Toxicology

signs and symptoms that are characteristic of a toxic substance ingestion

“red as a beet, dry as a bone, blind as a bat, mad as a hatter, and hot as a hare” Combative and delirious Tachycardic Dry mucus membranes and dry skin Pupils dilated, non-reactive Diminished bowel sounds, distended bladder

Antihistamines Tricyclic antidepressants Phenothiazines (anti-psychotic) Belladonna alkaloids (atropine, scopolamine) Certain mushrooms

Determination of the presence of toxic materials as a reason for illness or symptoms Ordered by a physician for medical care • –Negative screen suggests other cause for signs/symptoms • —Positive screen relevant if consistent with signs/symptions Broad coverage drugs of abuse prescription drugs OTC drugs household or industrial poisons plants Urine (best), blood, gastric, meconium, oral fluid (saliva-forensic, pre-employment) Rapid result turnaround Reduced level of proof (accuracy)

Acetaminophen-Tylenol Salicylates-Aspirin Ethanol Iron (ideally with U[T]IBC or transferrin) Dig, CBZ, VPA, Phenobarb, Theo, Li, Phenytoin COHgb and metHgb by CO-Oximeter Methanol and ethylene glycol (2-4 hr TAT) – —-not common Urine drugs of abuse (qualitative by immunoassay) —-Cocaine, opiates, barbiturates —-Amphetamines, propoxyphene, PCP, tricyclics if prevalent in area

Determination of the presence of toxic materials as they pertain to legal matters Post-mortem – determination of cause of death -Blood, urine, tissue – quantitation (blood, tissue) common Driving – EtOH and possibly others Drugs of abuse –compliance with legal limits -Probation -Pre-employment (esp. Federal) -Limited menu of drugs in urine, oral fluid, sweat Onerous requirements and regulations common -Chain of custody -Testimony may be required

Active ingredient in Tylenol® and many other “non-aspirin pain relievers” —Component of “multi-symptom” cold meds Overdose can lead to irreversible and fatal hepatic failure One of few drugs with specific antidote: N-acetylcysteine (Mucomyst) 100% effective when given w/in 8 hrs of ingestion

Usually via glucuronidation, and sulfation sometimes to a quinone

Rumack nomogram >200 mg/L @ 4 hr Probable risk >150 mg/L @ 4 hr possible risk T1/2 >4 hrs bad sign Samples before 4 hrs may not reflect peak & would under-estimate risk

Immunoassay Enzymatic Arylacylamidase plus o-cresol condensation (blue) Positive interference from bilirubin Therapeutic range: 10-20 mcg/mL Urine spot screening can detect routine use, not just overdose situations (potential clinical false positive) —-Not recommended – serum quantitation needed

Aspirin – acetylsalicylic acid (ASA) Was once the leading cause of childhood poisoning Rapid hydrolysis to salicylate (active metabolite) Salicylic acid – keratolytic gels Oil of wintergreen (methyl salicylate) enhanced toxicity due to inc. CNS penetration Salicylamide – not hydrolyzed to salicylate

Uncouples oxidative phosphorylation metabolic acidosis hyperthermia CNS stimulation hyperventilation respiratory alkalosis Tinnitus – ringing ears Done nomogram more controversial Beware units mg/dL vs mcg/mL (mg/L)

Trinder’s reaction Most common (cheap and stable rgt) Fe3+ complexes with salicylate Req. serum blank due to non-specificity 2-3 mg/dL common Salicylamide does not react (not hydrolyzed) Immunoassay Enzymatic – salicylate mono-oxygenase

Most commonly abused drug 10 mg/dL = 0.01% (w/v) 0.08% (80 mg/dL) is legal limit in all states Legal limit defined in terms of (whole) blood alcohol concentration (BAC), not S/P May be lethal in naive drinkers at 400 mg/dL

Distributes in total body water plasma/serum – 93-95% H2O rbc – 70-75% H2O whole blood – 85% H2O S/P EtOH = 1.14 (1.09-1.18) x BAC Metabolism is zero order (when >20 mg/dL) 15 (11-22) mg/dL/hr in males 18 (11-22) mg/dL/hr in females rate increases with continued alcohol use Medical ethanol results may be used in forensic situations, whether you like it or not

Enzymatic – alcohol dehydrogenase Ethanol + NAD+ ------> Acetaldehyde + NADH Linearity 10 – ~600 mg/dL (variable) Beware evaporation in open tubes/cups (esp. calibrators or controls that sit)

Corrosive – GI hemorrhagic necrosis Shock, acidosis  improvement  liver failure Maximum serum levels at 4-6 hrs post ingestion 500 µg/dL – serious toxicity likely >1000 µg/dL – may be fatal Trf sat’n >100% indicates free iron, likely toxicity Deferoxamine chelation – “vin rosé” urine affects iron assays – wait 4 hrs Stat availability required UIBC/TIBC probably optional but desirable

Colorless, odorless, tasteless gas Density ≈ air (0.97 @20°C) Formed from: incomplete combustion smoking heme metabolism (↑ in in vivo hemolysis) Binds reversibly to Hgb:O2 binding site Hgb:CO affinity ≈ 250x Hgb:O2 affinity Hgb:CO binding also inc. Hgb:O2 affinity Decreased delivery to tissues CO also binds to Mgb and cytochrome a3 CO reference ranges: rural non-smoker :

CO-Oximeter multi-wavelength spectrophotometer associated w/ blood gas instrument hemolyzer very short path length cuvet matrix coefficient calculation of: HgbO2, HHgb (deoxy), COHgb, metHgb Results presented as % of total Hgb Rarely (usually post-mortem) measured by GC Decomposition affects spectrophotometric assay Sample is stable (cf ABG, metHgb)

Remove from source Oxygen administration Dissociation half-life: 5-6 hrs on room air 1.5 hrs on 100% O2 25 minutes @ 2-3 atm O2 (COHgb >25%) Hyperbaric chamber

Hemoglobin with ferric (Fe3+) iron Does not bind O2 Oxidative environment always forming metHgb Countered by two enzyme systems w/in rbc Increased formation from : Nitrites (vasodilators, inhalation)–“locker room”, “rush” Chloroquine, Primaquine – anti-malarials Dapsone – Pneumocystis Rx Sulfonamide antibiotics Lidocaine, benzocaine – local anesthetics Congenital susceptibilities exist

Treatment - methylene blue Reduces ferric metHgb to ferrous HHgb

CO-Oximeter older models had interference from methylene blue Visual – metHgb is chocolate brown MetHgb is unstable Collect and transport on ice (not req’d for COHgb) Do not freeze Measure w/in 4-8 hrs

Methanol Isopropanol Acetone Ethanol Other solvents Acetonitrile – some nail polish removers Ethyl acetate - some nail polish removers Ether (diethyl) – automotive starting fluid Methylene chloride – paint strippe