Toxicology Principles and Exposure Testing

Toxicologic laboratory work starts with vocabulary and strategy. A xenobiotic is any exogenous substance capable of adverse biological effects, a term commonly used for environmental and pharmaceutical exposures. A poison is typically of biological, mineral, or gas origin, and a toxin specifically originates from a living organism. Exposure routes are ingestion, the most common clinically, inhalation, and transdermal absorption. Systemic effects require absorption into circulation, mostly by passive diffusion of the nonionized, lipophilic form.¹

Dose-response and testing strategy

Paracelsus’s statement that the dose makes the poison means every substance is toxic at a sufficient dose. Refined characterization plots cumulative response frequency against dose to define ED₅₀, the effective dose in 50%, TD₅₀, the toxic dose in 50%, and LD₅₀, the lethal dose in 50%. The wider the separation between ED₅₀ and TD₅₀, the safer the substance across its useful range, paralleling the therapeutic index in the TDM module. Acute toxicity follows a single sufficient short-term exposure; chronic toxicity follows repeated, individually sub-threshold exposure accumulating over months to years, and it may target different organ systems than acute exposure to the same agent.¹

Testing strategy. Immunoassay screens are presumptive. Confirm with chromatography or mass spectrometry when the clinical or forensic context requires it. Investigate discordant results and recollect when safe. Begin treatment for suspected poisoning while confirmation is pending. Specimen selection must match each compound’s toxicokinetics: methylmercury is predominantly fecal, so urine testing can miss that specific exposure, and 24-hour urine collections or creatinine-normalized random specimens compensate for diurnal excretion variability. Preanalytic contamination from clothing, skin, the collection environment, or container and preservative additives is a recognized hazard for trace-level toxicology and requires certified contaminant-free collection supplies of the kind the trace elements module describes.

Alcohols and glycols

Parent alcohols can cause CNS depression, but their metabolites determine much of the later toxicity. Ethanol forms acetaldehyde then acetate; methanol forms formaldehyde then formate; ethylene glycol forms glycolate and oxalate; isopropanol forms acetone without an acid metabolite.¹

Ethanol. Chronic misuse contributes substantially to hospital admissions and mortality, directly and through accidents, and fetal exposure causes fetal alcohol syndrome. A blood alcohol concentration of 80 mg/dL, 0.08%, is the common U.S. per-se limit for adult noncommercial drivers, but limits vary by jurisdiction and driver category, and the current applicable law controls. Chronic hepatic injury may progress from fatty infiltration to alcoholic hepatitis in some long-term heavy drinkers and then to cirrhosis; acetaldehyde-protein adduct formation is a proposed mediator of chronic tissue damage.

Methods. Enzymatic ADH-based assays monitor NADH generation at 340 nm and are relatively specific to ethanol. Headspace gas chromatography with flame ionization is the medicolegal reference method, simultaneously resolving methanol, isopropanol, and other volatiles. The osmolal gap is a nonspecific adjunct. Using the common ideal conversion, ethanol contributes approximately [ethanol mg/dL]/4.6 mOsm/kg, so 60 mg/dL contributes about 13 mOsm/kg; laboratories use their validated coefficient. The water-balance module owns the osmolal gap calculation.

Methanol is metabolized by hepatic ADH to formaldehyde, then to formic acid. Formic acid produces the characteristic high-anion-gap metabolic acidosis and retinal and optic-nerve injury of methanol poisoning. Isopropanol, rubbing alcohol, is metabolized to acetone, which has a long half-life and causes prolonged ethanol-like CNS depression without the severe acidosis of methanol or ethylene glycol, because isopropanol generates no organic-acid metabolite. Ethylene glycol, antifreeze, is metabolized to glycolic and oxalic acid, producing severe metabolic acidosis and calcium-oxalate crystal deposition that causes acute renal tubular injury. Its sweet taste makes pediatric ingestion a particular hazard.²

The two gaps move in opposite directions over the course of toxic-alcohol poisoning. Early after ingestion, the parent alcohol drives an increased osmolal gap while the anion gap and bicarbonate stay near normal. As the alcohol is metabolized, the osmolal gap falls and the anion-gap acidosis rises; late presentations can show a normal osmolal gap with severe high-gap metabolic acidosis, because the parent osmole is gone while its acid metabolites remain. A normal osmolal gap, like a normal anion gap at any single point, cannot exclude toxic-alcohol poisoning.

Gases and caustics

Carbon monoxide is a colorless, odorless combustion byproduct that binds hemoglobin roughly 200 to 225 times more avidly than O₂. It forms carboxyhemoglobin and left-shifts the oxyhemoglobin dissociation curve covered in the acid-base module, reducing O₂-carrying capacity and impairing unloading from the remaining capacity.³

The associations in the table are approximate. COHb level does not reliably predict symptom severity, prognosis, or treatment response and must be interpreted with exposure timing and clinical findings.

Differential spectrophotometry, multi-wavelength CO-oximetry, is the routine clinical method; gas chromatography is the reference method for accuracy. Hematology owns the erythrocytosis workup where CO exposure is one discriminator.

Cyanide inhibits mitochondrial cytochrome c oxidase, complex IV, blocking electron transport and oxidative phosphorylation and causing histotoxic hypoxia with ATP depletion despite adequate oxygen delivery; venous pO₂ and blood lactate can rise. Rapid enzymatic conversion to nontoxic thiocyanate is the principal clearance route, so chronic low-level exposure is assessed via urinary thiocyanate.

Toxic metals

Arsenic. Arsenic exists as arsine gas, the most acutely toxic route through inhalation; inorganic trivalent and pentavalent forms, highly toxic and found in contaminated water or soil; and organic fish arsenic, arsenobetaine and arsenocholine, which is relatively nontoxic and cleared within about 48 hours. A seafood meal within days of collection can transiently elevate a screening result without indicating true exposure, so interpretation excludes seafood intake before testing. Acute poisoning affects the GI tract with rice-water diarrhea, the bone marrow with pancytopenia and basophilic stippling, the cardiovascular system, and the CNS. Chronic exposure causes hyperkeratosis, hyperpigmentation, Mees’ lines, white transverse fingernail bands appearing about 2 weeks post-exposure, and peripheral vascular disease. Urine is the specimen of choice within about a week of exposure, with more than 90% of an exposure recoverable in urine over 6 days, while blood levels normalize quickly even when urine remains elevated. Representative reference intervals: blood under 13 ng/mL; urine under 35 µg/L, laboratory-specific.⁴

Cadmium. Cadmium has no physiologic role. Sources include tobacco smoke, which doubles lifetime body burden in smokers; battery and pigment manufacturing; and contaminated food from polluted soil. Protein binding mediates cadmium toxicity and concentrates cadmium in the kidney, where it causes early tubular proteinuria, glucosuria, and aminoaciduria; chronic high-dose exposure causes severe osteomalacia and osteoporosis called itai-itai disease. The biological half-life runs 10 to 30 years, so blood levels reflect recent exposure over months while urine levels better reflect cumulative body burden at low exposure. Representative reference interval: blood under 5.0 ng/mL.⁴

Lead. Sources include lead-based paint in pre-1978 housing, contaminated soil and drinking water, and other environmental exposures. Children absorb lead more efficiently. No safe pediatric blood lead level is established, and whole blood, EDTA, is the specimen of choice. The CDC childhood blood lead reference value is 3.5 µg/dL. It is a population reference value used to identify children with higher exposure, not a toxicity threshold, and exposure can harm health below it. Confirm capillary results of 3.5 µg/dL or higher with venous blood. Chelation is specialist management, typically considered at a confirmed venous BLL of 45 µg/dL or higher. Hematology owns the lead-associated anemia and sideroblastic patterns.⁵

Mercury. Mercury occurs as elemental mercury, Hg⁰, one of only two elements, with bromine, that are liquid at room temperature; as inorganic salts of Hg¹⁺ and Hg²⁺; and as organic compounds such as methylmercury, predominantly Hg²⁺ bound to carbon. Sources span dental amalgam, fluorescent lighting, contaminated predatory fish, and historical medicinal and cosmetic use; environmental release occurs both naturally through volcanic degassing and anthropogenically through coal combustion and smelting. Mercury primarily causes toxicity by binding protein sulfhydryl groups, which damages protein structure and function and inhibits enzymes. The three forms differ sharply in behavior:⁶

• Elemental mercury is poorly absorbed by ingestion, where its viscosity lets it largely pass through the GI tract unabsorbed, but its vapor is about 80% absorbed by inhalation and is the most hazardous route. Inhaled vapor readily reaches the CNS and can produce tremor, erethism, and neuropsychiatric disturbance before overt symptoms appear.
• Inorganic mercury salts are only partially GI-absorbed but locally corrosive. Ingestion of moderate amounts can cause severe bloody diarrhea from GI ulceration and necrosis, with the absorbed fraction affecting the kidney through glomerular proteinuria and tubular dysfunction, the heart with tachycardia, and the thyroid.
• Organic mercury. Methylmercury from contaminated fish is efficiently absorbed after ingestion. Dimethylmercury is a separate, exceptionally hazardous laboratory compound that can penetrate ordinary latex gloves. Methylmercury distributes extensively to tissues within about 48 hours, crosses the blood-brain barrier through cysteine-coupled transport, and concentrates in brain and peripheral nerve. It is eliminated mainly in feces, making urine unsuitable for assessing methylmercury exposure, and it persists in brain tissue for years even as whole-body mercury clears within roughly two months.

Total mercury in blood and urine is measured by ICP-MS or cold-vapor atomic absorption spectroscopy without distinguishing chemical form. Hair analysis can establish an exposure timeline but is vulnerable to external contamination. Representative reference interval: under 10 ng/mL, laboratory-specific.

Pesticides

Organophosphates and carbamates inhibit acetylcholinesterase, causing acetylcholine accumulation at central, peripheral, and neuromuscular synapses. Direct parent-compound testing is often limited by rapid metabolism, collection timing, and assay availability. RBC acetylcholinesterase more closely reflects neural acetylcholinesterase inhibition, while plasma or serum butyrylcholinesterase is more available but less specific as an exposure indicator. Butyrylcholinesterase is also depressed by acute infection, pulmonary embolism, hepatitis, cirrhosis, and inherited low-activity variants, all of which must be interpreted before attributing a low value to pesticide exposure.¹