The document provides an overview of toxicology including definitions, sub-disciplines, related terms, mechanisms of toxicity, dose-response relationships, time-effect relationships, classification of toxic agents, factors affecting toxicity, and general management techniques. It also discusses the mechanisms and management of specific toxicities including acetaminophen, benzodiazepines, antidepressants, opiates, and lead poisoning.
2. Definition
The traditional definition of toxicology is “the science of poisons.”
As our understanding of how various agents can cause harm to humans and
other organisms, a more descriptive definition of toxicology is “the study of
the adverse effects of chemicals or physical agents on living organisms.”
Explanation:
The word “toxicology” is derived from the Greek word “toxicon” which
means “poison” and logos means to study. It also includes study of special
effects of toxicants developmental toxicity, teratogenicity, carcinogenicity,
mutagenesis, immune-toxicity, neurotoxicity, endocrine disruption, etc.
Adverse effects may occur in many forms, ranging from immediate death to
subtle changes not realized until months or years later.
3. Sub-disciplines of Toxicology
Clinical toxicology: impact of drugs and other chemicals on humans.
Mechanistic toxicology: observations on how toxic substances cause
their effects.
Toxicodynamics: biochemical and physiological effects of toxicants
and their mechanism of action.
Toxicokinetics: absorption, distribution, metabolism, and excretion of
toxicants in the body.
4. Food toxicology: natural contaminants, food and feed additives, and toxic effects of
compounds in food.
Analytical toxicology: detection, identification, and measurement of foreign compounds
(xenobiotics) in specimens.
Occupational (industrial) toxicology: Health effects from exposure to chemicals in the
workplace.
Descriptive toxicology: Gathering toxicological information from animal experimentation.
These types of experiments are used to establish how much of a chemical would cause illness
or death.
5. Some Related terms & definitions:
Poison.
Poison is derived from Latin “potus,” a drink that could harm or kill..
Although the word toxicant has essentially the same medical meaning,
there are psychological and legal implications involved in the use of the
word poison that makes manufacturer reluctant to apply it to
chemicals, particularly those intended for widespread use in large
quantities, unless they are required to do so by law.
The term toxicant is more acceptable to both manufacturer and
legislators.
6. Toxicants
Toxicants are man-made products, artificial products introduced
into the environment due to human activity; examples are
industrial waste products and pesticides.
Toxin
Toxin is synonym of poison, produced by living organism in small
quantities and is generally classified as bio-toxin. These may be
phyto-toxins (produced by plants), mycotoxins (produced by
fungi), zootoxins (produced by lower animals), and bacterio-
toxins (produced by bacteria).
Venom
Venom is a toxicant synthesized in a specialized gland and ejected
by the process of biting or stinging. Venom is also a zootoxin but
the difference is way of delivery (transmitted by the process of
biting or stinging)
7. Toxic effects
• These are undesirable effects produced by excessive pharmacological
action of toxicant/drug
• detrimental to either survival or normal functioning of the individual
• resulting from the prolong use or over-dosage.
8. CLASSIFICATION OF TOXIC AGENTS
1. Use, e.g., pesticides (atrazine), solvents (benzene), food
additives (NutraSweet), metals, and war gases
2. Effects, e.g., carcinogen (benzo[a]pyrene), mutagen
(methylnitrosamine), and hepatotoxicant (CHCl3).
3. Physical state such as oxidant (ozone), gas (CO2), dust (Fe2O3),
and liquid (H2O).
4. Chemistry such as aromatic amine (aniline) and halogenated
hydrocarbon (methylene chloride).
5. Sources of toxicants, e.g., plant or animal or natural.
9. FACTORS AFFECTING TOXICITY
1. Host factors (factors related to subject) size age species
gender genetics tolerance
2. Factors related to toxicant or associated with xenobiotics:
Dose, Chemical structure & physical form of the chemical,
Duration, Frequency & route of exposure.
3. Environmental factors
4. Individual or non-individual factors
10. Mechanisms of toxicity- How it
develops?
An understanding of the mechanisms of toxicity provides a
rational basis for interpreting descriptive toxicity data.
The cellular mechanisms that contribute to toxicity are related to
a series of events that begins with
exposure,
involves a multitude of interactions between the invading
toxicant and the organism, and
culminates in a toxic effect.
11. • STEP-1: First, the toxicant is delivered to its target or
targets
• STEP-2: interaction with endogenous target
molecules (step 2a) or altering the environment
(step 2b)
• STEP-3: triggering perturbations in cell function
and/or structure
• STEP-4: initiate repair mechanisms at the molecular,
cellular, and/or tissue levels
When the perturbations induced by the toxicant
exceed repair capacity or when repair becomes
malfunctioned, toxicity occurs. Tissue necrosis,
cancer, and fibrosis are examples of chemically
induced toxicities that follow this four-step course
12. DOSE-RESPONSE RELATIONSHIP
• The dose-response relationship, or exposure-response relationship,
describes the change in effect on an organism caused by differing
levels of exposure (or doses) to a stressor (usually a chemical) after a
certain exposure time.
• This may apply to individuals (e.g., a small amount has no significant
effect, a large amount is fatal) or to populations (e.g. how many
people or organisms are affected at different levels of exposure).
13. Types of dose response relationships
1. Graded or gradual:
• describes the response of an individual
organism to varying doses of a chemical
• because the measured effect is continuous
over a range of doses.
• This type of relationship is useful in
measuring the incremental responses of a
compound and can be seen in an individual
organism.
• e.g., contraction of small intestine produced
by carbachol, convulsions produced by
strychnine
14. 2. Quantal (all-or-none) such as death:
• an all-or-none response, i.e., on
increasing the dose of a compound, the
response is either produced or not.
• This relationship is seen with certain
responses that follow all-or-none
phenomenon and cannot be graded,
e.g., death.
15. TIME-EFFECT RELATIONSHIP
• The chemical effects do not develop instantaneously or
continue indefinitely; they change with time.
• Thus, the magnitude of a chemical effect at any given moment
is a function not only of the dose but also of the amount of time
elapsed since the chemical made contact with the reactive
tissues.
16. This curve represents several important
features (there are three distinct phases and a
fourth phase that may be present or
pronounced with some chemicals while
absent with others), which include:
• Time of onset of action (Ta)
• Time to peak effect (Tb)
• Duration of action (Tc)
• Residual effects (Td)
17. GENERAL MANAGEMENT TECHNIQUES:
1. GASTRIC EMPTYING:
a) Emesis:
Emesis can be achieved by administration of syrup of ipecac. Dosing: 15 mL for
children 1 to 12 years of age, and
30 mL for adults,
usually followed by sips of water.
The dose may repeated only once if vomiting does not occur within 30 min.
Approximately 90 percent of patients vomit within 20 min after the first dose, and
up to 97 percent vomit after a second dose.
A typical patient vomits less than three to five times, and symptoms usually resolve
within 2 h.
18. Contraindications:
• ingestions that have the potential to alter mental status;
• active or prior vomiting;
• caustic ingestion;
• a toxin with more pulmonary than GI toxicity (e.g., hydrocarbons);
• ingestions of toxins that have the potential for inducing seizures.
19. b) Orogastric Lavage:
• The principal method of gastric emptying in the emergency
department
• performed with the patient lying in the left lateral decubitus
position.
• A 36- to 40-French catheter is used for adults and a 22- to
24-French catheter for children.
• The tube is inserted after careful measurement of the length
from the chin to the xiphoid process.
• Correct positioning must be assessed
• Lavage with room temperature water is commonly continued
until the effluent becomes clear.
• Before the tube is removed, activated charcoal should be
instilled in a dose of 1 g/kg, if indicated.
20. Contraindications:
• pills that are known not to fit into the holes of the orogastric lavage hose,
• nontoxic ingestions,
• non-life-threatening ingestions,
• caustic ingestions,
• any patient whose airway integrity is not assured,
• toxic ingestions that are more damaging to the lungs than to the GI tract.
Complications: insertion of the tube into the trachea, aspiration, esophageal or
gastric perforation and inability to withdraw the tube once inserted (knot
formation).
Indications for this procedure are generally limited to recent ingestion of a life-
threatening toxin
21. 2. TOXIN ADSORPTION IN THE GUT
Activated Charcoal
• The most important agent for GI decontamination.
• Prevents absorption by binding to the drug.
• May also increase elimination of drug already absorbed by
pulling drug from the bloodstream into the gut by creating a
favorable diffusion gradient between blood and gut ("GI
dialysis").
• It can also prevent reabsorption of drugs that have an
enterohepatic circulation.
• typically given in a slurry of water or juice by mouth or
through a nasogastric tube
• In adults, the first dose of activated charcoal is often given
with a cathartic to reduce GI transit time. Sorbitol and
magnesium citrate solution are the most commonly used
cathartics
22. Limitations of Charcoal:
• Need 10:1 ratio for 100% absorption, it is difficult to give 10 times as much
charcoal as toxin in some intoxications where many grams of drug may be
ingested ( i.e., 60 gm. of theophylline requires 600 gm. of charcoal).
• Does not bind small, charged molecules like iron, lithium, arsenic, lead,
cyanide...
• Does not bind alcohols, hydrocarbons, and pesticides.
• Does not bind caustics (strong acids and bases).
• Aspiration of charcoal has been associated with aspiration pneumonia.
23. 3. Whole-bowel irrigation
• Whole-bowel irrigation is the installation of large volumes of polyethylene glycol
in an osmotically balanced electrolyte solution that causes neither fluid nor
electrolyte shifts.
• adults = 2 L/h
• Children = 50 to 250 mL/kg/h
• produces a rapid catharsis by mechanically forcing ingested substances through
the bowel at a rapid rate.
Contraindications : patients with preceding diarrhea;
ingestions that are expected to result in significant diarrhea
and patients with obstructions
Complications:
• Vomiting, bloating, and rectal irritation.
Helpful for Heavy metals Iron Lithium
24. 4. Hemodialysis:
• Useful for small, water soluble, poorly protein bound drugs, with
small volumes of distribution, that are usually eliminated by the
kidney.
Indications:
• Intoxications with severe end-organ compromise, renal failure,
metabolic acidosis or electrolyte disturbances not easily correctable
by medical methods, or pulmonary edema
• The five most commonly dialyzed drugs are methanol, ethylene
glycol,lithium, and theophylline.
26. Acetaminophen:
Mechanism of toxicity:
It is an antipyretic-analgesic that can produce fatal
hepatotoxicity in untreated patients through the
generation of a toxic metabolite i.e. NAPBQI (N-
Acetyl Para Benzo Quinone Imine) which normally
binds with glutathione (GSH) but in
acetaminophen’s over dosage, the formation of
this toxic metabolite is stimulated and thus
saturation of GSH occurs which results in binding
of this excessive NAPBQI with hepatocytes leading
to hepatocellular necrosis.
27. • Therapeutic dose for adults: 4g/day.
• Toxic dose:
• Adult patients: > 10 g
• Children: >200 mg/kg
• Elderly and alcoholic patients have an increased susceptibility to
acetaminophen hepatotoxicity.
Available dosage forms: A variety of OTC and prescription drug products.
Clinical presentation: Nausea, vomiting, anorexia, abdominal pain,
diaphoresis, increased Prothrombin Time, bilirubin and liver enzymes (ALT,
AST).
28. Treatment:
1. GIT decontamination with activated Charcoal or by gastric lavage.
2. Antidotal therapy with N-Acetyl Cysteine (Mucomyst)
Dosage is 140 mg/kg as a loading dose followed by 70 mg/kg every 4 hr. For
a total of 17 doses.
NAC is administered either orally or via a nasogastric tube.
Each dose must be diluted 1:3 in either cola or fruit juice to mask the
unpleasant taste and smell.
NAC itself binds with toxic metabolite NAPBQI and prevents it from binding
to hepatocytes thus preventing further toxicity.
29. Benzodiazepines
Mechanism of toxicity:
• Benzodiazepines enhance the action
of the inhibitory neurotransmitter
GABA. The result is generalized
depression of CNS and the reticular
activating system. This can cause
coma and respiratory arrest.
Clinical presentation:
• Drowsiness, Ataxia, and Confusion.
.
30. Available forms:
Chlordiazepoxide (Librium), Diazepam (Valium), Lorazepam (Ativan),
Alprazolam (Xanax).
Treatment:
a. Supportive treatment by gastric emptying, activated charcoal and a
cathartic.
b. Flumazenil is given 0.2 mg IV over 30 sec; repeat doses of 0.5 mg
over 30 sec at 1-min intervals for a maximum dose of 5 mg
31. Antidepressants
Tricyclic antidepressants (TCAs):
Mechanism of toxicity:
Most of the toxic effects of TCAs are caused by
four major pharmacological effects.
• TCAs have anticholinergic effects,
• cause excessive blockade of norepinephrine
reuptake at the preganglionic synapse,
• direct alpha adrenergic blockade, and
• block sodium membrane channels with
slowing of membrane depolarization, thus
having quinidine-like effects(reduced heart
rate) on the myocardium.
33. • Treatment:
(1) GI decontamination.
(2) Alkalinization with sodium bicarbonate.
(3) Phenytoin (Dilantin) and/or benzodiazepines may be required to
control seizures. Phenytoin must be administered at a rate not
exceeding 25 mg/min because of hypotensive side effects.
(Fosphenytoin [Cerebyx] may be used because it has a lower incidence
of hypotension than phenytoin).
34. Opiates
• Mechanism of toxicity:
In general, opioids stimulate a number of specific opiate receptors in
the CNS, causing sedation and respiratory depression. Death results
from respiratory failure, usually as a result of apnea or pulmonary
aspiration of gastric contents.
• Available dosage forms: oral and parenteral agents.
• Clinical presentation: respiratory depression, decreased level of
consciousness, hypotension, bradycardia, and pulmonary edema.
• Treatment: Naloxone is given 0.4-2 mg every 5 min up to 10 mg.
35. Lead
Mechanism of toxicity:
• Lead is a ubiquitous environmental toxin that is capable of causing
numerous acute and chronic circulatory, neurological, hematological,
gastrointestinal, reproductive and immunological pathologies.
• The mechanism of lead induced toxicity is not fully understood yet the
prime targets to lead toxicity are the heme synthesis enzymes, thiol-
containing antioxidants and some other enzymes (catalase, glutathione
peroxidase, glucose 6-phosphate dehydrogenase and antioxidant
molecules like GSH).
• The low blood lead levels are sufficient to inhibit the activity of these
enzymes and induce generation of reactive oxygen species and
intensification oxidative stress.
36. • The primary target of lead toxicity is the central nervous system.
There are different cellular, intracellular and molecular mechanisms
of lead neurotoxicity: such as induction of oxidative stress,
intensification of apoptosis of neurocites, interfering with Ca(2+)
dependent enzyme like nitric oxide synthase
• Inorganic forms of lead are initially distributed to the soft tissues and
more slowly to bone, teeth, and hair. Most lead will eventually make
its way to bones. Lead has blood half-life of about 1 to 2 months,
whereas its half-life in bones is 20 to 30 years. Chronic exposure to
lead can have serious effects on several tissues i.e.
37. • Available forms/ sources: lead-containing paint, gasoline fume inhalation,
drinking water, industrial pollution, food, and contaminated dust.
• Clinical presentation: nausea, vomiting, abdominal pain, convulsions, and
coma.
• Treatment:
1. Administer parenteral chelating agents I/M (1st line therapy):
a. Edetate calcium disodium
b. Dimercaprol
2. Administer oral chelating agents (2nd line therapy):
Succimer or D-Penicillamine
38. Lithium (Eskalith)
• Mechanism of toxicity:
Lithium is a cation that enters the cells and substitutes for sodium or potassium thus affecting ion
transport and cell membrane potential . Lithium is thought to stabilize cell membranes. With excessive
levels, it depresses neuronal excitation and synaptic transmission.
• Available dosage forms: liquid, capsules and tablets
• Clinical presentation:
Mild: Polyuria, blurred vision, weakness, slurred speech, ataxia, tremors.
Severe: Delirium, hypothyroidism (inhibit synthesis of thyroxin), nephrogenic diabetes insipidus (inhibit
ADH release), coma, seizures, and hyperthermia.
• Treatment:
Decontamination:
1. Whole-bowel irrigation for large ingestions.
2. Hemodialysis for severely symptomatic patients.
39. Cyanide
• Mechanism of toxicity:
Cyanide poisoning is a form of histotoxic hypoxia because the cells of an
organism are unable to create ATP, primarily through the inhibition of
the mitochondrial enzyme cytochrome c oxidase.
Its principal toxicity occurs as a result of the inactivation of the cellular
enzyme cytochrome oxidase, leading to the inhibition of cellular
respiration as it blocks the aerobic utilization of oxygen.
Therefore, even in the presence of oxygen, those tissues, such as the
brain and heart, which require a high oxygen demand, are adversely
affected. Death can occur quickly due to respiratory arrest thus it’s also
called as a chemical asphyxiant(death by suffocation).
40. • Available forms: Industrial chemicals and some nail-polish removers.
• Clinical presentation: headache, dyspnea, ataxia, coma, seizures, and death.
Treatment:
1. Cyanide antidote kit:
(a) Amyl nitrite Pearls are crushed and held under the patient's nostrils.
(b) Sodium nitrite converts hemoglobin to methemoglobin which binds the cyanide ion.
2. 100% Oxygen.
3. Sodium bicarbonate for severe acidosis.
4. Hydroxocobalamin (Cyanokit): Hydroxocobalamin is a form of vitamin B-12. It is used as
an antidote to cyanide poisoning. Hydroxocobalamin works by helping cells in the body
convert cyanide to a form that can be removed from the body through urination
42. • Toxicological screening is very important for the development of new
drugs and for the extension of the therapeutic potential of existing
molecules.
• The US-FDA states that it is essential to screen new molecules for
pharmacological activity and toxicity potential in animals (21CFR Part
314).
• Toxicity tests are mostly used to examine specific adverse events or
specific end points such as cancer, cardiotoxicity, and skin/eye
irritation.
• Toxicity testing also helps calculate the No Observed Adverse Effect
Level (NOAEL) dose and is helpful for clinical trails
43. BIOMEDICAL ETHICS
• Before conducting any toxicological testing in animals or collecting
tissue/cell lines from animals, the study should be approved by the
Institute Animal Ethics Committee (IAEC) or the protocol should satisfy
the guidelines of the local governing body.
44. NECESSITIES OF TOXICOLOGICAL STUDIES
• Benefit –risk ratio can be calculated
• Prediction of therapeutic index
Therapeutic index= Maximum tolerated dose/ Minimum curative dose
• Smaller ratio, better safety of the drug.
45. RELEVANT TEST MODELS
• Pharmacokinetic profile
• Pharmacodynamic response
• Species, sex, age of experimental animals
• Susceptibility, sensitivity and reproducibility of test system
• In vitro: Isolated organs, tissues cell-cultures
• Mechanism of effect in vivo
46. 1.In Vivo Studies: In vivo safety pharmacology studies should be
designed to define the dose-response relationship of the adverse effect
observed The time course of the adverse effect should be investigated
e.g. onset and duration of response
2.In Vitro studies: In vitro studies should be designed to establish a
concentration-effect relationship
48. Single dose studies/ Acute Oral Toxicity Tests
• Acute toxicity tests can provide preliminary information on the toxic
nature of a material for which no other toxicology information is
available. Such information can be used to:
• deal with cases of accidental ingestion of a large amount of the
material (e.g., for poison control information);
• determine possible target organs that should be scrutinized and/or
special tests that should be conducted in repeated-dose toxicity tests
• In most acute toxicity tests, each test animal is administered a single
(relatively high) dose of the test substance, observed for 1 or 2 weeks
for signs of treatment-related effects, then necropsied
49. • Some acute toxicity tests (such as the "classical" LD50 test) are
designed to determine the mean lethal dose of the test substance.
The median lethal dose (or LD50) is defined as the dose of a test
substance that is lethal for 50% of the animals in a dose group.
• However, many important observations of toxicity are not
represented by LD50 values.
• alternative test protocols can provide useful information about the
acute toxicity of a substance. These protocols generally use fewer
animals, and are thus more cost efficient, than tests designed to
determine LD50s
50. The main focus of the acute toxicity test should be on observing the
symptoms and recovery of the test animals, rather than on determining the
median lethal dose (LD50) of the substance.
The rat often is used as the animal model in acute toxicity tests, but other
species also may be used.
Often only one sex is studied in an acute toxicity test; generally, the female is
assumed to be more sensitive to the acute toxic effects of chemicals than the
male.
Before deciding on the dose of a test compound that will be used in studying
its acute toxicity, the compound's chemical and physical characteristics
(including molecular weight, partition coefficient, and the toxicity of related
chemicals) should be considered.
51. Subchronic toxicity studies
• Subchronic toxicity studies with rodents are generally conducted for 90
days (3 months), but they may be conducted for up to 12 months. Results
of these studies
• (1) can help predict appropriate doses of the test substance for future
chronic toxicity studies,
• (2) can be used to determine NOAELs for some toxicology endpoints, and
• (3) allow future long-term toxicity studies in rodents and non-rodents to be
designed with special emphasis on identified target organs.
• Subchronic toxicity studies usually cannot determine the carcinogenic
potential of a test substance
52. • Testing should be performed on young animals, for rodents no later
than 6 to 8 weeks of age.
• Necropsy should be performed soon after an animal is sacrificed or
found dead, so that loss of tissues due to autolysis is minimized
• Animals should be exposed to the test substance 7 days per week for
a minimum of 90 consecutive days (3 months). Any other regime
must be justified
• Clinical Testing: Ophthalmological examination, hematology profiles,
clinical chemistry tests, and urinalyses should be performed as
described in Redbook 2000 Chapter IV.C.4.a.
53. Local toxicity studies
• TYPES OF LOCAL TOXICITY STUDIES
Dermal toxicity studies
• Rats & Rabbit
• Local signs (erythema, oedema)
• histological examination
Dermal photo-toxicity studies
• Guinea pig
• Used in treatment of leucoderma
• Examination of erythema & oedema formation
54. Inhalation toxicity studies
• One rodent and non rodent species
• Acute and sub chronic studies performed
• Observation of respiratory rate
• Histological examination of respiratory passages, lung tissue
55. Rectal tolerance studies
• Rabbit or Dog
• Signs of pain, blood or mucous
• histology examination of rectal mucosa
Ocular toxicity studies
• Inhalation toxicity studies
• Albino Rabbit
• Changes in cornea ,Iris & aqueous humor, histological examination of eye
56. Short-Term Tests for Genetic Toxicity
• Genetic changes known to be associated with adverse human health
effects include gene mutations, chromosomal rearrangements or deletions,
and loss or gain of whole chromosomes (aneuploidy) or chromosomal
segments.
• Genotoxicity tests are in vitro and in vivo tests designed to detect
compounds that induce genetic damage.
• Such tests include: (1) tests that directly assess the key types of genetic
alterations (gene mutations and chromosomal effects) and
(2) indirect genotoxicity tests that respond to types of DNA damage known
to lead to these alterations.
The latter category of tests may assess either DNA damage (e.g., DNA
adducts or DNA strand breakage) or cellular responses to DNA damage (e.g.,
unscheduled DNA synthesis).
57. Carcinogenicity / Oncogenicity studies
• Carcinogenicity studies (bioassays) in two rodent species (usually rats
and mice) are recommended for ingredients with the highest levels of
concern
• The carcinogenicity studies (preferably in rats) may be combined with
chronic toxicity studies
• These studies are designed to determine whether a food ingredient
possesses carcinogenic activity when administered to rodents in
regularly repeated oral doses for the "lifetime" of the test animal
