General Principles of Toxicology

Philip Sasi
 Background
• The field of toxicology is a broad-based
multidisciplinary science that examines the
harmful effects of substances on living
organisms, including humans.

• There are several major subdivisions of

toxicology.
• Descriptive toxicology
– focuses on toxicity testing with the intent of
defining the degree of risk associated with
substances.
• Environmental toxicology
– involves the detection and understanding of
environmental pollutants and their effects on
humans and other organisms.
• Forensic toxicology
– is primarily concerned with detection and
quantification of toxic substances for legal
purposes.

• Mechanistic toxicology
– is focused on determining the mechanisms by
which substances exert toxic effects
• Regulatory toxicology
– uses toxicologic data to establish policies
regarding exposure limits for toxic substances.

• Medical or clinical toxicology

– focuses on the diagnosis and treatment of toxic
effects in humans.
 Objective of this Discussion
• The understanding of the concepts of medical
toxicology
• In principle, these concepts are similar in to
those of pharmacodynamics and
pharmacokinetics.
• This is not surprising, because any substance
can be toxic under the appropriate conditions.
 Objective continued
• Indeed, Paracelsus, an early toxicologist,
stated, “All things are poison and nothing is
without poison, only the dose permits
something not to be poisonous.”
• In fact, even water in excess can exert toxic
effects (water intoxication) by disrupting
electrolyte balance.
• Thus toxicity may be associated with
therapeutic agents and nontherapeutic agents
alike.
 Terminology
Some useful definitions in toxicology include:
• Poison
• is any substance that may disrupt biologic function
and potentially kill an organism.

• Toxin, by strict definition,

• is a poison of biologic origin that does not have the
ability to replicate. However, the term toxin has been
used more loosely. For example, environmental
toxin has been used to describe toxic substances of
nonbiologic origin.
• Venom
– is a toxin that is injected into the victim by some
means (e.g., bee sting, snake bite).

• Toxicant
– is a general term that refers to any
harmful substance and is generally
interchangeable with poison.
• Toxicodynamics
• refers to the general concepts of
pharmacodynamics (interaction with molecular
targets and mechanisms of effects) as applied to
interactions and mechanisms that generate toxic
effects

• Toxicokinetics
• refers to the general concepts of
pharmacokinetics (absorption, distribution,
biotransformation, and elimination) as applied to
toxic substances
 General Mechanisms of Toxicity
• Toxicity can be caused by both therapeutic
and nontherapeutic substances.
• In terms of therapeutic drugs, toxicity may
arise from a direct extension of the drug’s
primary action. For example, central nervous
system (CNS) depression or coma may occur
with excessive doses of barbiturates used in
the treatment of epilepsy.
• The toxic effect may also be unrelated to the
primary therapeutic effect but related to the
general pharmacology of the drug
(nonsteroidal antiinflammatory agents may
increase edema in heart failure patients).

• The toxic effect may also have no relationship

to the therapeutic action of the
drug(ototoxicity induced by aminoglycoside
antibiotics).
• There are several general mechanisms by
which toxic effects occur. These mechanisms
can be classified as follows:
• Physical
– The physical presence of the toxicant triggers
reactions that are harmful (e.g., asbestos fibers in
the lung).
• Chemical
– Toxicants react chemically with the tissues or body
fluids such as blood to produce harmful effects
(e.g., strong acids or bases cause burns).
• Pharmacologic
• Toxicants interact with endogenous pharmacologic
pathways, resulting in inhibition or
overstimulation (e.g., botulinum toxin inhibits
release of acetylcholine to cause paralysis).
• Biochemical
• Toxicant reacts biochemically with cellular
constituents to produce cellular damage (e.g.,
venom of many snakes contains phospholipases
that destroy cell membranes).
• Genomic (genotoxic)
• Toxicant alters the genetic material of the cell,
resulting in disruption of function.
• Genotoxic substances may be mutagenic or
carcinogenic.

• Mutagenic (carcinogenic)
• Toxicants alter DNA structure or function
sufficiently to cause mutations (benzene) or
initiate and promote the development of cancers
(polycyclic aromatic hydrocarbons such as
benzo[a]pyrene, found in cigarette smoke).
• Immunologic
• Toxicant may trigger an immune response that
leads to cellular damage (e.g., penicillin-induced
hemolytic anemia) or conversely suppresses the
immune system, causing an increased
susceptibility to infection (e.g., procainamide-
induced agranulocytosis).
• Teratogenic
• Toxicant alters fetal development, resulting in
birth defects (e.g., phenytoin is associated with
development of cleft lip)
 Target Organs
• Toxicity may be systemic, affecting the whole
body, or it may be largely confined to select
target organs, the so-called toxic effect organs.

• Some organs, such as the liver, brain, lungs,

heart, and kidney, play a central role in
poisonings
• A number of factors interact to determine the
susceptibility of organs to toxic effects.
• These include :
– the organ’s anatomic location
– blood flow
– metabolic processes and activity
– affinity for the toxicant
– capacity for self-repair.
• Major toxic effect organs include the
following:
• Liver
– The liver is exposed to a high concentration of
toxic substances

– Orally absorbed toxicants are presented first to

the liver via the portal circulation.

– The liver also receives a large proportion of

systemic blood flow.
• Liver continued
– Enterohepatic cycling extends exposure to
toxicants excreted through the bile.

– The high metabolic activity of the liver also

results in the generation of reactive intermediates
that may have toxic actions
• Kidney
– The kidney receives a high proportion of the
cardiac output. Many toxic substances
are excreted by the kidney

– These toxicants are concentrated in the urine as

fluid is reabsorbed from the renal tubule
• Heart
– The total blood volume passes through the heart.
Thus it is exposed to all blood-borne toxicants.
• Lungs
– The lungs represent an extremely large surface
area for interaction with toxicants, particularly
those that are airborne.

– The total cardiac output passes through the lungs,

so blood-borne toxicants are also distributed
extensively to the lungs.
• Brain
– The brain is a critical target organ because of its
central role in homeostasis
– Thus toxicants that affect the brain may influence
multiple systems and result in widespread
systemic toxicity.
 Liver
•Exposed to high concentrations of toxicants absorbed from GI tract
•Repeated exposure via entero hepatic recycling
•High blood flow
•High biotransformation activity

Brain
•Central homeostatic regulator

Major target organs

Heart
•High blood flow Lungs
•Large surface area
Kidneys •High blood flow
•High blood flow •Exposed to atmospheric
•Toxicants concentrated in urine toxicants
 Risk Assessment
• Poisoning remains a significant public health
issue that affects up to approximately 5% of
the population per year in industrialized
countries.
• Many countries have established national
poison control centers that can serve as
valuable sources of information.
• The World Health Organization maintains a
directory of these centers (see Websites).
• Because virtually all substances are potentially
toxic, key questions in toxicology are:
– how much risk is associated with a particular
substance and under what conditions does this
risk become apparent?

– In addition, the level of acceptable risk will vary.

– In some circumstances, very toxic substances (e.g.,

anticancer drugs) are used therapeutically despite
their known toxic effects because the benefits of
such treatments outweigh the risks.
• Accordingly, risk assessment is a primary
consideration in the management of toxic
events
• Key factors contributing to risk assessment
include the following:
• Hazard identification
– What substances are involved and what are the
adverse effects of each substance?
– Knowledge of the physicochemical properties,
toxicokinetics, and toxicodynamics of the
suspected toxicant(s) is invaluable in designing
treatment strategies.
• Dose response
– Is there a known dose response relationship for
the toxic effects of the toxicant?
– Do toxic effects mirror plasma concentrations?
– At what dose (concentration) do toxic effects
appear?
• Exposure assessment
– Exposure assessment is a key process in
determining the urgency and strategy for
treatment of toxic events.
• Exposure assessment includes estimation of
the following:
• Degree of exposure
– An estimate of the degree of exposure is essential

– This may be the dose of drug ingested, the

concentration of chemical to which a patient was
exposed, or some other measure (e.g., parts per
million) of the amount of toxicant.

– Included in this assessment is whether the

exposure was acute or chronic.
• Route of exposure
– The route of exposure is an important
determinant of both the extent and rate of
absorption of the toxicant.

– For example, dermal exposure is generally

associated with reduced rates and extent of
absorption compared with oral ingestion or
inhalation.
• Time since exposure
• An estimate of the time since the exposure
will be helpful in estimating the following:
– Degree of absorption at presentation.
– Usefulness of blood sampling
• Blood sampling is useful for toxicants that exhibit a
relationship between the plasma concentration and
toxic effect(s).
• However, if the time of exposure has been long, it is
most likely that plasma concentrations have reached a
maximum value and are of lesser benefit compared
with symptomatology in determining course of
treatment.
• Time since exposure continued
– Value of certain therapies
• The time since exposure will dictate to a certain extent
the appropriateness of treatment approaches.

• For example, if the time since initial exposure has been

very long, then therapies aimed at inhibiting absorption
may have only a minor influence on the course of
poisoning.
• Clinical Status
– In many cases, information about the degree and
time of exposure may be lacking

– In such cases, careful determination of the clinical

status of the patient coupled with knowledge of
potential hazards can assist in determining the
type of toxicant, the suspected time course, and
the treatment protocol.

– In addition, recognition of compromised airway,

circulatory, or neural function requires immediate
supportive measures.
• Patient Characteristics
– The specific characteristics such as
anthropomorphic characteristics, genetic
background, and preexisting conditions of each
patient also factor into risk assessment

– Some (e.g., weight) may affect the course of

poisoning indirectly, whereas others may have a
more direct effect (e.g., alcoholism) by influencing
the production or elimination of toxic substances.

– Genetic polymorphisms may affect absorption,

biotransformation, or elimination of toxicants
Hazard Identification Exposure
•What toxicant(s) are involved •What was the extent of exposure
•What are the physicochemical •What was the route of exposure
properties of each •Time since exposure
•What are the toxicokinetic and
toxicodynamic properties of each
toxicant

Dose Response
•Do toxic effects exhibit a dose Risk
dependent response relationship Assessment
•What are the critical plasma
concentrations

Clinical Status Patient Characteristics

•May suggest identity of toxicant •Genetic background
•May suggest extent and time of •Pre existing conditions
exposure •Anthropometric characteristics
•May suggest treatment strategy (e. g. weight)

Risk assessment during management of toxic events

THANK YOU!