TOXICOLOGY

Stony Brook University, School of Health Technology and Management -- HAD 432

INTRODUCTION
Toxicology is the study of poisons. Four major disciplines within toxicology:

Mechanistic: cellular & biochemical effects of toxins Descriptive: uses results of animal experiments to predict what level of exposure will cause harm in humans Forensic: medicolegal consequences of toxin exposure Clinical: interrelationships between toxin exposure & disease

EXPOSURE TO TOXINS AND ROUTES OF EXPOSURE

Exposure to Toxins

50% of poisoning cases are intentional suicide attempts. 30% of cases are from accidental exposure. Remainder are a result of homicide or occupational exposure. Most common: ingestion, inhalation, & transdermal absorption Toxins are absorbed by processes intended for dietary nutrients or passive diffusion. Factors affecting absorption: pH, rate of dissolution, gastric motility, resistance to degradation in GI tract

Routes of Exposure

DOSE-RESPONSE RELATIONSHIP
Poison: any substance that causes a harmful effect on exposure Dose & Toxicity

Several systems have been established to index relative toxicity of substances to allow assessment of their potential to harm. Most systems correlate dose of a toxin with harmful responses. More in-depth approach: evaluating data from a cumulative frequency histogram of toxic responses over a range of doses

Acute and Chronic Toxicity

Acute: a single, short-term exposure to a substance Chronic: repeated, frequent exposure for extended periods

DOSE-RESPONSE RELATIONSHIP (CONTD)

Comparison of responses of a therapeutic drug over a range of doses

ANALYSIS OF TOXIC AGENTS

Two-Step Procedure

1. Screening test A rapid, simple, qualitative procedure Intended to detect specific substances or classes of toxicants Has good analytic sensitivity but lacks specificity 2. Confirmatory test Used to confirm a positive result from screening test
Immunoassays (screening), thin-layer chromatography, gas chromatography

Analytic Methods

TOXICOLOGY OF SPECIFIC AGENTS

Alcohol

General toxic effects: disorientation, confusion, euphoria; progressing to unconsciousness, paralysis, & even death Specific toxic effects Ethanol Associated with abusive alcoholic consumption Results in diminution of judgment & motor performance Chronic consumption leads to alcoholic hepatitis, cirrhosis.

TOXICOLOGY OF SPECIFIC AGENTS (CONTD)

Alcohol

Specific toxic effects Methanol (a common solvent) Can cause severe acidosis, leading to death; blindness Isopropanol (rubbing alcohol) Can cause severe acute-phase ethanol-like symptoms Ethylene glycol (component of hydraulic fluid & antifreeze) Ethanol-like effects, severe metabolic acidosis, renal tubular damage

TOXICOLOGY OF SPECIFIC AGENTS (CONTD)

Carbon Monoxide

Produced by incomplete combustion of carbon-containing substances Primary environmental sources: gasoline engines, improperly vented furnaces, & wood or plastic fires A colorless, odorless, tasteless gas rapidly absorbed into blood from inspired air Considered highly toxic due to its affinity for & binding to hemoglobin Decreases amount of oxygen to tissue, producing hypoxia Tests: differential spectrophotometry & gas chromatography

TOXICOLOGY OF SPECIFIC AGENTS (CONTD)

Caustic Agents

Found in many household products & occupational settings Aspiration leads to pulmonary edema, shock, death. Ingestion leads to lesions in esophagus & GI tract, leading to perforations, hematemesis, abdominal pain, shock.

Cyanide
Found in industrial processes, insecticides, rodenticides; produced by burning of some plastics; common suicide agent Expresses toxicity by binding to heme iron Causes headaches, dizziness, respiratory depression, leading to seizure, coma, & death

TOXICOLOGY OF SPECIFIC AGENTS (CONTD)

Pesticides
Substances intentionally added to environment to kill or harm an undesirable life form (insecticides & herbicides) Contamination of food is major route of exposure. Inhalation, transdermal absorption, & ingestion are common occupational/accidental routes of exposure. Wide range of toxic effects: chronic & acute disease states, death Types: organophosphates, carbamates, & halogenated hydrocarbons

TOXICOLOGY OF THERAPEUTIC DRUGS

Salicylates

Aspirin (acetylsalicylic acid) is a common analgesic, antipyretic, & anti-inflammatory drug. Function: decreases thromboxane & prostaglandin formation through inhibition of cyclooxygenase Toxic effects (when ingested at high doses) Metabolic acidosis, possibly leading to death Hyperventilation, respiratory alkalosis, acidbase disturbance Inhibition of Krebs cycle, resulting in excess conversion of pyruvate to lactate Excess ketone body formation

TOXICOLOGY OF THERAPEUTIC DRUGS (CONTD)

Acetaminophen

A commonly used analgesic drug Overdose is associated with severe hepatotoxicity. In overdose, accumulation of reactive intermediates, including free radicals, in cell results in toxic effect, necrosis of liver Onset of hepatocyte damage is long: 35 days after ingestion. Initial symptoms of toxicity are vague, nonspecific, & not predictive of hepatic necrosis. Quantitation: immunoassay (most common); high-performance liquid chromatography (reference)

TOXICOLOGY OF THERAPEUTIC DRUGS (CONTD)

Prediction of acetaminophen-induced hepatic damage based on serum concentration

TOXICOLOGY OF DRUGS OF ABUSE

Reasons for Testing for Drugs of Abuse

To identify drug in overdose to ensure appropriate treatment To identify drug abuse in non-overdose cases to provide a rationale for treatment

Drug Testing
Screening of a single urine specimen for many substances Identification of chronic abuse involves several positive tests in conjunction with clinical evaluation. Analytic methods: immunoassays (screening & confirmation); thin-layer chromatography (screening); liquid & gas chromatography (confirmation)

TOXICOLOGY OF DRUGS OF ABUSE (CONTD)

Amphetamines

Therapeutic drugs used for narcolepsy & attention deficit disorder Stimulants with a high abuse potential Produce initial sense of increased mental & physical capacity & perception of wellbeing Initial effects followed by restlessness, irritability, & possible psychosis Overdose: hypertension, cardiac arrhythmias, convulsions, death Testing: urine analysis, immunoassay screening, confirmation by liquid or gas chromatography

TOXICOLOGY OF DRUGS OF ABUSE (CONTD)

Anabolic Steroids

Group of compounds related chemically to male sex hormone testosterone Increase muscle mass & can improve athletic performance Toxic effects Toxic hepatitis; accelerated atherosclerosis, abnormal aggregation of platelets, stroke & myocardial infarction Enlargement of heart, leading to ischemia, cardiac arrhythmias, & possible sudden death Males: testicular atrophy, sterility, impotence; females: development of masculine traits, breast reduction, sterility

TOXICOLOGY OF DRUGS OF ABUSE (CONTD)

Cannabinoids

Group of psychoactive compounds found in marijuana Of these, tetrahydrocannabinol (THC) is most potent & abundant. Marijuana can be smoked or ingested. Produce sense of well being & euphoria Associated with impairment of short-term memory & intellectual function Overdose not associated with specific physiologic toxic outcomes Immunoassay for THC-9-carboxylic acid is screening test. Gas chromatography with mass spectrometry is confirmation test.

TOXICOLOGY OF DRUGS OF ABUSE (CONTD)

Cannabinoids

TOXICOLOGY OF DRUGS OF ABUSE (CONTD)

Cocaine

An effective local anesthetic with few adverse effects at therapeutic concentrations At higher concentrations, it is a potent CNS stimulator that elicits a sense of excitement & euphoria; high abuse potential. An alkaloid salt that can be administered directly (insufflation or IV injection) or inhaled as vapor when smoked (crack) Toxic effects: hypertension, arrhythmia, seizure, myocardial infarction Testing: detection of benzoylecgonine in urine by immunoassay (screening); gas chromatography with mass spectometry (confirmation)

TOXICOLOGY OF DRUGS OF ABUSE (CONTD)

Cocaine

TOXICOLOGY OF DRUGS OF ABUSE (CONTD)

Opiates

A class of substances capable of analgesia, sedation, & anesthesia; high abuse potential Derived from opium poppy; heroin is a chemically modified form Toxic effects: respiratory acidosis, myoglobinuria, cardiac damage, death by cardiopulmonary failure

Phencyclidine
Illicit drug with stimulant, depressant, anesthetic, & hallucinogenic properties; high abuse potential Adverse effects: agitation, hostility, paranoia Toxic effects: stupor, coma

TOXICOLOGY OF DRUGS OF ABUSE (CONTD)

Opiates

A class of substances capable of analgesia, sedation, & anesthesia; high abuse potential Derived from opium poppy; heroin is a chemically modified form Toxic effects: respiratory acidosis, myoglobinuria, cardiac damage, death by cardiopulmonary failure

TOXICOLOGY OF DRUGS OF ABUSE (CONTD)

Sedative-Hypnotics

Tranquilizers; CNS depressants Wide range of therapeutic roles & are commonly used Barbiturates & benzodiazepines are most common types abused. Toxic effects: lethargy, slurred speech, coma, respiratory depression, hypotension