Toxicology

• Toxicos = poison; Logos = study

Toxicology • Disciplines of Toxicology
– Mechanistic: dose-response relationship between
the xenobiotic and the adverse effect
– Descriptive: predicts harmful levels using animal
experiments
– Regulatory: interprets mechanistic and descriptive
studies to establish safe exposure level
Toxicology Toxicology
• Special fields in toxicology • Xenobiotics – exogenous agents that may have
– Forensic an adverse effect on a living organism
• Medicolegal consequences of exposure to chemicals or
drugs
• Poisons – agents that have an adverse effect
– Environmental on a biological system
• Evaluation of environmental chemical pollutants and human • Toxins – biologically synthesized substances
health
either in living cells or in microorganisms
– Clinical
• Interrelationships between xenobiotics and disease states • Toxicants – toxic environmental chemicals
• Includes diagnostic testing and therapeutic intervention
Routes of Exposure Factors Affecting Absorption
• Ingestion • pH of the body
• Inhalation • Rate of dissolution
• Transdermal absorption • Gastric motility
• Resistance to degradation in GI tract
 Dose-Response Relationship Dose-Response Relationship
• Alle Dinge sind Gift, und nichts ist ohne Gift, allein die • Therapeutic index – ratio of TD50 (or LD50) to
Dosis macht dass ein Ding kein Gift ist. —Paracelsus
– "The dose makes the poison.“
ED50
• ED50 – ↑ index = ↓ toxic effects if dose is in therapeutic
– dose which is effective or have therapeutic benefit in 50% range
of the population
• TD50
– dose which produce a toxic response in 50% of the
population
• LD50
– dose which predict death in 50% of the population
Dose-Response Relationship Dose-Response Relationship
• Individual dose-response relationship • Acute toxicity
– pertains to changing health effects based on the – Single, short-term exposure to a substance
change in xenobiotic exposure levels – Dose is sufficient to cause immediate toxic effects
• Quantal dose-response relationship • Chronic toxicity
– describes the change in health effects of a defined – Repeated frequent exposure for extended periods
population based on changes in the exposure to for >3 months or more
xenobiotics – Doses are insufficient to cause an immediate
acute response
Toxicology of Specific Agents
1. Alcohol
2. Carbon Monoxide
3. Caustic Agents
4. Cyanide
5. Metals and Metalloids
a. Arsenic
b. Cadmium
TOXICOLOGY OF SPECIFIC AGENTS c. Lead
d. Mercury
6. Pesticides
 Alcohol Alcohol
• Ethanol (grain alcohol)
• Common CNS depressant
– Most common abused drug
• Causes disorientation, euphoria, confusion and
– It causes diuresis by inhibiting ADH
may progress to unconsciousness, paralysis and
even death – Readily absorbed in the GIT and diffuses easily in
tissues
• Metabolism: – Causes acidosis
• Accumulation of ketones and lactate
• Direct generation of hydrogen ions as alcohol is
oxidized
– ↑ blood osmolality
Alcohol Alcohol
• Ethanol (grain alcohol) • Ethanol (grain alcohol)
– Chronic consumption: 50 g of ethanol per day for
about 10 years – Antidote for chronic intoxication: diazepam (for
• Accumulation of lipids in hepatocytes alcoholic mania)
• Alcoholic hepatitis
• Cirrhosis
– Specimen: serum
– Symptoms of intoxication: • Specimen must be capped all the time to avoid
• Blurred vision evaporation of alcohol
• Incoordination • Alcohol-free skin cleanser must be used instead of
• Slurred speech isopropanol (Benzalkonium chloride)
• Coma
• “hangover symptoms” – due to effects of acetaldehyde – Major metabolic pathway:
Alcohol Alcohol
• Ethanol (grain alcohol)
– Methods for testing: enzymatic, GLC and electrochemical
oxidation
– Preferred method: enzymatic (alcohol dehydrogenase
reagent)
– Common lab results:
• Elevated GGT, AST, AST/ALT ratio (de Ritis ratio), HDL and MCV
– Fatal dose: 300 – 400 mL of pure alcohol consumed in less
than 1 hour
– Toxic blood level: >400 mg/dL; >500 mg/dL (for
hemodialysis)
– Peak blood level: within 1 hr after intake
 Alcohol Alcohol
• Methanol (wood alcohol) • Isopropanol (rubbing alcohol)
– Commonly used solvent and a contaminant of homemade
liquors – Rapidly absorbed by the GIT
– Metabolism: – Metabolism:
– Symptoms of intoxication: frank blindness (ocular toxicity)
– Symptoms of intoxication: CNS depression and
and metabolic acidosis hypertension
– Screening test: computation of osmolal gap – Preferred method: gas chromatography
– Preferred method: GC-MS – Antidote: activated charcoal
– Fatal dose: 60 – 250 mL
– Toxic blood level: > 50 mg/dL – Fatal dose: 250 mL
Alcohol Alcohol
• Ethylene glycol (1,2-ethanediol) • Ethylene glycol (1,2-ethanediol)
– Common constituent of hydraulic brake fluid and
antifreeze in coolingg systems
y – Mode of treatment: inhibit the action of alcohol
ism
s :
– Metabolism: dehydrogenase
– Indication of toxicity: calcium oxalate crystals in
the renal tubules
– Major metabolite: glycolic acid (acute toxicity and
– Symptoms of intoxication:
• Metabolic acidosis death)
• Depressed reflexes – Preferred method: HPLC
• Anuria
• Necrosis – Fatal dose: 100 grams
Carbon Monoxide Carbon Monoxide
• Colorless, odorless, tasteless gas • Major toxic effect: tissue hypoxia
• Produced by incomplete combustion of carbon • Toxic level: 20% CO
containing substances like gasoline engines,
organic materials in fire and cigarette smoke • Indication for acute toxicity: “cherry red” color
of the skin
• Binds with heme proteins
• Treatment: 100% oxygen therapy or hyperbaric
• 200x higher affinity to hemoglobin than oxygen oxygen
– Carboxyhemoglobin – Impaired oxygen transport
• Sample for testing: EDTA whole blood
• Stimulates production of nitrous oxide
• Definitive method for testing: cooximetry
– Leads to hypotension and neurologic changes
(carboxyhemoglobin measurement)
 Caustic Agents Cyanide
• Corrosive substances with strong acids or bases • Can be solid, gas or in solution
• Aspiration • Super toxic substance (fast acting)
– pulmonary edema, shock, death – Death may occur less than an hour
• Ingestion • Components of insecticides and rodenticides
– Lesions and perforations in the esophagus and GI tract
• Common suicidal agent
– Hematemesis, abdominal pain, shock
– Metabolic acidosis or alkalosis
– Corrective therapy: dilution
Cyanide Metals: Arsenic
• Pyrolysis product – burning of plastics and • Ant poisons, rodenticides, paints and metal alloys
• Common agent for homicide or suicide and heavy
foams metal poisoning
• Binds to iron (ferric and ferrous) → hypoxia • 3 major groups
– Arsine gas (arsine trioxide) – acute toxicity
– Inhibition of electron transport and cell death – Organic forms (arsenobetaine and arsenocholine) – found
• Indication of toxicity: “odor of bitter almonds” in seafood, absorbed in GI tract
• Cleared in urine within 48 hours
breath and altered mental status – Inorganic forms (trivalent and pentavalent)
• Half-life: 10 hours
• Toxic levels: >2ug/mL • Inhibits sulfhydryl enzymes throughout the body;
crosses the placenta
Metals: Arsenic Metals: Cadmium
• Chronic toxicity • Uses
– bioaccumulation due to low level, persistent exposure – Electroplating and galvanizing
• Specimen – Pigment in paints and plastics
– Long-term: Hair and nail (“Mees’ lines”)
– Short-term: Blood and urine – Cathodal material of nickel-cadmium batteries
• Indication of toxicity : “odor of garlic” breath and metallic • Binds strongly to organic matter in soil → plants and
taste agricultural crops → consumption
• Acute fatal dosage: 120 mg (arsenic trioxide) and 30 ppm • Toxicity: destruction of epithelial cells in the lungs and
(arsenic gas) accumulation in renal tubules
• Antidote: British anti-lewisite (BAL) – arsenic rescue of
affected cells • Itai-itai disease: severe osteomalacia and osteoporosis
• Test: Reinsch test, AAS – Long-term consumption of cadmium-contaminated rice
 Metals: Cadmium Metals: Lead
• Half-life: 10-30 years • Potent enzyme inhibitor
• Specimen: urine or whole blood – Blocks delta aminolevulinic
acid (ALA) synthetase,
• Toxic renal indicator: GGT in urine pyrimidine-5’-nucleotidase,
and Na-K—dependent ATPase
• Lab method: AAS • Sources: paints, gasoline, lead
pipes in plumbing
• Mode of acquisition:
ingestion or inhalation
– Toxicity depends on age
– Susceptible areas: CNS and
PNS
Metals: Lead Metals: Lead
• Toxic effects: • Specimen
– Whole blood: quantitative tests
– Vit D and heme synthesis interference – Urine: recent exposure
– Diminished integrity of RBC membrane – Morning urine for delta ALA: diagnosis of lead poisoning
– Combines with matrix of the bones (half-life: 32 years) – Serum or plasma should not be used because lead is rapidly
eliminated from plasma
– “wrist drop or foot drop” manifestation (peripheral • Lab tests:
neuropathy) – Screening:
• Toxicity indicators: urinary ALA, free RBC • Zinc protoporphyrin test (fluorometric test)
• ALAD test (D-ALA dehydratase) – sensitive method
protoporphyrin and basophilic stippling in RBCs – In vivo x-ray fluorescence of bones – lead burden
• Toxic dose: > 0.5 mg/day; fatal: > 70 ug/dL – AAS
– Inductively coupled plasma emission spectrophotometry (ICP-MS)
• Chelation therapy: EDTA and dimercaptosuccinic
acid (DMA)
Metals: Mercury Metals: Mercury
• 3 Forms • Toxic effects:
– Elemental/metallic (liquid at room temp) – General: organ dysfunction
– Inorganic salts – Elemental: pink disease (acrodynia) and erethism
– Organic (alkyl/methyl mercury) – Alkyl/Methyl: Minamata disease
• Binds with sulfhydryl proteins (change in
structure and functions) • Samples: whole blood and 24-hr urine
• Potent inhibitor of catecholamine • Route of excretion: bile
methyltransferase • Method: Reinsch test
• Acquisition: inhalation, skin absorption, and • Reference level: <10 ug/dL
ingestion
• Significant exposure: >50 ug/dL
 Pesticides
• Includes the organophosphates and carbamates
• Act by inhibiting the action of
acetylcholinesterases
– acetylcholine accumulates at the neuromuscular
junction
• Route of exposure:
– Ingestion – mostly food contamination TOXICOLOGY OF THERAPEUTIC
– Transdermal absorption DRUGS
– Inhalation
Salicylates Salicylates
• Aspirin/Acetylsalicylic acid • Toxic effects:
• Used as analgesic, antipyretic and anti- – Hepatotoxicity
inflammatory – Mixed acid-base disturbance (metabolic acidosis and
respiratory alkalosis)
• Cyclooxygenase inhibitor – Hypoglycemia
– ↓ thromboxane and prostaglandin formation – Reye’s syndrome
– Has anti-platelet activity • Therapeutic level: 5 mg/dL
• Side effects: GI disturbance and platelet • Toxic level: >30 mg/dL
aggregation interference • Method: Trinder assay, enzyme assay (salicylate
• Acute toxicity: fatal drug poisoning in children hydroxylase), HPLC
Acetaminophen Acetaminophen
• Used as analgesic and antipyretic • Therapeutic level: 25 ug/dL
• Prostaglandin inhibitor • Toxic level: >50 ug/dL
• Toxic effects – 100-300 ug/mL (hepatic necrosis)
– Hepatotoxicity • Method: HPLC
– Cyanosis due to methemoglobinemia
– CNS depression
– Seizure
 Drugs of Abuse
• Drug – A chemical substance that brings about
physical, physiological, behavioral and/or
psychological change in a person taking it
– All medicine are drugs but not all drugs are medicine
• Drug Abuse
– Any non-medical use of drugs that cause physical,
DRUGS OF ABUSE psychological, legal, economic, or social damage to
the user or to people affected by the user’s behavior
• Not only refers to illegal drugs; also applicable to drugs
which are available legally
Classification of Drugs Classification of Drugs
• According to origin • According to legal classification (Philippines)
– Natural – RA 9165: Comprehensive Dangerous Drug Act of 2002
– Synthetic
– PD 1619: for volatile substances (rugby, thinners)
• According to effects
– Stimulants: increase alertness and physical disposition – RA 6425: Dangerous drugs act of 1972; prohibited and
• Amphetamines, caffeine, cocaine, methamphetamine, shabu regulated drugs
– Hallucinogens: drugs that affect sensation, thinking, self-awareness • According to international classification
and emotion.
• Molly, Ecstasy, Lysergic acid diethylamide (LSD), Marijuana, mescaline,
– Narcotics: any drug that produces sleep or stupor and also
phencyclidine (PCP), psilocybin relieves pain
– Narcotics: drugs that relieve pain and often induce sleep – Psychotropic substances: any drug having a particular
• Codeine, heroin, morphine affinity or effect on the psyche
– Sedatives/depressants: drugs which may reduce anxiety and
excitement – Designer drugs: substance chemically related to but
• Alcohol, barbiturates slightly different from controlled substances; designed by
clandestine chemists
Laboratory Testing Laboratory Testing
• Specimen: • Immunochemical method
– Urine – Enzyme mediated for immunologic techniques
– Serum (EMIT)
– Hair – Fluorescent polarization
– Nails – Principle: competitive binding immunoassay
– Whole blood or plasma (for alcohol) • Direct competition
– Immobilized drug conjugate competes with drug/metabolites
– Sweat of a limited amount of chemical labeled antibody
– Saliva • Displacement
– Displacement of a chemically labeled drug conjugate already
– Exhaled breath (for alcohol) bound to an equal amount of test antibody.
 Laboratory Testing Laboratory Testing
• Chromatographic procedures • Cross reactivity (interferences)
– Thin layer chromatography (TLC) – Drug and drug metabolites with significant
– High performance liquid chromatography (HPLC) structural similarities to the target analyte may
– Liquid chromatography mass spectroscopy (LC- cross-react with target analyte specific antibodies,
MS) producing false positive results
– Gas chromatography – Degree to which any substrate other than the
• Gas liquid chromatography (GLC) target substrate interacts with an antibody
• GC with IR spectroscopy
• Gas chromatography mass spectroscopy (GC-MS)
– Gold standard
Drugs of Abuse Amphetamines
1. Amphetamines • Street names: eye opener, lid poppers, pep pills,
2. Anabolic Steroids uppers, hearts
• Therapeutically used for treatment of narcolepsy and
3. Cannabinoids attention deficit disorder
4. Cocaine • Has anorectic property
5. Opiates • Increases mental alertness and physical capacity
6. Phencyclidine – Followed by restlessness, irritability, and psychosis
7. Sedative-Hypnotics • Overdose: hypertension, cardiac arrhythmias,
convulsions and death
8. Lysergic Acid Diethylamide • Structurally similar to dopamine and catecholamines
9. Tryptamines – Ephedrine, pseudoephedrine and phenylpropanolamine
(allergy and cold medications)
Amphetamines Amphetamines
• Methamphetamines • Methylenedioxymethylamphetamine (MDMA) –
ecstasy/molly
– Street names: “Speed”, “ice”, “chalk”, “crystal”, “glass”, – Methamphetamine derivative recognized as a designer drug
Poor man’s cocaine, S, shabu, Siopao, sha – RoA: oral, inhalation, injection or smoking
– Taken by ingestion, inhalation (chasing the dragon), – Half-life: 8 to 9 hours
sniffing, injection, smoke – Onset of effect: 30-60 minutes
• Lasts for 3.5 hours
– Effects: – Desired effects: hallucinations, euphoria, empathic and
• General: anxiety, irritability, irrational behavior emotional responses and increased visual and tactile sensitivity
• Long term: psychosis similar to schizophrenia, difficulty in – Adverse effects: anxiety agitation, violent behavior, tachycardia,
concentrating, loss of interest in sex respiratory depression, seizures, hyperthermia, cardiac, liver
• Physical: chest pain, irregular heartbeat, hypertension, and renal toxicity
convulsion, death
 Amphetamines Anabolic Steroids
• Methylenedioxymethylamphetamine (MDMA)
• Chemically related to
testosterone
• Improves athletic performance
by increasing muscle mass
– ↑ vigor, ↑ stamina
• Toxic effects: chronic hepatitis,
atherosclerosis, abnormal
platelet aggregation,
cardiomegaly
Cannabinoids Cannabinoids
• Naturally occurring cannabinoids: marijuana • Lipid-soluble; readily enters the brain and may
and hashish act by producing cell membrane changes
– Cannabis sativa • Effects: reddening of conjunctiva, increased
– Cannabis indica pulse rate, muscle weakness, deterioration in
• Tetrahydrocannabinol – most psychoactive motor coordination
ingredient • Half life:
– More THC in C. sativa than C. indica – 1 day (single use)
– Less cannabidiol (CBD) in C. sativa than C. indica – 3-5 days (chronic use)
• RoA: Smoking, ingestion • Urinary metabolite
• Street names: pot, mary jane, MJ, weed, grass, – 11-nor-tetrahydrocannabinol-9-carboxylic acid
Cocaine Cocaine
• Street name: coke, crack, gold dust, stardust, • Cocaethylene (ethanol + cocaine) – blocks
white girl, speedballs reuptake of dopamine
• From coca plant; Derivative of the alkaloid – Effect: pronounced vasoconstriction of coronary
ecgonine arteries; induces increased myocardial oxygen
demand
• CNS stimulator – elicits a sense of excitement
and euphoria • Toxic effects: Cardiotoxicity; Passes readily
across the placenta and lactating mammary
• Also used as local anesthetic gland
• RoA: insufflation, IV, vapor inhalation • Treatment: benzodiazepine
(smoking crack)
• Half-life: 0.5 to 1 hour
 Opiates
• Capable of analgesia, sedation, and anesthesia • Derivatives
• Derived from the opium poppy plant
• Provides a quick, intense feeling of pleasure
followed by a sense of well-being and calm
• Toxic effects: respiratory acidosis,
myoglobinuria, cardiopulmonary failure,
pupillary constriction (pinpoint pupils)
– ↑ serum cardiac markers
Opiates
• Morphine • Codeine
– Street names: “M”, “Dreamer”, “Ms. Emma”,
“Cube juice”, “hard stuff”, “Morph”, emsel, pulbos
– Derivative of opium and a metabolite of heroin
– Uses:
• Powerful analgesic
• Treatment of acute congestive heart failure
Opiates
• Heroin • Opium
– Street names: blanco, brown, sugar, kabayo,
kengkoy, gamot, matsakao, pulbos, sapsap, tinik
– RoA: IV
– Highly addictive (true physical dependence)
– Crosses BBB – if levels are elevated in CNS
Opiates
– Naturally occurring: opium, morphine and codein
– Chemically modified: Heroin, hydromorphone and
oxycodone
– Synthetic: Meperidine, methadone,
propoxyphene, pentazocine and fentanyl
Opiates
– Street name: school boy
– Used as a mild analgesic and as an anti-tussive
– Highly addictive
– RoA: IV
– Addiction recognized by: Needle tracks on the
user’s arms and hands
– Analog: dextromethorphan (D-3-Methoxy-N-
Methylmorphine)
– Block NMDA receptors (like PCP)
• Neuronal plasticity and memory
Opiates
– RoA: IV, smoking, oral (pill)
– Half-life: 3 minutes; effect lasts for 3 hours
 Phencyclidine (PCP)
• Street names: “angel dust” or “angel hair”,
crystal super grass, killer joints, ozone, wack,
rocket fuel
• With stimulant, depressant, anesthetic and
hallucinogenic properties
• RoA: ingested or inhaled via smoking
Sedative Hypnotics
• Most common: Barbiturates and
benzodiazepines
• Used to potentiate effects of heroin
• Toxicity is initiated by ethanol
• Toxic effects:
– Cheyne-Stokes respiration, depression, cyanosis,
stupor, coma
Sedative Hypnotics
• Benzodiazepines
– Commonly used: Diazepam (Valium),
chlordiazepoxide (Librium) and lorazepam (Ativan)
– Used for treatment of cocaine addiction
– Diazepam – control of acute seizure activity; minor
tranquilizer
Phencyclidine (PCP)
• Elimination: about 10-15% remain unchanged
in urine
• Major metabolite: phencyclidine HCl
– Detected up to 7-30 days (chronic use) after
abstinence
• Toxic effects: tachycardia, seizure, coma, death
• Treatment: isolation, keep in dark, quiet room
Sedative Hypnotics
• Barbiturates
– Street names: Lily, bala, downers, yellow jackets,
blue heavens
– Symptoms of abuse: slurred speech, slowing of
mental functions, constricted pupils CNS
depression
– Commonly abused: Secobarbital, pentobarbital,
thiopental and phenobarbital
• Phenobarbital – structurally resembles phenytoin (anti-
seizure)
– Condensation product of urea and malonic acid
Lysergic Acid Diethylamide
(Lysergide)
• Street names: Lucy in the sky of diamonds,
wedding bells, acid, white sugar, lightning,
cubes, brain eaters
• A semisynthetic indolalkylamine; a
hallucinogen
• Effects: Visual hallucination (undulating
vision), perceptual distortion, synesthesia
(overflow pf sensory input so that colors are
“heard” and music becomes “palpable”),
papillary dilatation, uterine contraction,
 Lysergic Acid Diethylamide Tryptamines
• Usual dosage: 1-2 mcg/kg • Derivative of serotonin; some compounds are
• Experience: begins 1 hr after; peaks 2-3 hrs; present in plants
lasts 8-12 hrs • N,N-dimethyltryptamine (DMT)
– “businessman’s lunch”
• Metabolized in the liver, excretion through bile
– Short term hallucinogen
• Treatment: frequent reassurance, quiet and – RoA: smoking
calm environment, diazepam • Psilocybin
• Deaths are usually due to suicides or accidents – Component of “magic mushrooms”
– Hallucinogen
• Ayahuasca
– Tea which contains tryptamines
Tryptamines
• Monoamine oxidase inhibitors
– Enhances the hallucinogenic effect of tryptamines
• Antagonist: benzodiazepines Toxicology
• Toxic effects: tachycardia, hypertension,
dystonia, seizures, rhabdomyolysis, paralysis