TOXICOLOGY
DEFINITION OF TERMS
 Toxicology - the study of poisons. Toxicity is the intrinsic
capacity of a chemical agent to affect an organism
adversely. (from the Greek words - toxicos "poisonous"
and logos) is a branch of Biology, chemistry, and
medicine. Concerned with the study of the adverse effects
of chemicals on living organisms. It is the study of
symptoms, mechanisms, treatments and detection of
poisoning, especially the poisoning of people.
 Hazard - likelihood an event will occur based on how the
product is packaged, formulated, or its accessibility.
Hazard is the potential for the toxicity to be realized in a
specific setting or situation.
 Risk - the probability that an event will occur based on
patient vulnerability
 Risk is the probability of a specific adverse effect to occur.
It is often expressed as the percentage of cases in a given
population and during a specific time period.
 A risk estimate can be based upon actual cases or a
projection of future cases, based upon extrapolations
 Toxicity rating is an arbitrary grading of doses or exposure
levels causing toxic effects.
 The toxicity grading can be “supertoxic,” “highly toxic,”
“moderately toxic” and so on.
 Toxic substance - poisons
 Poison - any chemical substance which can cause harm
(Toxicants)
 Drug overdose - taking a harmful amount of a drug
 The dose-effect relationship is the relationship between
dose and effect on the individual level
 An increase in dose may increase the intensity of an
effect, or a more severe effect may result.
 A dose-effect curve may be obtained at the level of the
whole organism, the cell or the target molecule.
 A dose is often expressed as the amount of a xenobiotic
entering an organism (in units such as mg/kg body
weight).
 Antidotes: from the Greek anti - against and didonai - to
give the remedy for counteracting a poison
 Additive effects occur as a result of exposure to a
combination of chemicals, where the individual toxicities
are simply added to each other (1+1=2). When chemicals
act via the same mechanism, additively of their effects is
assumed although not always the case in reality.
CONTRIBUTORS TO TOXICITY:
1. PHYSICAL STATE
- The purity of a compound is important to evaluate the
toxicity (impurities can have very strong effects)
- The physical state of a compound cam influence the
toxicity:
o vapor or aerosols are easily taken up by the
lungs
o some solids are not easily dissolved and
thus not toxic
o finely ground arsenic oxide is much more
toxic compared to granlulates
o Solution can be taken up by the skin.
Example: mercury
2. EXPOSURE
- intravenous (ivn) - injected in a vein
- inhalated (ihl)
- intraperitoneal (ipr) - injected in the peritoneal cavity
- subcutaneous (scu) - injected into the skin
- oral (orl) - swallowed
- dermal (d) - applied on the skin
3. THE VICTIM
- Sex-related differences
o there are usually differences between males
and females
- Age-related differences
o in general, infants (undeveloped systems)
and old people (poor immune system) are
more sensitive to toxic chemicals
4. DOSE RESPONSE RELATIONSHIP
- LD50 -the dose that will kill 50% of the exposed
individuals
- LD10 -the dose that will kill 10% of the exposed
individuals
- LDlow -the lowest dose known to cause death
- LC50 -the concentration (mg/m3) that will kill 50% of
the exposed individuals
- TDx -the dose that will give a toxic effect in X% of the
exposed individuals. ex. LD50 = 25 mg/kg (or, rat)
- Economical and ethical issues. (more than 100
animals for a normal test)
5. TARGET ORGAN AND INTERACTION BETWEEN
CHEMICALS
- Target organ is the primary or most sensitive organ
affected after exposure.
- The same chemical entering the body by different
routes of exposure dose, dose rate, sex and species
may affect different target organs.
- Interaction between chemicals, or between chemicals
and other factors may affect different target organs as
well.
- (Most often)CNS – circulatory system – liver- kidney –
lungs – skin – muscles – bone (rare)
6. TOLERANCE
- Tolerance to a chemical may occur when repeat
exposures result in a lower response than what would
have been expected without pretreatment.
DOSE CONCEPT:
 The dose may be expressed in different (more or less
informative) ways:
TOXICOLOGY
 Exposure dose, which is the air concentration of pollutant
inhaled during a certain time period (in work hygiene
usually eight hours),
 Retained or absorbed dose (in industrial hygiene also
called the body burden), which is the amount present in
the body at a certain time during or after exposure
 The tissue dose is the amount of substance in a specific
tissue and the target dose is the amount of substance
(usually a metabolite) bound to the critical molecule.
 The target dose can be expressed as mg chemical bound
per mg of a specific macromolecule in the tissue. The
target dose is more exactly associated with the toxic
effect.
 The exposure dose or body burden may be more easily
available, but these are less precisely related to the effect.
 In the dose concept a time aspect is often included, even if
it is not always expressed.
 The theoretical dose according to Haber’s law is D = ct,
where D is dose, c is concentration of the xenobiotic in the
air and t the duration of exposure to the chemical.
 If this concept is used at the target organ or molecular
level, the amount per mg tissue or molecule over a certain
time may be used.
 A dose threshold is a dose level below which no
observable effect occurs.
 Thresholds are thought to exist for certain effects, like
acute toxic effects; but not for others, like carcinogenic
effects (by DNA-adduct-forming initiators).
 Threshold dose: the point at which toxicity first appears.
NOAEL: no observed adverse effect level
 LD50 (effective dose) is the dose causing 50% lethality in
an animal population.
 The LD50 is often given in older literature as a measure of
acute toxicity of chemicals.
 The higher the LD50, the lower is the acute toxicity.
 A highly toxic chemical (with a low LD50) is said to be
potent.
 There is no necessary correlation between acute and
chronic toxicity.
 ED50 (effective dose) is the dose causing a specific effect
other than lethality in 50% of the animals.
 NOEL (NOAEL) means the no observed (adverse) effect
level, or the highest dose that does not cause a toxic
effect.
 To establish a NOEL requires multiple doses, a large
population and additional information to make sure that
absence of a response is not merely a statistical
phenomenon.
 LOEL is the lowest observed effective dose on a dose-
response curve, or the lowest dose that causes an effect.
 A safety factor may also be used for extrapolation of data
from small populations to larger populations.
 Safety factors range from 100 to 103.
 A safety factor of two may typically be sufficient to protect
from a less serious effect (such as irritation) and a factor
as large as 1,000 may be used for very serious effects
(such as cancer).
 The term safety factor could be better replaced by the
term protection factor or, even, uncertainty factor.
 The use of the latter term reflects scientific uncertainties,
such as whether exact dose-response data can be
translated from animals to humans for the particular
chemical, toxic effect or exposure situation.
 Extrapolations are theoretical qualitative or quantitative
estimates of toxicity (risk extrapolations) derived from
translation of data from one species to another or from
one set of dose-response data (typically in the high dose
range) to regions of dose-response where no data exist.
 Extrapolations usually must be made to predict toxic
responses outside the observation range.
 Mathematical modelling is used for extrapolations based
upon an understanding of the behavior of the chemical in
the organism (toxicokinetic modelling) or based upon the
understanding of statistical probabilities that specific
biological events will occur (biologically or mechanistically
based models).
ANTIDOTE CONCEPT:
 3 types of antidote
 chemical - reacts chemically with the poison to form
a harmless compound, ie. chelators and heavy metals
 mechanical - prevents absorption, ie. activated
charcoal
 physiologic - counteracts the effects of the poison by
producing opposite physiologic effects, ie. atropine
and organophosphate poisoning
TOXICOLOGY
 Universal antidote - 2 parts activated charcoal, 1 part
magnesium oxide and 1 part tannic acid
INTERACTION BETWEEN CHEMICALS:
 Interaction between chemicals may result in an inhibition
(antagonism), with a smaller effect than that expected
from addition of the effects of the individual chemicals
(1+1<2).
 A combination of chemicals may produce a more
pronounced effect than would be expected by addition
(increased response among individuals or an increase in
frequency of response in a population), this is called
synergism (1+1>2).
 Latency time is the time between first exposure and the
appearance of a detectable effect or response.
 The term is often used for carcinogenic effects, where
tumours may appear a long time after the start of
exposure and sometimes long after the cessation of
exposure.
 The mere absence of a response in a given population
should not, however, be taken as evidence for the
existence of a threshold.
 Absence of response could be due to simple statistical
phenomena: an adverse effect occurring at low frequency
may not be detectable in a small population.
RELATIONSHIP BETWEEN DRUG DOSAGES:
Reasons for sub-therapeutic level:
- Non compliance
- Dose too low
- Malabsorption
- Rapid metabolism
Reasons for toxic level:
- Overdose
- Dose too high
- Dose too frequent
- Impaired renal function
- Reduced hepatic metabolism
FACTORS INFLUENCING THE RELATIONSHIP BETWEEN
DRUG DOSAGE AND INTENSTIY OF EFFECT:
- Drug prescribed
o Compliance, correct drug, monitoring
- Dose taken
o Absorption, distribution, metabolism,
excretion
- Plasma concentration
o Diffusion/ active transport
o Protein binding in blood
- Concentration at the site of action
o Tissue responsiveness
o Effects of other drugs
- Intensity of effect
o Over/underdose
FACTORS AFFECTING THE BODY’S RESPONSE TO A
DRUG:
1. Weight
2. Age:
3. Gender
4. Physiological factors: Diurnal rhythm of the nervous and
endocrine system, acid-base balance, hydration, and
electrolyte balance.
5. Pathological factors
6. Genetic factors
7. Immunological Factors
8. Environmental factors
9. Tolerance
10. Accumulation
TOXIC EFFECT CONCEPT:
 Acute effects occur after limited exposure and shortly
(hours, days) after exposure and may be reversible or
irreversible.
 Chronic effects occur after prolonged exposure (months,
years, decades) and/or persist after exposure has ceased.
 Acute exposure is an exposure of short duration, while
chronic exposure is long-term (sometimes life-long)
exposure.
 Acute effects are observed immediately or shortly after
an exposure at one single occasion
 or multiple doses within 24 h.
 Subacute effects means exposure during less than 1
month
 Subchronic means exposure over 1-3 months
 Chronic effects are the result of a continuous exposure
during at least 3 months
 Reversible effects disappear if the exposure stops -
example: narcotic effect of solvents
 Irreversible effects never disappear -example: damages
to nerves, tumors
 Local effects are observed on the part of the body that
first came in contact with the chemical. example: acid
burns
 Systemic effects require that the chemical is taken up
and distributed to the target organ. These are toxic effects
in tissues distant from the route of absorption.
 Independent effect - two compounds are toxic
independent of each other. 2 + 2 = 2
 Additive effect - the total effect is the sum of the the two
independent effects. example: toluene + xylene! 2 + 2 = 4
 Synergistic effect - the united effect is stronger than the
additive effect. example: ethanol + carbon tetrachloride 2
+2=8
 Potentiating effect - one of the compounds is not toxic in
itself but enhance the effect of another compound 0 + 2 =
4 ; example: 2-propanol + carbon tetrachloride
 Antagonistic effect - one compound opposes the effect
of another 2 + 2 = 1
 -functional: one raise blood pressure and
one lowers it
TOXICOLOGY
 -chemical: two compounds neutralize each
other
 -dispositional: one compound lowers the
uptake of another
 -receptoric: the two compounds bind to the
same receptor
BRANCHES OF TOXICOLOGY:
I. Based on research toxicology
A. Descriptive
- Descriptive toxicology deals with toxicity tests on
chemicals exposed to human beings and environment
as a whole.
B. Mechanistic
- Mechanistic toxicology deals with the mechanism of
toxic effects of chemicals on living organisms.
- This is important for rational treatment of the
manifestations of toxicity (e.g. organophosphate
poisoning reversed by oximes) ,prediction of risks
(e.g. organophosphate poisoning →
- leads to accumulation of acetylcholine→ activates
muscarinic and nicotinic receptors--- respiratory
failure) & facilitation of search for safer drugs (e.g.
Instead of organophosphates, drugs which reversibly
bind to cholinesterase would be preferable in
therapeutics)
C. Regulatory
- studies whether the chemical substances have low
risk to be used in living systems.
- E .g - Food and drug administration regulates drugs,
food, cosmetics medical devices &supplies.
Environmental protection agency regulates pesticides,
toxic chemicals, hazardous wastes and toxic
pollutants
D. Predictive
- Predictive toxicology studies about the potential and
actual risks of chemicals /drugs.
- This is important for licensing a new drug/chemical for
use.
II. Based on specific socio-medical issues
A. Occupational
- Deals with chemical found in the Workplace.
- Industrial workers may be exposed to these agents
during the synthesis, manufacturing or packaging of
substances.
B. Environmental
- Deals with the potentially deleterious impact of
chemicals, present as pollutants of the environment,
to living organisms.
C. Clinical
- deals with diagnosis and treatment of the normal
diseases or effects caused by toxic substances of
exogenous origin
D. Forensic
- Closely related to clinical toxicology.
- It deals with the medical and legal aspects of the
harmful effects of chemicals on man, often in post
mortem material, for instance, where there is a
suspicion of murder, attempted murder or suicide by
poisoning.
III. BASED ON ORGAN/ SYSTEM EFFECT
1. Cardiovascular toxicology
2. Renal toxicology
3. Central nervous system toxicology
4. Gastrointestinal toxicology
5. Respiratory
Toxicokinetics deals with absorption, distribution,
biotransformation (biotransformation) and excretion of
chemicals.
Toxicodynamics deals with the biochemical and physiological
effects of chemicals to the body and mechanisms of their
actions.
TRANSPORT PROCESSES:
 Diffusion. In order to enter the organism and reach a site
where damage is produced, a foreign substance has to
pass several barriers, including cells and their
membranes.
 Most toxic substances pass through membranes passively
by diffusion.
 Passive Diffusion—no ATP required;
gradient driven
 A. Simple Diffusion—hydrophobic molecules
 passively diffuse across the membrane.
 Rate of transport proportional to the octanol/ water
partition coefficient or logP.
 B. Facilitated diffusion. The passage of a substance
may be facilitated by carriers in the membrane.
 Facilitated diffusion is similar to enzyme processes in
that it is protein mediated, highly selective, and
saturable.
 Active transport. Some substances are actively
transported across cell membranes.
 One exception is the active tubular secretion and
reabsorption of acid metabolites in the kidneys
TOXICOLOGY
 Active Transport—
a) chemicals are moved against an electrochemical
gradient;
b) the transport system is saturable;
c) requires the expenditure of energy.
EXAMPLES:
 1. multi-drug-resistant protein (mdr)—decreases GI
absorption, blood-brain
 barrier, biliary excretion, placental barrier
 2. Multi-resistant drug protein (mrp)—urinary
excretion, biliary excretion
 3. Organic-anion transporting polypeptide (oatp)—
hepatic uptake of organic
 anions
 4. Organic anion transporter (oat)—kidney uptake of
organic anions
 5. Organic cation transporter (oct)—kidney, liver and
placental uptake of organic cations
 6. Divalent-metal ion transporter (dmt)—GI absorption
of divalent metals (Fe2+, Cu 2+, Mg2+, etc.)
 7. Peptide transporter (pept)—GI absorption of
peptides
 Phagocytosis is a process where specialized cells such as
macrophages engulf particles for subsequent digestion.
 This transport process is important, for example, for the
removal of particles in the alveoli.
 Bulk flow. Substances are also transported in the body
along with the movement of air in the respiratory system
during breathing, and the movements of blood, lymph or
urine.
ABSORPTION ACROSS MEMBRANES
- The membrane is a phospholipid bi-layer consisting of
a polar head group, phosphate, glycerol backbone
and 2 fatty acid molecules esterified to the glycerol
backbone. • hydrophobic compounds can diffuse
across the membrane: • hydrophilic compounds will
not diffuse across the membrane
Freebasing has been done with baking soda (sodium
bicarbonate) or ammonia (NH3) to increase absorption of
cocaine (crack) via nasal installation.
FACTORS AFFECTING ABSORPTION:
 Routes of entry
GI tract can be viewed as a tube traversing the body.
 Although the GI tract is in the body, its contents can
be considered exterior to most of the body’s
metabolism.
 Unless the toxicant is an irritant or has caustic
properties, poisons in the GI tract do not produce
systemic injury until absorbed.
 Absorption can occur anywhere in the GI tract
including the mouth and rectum.
 Initial metabolism can occur in gastric cells.
 Weak acids and bases will be absorbed by simple
diffusion to a greater extent in the part of the GI tract
in which they exist in the most lipid-soluble (non-
ionized) form— hydrophilic substances will be
transported to the liver by the portal vein
 Highly hydrophilic substances may be absorbed
through transporters (xenobiotics with similar
structures to endogenous substrates).
 Highly hydrophobic compounds may be absorbed
into the lymphatic system via chylomicrons and
drained into venous circulation near the heart.
 The greatest level of absorption for most ingested
substances occurs in the small intestine.
Absorption through GUT
Stomach: acidic compounds
Intestine: alkaline compounds
 Polar substances that are absorbed:
1. go to the liver via the portal vein.
2. may undergo first-pass metabolism or
presystemic elimination in gastric and/or liver cells
where xenobiotics may be biotransformed.
TOXICOLOGY
3. Can be excreted into the bile without entrance into
the systemic circulation or enter the systemic
circulation.
 The liver and first-pass metabolism serve as a
defense against most xenobiotics.
 The liver is the organ with the highest metabolic
capacity for xenobiotics
 Lipophilic, non-polar substances (e.g. polycyclic
aromatic hydrocarbons) Polar versus Non-Polar GI
Absorption
 1. Ride on the “coat-tails” of lipids via micelles and
follow lipid absorption to the lymphatic system (via
chylomicrons) to the lungs.
 2. Non-polar substances may by-pass first-pass
metabolism. e.g. PAH have selective toxicity in the
lung, where they may be metabolically activated
 Degree of exposure
Inhalation (Lung)
 Toxicants absorbed by the lung are:
1. Gases (e.g. carbon monoxide, nitrogen dioxide,
sulfur dioxide, phosgene)
2. Vapors or volatile liquids (e.g. benzene and carbon
tetrachloride)
3. Aerosols
Gases and Vapors
 The absorption of inhaled gases and vapors starts in
the nasal cavity which has:
1. Turbinates, which increase the surface area for
increased absorption (bony projections in the
breathing passage of the nose improving smell).
2. Mucosa covered by a film of fluid.
3. The nose can act as a “scrubber” for water-soluble
gases and highly reactive gases, partially protecting
the lungs from potentially injurious insults (e.g.
formaldehyde, SO2).
 Rats develop tumors in the nasal turbinates when
exposed to formaldehyde.
Absorption of Gases
 Absorption of gases differs from intestinal and
percutaneous absorption of compounds because:
1. Ionized molecules are of very low volatility, so their
ambient air concentration is insignificant.
2. Epithelial cells lining the alveoli (type I
pneumocytes) are very thin and the capillaries are in
close contact with the pneumocytes, so the diffusion
distance is very short.
3. Chemicals absorbed by the lungs are rapidly
removed by the blood (3-4 seconds for blood to go
through lung capillary network).
 When a gas is inhaled into the lungs, gas molecules
diffuse from the alveolar space into the blood and
then dissolve.
 The gas molecules partition between the air and
blood during the absorptive phase, and between
blood and other tissues during the distributive phase.
 Note that inhalation bypasses first-pass
metabolism
 Examples of Toxicant Gases or Volatile Liquids
1. Carbon monoxide—binds hemoglobin (with >200x
affinity compared to O2) and displaces oxygen
leading to impaired oxygenation of tissues, energy
impairment, and death
2. Chloroform—anesthetic that depresses the
nervous system, but can also be metabolized to
phosgene, a reactive metabolite that modifies proteins
and causes toxicity in lung, kidney, and liver.
3. Sarin gas—chemical warfare agent (recently used
in Syria) that causes excessive neuronal excitation,
convulsions, seizures, tearing, salivation, suffocation,
and death through inhibition of acetylcholinesterase
4 Carbon tetrachloride—volatile liquid used widely
as a cleaning agent and refrigerant, currently
banned—greenhouse gas and carbon tetrachloride
can be bioactivated in the liver to produce a potent
hepatotoxin
5. Benzene—largely found in crude oil, but also found
in tobacco smoke and used to be found in glues,
paints, and detergents— benzene metabolism leads
to bioactivated carcinogens that cause leukemia
AEROSOLS AND PARTICLES (SIZE AND LOCATION OF
ABSORPTION):
 Deposited in tracheobronchiolar regions of the
lungs. 2-5 μm
 1. Cleared by retrograde movement of mucus layer in
ciliated portion of respiratory tract.
TOXICOLOGY
 2. Coughing can increase expulsion rate.
 3. Particles can be swallowed and absorbed from the
GI tract. (asbestosis—lung fibrosis, wheezing)
 Penetrates to alveolar sacs of lungs and is absorbed
into blood or cleared (<1 μm) through lymphatic
system after being scavenged by alveolar
macrophages.
 (asbestos and silica dust can cause silicosis—cough,
shortness of breath,
 inflammation, immunodeficiency through damaging
pulmonary macrophages
 Deposited in nasopharyngeal region (or mouth). >5
μm
1. Removed by nose wiping, blowing or sneezing.
2. The mucous blanket of the ciliated nasal surface
can propel insoluble particles by movement of cilia
and be swallowed.
3. Soluble particles can dissolve in mucus and be
carried to the pharynx or nasal epithelia and into
blood. (asbestos-lung cancer)
Pulmonary clearance
• Particles trapped in fluid layer of conducting airway removed
by mucociliary escalator.
• Particles phagocytized by alveolar macrophages removed by
lymph.
• Substances dissolved from particle surface removed in blood.
• Small particles directly penetrate epithelial membranes.
Absorption through skin:
- Many organic compounds readily absorbed:
o Solvents
o Pesticides
o Organo-metal compounds
- Routes of Exposures: Dermal (skin)
o Human skin comes into contact with many
toxic agents.
o Fortunately, the skin is not very permeable
and is a good barrier for separating
organisms from their environment.
o To be absorbed through the skin, a toxicant
must pass through the epidermis or the
appendages (sweat and sebaceous glands
and hair follicles).
o Once absorbed through the skin, toxicants
must pass through several tissue layers
before entering the small blood and lymph
capillaries in the dermis.
o The rate-determining barrier in the dermal
absorption of chemicals is the epidermis—
especially the stratum corneum (horny
layer), the upper most layer of the epidermis.
o The cell walls are chemically resistant, two-
times thicker than for other cells and dry, and
in a keratinous semisolid state with much
lower permeability for toxicants by
diffusion—the stratum corneum cells have
lost their nuclei and are biologically inactive
(dead).
o Once a toxicant is absorbed through the
stratum corneum, absorption through the
other epidermal layers is rapid.
- All toxicants move across the stratum corneum
by passivediffusion
• Polar substances diffuse through the outer surface
of protein filaments of the hydrated stratum corneum.
• Non-polar molecules dissolve and diffuse through
the lipid matrix between protein filaments.
• The rate of diffusion is proportional to lipid solubility
and inversely proportional to molecular weight.
- Once absorbed, the toxicant enters the systemic
circulation by-passing first-pass metabolism.
- Factors that Affect Stratum Corneum Absorption
of Toxicants
1. Hydration of the stratum corneum
• The stratum corneum is normally 7% hydrated which
greatly increases permeability of toxicants. (10-fold
better than completely dry skin)
• On additional contact with water, toxicant absorption
can increase by 2- to 3-fold.
2. Damage to the stratum corneum
• Acids, alkalis and mustard gases injure the
epidermis and increase absorption of toxicants.
• Burns and skin diseases can increase permeability
to toxicants.
3. Solvent Administration
- • Carrier solvents and creams can aid in increased
absorption of toxicants and drugs (e.g.
dimethylsulfoxide (DMSO)).
Summary on Absorption
• Route of exposure and physicochemical properties of
xenobiotic determine how a chemical is absorbed and
whether it goes through first-pass metabolism or is
subjected to systemic circulation.
• The degree of ionization and the lipid solubility of
chemicals are very important for oral and percutaneous
exposures.
• For exposure to aerosols and particles, the size and
water solubility are important.
TOXICOLOGY
• For dermal absorption, polarity, molecular weight and
carrier solvent of the toxicant and hydration of the
epidermis are important.
Special Routes of Exposure
Toxicants usually enter the bloodstream after absorption
through the skin, lungs or GI tract. Special routes include:
1. Subcutaneous injection (SC) (under the skin)
-by-passes the epidermal barrier, slow absorption but directly
into systemic circulation; affected by blood flow
2. Intramuscular injection (IM) (into muscle)
-slower absorption than IP but steady and directly into systemic
circulation; affected by blood flow
3. Intraperitoneal injection (IP) (into the peritoneal cavity)
-quick absorption due to high vascularization and large surface
area -absorbed primarily into the portal circulation (to liver—
first-pass metabolism) as well as directly into the systemic
circulation.
4. Intravenous injection (IV) (into blood stream) -directly into
systemic circulation
SUBSTANCES MOST FREQUENTLY INVOLVED IN HUMAN
EXPOSURES:
 Analgesics - 10%
 Cleaning substances - 9.5%
 Cosmetics and personal care products - 9.4%
 Foreign bodies - 5.0%
 Plants - 4.9%
 Cough and cold preparations - 4.5%
 Bites and envenomations - 4.2%
SUBSTANCES MOST FREQUENTLY INVOLVED IN
PEDIATRIC POISONING:
 Cosmetics and personal care products - 13.3%
 Cleaning substances - 10.5%
 Analgesics - 7.2%
 Foreign bodies - 6.8%
 Plants - 6.6%
 Topicals - 6.3%
 Cough and cold preparations - 5.3%
SUBSTANCES MOST FREQUENTLY INVOLVED IN ADULT
POISONING:
 Analgesics - 13.3%
 Sedatives/hypnotics/antipsychotics - 9.8%
 Cleaning substances - 9.5%
 Antidepressants - 8%
 Bites/envenomations - 7.9%
 Alcohols - 5.4%
 Properties of chemicals
DISTRIBUTION:
- After a toxicant enters portal circulation, systemic circulation,
or lymph, it is available for distribution (translocation)
throughout the body, which usually occurs very rapidly. The
rate of distribution to organs or tissues is determined by:
1. Physicochemical properties of the chemical
2. Blood flow
3. Rate of diffusion out of the capillary bed into the cells of a
organ or tissue.
4. Affinity of a xenobiotic for various tissues.
- Penetration of toxicants into cells or tissues occurs by
passive diffusion or active transport (as discussed earlier
Distribution of toxicants
Distribution can be highly localized, restricted or disperse
depending on:
1. Binding and dissolution into various storage sites (fat, liver,
bone)
2. Permeability through membranes
3. Protein binding
4. Active transport
If the toxicant accumulates at a site away from a toxic site of
action, it is considered as a protective storage site
Storage of Toxicants in Circulation and Tissues
1. Plasma Proteins as Storage Depot:
a. Albumin -the most abundant protein in plasma- can bind to
a very large number of different compounds—(e.g. bilirubin,
Ca2+, Cu2+, Zn2+, vitamin C, fatty acids, digitonin, penicillin,
sulfonamides, histamine, barbiturates, thyroxine, etc.)
TOXICOLOGY
- Contains 6 binding regions on the protein
- Protein-ligand interactions occur primarily through
hydrophobic forces, hydrogen bonding, and van der Waals
forces.
- Bilirubin, a heme byproduct, is neurotoxic at high
levels, but is normally bound to albumin to make it less toxic
2. Liver and Kidney as Storage Depots—have the highest
capacity for binding chemicals.
Ligandin: this cytoplasmic protein in the liver is a high-affinity
binding protein for many organic acids—can bind bilirubin,
azodye carcinogens, steroids, etc.
Metallothionein: found in the kidney and liver and has high
affinity for cadmium and zinc--in the liver, metallothionein binds
Lead (Pb) and concentrates it to 50-fold more than plasma.
3. Fat as a Storage Depot
Many highly lipophilic toxicants are distributed and
concentrated in fat (e.g. dioxin, DDT, polychlorinated
biphenyls)
4. Bone as Storage Depot
- Compounds such as fluoride, lead, and strontium may be
incorporated and stored in bone matrix.
-90% of lead in the body is eventually found in the skeleton.
-The mechanism of storage is through exchange of bone
components for the toxicant (e.g. F- may displace –OH; Pb2+
and Sr2+ may substitute for Ca2+ in the hydroxyapatite lattice
matrix).
Effects of Storage on Toxicity
1. Reduces toxicity of some substances by taking toxic
substances out of the sites of action.
2. Increases toxicity if: a)toxicity at storage site, b)
displacement of one substance by another (e.g. bilirubin), loss
of storage site.
3. Can produce chronic toxicity from prolonged exposure.
There are four major anatomic and physiologic reasons why
some toxicants do not readily enter the CNS.
1. Capillary endothelial cells of the CNS are tightly joined,
leaving few or no pores between cells.
2. Brain capillary endothelial cells contain an ATP-dependent
transporter, the multi-drug-resistant (mdr) protein that
transports some chemicals back into the blood.
3. Capillaries in the CNS are surrounded by glial cells
(astrocytes) to further restrict access.
4. The protein concentration in the interstitial fluid of the
CNS is much lower than in other body fluids.
Blood Brain Barrier
• For water-soluble molecules, the tighter junctions of the
capillary endothelium and the lipid membranes of the glial cells
represent the major barrier.
• Many lipid soluble compounds are restricted due to the many
lipid membranes to be crossed (capillary and glial cell
membranes) and low protein content.
• The blood-brain barrier is more effective against water
soluble substances.
Methyl Mercury Transport Across the Blood-Brain Barrier
- Methyl mercury combines with cysteine, forming a
structure similar to methionine, which is transported
across the blood brain barrier through the methionine
transporter in endothelial cells
- Once in the brain, methyl mercuric cysteine can react with
reactive cysteines on proteins and cause neurotoxicity
Children are more susceptible to neurotoxicants
• The blood-brain barrier is not fully developed at birth, and
this is one reason why some chemicals are more toxic in
newborns than adults.
• Morphine is 3-10 times more toxic to newborns than
adult rats because of higher permeability into the brain.
• Lead produces toxicity in the brain and spinal cord
(encephalomyelopathy) in newborn rats but not in adults,
because of differences in the stages of development of the
blood brain barrier.
Family of ATP Binding Cassette (ABC) Proteins
- The ATP-binding cassette (ABC) transporters form a
large family of membrane proteins that transport a
variety of compounds through the membrane against
a concentration gradient at the cost of ATP hydrolysis.
- Substrates include lipids, bile acids, xenobiotics, and
peptides for antigen presentation. As they transport
exogenous and endogenous compounds, they reduce
the body load of toxicants.
- One by-product of such protective function is that they
also eliminate various useful drugs from the body,
causing drug resistance. Many types of cancer cells
can up-regulate MDR (multidrug resistant).
- MRP1 (multi-resistant protein) was originally cloned
from a lung tumor cell.
TOXICOLOGY

Three subfamilies of the human ABC family based on motifs in

ATP binding domains:

1. ABCB1 (MDR1/P-glycoprotein of subfamily (hydrophobic

and cationic compounds)

2. ABCC (MRPs) (phase II conjugate metabolites)

3. ABCG2 (phase II conjugates)

Xenobiotic substrates:

1. Alkaloids (bases)

2. Metals—arsenic, oxidized GSH (GSSG)

3. Conjugates of glutathione, glucuronic acid, and sulfates

4. Neutral compounds (e.g. PAH)

DISTRIBUTION: BASIC TECHNIQUES FOR DETECTING DRUGS IN SERUM

AND URINE:
- Transport by blood
- Rate 1. Immunochemical
- Substances released from storage a. EMIT (Enzyme Mediated Immunologic Technique)
-uses a drug-enzyme complex (marker) w/c is
STORAGE covalently linked to each other
-concentration of drug in sample is directly
- Fats: lipophilic compounds proportional to the enzymatic activity
- Bones: chemicals similar to calcium (fluorine, lead, b. FPIA (Fluorescent Polarization Immunoassay)
strontium) -sensitive and specific method (nanomolar range)
- Blood -uses a drug probe complex
- Liver & kidney -polarization is inversely proportional to concentration
- Other organs/ tissues of drug in sample
-Abbot laboratories (Chicago, Il) TDX, AXSYM
BIOTRANSFORMATION analyzers
-Rosche Diagnostic Laboratories (Nutley, NJ)
- Occurs mainly in liver COBAS, INTEGRA analyzers
- Also in lungs, kidney and intestine
- Catalyzed by enzymes (Cytochrome P450) 2. Chromatographic
- Increases water solubility for excretion via kidney
- Metabolites or intermediaries can be toxic Mainly for qualitative detection

TLC – Thin Layer Chromatography

-Polar solid stationary phase (usually hydrated silicate)

-Non-polar mobile phase (10% methanol in chloroform)

Principle:

-For a given solvent system, the ratio of the distance

transversed by the compound to the distance transversed by
the solvent front is a constant for the compound and can be
used to identify the compound in the mixture, this ratio is called
rf

Applications:

-testing for drugs of abuse

TOXICOLOGY

-Toxi-Lab (Irvine, CA) SCREENING FOR DRUGS OF ABUSE

-Best specimen is urine 2 levels:

(because large quantities can be collected noninvasively) 1. Emergency room testing

-identification by color change mechanism (fluorescence) -rapid, stat screening methods

-Steps: EMIT/FPIA/TLC

-collection of samples -sample: urine

-concentration 2. Employment/Forensic testing

-extraction (acidic separation from basic) -GS-MC/HPLC

almost all drugs of abuse are basic drugs, all of which are
amine derivatives
-important acid drugs comprise almost exclusively the
barbiturates
HPLC – High Performance Liquid Chromatography
-quantitative detection (allows sharper separation)
Note: Strictly by law, any confirmatory method is valid,
provided it is a completely different method from the primary
one.
COCAINE
-cocoa plant derivative (food additive)
-beginning of the 20th century, used in Coca-Cola
-derivative of the alkaloid ecgonine (methyl ester of
benzoylecgonine)

-mainly utilized for quantitation of the tricyclic antidepressants

Fatal aspects:
and their metabolites
-direct drug toxicity
-most commolnly prescribed drugs and are also used in excess -crime related to illicit acquisition
as drugs of abuse in suicide attempts.
Administration:
-nasal (inhalation,snorting)

Stationary phase: Half-life: 1-2 hours (2 days in body)

-Polar (silicic acid) Applications:

-local anesthesia (nasopharyngeal surgery)
-non-polar (C-18 columns) -induction of euphoric state (‘HIGH’)
-induction of hallucinatory states

GC-MC – Gas Chromatography-Mass Spectroscopy (GOLD
STANDARD; volatile drugs and poisons)
-great sensitivity and reliability
Others:
CE – Capillary Electrophoresis
LC-MS – Liquid Chromatography-Mass Spectroscopy
-used for nonvolatile compounds
-confirmation for drugs of abuse, poisoning detection in acute
or chronic intoxication, therapeutic drug identification and
quantitation
Effects:
- can also promote violent behavior many of the results of
which is attributed to its dopaminergic effects
- increase Ca ion (intracellular)
- increase dopamine
- neurotoxic
- General cytotoxic effects from formation of an N-oxide free
radical produced in the metabolism of this compound in
the liver.
- cardiotoxicity (progressive atherosclerosis)
- can pass in placenta and lactating mammary glands
(babies: mental retardation, delayed development and
strong drug dependence and malformations in-utero)
Mechanism:

-pharmacokinetic and drug metabolism studies.

TOXICOLOGY

- -induce release of beta-endorphins that bind to mu- - ‘angel dust’/’angel

receptors in the limbic system giving a pleasant and Effects:
positive feeling of reinforcement. -analgesic and anesthetic and stimulatory
-a wide variety of bizarre and apparently paradoxical
MORPHINE symptoms can be seen in the same patient.
-powerful analgesic
-treating acute congestive heart failure by lowering venous BARBITURATES
return to the heart
- Sedative hypnotics
CODEINE - Barbituric acid
-mild analgesic and as an antitussive o condensation product of urea and malonic acid
Half-life: o anticonvulsants
Intravenous – 3 minutes o fat soluble and therefore pass easily across the blood-
Effects – 3 hours brain barrier
Fatalities: - Effects:
-coma -sedation
-respiratory arrest -drowziness
Treatment; -sleep
-intravenous naloxone (Narcan) -impairment of judgement
-as a chronic problem, is treated pharmacologically with a -anesthetic (high-does)
partial agonist of heroine, -stupor, coma, death (lethally high-dose)
-methadone
PROPOXYPHENE
METHADONE - analgesic (similar pharmacologically to opiates and
-nonbicyclic drug that binds competitively with morphine to mu- morphine)
receptors in the brain - Effects:
-less addictive than heroine (binding affinity is lower) -same as opiates
-nephrogenic diabetes insipidus
AMPHETAMINES - Treatment: Naloxone (Narcan)
-
- Bears close resemblance to the adrenergic amines such METHAQUALONE:
as epinephrine and norepinephrine and may be expected - Half-life: 20-60 hours
to exert sympathomimetic effects. - Effects:
- Also resemble dopamine and may also be expected to o Hypnotic and sedative (150-300 mg/day)
have effects on dopaminergic pathways. - anticonvulsant
- antispasmodic
Effects: - local anesthetic
- antitussive
-cause euphoria
-increased mental awareness MARIJUANA
-pronounced adrenergic effects (delirium, confusion, delusion,
disorientation, hallucinations, restlessness, homicidal and - one of the oldest and most widely used of the mind
suicidal tendencies, panic states, paranoia) altering drugs
- a mixture of cut, dried, and ground portions of the hemp
BENZODIAZEPINES plant Cannabis sativa
- Valium is most prominent in use (minor tranquilizers) - Hashish refers to a more potent product produced by
Effects: extraction of the resin from the plant
- calming (2.5-10 mg)
- muscle relaxing (higher doses) - Delta-9-tetrahydro cannabinol (THC)
- used by drug addicts to counter the excitatory effects of -principal psychoactive agent in marijuana
other drugs of abuse or as a means of inducing tranquil -Lipid-soluble; readily enters the brain and may act by
states producing cell membrane changes
- physical and psychological dependence occur in chronic - Administration
users  oral
- Half-life: 20-70 hours to 50-100 hours  smoking
- Half-life:
PHENCYCLIDINE  1 week
- used almost exclusively as a drug of abuse  1-4 weeks (detection in urine)
TOXICOLOGY

Effects:  Toxic Effect.

 reddening of conjunctiva
 increased pulse rate 1 ) Toxic effects that is direct and predictable following an
 muscle weakness overdose of the drug
 deterioration in motor coordination
2) Toxic effects may be direct and predictable following
LYSERGIC ACID DIETHYLAMIDE repeated dosing of the drug. The effect may be mediated by
- semisynthetic indolalkylamine and hallucinogen metabolites, it may be pharmacologic in nature, or it may be
- one of the most potent pharmacological materials known, immunologic.
producing effects at doses as low as 20 ug
3.) These effects often represent the idiosyncratic response to
- Administration:
drugs and may be immunologic or pharmacologic in
-injection
mechanism. Toxic effects that are the result of some drug
-oral
interaction.
- Effects
 CNS hyperarousal 4.) Many times the treatment for a drug must be supportive in
 hypertension approach (e.g. anti-arrhythmics for arrhythmic effects, fluids for
 panic reactions replacement, et c.) or there may be specific antidotes (i.e. N-
 BAD TRIP’ acetylcysteine for paracetamol, pralidoxime for
 mydriasis cholinesterase inhibitors, or naloxone for morphine).
 piloerection
 tachycardia COMMON DRUGS THAT CAUSE CERTAIN CLASSES OF
TOXICITY:
- Treatment: -diazepam
Acetaminophen (Paracetamol, APAP).
PHARMACOKINETICS:
Administration of drugs:  The toxic effect of acetaminophen is due to the
Continously accumulation of the toxic metabolite N-acetyl
 steady-state concentration of drug is reached once the parabenzoquinone imine.
amount of drug infused in a unit of time equals the amount
of drug eliminated in the same unit of time)  Normally, APAP is metabolised by glucuronide, sulphate,
cysteine, and cytochrome P450 systems.
Discontinously (most common)
 The conjugated metabolites are excreted while the P450
 -medication taken orally at fixed periods.
metabolite (N-acetyl parabenzonequinone imine) which is
 -taken at discrete times between which a certain amount
highly reactive is conjugated by glutathione (GSH).
will be excreted before the next dose is given.
 In overdose situations, the conjugation pathways are
Note:
saturated and metabolism shifts to the P450 pathway.
 All drugs are eventually excreted in urine. Occasionally,
some drugs enter the enterohepatic circulation (metabolic  Glutathione is then depleted, resulting in an accumulation
conversion occur in the liver) and are excreted in stool. of the reactive intermediary which will bind to hepatic
 -unchanged proteins, causing necrosis.
 - as metabolites of the parent drug
Metabolism in the liver – Conversion occurs in the Aspirin
extramitochondrial, microsomal system in hepatocytes
(mainly an oxidative one) by utilizing a special cytochrome  Aspirin, which produces a classic toxic response with
system P450. salicylism and the consequent metabolic changes,

Half-life – The time taken for half the drug that was initially  EXCEPT, it toxic effect not through immune responses,
present in serum to be excreted. active metabolites, or wayward enzyme systems,

FACTORS INFLUENCING TOXICITY:
- Demographic profile of affected person
- Toxic Response of Drugs and Toxicants
- Toxic responses can vary substantially depending on the
species. Most species differences are attributable to
differences in metabolism. Others may be due to
anatomical or physiological differences
 BUT simply as a direct result of the various actions of the
drug and its active moieties.
 Moreover, mild ASA toxicity (salicylism) may be observed
at acute doses greater than 150 mg/Kg while severe
toxicity may not occur until doses greater than 400 mg/Kg
are ingested.
TOXICOLOGY

Amphetamines and other CNS Stimulants. -commonly used to treat congestive heart failure and cardiac
arrhythmias
These drugs include amphetamine derivatives and other CNS
stimulants. Toxicity from these drugs most often presents as - Effects: slows down electrical conduction
consequences from substance abuse, however overdose with
oral decongestants such as pseudoephedrine may also be 4 Classes:
seen clinically.
1. Class I
More commonly abused drugs having stimulant activity in the
U.S.A. include methamphetamine, -blocks sodium influx
methylenedioxymethamphetamine (MDMA), cocaine, and the
-decreases the rate of ventricular diastolic depolarixation
psychedelic phencyclidine (PCP).
(quinidine, procainamide, lodocaine, phenytoin)
Anticholinergics -- atropine, antihistaminics, Amanita
2. Class II
mushrooms.
-Beta-adrenergic blockers (propanolol-inhibit chronothropic
 Toxicity from drugs possessing anti-muscarinic activity
effects of adrenergic neurotransmitters like epinephrine and
presents with a distinct profile that has been described as
norepinephrine)
"red as a beet" (flushing); "hot as a hare" (hyperthermia);
"dry as a bone" (decreased sweating and mucous 3. Class III
membranes);
-Potassium channel blockers (amiodarone-block repolarizing
 "blind as a bat" (blurred vision); and "mad as a hatter" potassium currents, increasing the length of the action
(behavioural effects including delirium, hallucinations, and potential)
confusion
4. Class IV
Antidepressants (Tricyclics) -- amitryptiline, nortryptiline,
imipramine, -Calcium channel blockers (verapamil-slows calcium ion influx,
prolonging action potential)
 A class of drugs represents one of the most common
classes involved in life-threatening overdoses.

 Ingestion of as little as 15 mg/Kg (roughly 1 G) may be

fatal.

Beta-adrenergic antagonists (propranolol).

 It can be seen that an overdose of these drugs with beta-

blockers (even those with beta-1 selectivity, which is lost
at higher doses) will prevent adrenergic activity at both
beta-1 and beta-2 receptors.

 However, little as double or treble the normal therapeutic

dose of propranolol may cause fatalities.

 Common presentation signs and symptoms include

bradycardia, hypotension (partial agonists such as pindolol
may cause tachycardia and hypertension at higher doses),

 Reduced cardiac output to the point of causing

cardiogenic shock, seizures, and arrhythmias.

Calcium channel antagonists

 These agents will produce severely compromised cardiac

output, bradycardia and hypotension as a toxic response.

 Cardiogenic shock may ensue.

CARDIOTHROPICS