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ACMT MEDICAL TOXIOLOGY SUB-BOARD
REVIEW COURSE: INDUSTRIAL TOXINS- DUSTS
AND GASES Jeffrey Brent, M.D., Ph.D. Toxicology Associates University of Colorado
School of Medicine
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Occupational Exposure levels
• OSHA PEL = an 8 hr TWA STEL/Ceil = 15 minute max
• ACGIH TLV = TWAs– also 8 hr STEL
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Pneumoconiosis
• The accumulation of dusts in the lung and reactions, if any, to them
• Radiographically evaluated by B-readers using ILO classification
• CT more sensitive
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Which Pneumoconioses Are Fibrogenic?
Fibrogenic dusts Silica (crystalline) Mica Graphite Beryllium Coal dust Asbestos Talc Not all patients with
pneumoconiosis from the above develop fibrosis
Non-fibrogenic dusts Tin (stannosis) Barium (baritosis) Iron (siderosis)
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What is this?
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Coal workers’ Pneumoconiosis “Black Lung”
• Caused by iron in coal dust Types
Simple coal workers pneumoconiosis CWP complicated by fibrosis Silicosis COPD • Pathognomonic lesion is the coal dust macule = coal
dust filled macrophages • Smoking not a risk factor • Not an accepted risk factor for lung ca • Exposure limits based on amount of silica exposure
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What do you see in this slide?
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Asbestos
• Natural hydrated magnesium silicate fibers
• OSHA expresses the asbestos PEL as fibers/mm3 in air
• All disease caused only by inhalation exposure
• It is not systemically absorbed by any route but inhaled fibers can migrate
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Types of Asbestos Fibers 2 types
1. Serpentine (“white asbestos”) = chrysotile Fibers tend to be degraded after inhalation Curly fibers
2. Amphiboles (“brown asbestos”) 5 sub-types (most disease assoc. with crocidolite) Fibers resist degradation Tendency to migrate Straight fibers This is the form that causes mesothelioma
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Asbestos – Related Diseases • Only clearly established target organ is lung
and surrounding tissues • All have long latencies 1. Asbestosis 2. Malignancies
A. Bronchogenic carcinoma B. Mesothelioma C. Larynx D. Ovary
3. Non-malignant pleural disease • Does not cause:
COPD
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Asbestosis • A fibrogenic
pneumoconiosis • ↑ Risk c smoking • Due to persistent
inflammation of non-degradable fiber
• CXR may be read by B-reader
• HRCT is better
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2 Pulmonary Asbestos-Related Malignancies Established
Bronchogenic Ca • Risk ↑ > 10 X for smokers Mesothelioma • Only non-asbestos cause =
eronite (a naturally occurring fiber found in Turkey)
• No ↑ risk with smoking
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Asbestos-Related Pleural Disease
• Effusions • Plaques
– The most specific sign of asbestos exposure
• Pleural thickening • Rounded atelectasis
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Diagnosis of Asbestos-Related Diseases
• Asbestos bodies are only a marker of exposure, not dose or disease
• Fiber counts – Obtained PM, or by bx (not BAL) – Correlate with dose, hence risk
• CXR Useful but can be of low
sensitivity • CT (partic high resolution)
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ORGANIC TOXIC DUST SYNDROME
• Occurs after inhaling dust containing large amounts of mold spores
• May be due to spores or substances produced by them
• Immunological reaction
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Man Made Mineral Fibers
• Fiber Glass • Mineral wool • Refractory Ceramic fibers
Documented Health Effects 1. Skin irritation 2. Upper respiratory tract irritation
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CO • Sources:
– Incomplete combustion – Metabolism of methylene chloride
• 200 – 250 X the affinity of O2 for Hb • Approx. 15% of an inhaled dose is
distributed into tissues • Elimination T1/2s (of COHb)
– Room air: 4-5 hrs – 100% O2: 1-2 hrs – HBO: 20 – 30 min
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Methylene Chloride
• CH2Cl2 (aka dichloromethane) • Good dermal and pulmonary
absorption • Used for paint-stripping, bath tub
refinishing • Metabolized to CO • Peak may be many hrs post-exposure • Ongoing production gives an apparent
T1/2 of approx. 13 hrs
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Pathophysiology of CO Poisoning
• Binds heme groups • Ischemia reperfusion type injury • Ultimately neuronal necrosis or
apoptosis • Structures affected:
– Basal ganglia – hippocampus – Cortex – Cerebellum – Substantia nigra
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CO
Inhibition of Cytochrome Oxidase
Glutamate Peroxynitrite
NO release from platelets
Endothelial Damage
Tissue Hypoxia
WBC Adherence
Proteases Xanthine DH Xanthine
Oxidase Free radials
Ca++ release/lipid peroxidation
NMDA Receptor Agonism
Neuronal Injury
Necrosis/Delayed Apoptosis
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Diagnosis of CO Poisoning • Generally from COHb level
– CO endogenously formed from catabolism of protoporphyrin to bilirubin
– Refrigerated samples stable for weeks – Should be measured c a co-oximeter – Bedside reagent based tests unreliable
• Pulse oximeters read COHb as oxyHb • Plasma CO can be measured but interpretation
not validated • Back extrapolations unreliable
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HBO Therapy of CO Poisoning • Indications controversial
– Neuro impairment • Cerebellar dysfxn • > 36 yrs old
– CV dysfunction – Pregnancy – CO Hb Levels?
• Supplies enough dissolved O2 in the plasma to meet metabolic needs
• Inhibits lipid peroxidation • Speed regeneration of cytochrome oxidase • Reduces leukocyte adherence to endothelium • Prevents learning/memory deficits in CO poisoned
rodents • Meta-analysis (Buckley et al, Toxicological Reviews,
2006: RR for neuro sequelae 0.77 ( 0.51 – 1.14)
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CO Poisoning in Pregnancy
• Primates - CO exposure preferentially affects fetus: – Intrauterine hypoxia – Fetal brain injury – Fetal demise
• Effects can occur with clinically normal mothers • HBO standard of care? • Indications controversial – hopefully not a board
question
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Cyanide
• HCN causes the acute toxicity • pKa = 9.5 • So, HCN formed if pH < 10-11
Ex. NaCN + HCl → ↑ HCN + NaCl
• This can even happen with H2O such as when cyanide salts are used in fumigation or rodent burrows
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Cyanide detoxification
• Naturally occurs by combination with sulfane sulfur to form thiocyanate
• Rapidly taken up into RBCs • Has high affinity for Fe3+ • Has high affinity for Co2+
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Glucose
glycolysis
Pyruvate
NAD
NADH
Krebs cycle
NAD
FAD
FADH
FADH NADH
Electron Transport Chain (cytochrome aa3)
ATP ADP
FAD
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Glucose
glycolysis
Pyruvate Lactate
NAD
NADH
Krebs cycle
NAD
FAD
FADH
FADH NADH
Electron Transport Chain (cytochrome aa3)
ATP ADP
FAD
CN-
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Cyanide Poisoning ACUTE
• > 10 PPM: toxic effects > 100 PPM: potentially lethal
• Metabolic acidosis • Lactic acidosis • Distribution into brain and myocardium • Carotid body stimulation → hyperventilation • Inhibits glutamate decarboxylase → ↓GABA • Persistent neuro deficits possible
– One of the basal ganglia toxins
Chronic • SCN- competes with iodine for uptake into thyroid → goiter &
hypothyroidism
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Diagnose CN- poisoning by serum (or plasma) levels
• These best correlate with tissue levels • Whole blood levels may be artificially
elevated during the analysis
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Methemoglobin as a cyanide antidote
• Effective because: – Affinity of CN- for Fe+3 – Concentration of CN- in RBCs
• Sodium nitrite: – Dose: 300 mg (adult) = 10 cc of 3% – Generates MetHg fraction in the teens – MetHb fraction ↑ with anemia or children so ↓ dose – Pediatric dose (nl HCT) 10 mg/kg = 0.33 cc of 3%/kg – May also work as a vasodilator
• 4-Dimethylaminophenol – Also a MetHb former – Used primarily in Germany
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CN- MetHb Cytochrome aa3
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Sodium Thiosulfate
• Source of sulfane sulfur • Synergistic with nitrites (or
hydroxycobalamin) • Adult dose 12.5 grams (50 cc of 25%) • Pediatric dose:
– 410 mg/kg (1.65 cc of 25%/kg)
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The antidotal treatment of cyanide poisoning has
completely changed • The old – cyanide treatment kit
1. Amyl nitrite pearls – good for getting high, doesn’t’ do much for cyanide toxicity
2. Sodium nitrite 1. MetHb former 2. Vasodilator
3. Sodium thiosulfate – complexes with CN-
• The new – hydroxocobalamin
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Hydroxocobalamin
What it is – “Vit B12” (cobalamins) = a group of
compounds that can be interconverted – Hydroxocobalamin (HC) is one – The most common is cyanocobalamin – The active form is methylcobalamin – HC + CN-→ cyanocobalamin (irreversible)
Methylcobalamin Urine
Geraci 2011
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Doses of hydroxocobalamin to know
• Adults: – 5 g IV over >15 min
• Peds: – 70 mg/kg over > 15 min
• Adverse effects: – Flushing – Turns skin red – Interferes with colorimetric tests – BP
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NITROGEN OXIDES • NOX =
– Nitric oxide (NO) – Nitrogen dioxide (NO2) – Nitrogen tetroxide (N2O4)
• NO2 has low water solubility – Penetrates deep into resp tract – Causes oxidative injury – Excreted after oxidation as nitrate – Chronic low level exposure can cause ↑ airway reactivity
and respiratory illnesses • NO has low water solubility
– Penetrates deep and is absorbed as NO – Very high affinity for Hb → metHB – Excreted as urinary nitrate
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Sources of NOX to know
• Major environmental source is the burning of fossil fuels
• Contact of nitrogen acids with organic material
• Ice skating rinks (from Zambonis) • Welding • Gas stoves • Silos (Silo Filler’s disease)
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Acute inhalation of NOX may have a multiphasic course
1. Acute pulmonary sxs at time of exposure • CXR may be normal at this time • Initial sxs can be mild • Can see bronchospasm • ? Use minimal oxygen supplementation
2. May have asymptomatic period of hours (up to 12) 3. May then develop ALI (can see methemoglobinemia in this
stage) 4. Apparent recovery 5. May develop BO up to a month after exposure
• Initially prevents as acute febrile illness • May occur even in absence of stage 3
6. Some patients may develop chronic bronchitis with obstructive or restrictive patterns on PFTs
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Sulfur Oxides
SO2 is the principal one – Highly irritating – Water soluble → affects upper resp tract
and mucus membranes and bronchoconstriction
– Massive exposures can cause deep pulmonary injury
– Pungent odor
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What causes the effects of SO2 exposure?
Effects may be due to: 1. SO2 2. H2SO4 3. Bisulfite (strong bronchoconstrictor in
asthmatics) • Asthmatics and atopics have ↑ susceptibility
4. Hydrogen bisulfite
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H2S • Irritant • Rotten egg odor • Combines with Fe+3 • Sources:
Decomposition of organic matter Oil wells/petroleum refineries Kraft Paper mills Smelters Tanning processes Natural springs Waste water treatment
• Can be released when sulfur containing molecules are acidified
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H2S Poisoning • “Gas eye”: Keratoconjunctivitis • Mucus membrane and pulmonary irritant
– Impairs ciliary action → pneumonia • Pulmonary edema/ARDS • Respiratory depression at approx 1,000 PPM • CNS depression • AA3 poison • Non-specific enzyme inhibitor • Forms sulfHb, but levels not clinically predictive • Darkens coins • Does not bioaccumulate
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Treatment of H2S Poisoning
• Supportive care/O2 • Rescuers beware:
– Knock down potential at approx. 1,000 PPM
– Olfactory fatigue at approx. 100 PPM – Rescuers have been poisoned by mouth-
to-mouth resuscitation • ? metHb induction with sodium nitrite
– No role for thiosulfate • HBO - anecdotal
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RADON
• Naturally occurring • Formed from decay of U238 in rocks &
soil • Radon & its daughters emit α particles
Radon also emits beta particles
• Can concentrate in houses due to negative pressure created by air rising from lower levels
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U 238
Radium 226
α particles T1/2 1600 yrs.
Radon 222
T1/2 3.8 days α & β particles
Multiple steps – Radon Daughters
Pb
α particles
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Radon Levels If it is not in green forget it for
the test • Measured in picocuries/L or becquerels/M3 • Typical levels are:
– Outdoor 0.2 pc/L – Indoor 1.2 pc/L
• One “Working level” (WL) = 1.3 X 105 MeV of α energy/L
• 1 pc approximates 0.0005 WL • One WLMonth = exposure to 1 WL X 170 hours • Level for home remediation = 2 WLM • ¾ of US homes have levels < 4 pc/L • It is generally recommended that remediation take
place at 11 pc/L
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Radon- Health Effects
• Lung cancer from breathing in α particles – Based on studies done on uranium miners
• Synergistic effect with smoking
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That’s it. Good Luck on the boards!!