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Toxicology of Specific Agents: Alcohols, gas, metals, caustic agents,…
Toxicology of Specific Agents: Alcohols, gas, metals, caustic agents, pesticides, therapeutic drugs, drugs of abuse.
Poison : any (exogeneous) substance that causes
harmful effect upon exposure. It is adverse effect on biological system. Ex: Venoms, poison hemlock, arsenic, lead, co.
Three disciplines: 1. mechanistic: development of
tests to assess the degree of exposure to cause cellular/biochemical effects of toxins. 2. descriptive: by animal experiment to predict level of exposure will cause
harm to humans. 3. Regulatory: Based 1 and 2 to Establish standards that define acceptable levels of exposure .
3 Specialties : Forensic, Clinical, Environmental.
Clinical Toxicology: focused on human poisoning. d/t: Drug overdose, Toxic exposure: environmental, occupational, accidental
Xenobiotics = exogenous agents; ex: antibiotics, medications (antidepressants
Toxins= endogenous biological substances, synthesized in a cell or microbe. Eg. C. botulinum toxin, hemotoxin (snake venom),
Common route of exposure: Transdermal absorption, Inhalation, Ingestion (can cause systemic effect or local effect: diarrhea, , bleeding , malabsorption.).
Carbon Monoxide
odorless, colorless, and tasteless
Primary environmental sources: gasoline engines, improperly vented furnaces, wood or plastic fires
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Decreases amount of O2 to tissue, producing hypoxia (left shift of the oxygen-hgb curve)
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Quantitative tests: 1. Differential spectrophotometery: different forms of Hgb present with different absorbance curves. 2. GC: reference method
Cyanide
as a gas (smells like almonds), solid (white)or in solution (Colorless liquid).
Exposure: inhalation, ingestion, transdermal absorp
Cyanide binds to ferric heme iron in mitochondrial cytochrome oxidase--Blocks electron transport -- O2 cannot accept electrons-- No ATP--cytotoxic hypoxia & lactic acidosis
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Arsenic (AS)
shellfish (Rapidly absorbed & cleared (w/in 48hrs), less harmful), Arsine gas (inhalation is most acute/toxic), agriculture and industry
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Lower dose chronic exposure: peripheral sensor motor neuropathy, skin eruptions, and hepatotoxicity. cancer (Bowen's disease)
Atomic absorption spectrophotometry. Sample: for acute within hours withdraw blood, or urine within 6 days. Chronic: hair and fingernail (Mee's lines) d/t bind to sulfhdryl groups in keratin. Detected 2 weeks after exposure
Lead (Pb)
toxicity effects dose
Low exposure: decrease IQ, hearing and growth. Behavioral changes, hyperactivity, ADD
High dose: Encephalopathy (cerebral edema and ischemia). Stupor, convulsions and coma
leaded dust / airborne, contaminated soil, 75-120μg/day/adult which is largely tolerated
Toxicity: Binds to many macromolecular to inhibit many enzymes, decrease vitamin D metabolism & heme synthesis. slowly elimination by kidney
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Basophilic stippling: rbc process occur the granules represent ribosomal precipitates. small, dark blue granules within red blood cells
Treatment: with chelators. Blood draw: tan-top K2EDTA tube. Analysis: Graphite furnace AAS or ICP-MS
Mercury Hg
3 forms: elemental (liquid at RT) – least toxic, inorganic salts – moderately toxic, component of organic salts – extremely toxic (tuna,swordfish))
Exposure: inhalation, ingestion.
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bind intestinal protein, acute GI ex: ulceration, necrosis --bloody diarrhea
symptoms: Tachycardia, tremors, thyroiditis. Disruption of renal function, neurologic symptoms
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Alcohol determination: cleaned with alcohol free disinfectant. Serum, plasma, whole blood (fluoride oxalate for non-sterile spec/long term storage): keep capped. Legal blood alcohol level (80 mg/dL = 0.08%
BAC) “chain-of-custody”
Method: Ethanol + NAD+ --- non-human ADH --> acetaldehyde NADH. NADH : sepctrophotometer 340mm. However, It cannot rule out other alcohols.
Method 2: GC (Gas Chromatography): reference method. separating, identifying, and quantifying components in a mixture, widely used. Quantitative for all kinds of alcohols. only method that is valid for legal cases & acceptable in the court of law
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Cadmiun (Cd)
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contaminated work places (Electroplating, galvanizing), eating contaminated foods (bind with soil and agricultural crops ), tobacco
Toxicity: binds to protein or cellular, can Accumulates in the kidneys , causes nephrotoxicity f/t the half life 10 yrs.
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Pesticides
Exposure: ingestion (major route), inhalation, transdermal
Organophosphates & Carbamates is acetylcholinesterase (AChE) inhibitors. acetylcholine = neurotransmitter that stimulates muscle cells & endocrine/ exocrine glands. when AChE is inhibited uncontrolled firing of nerves)
Low: salivation, involuntary urination/defecation. High: muscular twitching, cramps, abnormal heart rate, weakness, paralysis, respiratory failure
AChE testing: measure in erythrocytes. it is Sensitive & specific. 2. screening test, more common: Serum pseudocholinesterase (SChE) activity. Treat: Pralidoxime (AChE regenerator)
Labs
- Resp acidosis = narcotics (CNS depressant)
- Resp alkalosis = early salicylate ingestion
- Metabolic acidosis = ethylene glycol, mannitol
- Anion Gap (MUDPILES): Methanol, Uremia, Diabetic ketoacidosis, Propylene glycol, Iron/infection, Lactic acidosis, Ethylene glycol, Salicylates
- Alcohol: Widespread usage: acute alcohol intoxication, and chronic usage/dependence. Biotransformation: Alcohol --AHD--> Aldehyde --ALDH--> Acid
Ethanol--the middle produce: acetaldehyde is toxic, carcinogen, can covalently bind to various proteins to alter fcn & structure
Then the process also cause Lots of NADH : suppress glycolysis , TCA cycle. hypoglycemia + possible lactic acidosis
Or increase Acetyl-CoA: increase Fatty acid synthesis and decrease metabolism of FA--hence fatty liver)
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Sx type & collection timing depend on toxicokinetics: ex analyte stability, elimination patterns,
2 steps: 1.Screening: rapid, simple, qualitative to detect presence or absence (good sensitivity but lack specificity). Immunoassay, TLC
- Confirmation: screening is positive, commonly use gas chromatography. Generally quantitative. GC-MS, ICP-MS, AA
Caustic Agents
Common Exposure Routes
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Once exposure, rapid onset of metabolic acidosis/alkalosis. Therapy (for ingestion): dilution
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Drug testing
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- “Spot” testing: screen with good sensitivity, Eg. immunoassays and TLC)2. Confirmatory testing: quantitative; high specificity & sensitivity (Eg. GC-MS methods)
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Acute toxicity: single, short-term exposure , but sufficient dose to cause immediate toxic effects
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Methanol: under the hepatic by NAD-->NADH. metabolism into Formic acid --severe acidosis (leading to death) & optic neuropathy (leading to blindness). 50-100 ml can be lethal.
Isopropanol (called rubbing alcohol with long half-life, severe acute–phase ethanol like symptoms) under the hepatic ADH--> acetone (“fruity” odor on breath). Both has CNS depressant effects.
Ethylene Glycol= hydraulic fluid and antifreeze. Under the hepatic ADH and ALDH-->Glycolic acid -->Oxalic acid . Both acid can cause severe acidosis and renal tubular damage from calcium oxalate. Lethal dose: 100ml.
MDMA. Amphetamine derivative. Causes; Hallucinations, euphoria, increased visual & tactile sensitivity, tachycardia, respiration depression. onset effect 30-60min.
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Sedative: Barbiturates: Phenobarbital, Benzodiazepines: Diazepam (Valium), ),
Nomograms: Predicts toxicity, but Not appropriate for
alcohol users