Toxicology

Toxicology
• is the study of the adverse effects of xenobiotics in
humans.

Three (3) major disciplines:

A. Mechanistic toxicology
B. Descriptive toxicology
C. Regulatory toxicology
Regulatory toxicology
• The Food and Drug Administration
• human safety issues associated with therapeutic drugs, cosmetics, and food
additives.
• The U.S. Environmental Agency
• regulatory oversight with regard to pesticides, fungicides, rodenticides, and
industry-related chemicals that may threaten safe drinking water and clean air.
• The Occupational Safety and Health Administration (OSHA)
• responsible for ensuring safe and healthy work environments.
• Consumer Product Safety Commission
• regulates household chemicals,
• Department of Transportation
• transporting of chemical hazards
Additional areas of toxicology
• Forensic toxicology
• the analysis of biological samples for the presence of toxins,
including drugs.
• Clinical toxicology
• the study of interrelationships between xenobiotics and disease
states. This area emphasizes not only diagnostic testing but also
therapeutic intervention
• Environmental toxicology
• includes the evaluation of environmental chemical pollutants and
their impact on human health.
Definition of Terms
• Xenobiotics
• Are defined as exogenous agents that may have an adverse effect on
a living organism.
• Poisons
• Are also agents that have an adverse effect on a biological system.
This term is more often used when describing animal, plant, mineral,
or gas poisons.
• Toxins
• Are substances that are biologically synthesized either in living cells
or in microorganisms.
Routes of Exposure
• Ingestion
• Inhalation
• Transdermal
Dose–Response Relationship
• TD50
• the dose that would be predicted to produce a toxic response
in 50% of the population.
• LD50
• is the dose that would predict death 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.
• Therapeutic index
• is the ratio of the TD50 (or LD50) to the ED50.
Types of Toxicity
• Acute toxicity
• is associated with a single, short-term exposure to a
substance, the dose of which is sufficient to cause
immediate toxic effects.
• Chronic toxicity
• is usually associated with repeated frequent exposure for
extended periods for greater than 3 months and possibly
years, at doses that are insufficient to cause an immediate
acute response.
ENVIRONMENTAL CARCINOGENS
• Benzpyrene
• Engines, is a known potent carcinogen and has been implicated in
causing lung cancer.
• Nitrites
• Used as preservatives in red meats, have been associated with
colon cancer
• Aflatoxin
• Produced by the fungus aspergillus, has been implicated in causing
hepatocellular carcinoma
• Benzene and ionizing radiation
• Have been implicated in causing acute leukemias.
ENVIRONMENTAL CARCINOGENS
• Vinyl chloride & thorotrast
• Have been linked to angiosarcoma
• Β-naphthylamine & dimethylbenzanthracene
• Have been linked to multiple malignancies occurring in
humans
• Asbestos
• Has been strongly implicated as a carcinogen in lung
cancer and mesothelioma
CYANIDE
• classified as a supertoxic substance that can exist as a
gas or solid or in solution.
• Exposure can occur by inhalation, ingestion, or
transdermal absorption.
• Symptoms of cyanide overdose:
• Tachypnea (initially)
• Respiratory depression •Hypotension
• Cyanosis •Convulsions
• Coma
Antidotal therapy
1. Hemoglobin is converted to methemoglobin (fe3+
state) by using specific oxidants.
2. Methemoglobin directly competes with
ferricytochrome a3 to form a methemoglobin–cn−
complex.
3. Reagent reacts with cyanomethemoglobin to form
thiocyanate, which is harmless and is excreted in
urine.
CARBON MONOXIDE
• is a colorless, odorless, and tasteless gas that is rapidly
absorbed into blood from inspired air
• The affinity of carbon monoxide for hemoglobin is 200 to 225
times greater than for oxygen.
• Most susceptible organs:
• Brain
• Heart
• Cooximeter
•utilized to make the definitive diagnosis by measuring the
concentration of blood CO-Hb.
•Treatment is mainly with 100% oxygen,
CARBON MONOXIDE TOXICITY
• Direct cellular toxicity caused by its binding to myoglobin,
resulting in direct damage to skeletal and cardiac muscle.
• Co activates guanylyl cyclase in the cns; this results in
increased cyclic guanosine monophosphate that induces
cerebral vasodilatation and can cause loss of consciousness.
• Co also induces the synthesis of nitric oxide (no), a potent
vasodilator that causes large decreases in systemic blood
pressure.
ALCOHOL
• Ethanol
• is probably the most common drug of abuse and is frequently
responsible for the presentation of patients with altered mental status
to hospitals and emergency rooms
Ethanol → Acetaldehyde → Acetate → Acetaldehyde adducts
• Methanol
• is a common solvent. It may be ingested accidentally as a component of
many commercial products or as a contaminant of homemade liquors.
• Isopropanol
• also known as rubbing alcohol, is commonly available. It is metabolized
by hepatic ADH to acetone, which is its primary metabolic end product.
ALCOHOL
• Ethylene glycol (1,2-ethanediol)
• Is a common component of hydraulic fluid and antifreeze.
Ingestion by children is relatively common because of its
sweet taste.
Specimen collection:
• WB, plasma, serum – acceptable
• Venipuncture site cleaned with an alcohol-free disinfectant
• Specimens must be capped at all times to avoid
evaporation
• Preserved with sodium fluoride
ALCOHOL
• Methods:
• Gas Chromatography - is the reference method for ethanol
determination.
• Enzymatic methods for the determination of ethanol are
common.
Metals and Metalloids
• Arsenic
• Is a metalloid that may exist bound to or as a primary
constituent of many different organic and inorganic
compounds
• Three major groups:
• Arsine gas (arsine trioxide)
• Inorganic forms (trivalent and pentavalent),
• Organic forms (arsenobetaine and arsenocholine).
Toxic symptoms of arsenic poisoning

Low level High level

• Fever • Peripheral and central damage
• anorexia (nervous system)
• gastrointestinal distress • Renal effects
• Hemopoietic effects
• Vascular disease
• Death
Metals and Metalloids
• Cadmium
• is a pigment found in paints and plastics and is the cathodal
material of nickel–cadmium batteries.
• Accumulates in tobacco leaves - regular use of tobacco-
containing products is a common route of human cadmium
exposure.
• early finding of toxicity is manifested by renal tubular
dysfunction.
• Itai itai disease - characterized by severe osteomalacia and
osteoporosis from the long-term consumption of cadmium-
contaminated rice.
Metals and Metalloids
• Cadmium
• half-life of cadmium is 10 to 30 years
• AAS – for evaluation of Cadmium
• Specimen of choice whole blood or urinary content
Metals and Metalloids
• Lead
• Is a by-product or component of many industrial
processes, which has contributed to its widespread
presence in the environment.
• Two theoretical compartments:
• Bone – largest pool (half life more than 20 years)
• Soft tissue - half life 120 days
Mercury
• Is a metal that exists in three forms:
• Elemental (liquid at room temperature)
• Inorganic salts
• Component of organic compounds
• Gastrointestinal absorbance - primary factor that
determines toxicity
• Analysis – AA, using whole blood or an aliquot of a 24-
hour urine specimen
Organophosphates
• are the most abundant pesticides and are responsible
for about one third of all pesticide poisonings.
• function by inhibition of acetylcholinesterase
• Pseudocholinesterase (SChE) activity - considered a
screening test, and clinical correlation is needed.
Toxicology of Drugs of
Abuse
• Screening test – high sensitivity, low to marginal
specificity
• Confirmatory test - uses methods that have high
sensitivity and specificity
• GC–mass spectrophotometry (GC/MS) is the reference
method for confirmation of most analytes.
Amphetamine and methamphetamine
• Therapeutic drugs used for narcolepsy and attention deficit
disorder.
• produce an initial sense of increased mental and physical
capacity
• Screening test – commonly used immunoassay test
• liquid chromatography or GC – confirmatory test
Methylenedioxymethylamphetamine
(MDMA)
• is an illicit amphetamine derivative that is commonly referred to as
“ecstasy.”
• Associated with club culture in 1990s
• Administered orally
• half-life is 8 to 9 hours
• Elimination:
• Hepatic metabolism – majority
• Urine – 20%
• GC/MS - confirmation of MDMA
Anabolic steroids
• are a group of compounds related chemically to the male sex
hormone testosterone.
• developed in the 1930s as a therapy for male hypogonadism
• Chronic use of steroids has been associated with a toxic
hepatitis, accelerated atherosclerosis and abnormal
aggregation of platelets. Predispose stroke and myocardial
infarction.
• the ratio of testosterone to epitestosterone commonly used
screening test
Cannabinoids
• Are a group of psychoactive compounds found in
marijuana.
• Tetrahydrocannabinol (THC) - is the most potent and
abundant
• is a lipophilic substance, which is rapidly removed from
circulation by passive distribution into hydrophobic
compartments, such as brain and fat.
• Administration:
• Smoked
• Ingested
Cannabinoids
• 11-nor-tetrahydrocannabinol-9-carboxylic (THC-COOH)
• Major urinary metabolite
• Half-life of THC in circulation:
• 1 day after a single use
• 3 to 5 days in chronic, heavy consumers
• Primarily eliminated in urine
• Testing:
• Immunoassay for THC-COOH – screening test
• Gc/ms is used for confirmation.
Cocaine
• is an effective local anesthetic with few adverse effects at
therapeutic concentrations.
• it is a potent CNS stimulator that elicits a sense of excitement
and euphoria.
• Administration:
• Inhalation (as a vapor and smoked)
• Intravenous injection
• The half-life of the circulating cocaine is brief: 0.5 to 1 hour
• Benzoylecgonine - primary product of hepatic metabolism;
primary eliminated in the urine.
• half-life is 4 to 7 hours
Cocaine
• Benzoylecgonine
• can be detected in urine for up to 3 days after a single use.
• chronic heavy abusers, it can be detected in urine for up
to 20 days after the last dose
• Detection:
• Immunoassay - screening test for identification of cocaine
use is the detection of benzoylecgonine in urine
• GC/MS - Confirmation testing
Opiates
• are a class of substances capable of analgesia, sedation, and
anesthesia.
• All are derived from or chemically related to substances
derived from the opium poppy
• Divided into three (3):
• Naturally occurring
• Chemically modified
• Synthetic opiates
Opiates
• Testing:
• Immunoassay – screening test
• GC/MS is the confirmatory method of choice.
Phencyclidine (PCP)
• Is an illicit drug with stimulant, depressant, anesthetic, and
hallucinogenic properties.
• Produce the desired subjective effects, such as agitation,
hostility, and paranoia.
• Overdose is associated with stupor and coma.
• Administration:
• Ingestion
• Inhaled (smoking PCP-laced tobacco or marijuana)
Phencyclidine (PCP)
• PCP can be detected 7 to 30 days after abstinence
(heavy users); detection of parent drug in the urine
• Testing:
• Immunoassay - is used as the screening procedure.
• GC/MS is the confirmatory method.
Barbiturates and benzodiazepines
• Most common types of sedative hypnotics abused.
• Benzodiazepines - are more commonly found in abuse and
overdose situations
• Commonly abused barbiturates:
• Secobarbital
• Pentobarbital
• Phenobarbital
• Commonly abused benzodiazepines
• Diazepam (valium)
• Chlordiazepoxide (librium)
• Lorazepam (ativan)
Barbiturates and benzodiazepines
• Immunoassay is the most common screening procedure for
both barbiturates and benzodiazepines.
• GC or liquid chromatography can be used for confirmatory
testing.