Toxicity

By Dr.Saleh Al -Qadoori
B.Sc., M.Scs., Ph.D. Clinical Biochemistry
Baghdad University - College of Medicine
Study of poisons
There are four major disciplines:
1) Mechanistic: elucidate the cellular and biochemical effects of toxins.
2) Descriptive: uses results of animal experiments to predict harmful effects to humans.
3) Forensic: concerned with medicolegal consequences of exposure to a toxin.
4) Clinical: the study of interrelationships between toxin exposure and disease states (diagnosis & therapeutic
intervention)
Exposure to Toxins
Occurs by various routes:
• Suicide (50%)
• Accidental (30%)
• Rest are related to:
• occupational exposure
• or homicide
Routes of Exposure
• Toxins enter the body by several routes:
1 . Ingestion
• most often seen in a clinical setting
• to exert a systemic effect, they must be absorbed into circulation most are absorbed by passive diffusion.
• If not absorbed they may produce local effects, such as diarrhea, bleeding, or malabsorption of nutrients
2. Inhalation
3. Transdermal absorption
Dose -response relationship
Poison
• any substance that causes a harmful effect upon exposure.
• Dose is a key issue.
• There are various toxic effects from drugs based on dose including death.
• Dose-response implies that there will be an increase in the toxic response as the dose is increased.
Dose -response relationship
• Not all individuals display a toxic response at the same dose.
• Cumulative frequency histogram of the % of people producing a toxic response over a range of
concentrations

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 • TD50
is the dose that would be predicted to produce a toxic response in 50% of the population.
• ED50
is the dose that would be predicted to be effective or have a therapeutic benefit in 50% of the population.
• LD50
is the dose that would predict death in 50% of the population.

Therapeutic index:
The therapeutic index is the ratio of the TD50 to the ED50.

A high therapeutic index is preferable to a low one:

• this corresponds to a situation in which one would have to take a much higher dose of a drug to reach the
lethal threshold than the dose taken to elicit the therapeutic effect.
• Drugs with a large therapeutic index have few toxic adverse effects.

Acute and Chronic Toxicity

Acute toxicity:
associated with a single, short term exposure to a substance, the dose is sufficient to cause immediate toxic effect.
Chronic toxicity:
• associated with repeated exposure for extended periods, at a dose that are insufficient to cause immediate acute
response.

Analysis of Toxic Agents

Two -steps procedure
Screening test:
• which is a rapid , simple analysis that is qualitative procedure to detect specific drug or substance
• Sensitive but lack specificity
• Assay: E.g. immunoassays
Confirmatory test:
• Test utilizing more specificity- and quantitative
• Thin layer chromatography and gas chromatography.
Toxicology of Specific Agents
Alcohol:
Exposure to alcohol causes:
• disorientation
• confusion
• and euphoria
• can progress to unconsciousness, paralysis and with high-level exposure, even death.
• common depressant of the central nervous system.
• There is biotransformation of alcohols to toxic products
Alcohol → Aldehyde → Acid
• Chronic consumption of alcohol over a long period leads to accumulation of lipids in hepatocytes, which
may progress to alcoholic hepatitis and finally to liver cirrhosis.
Methanol:
• Common solvent ingested accidentally
• Death can occur due to the formation of formic acid leading to severe acidosis
• CNS depressant
Isopropanol:
• rubbing alcohol, metabolized by liver to acetone
• CNS depressant

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Ethylene glycol:
• common component of anti-freeze.
• causes crystallization of calcium oxalate within the renal system and cause
tubular damage if dosage high.

Determination of Alcohol
Specimen:
• Do not use alcohol to clean area for vein puncture
• must be capped at all times to avoid evaporation
Methods:
 Gas chromatography.
 Enzymatic method

ADH= alcohol dehydrogenase

Carbon Monoxide
• By product of incomplete combustion of carbon containing substances (gasoline engines, furnaces and
wood or plastic fires.)
• Colorless, odorless and tasteless gas that is absorbed into the blood from inhaled air.
• Toxic effect is due to its affinity for heme (Hb, myoglobulin, etc.).
• Hb affinity has the most effect due to the production of carboxyhemoglobin (~ 200 X greater affinity).
• Major toxic effect of carbon monoxide are seen in organs with high O2 demand (brain & heart)

Methods for CO determination

1 . Spot test:
• using 5 ml of 40% NaOH mixed with 5 ml of 1/20 aqueous dilution of whole blood
• a pink color if CO present at 20% or greater value.
2 . Quantitative method
• Gas chromatography,
• and spectrophotometric methods
Caustic Agents NaOH
• Occupational or household exposure of cleaning agents.
• Aspiration and ingestion present the greatest hazard.
• Ingestion produces lesions in the esophagus and gastrointestinal tract, which may produce perforations.

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• Corrective therapy for ingestion is usually by dilution.

Cyanide
• Supertoxic substance that exist as a gas, solid or in solution.
• Exposure can occur through inhalation, ingestion, or transdermal absorption.
• Found in insecticides and rodenticides
• Toxic effect involves its ability to bind heme iron.
• Cyanide clearance is mediated by enzymatic conversion to thiocyanate, a nontoxic product rapidly cleared
by renal filtration.
• Method for analysis: Ion specific electrode and photometric analysis.

Metals and Metalloids

• Arsenic:
• exist bound or as primary constituent of organic and inorganic compounds.
• Found naturally and can be manmade forms.
• Environmental exposure or occupational
• Absorption of arsenic depends on the form.
• Toxicity related to the binding ability to protein.
• Assay: atomic absorption spectrophotometry.
Lead
• Common environmental contaminant
• Use to be used in household paint and gasoline.
• Exposure can occur in various route- most is through dietary ingestion of contaminated material.
• Toxicity related to ability to bind to macromolecular structures.
• Distributes into the bones and soft tissue.
• Elimination occurs through the renal system.

• Lead toxicity has various physical effects (neurological, decreased intelligence).

• Potent inhibitor of many enzymes (Vit.D, heme synthetic pathway) resulting in changes in bone and
calcium metabolism and in anemia.
• Assay: chromogenic reaction
• Most common method Graphite furnace atomic absorption spectrometry.
Mercury
• Exposure occurs through inhalation and ingestion (contaminated food)
• Toxicity related to ability to bind protein resulting in a change of structure and function.
• Inhibits a number of enzyme activities.
• Many biological effects most noted is renal.
• Assay: AAS
Toxicology of Therapeutic Drugs
Analyze the overdose effects of pharmaceutical drugs.
• Salicylates:
• Aspirin: analgesic, antipyretic, and anti-inflammatory drug.
• Various bodily effects:
• Because aspirin is an acid leads to metabolic acidosis.
• Assay: Gas or liquid chromatography, Immunoassay & Chromogenic method
Cocaine
• Effective local anesthetic with few side effects at therapeutic concentration.
• At High levels it is a potent CNS stimulator.
• Alkaloid salt that can be administered by IV and /or inhaled in free base form.
• Primary product of hepatic metabolism is benzoylecgonine in urine.
• Detected in urine 4-7 hrs after use and detected up to 3 days after single use and 20 days in chronic use.
• Confirmation test is done by gas chromatography.

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Opiates
• Capable of analgesic and anesthesia
• Derived from opium poppy, naturally occurring substances include opium, morphine, and codeine.
• Heroin and hydromorphone are common synthetic substances.
• High abuse potential.
• Acute overdose present with respiratory acidosis due to depression of respiratory center and cardiac
damage.
• Initial detection immunoassay

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