Chapter 31: Toxicology

1. Chapter 31: Toxicology By Deborah E. Keil

2. Introduction • Toxicology is the study of adverse effects of xenobiotics in humans. • Xenobiotics—chemicals and drugs not normally found or produced in the body. • Three 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 • Regulatory: Used data from mechanistic and descriptive to establish standards regarding acceptable levels of exposure

3. Xenobiotics, Poisons, and Toxins • Xenobiotics—exogenous agents that may have adverse effects on a living organism; often used to describe environmental chemicals or drug exposures. • Poisons—also have an adverse effect on biological system; terminology used when describing animal, plant, mineral, or gas poisons. • Toxins—substances that are biologically synthesized in living cells or microorganisms.

4. Exposure to Toxins and Routes of Exposure • Exposure statistics: • 50% of poisoning cases are intentional suicide attempts. • 30% of cases are from accidental exposure. • Remainder are a result of homicide or occupational exposure. • Routes of 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

5. Dose-Response Relationship Dose and 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 • TD50– dose that would produce toxic response in 50% of pop. • If monitored response is death, the LD50 is dose that would predict 50% death in pop. • ED50– dose that would be effective (therapeutic) in 50% of pop. • Acute and Chronic Toxicity • Acute: a single, short-term exposure to a substance • Chronic: repeated, frequent exposure for extended periods

6. Dose-Response Relationship (cont’d) • Comparison of responses of a therapeutic drug over a range of doses

7. 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 • Analytic Methods • Immunoassays (screening), thin-layer chromatography, gas chromatography, ICP-MS, atomic absorption

8. Toxicology of Specific Agents • Alcohol • General toxic effects: disorientation, confusion, euphoria; progressing to unconsciousness, paralysis, & even death • Excessive ethanol (ETOH) exposure is leading cause of economic, social, and medical problems throughout the world. • Specific toxic effects • Ethanol - associated with abusive alcoholic consumption • Results in diminution of judgment & motor performance • Chronic consumption leads to alcoholic hepatitis, cirrhosis. • (Liver enzymes elevated usually first lab sign) but also impact hematologically (high MCV), and high serum HDL (specific for ethanol consumption). • Approximately ½ of the 40,000 to 50,000 auto fatalities per year in the US are alcohol related.

9. Toxicology of Specific Agents • 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

10. Toxicology • 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 (200X greater than O2) & binding to hemoglobin (called carboxyhemoglobin which is a bright cherry red color) • Decreases amount of oxygen to tissue, producing hypoxia • Tests: differential spectrophotometry & gas chromatography • Often a measurement that is made on blood-gas analyzers (cooximeter).

11. Toxicology of Specific Agents • 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

12. Toxicology of Specific Agents • Metal and Metalloids • Arsenic –environmental exposure (industry) • Cadmium • Lead (Lead based paints – old homes) • Hematological manifestations? • Basophilic Stippling (RBC inclusion) • Measure by atomic absorption or ICP-MS • Newer methods can use capillary blood (filter paper) • Mercury

13. Toxicology of Specific Agents (cont’d) • 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

14. 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, acid–base disturbance • Inhibition of Krebs cycle, resulting in excess conversion of pyruvate to lactate • Excess ketone body formation • Aspirin also known to impact platelet function (adhesiveness)

15. Toxicology of Therapeutic Drugs • Acetaminophen (Tylenol) • 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: 3–5 days after ingestion. • Initial symptoms of toxicity are vague, nonspecific, & not predictive of hepatic necrosis. • Quantitation: immunoassay (most common); high-performance liquid chromatography (reference)

16. Toxicology of Therapeutic Drugs (cont’d) • Prediction of acetaminophen-induced hepatic damage based on serum concentration

17. 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)

18. Toxicology of Drugs of Abuse • Amphetamines/Methamphetamine • Therapeutic drugs used for narcolepsy & attention deficit disorder • Stimulants with a high abuse potential • Produce initial sense of increased mental & physical capacity & perception of well-being • 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 • MDMA (ecstasy) is in this family of drugs.

19. Toxicology of Drugs of Abuse • 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

20. Toxicology of Drugs of Abuse • 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.

21. Toxicology of Drugs of Abuse • 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)

22. Toxicology of Drugs of Abuse • Opiates (Heroin, hydromophone, oxycodone, opium, etc) • 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 • Screen – immunoassay using a polyclonal antibody – if positive – test on chromatography (gas or liquid) • Phencyclidine (PCP) • Illicit drug with stimulant, depressant, anesthetic, & hallucinogenic properties; high abuse potential • Adverse effects: agitation, hostility, paranoia • Toxic effects: stupor, coma

23. Toxicology of Drugs of Abuse • Sedative-Hypnotics • Tranquilizers (muscle relaxers); CNS depressants • Wide range of therapeutic roles & are commonly used • Barbiturates & benzodiazepines are most common types abused. • Barbiturates = secobarbital, pentobarbital, and phenobarbital • Benzodiazepines = diazepam (valium), chlordiazepoxide, lorazepam • Toxic effects: lethargy, slurred speech, coma, respiratory depression, hypotension