fibrosis, amiodarone 6. hepatic – fatty change, cholestasis, diffuse hepatocellular damage 7. systemic – , lupus syndrome 8. CNS – tinnitus/ (aspirin), dystonic reactions, respiratory depression

Risks of exogenous oestrogens – OCP/HRT 1. endometrial hyperplasia/cancer (if unopposed – combine HRT with progestin) 2. breast cancer (?small risk – if <25 years) 3. cervical cancer (?related to lifestyle rather than drug, correlated with duration of use) 4. VTE (but ↓ risk if low dose, note other risk factors including family/phx VTE, smoking) 5. HTN (esp. older) 6. hepatic adenoma (esp older women and prolonged use) 7. gallstones (older formulations)

Benefits: - contraception - ?protective against endometrial cancer - protective against ovarian cancer - ↑ HDL, ↓ LDL - ↓ risk IHD - ↓ risk osteoporosis - no evidence ↓ risk dementia

Paracetamol - large therapeutic window: 0.5g – 15-25g - NVD/jaundice/liver failure/hepatic necrosis - centrilobular necrosis +/- renal and cardiac damage

Acetylsalicylic acid (aspirin) - respiratory alkalosis then metabolic acidosis - chronic toxicity = salicysism (, dizziness, tinnitus, decreased hearing, N/V/D, seizures, coma, erosive gastritis, GI bleed, petechiae, analgesic nephropathy (renal papillary necrosis)

Herbal medicines Echinacea – allergic reactions Ginkgo – potentiate anticoagulants Ginseng – interacts with MAOIs, hypoglycaemics, anticoagulants St Johns Wort – increase metabolism OCP, anticoagulants; serotonergic

Sources of ambient air 1. combustion of fossil fuels a. cars, factories, bbqs, fireplaces b. car emissions: CO, oxides of nitrogen, hydrocarbons, particles, lead oxide in lead petrol 2. photochemical reactions a. oxides of nitrogen and hydrocarbons interact in atmosphere to produce O 3 4 3. power plant emissions a. sulphur dioxide/, coal and oil - sulphur forming sulphates, acid sulphates - 4. waste incinerators, smelters a. release acid , metals and organic compounds

Major air pollutants and their health effects

Health Effects of Outdoor Air Pollutants Populations at Risk Effects Ozone Healthy adults and children ↓ lung fxn, ↑airway reactivity Lung inflammation Athletes, outdoor workers ↓ exercise capacity Asthmatics ↑ hospitalizations Nitrogen dioxide Healthy adults ↑airway reactivity Asthmatics ↓ lung fxn Children ↑ resp infxns Sulfur dioxide Healthy adults ↑ resp symptoms Patients with chronic lung disease ↑ mortality, ↑ hospitalization Asthmatics ↓ lung fxn Acid aerosols Healthy adults Altered mucociliary clearance Children ↑ resp infxns Asthmatics ↓ lung fxn, ↑ hospitalizations Particulates Children ↑ resp infxns, ↓ lung function Patients with chronic lung or heart disease ↑ mortality Asthmatics ↑ attacks Ozone – major component of Nitrogen dioxide – dissolves in water in airways to form nitric acid Sulphur dioxide – highly water soluble – dissolved in water in airways

Major indoor air pollutants and their effects

Health Effects of Indoor Air Pollutants Pollutant Populations at Risk Effects Carbon monoxide Adults and children Acute Nitrogen dioxide Children Increased respiratory infections Wood smoke Children Increased respiratory infections Formaldehyde Adults and children Eye and nose irritation, asthma Radon Adults and children Lung cancer Asbestos fibers Maintenance and abatement workers Lung cancer, mesothelioma Manufactured mineral fibers Maintenance and construction workers Skin and airway irritation Bioaerosols Adults and children Allergic rhinitis, asthma

- Carbon monoxide (odourless gas, byproduct of combustion from gasoline, oil, coal, wood and natural gas; natural pollutant of cigarette smoke) o ↓ exercise capacity, ↑ myocardial ischaemia, , dizziness, loss of motor control, coma - Nitrogen dioxide (from gas stoves and kerosene heaters) - Wood smoke (mixture nitrogen oxides, particulates and polycyclic aromatic hydrocarbons) - Formaldehyde (highly soluble, volatile chemical used in manufacture textiles, furniture) - Radon (radioactive gas, decay product of uranium) - Manufactured mineral fibres (from fibreglass) - Bioaerosols (eg. Legionella, allergens associated with pets or dust)

5 Human associated with industrial occupational exposure

Human Diseases Associated with Occupational Exposures Organ Effect Toxicant CVS Heart disease Carbon monoxide, lead, solvents, cobalt, cadmium Resp Nasal cancer Isopropyl alcohol, wood dust Lung cancer Radon, asbestos, silica, bis(chloromethyl)ether, nickel, arsenic, chromium, mustard gas COPD Grain dust, coal dust, cadmium Beryllium, isocyanates Irritation Ammonia, sulfur oxides, formaldehyde Fibrosis Silica, asbestos, cobalt CNS Peripheral neuropathies Solvents, acrylamide, methyl chloride, mercury, lead, arsenic, DDT Ataxic gait Chlordane, toluene, acrylamide, mercury CNS depression Alcohols, ketones, aldehydes, solvents Cataracts GI Toxicity Mercury, lead, glycol ethers, solvents Bladder cancer Naphthylamines, benzidine, rubber products GU Male infertility Lead, phthalate plasticizers Female infertility Cadmium, lead Teratogenesis Mercury, polychlorinated biphenyls Haem Benzene, radon, uranium Skin Folliculitis, acneiform Polychlorinated biphenyls, dioxins, dermatosis Cancer Ultraviolet radiation GI Liver angiosarcoma Vinyl chloride

Effects of volatile organic compounds in VOC’s used in manufacturing, degreasing, dry cleaning, paint removers, sprays. - aliphatic hydrocarbons (industrial solvents, dry cleaning: readily absorbed, cause acute CNS depression, liver and kidney toxicity eg. chloroform, carbon tetrachloride) - petroleum products (gasoline, kerosene, mineral oil, turpentine – dizziness, incoordination, CNS depression) - aromatic hydrocarbons (benzene, toluene, xylene in solvents in rubber and shoe industries, printing, papercoating – inhalation benzene causes bm toxicity, aplastic anaemia, acute leukaemia)

Role of polycyclic aromatic hydrocarbons in occupational disease Among the most potent chemical carcinogens. Prototype benzo[a]pyrene – binds to DNA, increased risk lung and bladder cancer. Also in cigarette smoke.

Plastics/rubber/polymers Vinyl chloride, absorbed by skin/lungs. → Metabolised by CYP, binds to DNA, mutagenic. ↑ risk leukaemia.

Lead poisoning In batteries, alloys, exterior red leaf paint, ammunition. Usually inhalation. Environmental sources: urban air (leaded gasoline), soil contaminated by lead paint, water contaminated by lead plumbing, house dust contaminated by indoor lead paint. Also lead-glazed ceramics, lead solder in food and drink cans. Intestinal absorption enhanced by calcium, iron or zinc deficiency. Taken up by bone, developing teeth, t1/2 30 years. Toxicity related to: - high affinity for sulfhydryl groups (inhibits enzymes involved in haem biosynthesis – hypochromic anaemia) - competition with calcium ions – stored in bone, interferes with nerve transmission and brain development - inhibits membrane-associated enzymes eg. Na-K pumps – decreased survival RBCs, renal damage and HTN - impairs metabolism of Vit D Consequences: 1. brain: adult – headache, memory loss; child – encephalopathy, mental deterioration 2. gingiva: lead line 6 3. blood: microcytic, hypochromic anaemic, red cell basophilic stippling, haemolysis 4. peripheral nerves: adults – demyelination 5. kidney: chronic tubulointerstitial disease 6. GIT: abdo pain 7. epiphyses of childrens bone: radiodense deposits 8. HTN 9. infertility: men – testicular injury, women – failure of implantation of fertilized ovum

Other metals Cobalt and tungsten carbide – interstitial lung fibrosis (“hard metal disease”) Cadmium – liver and kidney damage Chromium – carcinogenic Nickel – contact dermatitis, inactivates tumour suppressor gene

Pesticides and their health effects - insecticides (at high enough doses toxic to humans) - herbicides (low toxicity in general) - fungicides (moderately toxic) - rodenticides (highly toxic) - fumigants (highly toxic) 1. Insecticides a. organochlorines – low toxicity, but bio-accumulate i. eg. DDT ?oestrogenic effects ii. chlordane – , tremor, seizures, immune dysfunction iii. lindane: immune dysfunction b. organophosphates – irreversible inhibitors cholinesterases, absorbed by skin/GIT/lungs c. carbamates – reversible inhibitors cholinesterase 2. Herbicides a. dioxins eg. TCDD - ↑ leukaemia, lymphoma, sarcomas b. paraquat – acute lung injury c. arsenic compounds – hyperpigmentation, gangrene, anaemia, sensory neuropathy 3. Rodenticides a. Highly toxic, warfarin – haemorrhage, strychnine – respiratory failure

Natural toxins 1. Mycotoxins eg. aflatoxins from Aspergillus flavus – liver cancer 2. Phytotoxins eg. cycasin in cycad flour – amyotrophic lateral sclerosis 3. Animal toxins eg. venoms from snakes and bees, ciguatoxin from dinoflagellates – accumulates in fish – paraesthesia, paresis, D/V; tetrodotoxin – puffer fish – neurotoxin,

Radiation Energy distributed across the electromagnetic spectrum as waves (long wavelengths, low freq) or particles (short wavelengths, high freq). 1 - 50 Hz = electrical power ?effect 10 6 - 10 11 Hz radio waves and radar - thermal effects and cataracts 10 9 - 10 11 Hz = – lens opacities 10 11 - 10 14 Hz = – cataracts 10 15 - visible – retinal burns 10 15 - 10 18 Hz = ultraviolet light – skin burns and cancer 10 18 - 10 20 Hz = xrays, gamma rays – acute and delayed injury, cancer 10 27 Hz = cosmic radiation ?effects

Ionizing and non- Non-ionizing radiation = electromagnetic radiation – long wave-lengths, low frequencies – includes: electrical power, radio waves, micro waves, infrared, UV light. Produces vibration and rotation of atoms in biologic molecules.

Ionizing radiation = short wave-lengths, high frequency – can ionise biologic molecules and eject electrons. Includes: xrays, gamma rays, cosmic rays. Can be in the form of electromagnetic waves (eg xrays or gamma rays from natural sources, or particles released by natural decay of radioisotopes or by artificial acceleration of sub-atomic particles.

Units for measuring doses of ionising radiation - : unit of charge produced by xrays or gamma rays that ionise a specific volume of air

7 - : dose of radiation the will produce absorption of 100 ergs of energy per gram of tissue; 1gm of tissue exposed to 1 roentgen of gamma rays is equal to 93 ergs - (Gy): dose of radiation that will produce absorption of 1 joule of energy per kg of tissue; 1 Gy = 100 rad - rem: dose of radiation that causes a biologic effect equivalent to 1 rad of xrays or gamma rays - (Sv): dose radiation causes a biologic effect equivalent to 1 Gy of xrays or gamma rays; 1 Sv = 100 rem

Linear energy transfer The energy loss per unit of distance travelled as electron volts per micrometer. Depends on type of ionising radiation. Is high for alpha particles but less for beta particles and even less for gamma rays and xrays. (so alpha and beta particles penetrate short distances and interact with many molecules while gamma and xrays penetrate deeply but interact with relatively few molecules per unit distance.

Biologic effects of ionising radiation Depends on: - physical properties of the radioactive material - dose - dose rate: single dose can cause greater injury,divided/fractionated doses allow time for cellular repair - rapidly dividing cells more radio-sensitive than quiescent cells (haematopoietic/germ cells/GIT epithelium, lymphocytes susceptible; bone/muscle/peripheral nerves resistant) - single dose to whole body more lethal than regional doses with shielding - cells in G2 and mitotic phases of more sensitive - produces oxygen-derived radicals, so hyperbaric oxygen enhances cell injury

Cellular mechanisms of radiation injury Range from no effects to overt necrosis at high doses. Acute effects: - DNA lesions: by oxygen-derived free radicals - even small doses can alter gene expression - DNA damage causes increased expression genes DNA repair, cell cycle arrest, apoptosis - atrophy bm, thymus, lymph nodes; skin; oedema lung, brain, GIT; necrosis testis, atresia ovarian follicles; vasodilatation kidney, veno-occlusive disease in liver Delayed effects: - fibrosis: scarring, loss of function. Acute necrosis in organs that can’t regenerate or ischaemia - carcinogenesis: ↑ risk skin cancer, leukaemia, osteogenic sarcoma, lung cancer. Latent period 10-20 yrs = induced genetic instability

Acute radiation syndrome Due to whole-body irradiation, LD 50 at 60 days 2.5 – 4.0 Gy. Whole-Body Category Dose (rem) Symptoms Prognosis Subclinical <200 Mild nausea and vomiting 100% survival Lymphocytes <1500/μL Hematopoietic 200-600 Intermittent nausea and Infections Petechiae, hemorrhage May require transplant Maximum neutrophil and depression in 2 wk Lymphocytes <1000/μL Gastrointestinal 600-1000 Nausea, vomiting, Shock and death in 10-14 days even Hemorrhage and in 1-3 with replacement therapy wk Severe neutrophil and platelet depression Lymphocytes <500/μL CNS >1000 Intractable nausea and vomiting Death in 14-36 hr Confusion, somnolence, seizures, coma in 15min-3hr Lymphocytes absent If pt survives , sublethally injured cells may repair and apoptotic/necrotic cells may be replaced by more radioresistant stem cells. 8 Side effects of Acute radiation sickness, neutrophil/plt depress. , V, . Sterile, second neoplasm, delayed radiation injury

Effects of radiation on growth Four susceptible phases: 1. Preimplantation embryo – lethal 2. Critical stages organogenesis – implantation - 9 weeks , even small amounts cause congenital malformation 3. Fetal period – 9 weeks to birth: mental retardation, increased risk leukaemia, brain tumours 4. Postnatal period – retardation bone growth, maturation. Disturb development CNS, eyes, teeth

Delayed effects radiation injury Months – years post exposure: 1. Blood vessels: necrosis endothelial cells, subintimal necrosis, fibrosis wall – ischaemia distally 2. Skin: hair follicles and epidermis sensitive to radiation – , hyperkeratosis, hyper/hypopigmentation, impaired healing, ulcers, radiation dermatitis, skin cancers 3. Heart: pericardial fibrosis – constrictive pericarditis, myocardial fibrosis and ischaemia 4. Lungs: acute lung injury, delayed radiation pneumonitis – dyspnoea, chronic cough, fibrosis 5. Kidneys: peritubular fibrosis, vascular damage, hyalinisation glomeruli – HTN, atrophy 6. Bladder: acute epithelial necrosis, fibrosis, contracture, , ulceration, tumours 7. GIT: oesophagitis, gastritis, enteritis, colitis, proctitis, exfoliation mucosa, fibrosis 8. Breast: fibrotic reaction 9. Ovary/testis: infertility, fibrosis 10. Eyes/CNS: cataracts, retinal artery damage, CNS focal necrosis, demyelination, transverse myelitis

Effects of UV radiation

Table 9-19. Acute and Delayed Effects of Ultraviolet Radiation Radiation Wavelength (nm) Acute Effects Delayed Effects UVA 320-400 Erythema 8-48hr Tanning Depletion of Langerhans cells ? Skin cancer Pigment darkening Dermal inflammation UVB 290-320 Erythema 3-24hr Tanning Apoptosis of keratinocytes Solar elastosis Depletion of Langerhans cells Premature aging, actinic keratosis Skin cancer UVC 200-290 ? Skin cancer

Mechanisms to protect against UV radiation - ozone layer (absorbs all UVC and some UVB) - window glasses (absorbs UVA but transmits UVA) - sunscreens (absorbs or blocks UVA and UVB to variable degrees)

Mediators of damage resulting from exposure to UV radiation - erythema, oedema, acute inflammation mediated by histamine from mast cells in dermis and synthesis arachidonic acid metabolites - interleukin-1 induced by UVB exposure - UVA exposure produces oxidation of melanin with transient, immediate darkening - tanning induced by UVA and UVB due to delayed increase in number of melanocytes and transfer melanin to keratinocytes - UVA and UVB deplete Langerhans cells, so reduce processing of Ags in the epidermis, resulting in dyskeratotic, cells - skin damage induced by UVB caused by generation reactive oxygen species and damage to endogenous chromophores such as melanin - UV radiation damages DNA – formation cross-linking, single stranded breaks

Effects of UV compared to ionising radiation on the skin Ionising radiation increased deposition of collagen in dermis, UV causes degenerative changes in elastin and collagen causing wrinkling, increased laxity and leathery appearance.

9 Injuries caused by physical environment 4 categories: 1. mechanical force (abrasion, laceration, contusion, wounds) 2. heat and cold injuries (thermal) 3. electrical injuries 4. high altitude

Abrasion = skin injury, superficial epidermis torn off by friction or force. Regenerates without scarring. Laceration = irregular tear in the skin produced by overstretching - linear or stellate, depending on force - bridging strands or fibrous tissue across wound, not present in an incision - margins often haemorrhagic and traumatized Incision = made by a sharp cutting object - margins clean - no bridging strands - can be neatly approximated by sutures Contusion = blunt force damaging small blood vessels, interstitial bleeding, no disruption continuity of tissue.

Morphology of gun shot wounds Character and extent of injury depends on: - type of gun, calibre of bullet, type of ammunition, distance from body, locus of injury, trajectory of missile (at right angles or oblique to body), gyroscopic stability of bullet (wobbling or tumbling) Hand guns at close range: - grey-black discoloration at wound (=fouling) - discrete, larger particles of unburned powder produce halo of stippling - if >1 foot away but < 3 feet away: stippling, fouling; greater distance: no stippling or fouling Wounds slightly smaller than bullet. Exit wounds more irregular than entry wounds because develops wobbling trajectory passing through tissues – margins may be everted.

Clinical significance of thermal burns Depends on: - depth, percentage body surface, internal injuries (inhalation), promptness/efficacy treatment Full-thickness: epidermis and dermis, loss dermal appendages that would have provided cells for epidermal regeneration. White or charred, dry, no sensation (nerve-end destruction). (3 rd + 4 th degree) Partial-thickness: at least deeper portions of dermal appendages spared. (1 st – epidermis, and 2 nd degree - epidermis and superficial dermis). Pink or mottled, , painful. Histo: divitalised tissue with coagulative necrosis, accumulation inflammatory cells and exudation.

Systemic consequences of major burns 1. >20% BSA – rapid shift body fluids into interstitial compartments at burn site and systemically – hypovolaemic shock a. Mechanisms: ↑ local interstitial osmotic pressure from release of osmotically active constituents of dying cells; both neurogenic and mediator-induced increases in vascular permeability 2. as protein from blood is lost into interstitial tissue, generalized oedema, incl pulmonary oedema occurs esp if fluids used for volume replacement are not osmotically active 3. inhalation injury (trapped in burning building) from direct effect of heat or inhalation toxic components smoke a. water soluble gases form alkalis and acids, esp in upper airways, causing inflammation and swelling – may lead to partial or complete airway obstruction b. lipid-soluble gases eg nitrous oxide, products burning plastics more likely to reach deeper airways, produce pneumonitis c. pulmonary manifestations may not develop for 24-48 hours 4. Burn infection – – organ failure – leading cause death. Most commonly Pseudomonas aeruginosa, also S aureus or Candida a. cellular and humoral defences compromised, lymphocyte and phagocyte functions impaired b. serum and debris compromises blood flow, blocking inflammatory response c. direct bacteremic spread, release toxins from site – pneumonia or septic shock, renal failure, ARDS 5. Development hypermetabolic state with xs heat loss and ↑ nutritional needs. Results in loss of essential protein stores, comparable to in several weeks – keep room elevated to reduce heat loss and start nutrition

Effects of prolonged exposure to elevated ambient temperature - heat exhaustion: most common heat syndrome. Onset sudden, prostration, collapse – due to failure CVS to compensate for hypovolaemia secondary to water depletion – after collapse equilibrium restored

10 - heat stroke: high temp and high humidity. Thermoregulatory mechanisms fail, sweating ceases, core temp rises. Rectal temp >106F poor prognosis, mortality >50%. Underlying mechanism marked generalised peripheral vasodilation with peripheral pooling of blood and decreased effective circulating circulating blood volume. Necrosis of muscles and myocardium may occur; arrhythmias, DIC, other systemic effects

How does chilling or freezing of cells and tissues cause injury? 1. direct effects by physical dislocations within cells and high salt concs due to crystallization intracellular and extracellular water 2. indirect effects exerted by circulatory changes a. slowly developing chilling may induce vasoconstriction and increased permeability, leading to oedematous changes – typical in ; atrophy and fibrosis may follow b. sudden sharp drops in temp that are persistent, vasoconstriction and increased viscosity of blood in the local area may cause ischaemic injury and degenerative changes in peripheral nerves. When temp returns to normal vascular injury and increased permeability with exudation become evident. During ischaemia hypoxic changes and infarction develop

Effects of passage of electric current thru the body - no effect - sudden death by disruption neural regulatory impulses eg. Cardiac arrest - thermal injury to organs in path of current – superficial or deep burns; heat, coagulate or rupture vessels and cause haemorrhage or in solid organs cause infarctions or ruptures Variables: resistance of tissues (↑ resistance, ↑ heat generated; resistance inverse to water content), intensity of current

Syndromes produced by changes in atmospheric pressure 4 syndromes, depending on direction of change, rate of development and magnitude of change: 1. high-altitude illness: >4000m, lowered oxygen tension – progressive mental obtundation, increased capillary permeability with systemic and pulmonary oedema 2. blast injury: violent ↑ pressure in atmosphere or water; air blast – compression wave impinges on side toward explosion, may collapse thorax or abdomen with rupture of internal organs – following wave of decreased pressure, sudden expansion of abdomen and thorax, may rupture intestines or lungs 3.air or gas embolism: of scuba diving, mechanical positive-pressure ventilation and hyperbaric oxygen therapy; abnormal increase in intra-alveolar air or gas pressure – tearing of tissue with entrance of air into interstitium and blood vessels – may get emphysema or air emboli lead acutely to stroke-like syndromes or AMI 4. decompression (Caisson) disease: deep-sea diver, underwater workers; injury is a function of Henry’s law which states that the solubility of a gas in liquid is proportional to the partial pressure of that gas in the environment; as underwater depth and atmospheric pressure increases, larger amounts oxygen and nitrogen/helium dissolve in blood and tissue fluids – with ascent/decompression, dissolved gases come out of solution – bubbles. (Periarticular – bends, lungs – chokes, inner ear – staggers, CNS, skeletal muscles – later foci aseptic necrosis femoral/humeral heads, and medullary foci lower femur/upper tibia, due to embolic occlusion vascular supply

Primary vs secondary malnutrition Adequate diet should provide: energy (CHO, fats, proteins), essential amino acids and fatty acids, vitamins and minerals which act as coenzymes or hormones in metabolic pathways or as structural components. Primary malnutrition – one or all components missing from diet. Secondary/conditional malnutrition – supply of nutrients adequate but malabsorption, impaired use or storage, excess losses or increased needs.

Causes undernutrition in Western countries 1. ignorance and poverty (homeless, aged, children of poor) 2. chronic alcoholism (protein energy malnutrition + deficiency thiamine, pyridoxine, folate, Vit A – decreased intake, poor absorption, abnormal use and storage, increased metabolic needs, increased rate loss) 3. acute and chronic illness 4. self-imposed dietary restriction (eating disorders) 5. malabsorption syndromes, genetic disease, drug therapies (block uptake or use of particular nutrients)

Features of protein energy malnutrition PEM = a range of clinical syndromes characterized by inadequate dietary intake of protein and calories to meet the body’s needs. 2 protein compartments in the body: 1. somatic compartment (skeletal muscle – affected more by marasmus) 2. visceral protein compartment (affected more by Kwashiorkor) Child <80% normal weight = malnourished Child <60% normal weight = marasmus - growth retardation, loss of muscle due to catabolism, depletion of somatic protein compartment 11 - serum albumin near normal - loss of muscle and subcut fat – extremities emaciated - anaemia and multivitamin deficiencies, evidence of immune deficiency esp T CMI Kwashiorkor - protein deprivation greater than reduction in total calories, esp African children on exclusively CHO diet - more severe malnutrition than marasmus - severe loss visceral protein compartment, hypoalbuminaemia – generalized or dependent oedema - wt 60-80% of normal but masked by oedema - relative sparing subcut fat and muscle mass - skin lesions: alternating zones of hyperpigmentation, areas of desquamation, hypopigmentation – flaky paint appearance - hair: loss of colour or alternating bands pale/dark hair - enlarged fatty liver - also other vitamin deficiencies, defects in immunity and secondary infections

Features of PEM Common complication of advanced cancer and AIDS – cachexia. 2 syndromes: 1. Marasmus-like protein energy malnutrition – in chronic illness/months – history wt loss, muscle wasting, absent subcut fat, normal or mild reduced serum proteins, variable prognosis – depends on underlying disease 2. Kwashiorkor-like protein energy malnutrition – in acute, catabolic illness (severe trauma, burns, sepsis), occurs over weeks; normal fat + muscles, oedema, easily pluckable hair, low serum albumin – poor prognosis

Central morphologic changes of PEM - growth failure, peripheral oedema in kwashiorkor, loss body fat and atrophy muscle – marked in marasmus - liver in kwashiorkor enlarged and fatty - small bowel decrease in mitotic index in crypts of glands, assoc with mucosal atrophy and loss of villi and microvilli – disaccharidase deficiency - bone marrow hypoplastic due to decreased no red cell precursors - infant brain: cerebral atrophy - thymic and lymphoid atrophy - anatomic alterations induced by intercurrent infections, esp endemic worms - deficiencies other required nutrients

Clinical findings in anorexia nervosa Similar to those in severe PEM, with addition of prominent endocrine effects: - amenorrhoea – from ↓ secretion of GnRH - ↓ TSH release - skin dry and scaly, yellow dye to xs carotene - increased lanugo - bone density ↓ due to ↓oestrogen levels - anaemia, lymphopenia, hypoalbuminaemia - ↑ susceptibility to cardiac arrhythmia and sudden death, likely due to hypokalaemia - in bulimia aspiration gastric contents and oesophageal rupture

Vitamins Fat soluble vitamins = D, E, K, A D, K, biotin and niacin are endogenously synthesised to some degree

Vitamin A - a group of chemicals including retinol (=transport form), retinal (=form used in visual pigment), retinoic acid - dietary sources: animal derived, yellow and leafy green vegetables eg. carrots, squash, spinach – proved carotenoids, many of which are pro-vitamins that can be metabolised to active Vit A - fat-soluble vitamin – requires bile, pancreatic enzymes and anti-oxidant activity in food for absorption - β-carotene – intestinal mucosa – retinol transported in chylomicrons to liver for esterification and storage – mostly in Ito cells; reserves sufficient for at least 6 months deprivation - functions: normal vision in reduced light, potentiating differentiation of specialized epithelial cells, mainly mucus secreting cells; enhancing immunity to infections, esp in children - deficiency: impaired vision, night blindness, xerophthalmia – Bitot’s spots, corneal , keratomalacia; squamous metaplasia resp and urinary tracts; follicular or popular dermatosis; immune deficiency

12 - toxicity: acute hypervitaminosis: headache, vomiting, stupor, papilloedema; also weight loss, N/V, dry lips, bone and joint pain, hyperostosis, hepatomegaly with parenchymal damage and fibrosis; ↑ incidence congenital malformations if use synthetic retinoids in pregnancy

Vitamin D - major function: maintenance normal plasma levels calcium and phosphate o stimulates intestinal absorption calcium and phosphorus o collaborated with PTH in mobilization calcium from bones o stimulates PTH-dependent reabsorption calcium in distal renal tubules - sources: o endogenous synthesis in skin – 7-dehydrocholesterol in skin – UV converts to Vit D o diet – deep-sea fish, plants, grains – present as precursor ergosterol – converted to Vit D 2 in body - metabolism: o absorption in gut or synethesis from precursor in skin o binding to plasma α 1-globulin and transport to liver o conversion to 25-hydroxyvitamin D by 25-hydroxylase in liver o conversion to 1,25-dihydroxyvitamin D by α 1 – hydroxylase in kidney – biologically most active form

- production 1,25-dihydroxyvitamin D regulated by 3 mechanisms: o ↑ levels 1,25 down-regulate synthesis by inhibiting action of α 1 – hydroxylase, and ↓ levels have opposite effect o ↓ calcium stimulates secretion PTH, stimulating conversion 25- to 1,25 by activating α 1 – hydroxylase o ↓ phosphate directly activates α1 – hydroxylase - deficiency: o rickets or osteomalacia:  inadequate synthesis or dietary Vit D - ↓ , ↓ intake, ↓maternal nutrition, dark skin  ↓ absorption of fat soluble Vit D  deranged metabolism  end-organ resistance  phosphate depletion - morphology of rickets: o overgrowth epiphyseal cartilage due to inadequate calcification o persistence of distorted, irregular masses cartilage can project into marrow cavity o deposition osteoid matrix on inadequately mineralised cartilage remnants o disruption orderly replacement cartilage by osteoid matrix o abnormal overgrowth capillaries and fibroblasts – weak, poorly formed bone o loss of structural rigidity – deformation skeleton o infancy: frontal bossing, squared appearance head, rachitic rosary = deformation chest, pigeon chest deformity, Harrison groove due to inward pull at margin of the chest o ambulatory child: lumbar lordosis and bowing of the legs o adults: osteomalacia – deranged normal bone remodelling that occurs throughout life: xs persistent osteoid – bone weak and vulnerable to fractures or microfractures, most likely affect vertebral bodies and femoral necks. Persistent failure of mineralization in adults = osteopenia

Vitamin E - sources: vegetables, grains, diary products, fish and meat; diet sufficient to sustain life unlikely insufficient - fat soluble

13 - transported in blood in chylomicrons, accumulates in fat depots and in liver and muscle - one of a group of antioxidants that scavenge free radicals - plays a role in termination free -generated lipid peroxidation chain reactions - 3. possible role in prevention of atherosclerosis and cancer - deficiency: o occurs with fat malabsorption, infant low birth weight with immature liver and GIT, abetalipoproteinemia, rare AR syndrome of impaired Vit E metabolism o 1. degeneration axons in posterior columns of spinal cord, with focal accumulation lipopigment and loss nerve cells in dorsal root ganglia – depressed DTRs, ataxia, dysarthria, loss of position and vibration sense, loss of pain sensation, impaired vision o 2. Vit E-deficient erythrocytes more susceptible to oxidative stress, have shorter half-life in blood

Vitamin K - functions: cofactor for liver microsomal carboxylase necessary for production of clotting factors II (prothrombin), VII, IX, X o activation anticoagulant proteins C and S also requires glutamate carboxylation o Vit K may favour calcification of bone proteins - sources: o Vit K in liver oxidized to epoxide but then promptly recycled o endogenous intestinal bacterial flora synthesise Vit K o widely available in Western diet - causes of deficiency: o fat malabsorption syndromes o destruction endogenous Vit K-synthesizing flora (broad spectrum Abs) o neonatal when liver reserves small, flora not well developed, and Vit K in breast milk low o diffuse liver disease – hepatocyte dysfunction interferes with Vit K dependent clotting factors - deficiency consequences: o bleeding diathesis – haemorrhagic disease of the newborn, haematomas, haematuria, maelena, ecchymoses, bleeding gums

Thiamine - sources: widely available in diet - functions: o regulates oxidative decarboxylation of α keto acids, leading to synthesis of adenosine triphosphate o cofactor for transketolase in pentose phosphate pathway o maintains neural membranes and normal nerve conduction - causes of deficiency: o diets of polished rice, refined food only o alcoholism (subclinical deficiency may be converted to overt disease by iv glucose therapy/refeeding) o pernicious vomiting of pregnancy o debilitating disease that impairs appetite, predispose to vomiting or cause protracted diarrhoea - clinical effects of deficiency/ 3 syndromes: o polyneuropathy – dry beriberi (symmetric, lst in legs with foot or toe drop, sensory changes) o cardiovascular syndrome – wet beriberi (flabby, dilated heart, peripheral vasodilation, high-output cardiac failure, peripheral oedema) o Wernicke-Korsakoff syndrome (Wernicke encephalopathy – ophthalmoplegia, nystagmus, ataxia, confusion, apathy, listlessness, disorientation; Korsakoff psychosis – retrograde amnesia, inability to acquire new information, confabulation) o CNS lesions affect mamillary bodies, thalamus, floor of fourth ventricle, anterior cerebellum

Riboflavin - critical component coenzymes flavin mononucleotide, flavin dinucleotide, in a wide range of red-ox reactions - sources: meat, dairy products, vegetables - Ariboflavinosis occurs as primary or secondary deficency states: o chelosis (angle of mouth pallor, crack, secondary infection) o glossitis (atrophic red-blue tongue) o ocular changes: superficial interstitial keratitis o skin: greasy, scaling dermatitis over nasolabial folds, butterfly distribution o bone marrow hypoplasia

Niacin - = nicotinic acid – nicotinamide an essential component of 2 coenzymes: NAD and NADP - both play play central roles in cellular intermediary metabolism 14 - sources: grains, legumes, seed oils, small amounts in meats; synthesized endogenously from tryptophan - deficiency: pellagra o (3 D’s) – dermatitis, diarrhoea (atrophy/ulceration GI mucosa), dementia (degen neurons in brain) - causes: alcoholics, debilitating illnesses, protracted diarrhoea, diets deficient in protein, long tem drugs eg. isoniazid and 6-mercaptopurine

Pyridoxine - = Vit B6 - sources: virtually all foods, but food processing may destroy it - causes of deficiency: o infants fed cheap milk formula o secondary due to pyridoxine antagonists (isoniazid, oestrogens, penicillamine) o alcoholics due to acetaldehyde enhancing pyridoxine degradation o pregnancy – increased demand - clinical findings: o seborrheic dermatitis, cheilosis, glossitis, peripheral neuropathy, seizures

Vitamin C - ascorbic acid - sources: cannot be synthesized endogenously – dependent on intake in milk, fish, fruit, veges - functions: accelerates hydroxylation and amidation reactions, activates precursors for procollagen - antioxidant properties (with Vit E) - deficiency: scurvy o haemorrhages due to defect in collagen synthesis – inadequate support of walls of capillaries and venules – , ecchymoses in skin and mucosa o loose attachment of periosteum to bone, with vascular wall defects – subperiosteal haematomas, bleeding into joints o cartilaginous overgrowth, bowing of long bones of lower legs, abnormal depression sternum with outward projection of ribs o gingival swelling, haemorrhages and bacterial periodontal infection o perifollicular, hyperkeratotic, papular rash o wound healing and localization of focal infections impaired o anaemia due to bleeding and due to impaired iron absorption o potentiates other bleeding eg. SAH

Folate - function: essential cofactor in nucleic acid synthesis, conversion to active form required Vit B12 - sources: whole-wheat flour, beans, nuts, liver, green leafy veges (heat labile, depleted in cooked food) - causes of deficiency: dietary, OCP, anticonvulsants, ethanol, smoking interfere with absorption/metabolism; chronic diseases such as malabsorption and metastatic cancer - deficiency: either folate or Vit B12 – megaloblastic anaemia; increased incidence neural tube defects; ?increased risk colon cancer

Trace elements - metals that occur at concentrations smaller than 1 microgram per gram of wet tissue: iron, zinc, copper, selenium, iodine

Zinc - sources: meat, fish, whole-grain cereals, legumes - deficiency uncommon and usually only those on TPN or with genetic abnormality of absorption - deficiency: o distinctive rash (haemorrhagic dermatitis) – around eyes, nose, mouth, anus, distal parts = acrodermatits enteropathica o growth retardation in children o hypogonadism with infertility o also anorexia, diarrhoea, impaired wound healing, altered immune function, impaired night vision due to altered Vit A metabolism, depressed mental function, increased incidence congenital abnormalities in infants of zinc-deficient mothers

Selenium - component of glutathione peroxidase, protects against oxidative damage of membrane lipids - deficiency: Keshan disease o congestive cardiomyopathy, myopathy 15 Copper - component of cytochrome c oxidase, dopamine beta-hydroxylase etc - deficiency: muscle weakness, neurologic defects, hypopigmentation, abnormal collagen cross-linking

Other trace elements - iron – hypochromic macrocytic anaemia (essential component Hb) - zinc – component essential enzymes - iodine – thyroid hormones (deficiency: goitre, decreased thyroid hormone) - fluoride – deficiency: dental caries

Obesity - disorder of energy imbalance, where food-derived energy chronically exceeds energy expenditure, with excess calories stored as triglycerides in adipose tissue - body fat measure by: o BMI o skinfold measurements o ratio waist: hip circumference – central/visceral obesity higher risk o neurohumoral mechanisms involved in weight control  adipocytes communicate with hypothalamic centres that control appetite and energy expenditure by secreting a polypeptide hormone called leptin (antiobesity factor) - increased risk of: gallstones, pancreatitis, hernias, metabolic syndrome, type 2 DM, PCOS, increased lipids, HTN, CAD, CHF, arrhythmias, DVT/PE, OSA, OA, gout, LBP, infertility, BIH, cancers

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