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INTRODUCTION
What is Toxicology?
The science of poisons.
The study of the adverse effects of chemicals or
physical agents on living organisms.
TOXICOLOGY is the study of the qualitative and
quantitative effects of chemicals on living systems.
Then what is it? Toxicology is the study of interaction
of materials (drugs, chemicals, foods, polymers,
pesticides, etc.) with a biological system and its
responses.

Objectives
Upon successful completion of this module you will be able
to:

Define toxicology
Know the history of toxicology

Identify the six applied areas of toxicology

Explain ways in which toxicology is relevant to our

daily lives Outline the basic principles of toxicology

Introduction
Which of the following news headlines are concerned with
issues related to toxicology?
a. Arsenic Widespread in Bangladesh Water
b. Sarin Gas Attack on the Tokyo Subway
c. Ukrainian President Yuschenko Poisoned by Dioxin
d. Gas Leak Accident in Bhopal: An Indian Tragedy

e. All of the above

The
of the

correct answer is "Option E. All

above."

News has always had a penchant for the sensational and

toxicology often fills the bill. There would likely have been a
considerable buzz even in ancient times about events such
as the sentencing of Socrates to drink hemlock.
When not bombarded by high impact news stories, we have
to contend with personal worries about toxic substances:

What are the side effects of this drug?

Should I be picking these mushrooms?

Is it safe to be jogging outside with the ozone level

this high?

This is the human part of the story.

Toxicology is the science behind the stories, not always as
dramatic, but possibly as fascinating, and certainly
necessary in determining how certain chemicals can harm
us under particular conditions, and seeking ways to prevent
or alleviate the harm.
Toxicology is relatively new as a distinct scientific discipline
although many of its basic principles have been known for
some time. This section will explore this history, describe
how toxicology has changed over time, and offer a broad
definition of this discipline. In addition, the six areas of

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applied toxicology will be described as well as how these
areas are relevant to our daily lives.
Following this, the basic principle of toxicology - "the dose
makes the poison" - will be explicated and the strengths and
limitations of this principle will be explored. This exploration
will include discussions of the different types of dose, how
they are measured and how dose-response and dose-effect
curves are constructed and used, especially in assessing
risks to human health.
This module will provide the reader with an overview of
toxicology and provide the context for the more detailed
materials that follow.
This module includes the following sections:
1. Objectives
2. Introduction
3. What Is Toxicology?
4. Toxicology And Our Daily Lives
5. Determining Toxicity
What Is Toxicology?
History: Poisoning Highlights
Poisoning and the knowledge of poisons have a long and
colorful history although the science of toxicology has only
recently come into existence as a distinct discipline. Even
the cave dwellers had some knowledge of the adverse
effects of a variety of naturally occurring substances,
knowledge that they used in hunting and in warfare.

Famous early victims of plant and animal poisons were the

Greek philosopher Socrates and the Egyptian Queen
Cleopatra.
Socrates was forced to drink Hemlock for corrupting the
youth of Athens.
Cleopatra committed suicide through the bite of an asp, a
poisonous snake.
As time progressed, toxicological knowledge
and its applications expanded. Indeed,
poisoning became institutionalized in
a number of places, and some
governments utilized poisons for state
executions, a practice that continues
in some jurisdictions, via means such
as lethal injections.
The European Renaissance was a time
notorious
for
poisonings
and
poisoners. Born in 15th century Italy,
Cesare and Lucrezia Borgia used a
concoction
of
chemicals
to
assassinate their political rivals.
Their potion La Cantarella, may have included

arsenic, copper, and phosphorus.

Unintentional poisoning has always been with us.
Through the science of toxicology we now better
understand these risks and work to avoid harm to
human health. The naturally occurring element
lead was used in the Roman era to line vessels and
as a pottery glaze, as well as in cosmetics. In the 19th
century in the United States paint manufacturers
began to use lead as a pigment, although even in
1786, Benjamin Franklin outlined the hazardous
effects of lead on the body in a letter to Benjamin

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Vaughan, a friend. Though banned in paint today, society
needs to be ever vigilant in protecting children (who are
particularly susceptible to the effects of lead on the brain
and nervous system) from exposure to older flaking paint
chips. Lead was also used in gasoline to prevent engine
knocking. Because of bans of these uses and intensive
public health efforts, lead concentration in urban children
has decreased in the past several decades. Studies have
demonstrated a correlation between minimal lead exposure
and higher cognitive function.
Workers, because they tend to be exposed to higher levels
of chemicals than the general population, are in danger of
being unwittingly poisoned at rates higher than the general
population. Asbestos, as an example, was widely known in
antiquity but use increased as a result of the industrial
revolution. It has been used in textiles, building materials,
insulation, and brake linings. Capable of causing severe lung
damage, including asbestosis and mesothelioma, asbestos
is now strictly regulated. Today, we are not only concerned
about workers exposed to traditional industrial chemicals,
but also to those used in the electronics industry, as well as
bio- and nano-engineered products.

Chemical and biological warfare date to antiquity. The

mythological account of Paris slaying Achilles with a
poisoned arrow in the heel has a basis in the way some
battles were conducted at the time. Fast forward to 1914,
when poison gas was used in a more systemized and large-

scale fashion by the Germans in World War I. In 1988, Iraqi

government troops attacked the Kurdish town of Halabja
with chemical bombs involving multiple chemical agents
including mustard gas and the neurotoxic agents, sarin,
tabun and VX.
Another broad sphere of poisoning relates to toxicological
disasters. While some may be natural (e.g., sulfur and other
toxic gases emitted from volcanoes), others are related to
industrial mishaps. Love Canal is an iconic example. The
vicinity of the Canal was used by Hooker Chemicals as a
dumping ground for numerous hazardous substances, a
large population was put at risk, and hundreds of families
living in homes on top of the dumpsite needed to evacuate.
And in 1984, in Bhopal, India, a release of the chemical
methyl isocyanate resulted in many thousands of deaths
and many more injuries.
A more recent example of political poisoning is the
remarkable survival (albeit chloracne scarred) of the
Ukrainian president Viktor Yushchenko, after alleged
poisoning with dioxin, and, possibly endotoxin, prior to the
2004 elections.

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and, in one instance, with a glue which, when ingested,
metabolizes to GHB, the date rape drug. Recalls followed
swiftly.

In 2006, in a case with overtones of espionage, Alexander

Litvinenko, a former Russian spy, was fatally poisoned with
radioactive polonium-210. The radioactive isotope was
allegedly added to tea he drank at a London hotel. 2007 and
2008 have seen increasing incidents of product
contamination, often via international trade. Pet foods, for
example, have been found to contain melamine, an organic
compound used to make a variety of plastic products.
Although there is some doubt about the toxicity of melamine
to dogs and cats in the doses to which they were exposed, it
is an industrial chemical which should not have been added
to the food, and its effects may have been exacerbated by
other food ingredients. Toys have been discovered with lead

Thus toxicology, in its scope, casts a broad net,

encompassing hazardous effects of chemicals (including
drugs, industrial chemicals and pesticides), biological
agents, also known as toxins (e.g., poisonous plants and
venomous animals) and physical agents (e.g., radiation,
noise). It has been newsworthy since ancient times and will
continue to be a subject of fear and fascination, as well as
the important source of information protecting humans,
other animals, and the environment from dangerous
exposures.
History: Toxicology Research
During periods of intellectual ferment in
Europe, scholars began more systematic

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studies of poisons and their effect. Two noteworthy
examples, products of the 15th Century Renaissance, and
the 18th Century Age of Enlightenment respectively, were
the alchemist Paracelsus (born in Einsiedeln, now a city in
Switzerland) and the Spanish physician Orfila.
Paracelsus (1493-1541) identified the specific chemical
components of plants and animals that were responsible for
their toxic properties. He also was able to show that varying
the amount of the poison affected the severity of the
effects.
Orfila (1787-1853), who is often referred to as the father of
toxicology, was the first to establish a
systematic correlation between the chemical
properties and biological effects of poisons.
Using autopsy results, he was able to link the
presence of particular poisons with specific
damage to tissues and organs.
During the 19th century, there was a proliferation of
textbooks dealing with toxicology in relation to forensic
medicine, in which scientific tools and principles are used to
investigate crimes and accidents.

Toxicology developed as a modern science during the 20th

century, particularly after the Second World War, at least
partly in response to the rapid development and production
of many new drugs and industrial chemicals.
Thus, toxicology, ancient in practice,
came to be known simplistically as
the science of poisons.
As the understanding of the working
of
living
organisms
became
increasingly sophisticated, and a true

In part, this was due to the great advances in chemical

analysis, allowing for a more precise determination of the
amounts of toxicants in body tissues and fluids (from which
study analytical toxicology is derived).
scientific basis evolved, it has become clear that this
definition is not adequate.

In light of this, the U.S. Society of Toxicology uses the

following definition:

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"Toxicology
is
the
study
of
the
adverse
physicochemical effects of chemical, physical or
biological agents on living organisms and the
ecosystem, including the prevention and amelioration
of such adverse effects."
Examples of such agents include cyanide (chemical),
radiation (physical) and snake venom (biological).

Epidemiologists, who study populations exposed to

such agents to look for possible connections between
exposures and adverse health outcomes.

The ultimate objective of the combined research of such

toxicological specialists is to determine how an organism is
affected by exposure to an agent.
This includes an understanding of:

The effects on organisms can occur at multiple levels,

including the molecular and the organ levels.
Research and Application
Toxicological research is an exciting field of study utilizing
and integrating principles developed in a variety of
disciplines including chemistry, biochemistry, physiology,
pathology, biology, genetics and pharmacology. These
inputs are reflected in the names of the areas of
toxicological research such as biochemical toxicology,
pathotoxicology, toxicogenomics, pharmacokinetics, and
pharmacodynamics. Combining the understanding gained
through these disciplines, toxicologists are able to
characterize the disposition of agents in living organisms,
the types of adverse effects that may be produced after
exposure, the mechanisms of action behind these effects
and the impacts of possible interactions among agents.
Toxicological studies may be carried out by scientists with
training in these diverse disciplines. For example:

Biochemists, who study the fates of agents in living

organisms and the mechanisms by which they exert
their effects;
Geneticists, who investigate the effects of agents on
genetic material and the impact of genetic variation
on responses to toxic insults; and

How the agent moves throughout the organism;

How it may be changed by interacting with living
cells and tissues;

What parts of the organism are affected by its

presence; and

The health outcomes of this exposure.

The more thorough this understanding, the more accurately

toxicologists can predict what will happen when different
types of organisms, particularly humans, are exposed to
agents in the ambient environment, the workplace, or via
exposure to food and drugs.
Today, one way of looking at toxicology divides it into six
applied areas - clinical, forensic, analytical, environmental,
occupational, and regulatory.
Clinical toxicology, the diagnosis and treatment of human
poisoning, and forensic toxicology, the medical-legal aspects
of clinical poisoning, are discussed further in a later slide.
The related discipline of analytical toxicology is concerned
with the identification and quantification of toxic chemicals
in biological materials.

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Environmental and occupational toxicology are selfexplanatory in that they deal with toxic hazards in the
environment and in the workplace, respectively. Regulatory
toxicology focuses on laws and regulations and their
enforcement, an important component of toxicology. Risk
assessment, covered in a later module, is often considered a
part of regulatory toxicology.
All of these branches of toxicology rely on the same basic
science to achieve their goals, and are not all mutually
exclusive. Thus, poisoning at the workplace would
encompass aspects of both clinical and occupational
toxicology.

of

results obtained in vitro.

Regulatory toxicology (i.e., the regulation of potentially toxic

substances) has recently been a major driving force in
toxicological research.
Much of the support for toxicology is predicated on
the idea that increased knowledge will lead to
better management of potentially toxic agents,
actions which, in turn, will result in improved
public health.
Accurate predictions of effects of chemicals on
humans depend upon scientific studies. Most toxicological
studies are empirical in nature, and are performed on
experimental animals (in vivo) or in vitro test systems (i.e.,
cell culture or other systems used to mimic the results in
part of a living organism).
Since the results are often used for regulatory purposes, the
goal of such studies is to predict effects in humans.
To achieve this goal, scientists need to understand the
differences between experimental animals and humans in
the way that they process foreign chemicals (xenobiotics)
and physical agents, as well as the applicability to humans

Toxicology and Our Daily Lives

Toxicology was relevant historically because knowledge of
plant and animal poisons served various ends, some
beneficial to society and others not.
In particular, this knowledge could be used for hunting large
game, defense against enemies and understanding which
plants and animals were safe to eat and which should be
avoided.
Toxicology is just as important to us today. Our improved
health status and increase in life expectancy are due in part
to advances in pharmacology. Toxicology research helps
ensure that the beneficial effects of therapeutic agents are
not outweighed by unwanted side effects. There are about
100,000 chemicals in commercial use and 1,000 new ones
added every year.

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Accidental contaminants are generally synthetic or natural
environmental contaminants in the food chain, such as
polychlorinated biphenyls (PCBs) and methyl mercury, found
in fish, microbial toxins such as produced by E. coli in
contaminated food, and fungal toxins (like aflatoxins) which
may contaminate grains.

We have modern toxicology to thank for the safety of our

food and drinking water, consumer products, and other
industrial chemicals we use or to which we are exposed.
Toxicology knowledge helps in the prevention of adverse
effects. More specialized branches of toxicology, such as
toxicogenomics and nanotoxicology, increasingly have a
significant bearing on our daily lives.

Recently scientists have been investigating and debating

the safety of Genetically Modified Organisms (GMOs ) as
food products.

Food Toxicology
Despite great advances made by toxicology in assuring that
our food is uncontaminated, it is still important to know
what products are safe to eat and in what quantities. In
addition to concerns about naturally occurring substances in
foods, food toxicologists also investigate the safety of other
components of food that have been added deliberately or
accidentally.
Deliberate additions include a variety of natural and
synthetic additives and artificial substitutes for naturally
grown food components. These include sweeteners, color
and texture additives, fat substitutes and preservatives.

Safety of Pharmaceuticals
Toxicological research is critical in the
development
and
production
of
pharmaceuticals.
At the beginning of the drug discovery process, toxicity tests
help to determine which potential pharmaceuticals are likely
to be safe enough for humans and thus warrant further
development.
All along the development process, additional testing is
performed to ensure that the final product will not only be
efficacious but also free of unreasonable side effects. For

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each and every pharmaceutical, prescription or over-thecounter, safety evaluation studies are performed. Safety
evaluation studies often include experimental animals and
clinical trials involving humans. This scrutiny includes multiyear studies of possible chronic effects, including cancer.

In the clinical setting, toxicologists assist in making

diagnoses of possible agent-induced harm in individuals
exposed occupationally or environmentally.

Toxicology of Industrial Chemicals and Consumer

Products
Before new industrial and consumer products can be
developed and marketed, toxicological research is needed to
ensure that these can be used safely as intended.
Clinical toxicologists are also concerned with drug toxicity.
Prescription and non-prescription drugs, just like other
chemicals, may cause adverse effects dependent upon
many factors, including the dose, individual age,
hypersensitivity, etc. Drugs of abuse, typically taken for
pleasurable effects or sometimes for suicidal purposes, may
pose threats ranging from mild to severe.

This involves investigations of possible adverse effects on

humans due to exposure to these products in the workplace,
home, or in the general environment, and possible dangers
to other animals, such as wildlife.
For agents that have been on the market for some time and
are already out in the environment, toxicology can help to
determine whether or not remediation of sites contaminated
by these agents is needed and, if so, how thorough the
clean-up must be to protect the local population and the
environment.
Clinical and Forensic Toxicology
Toxicology continues to be important in the clinical and
forensic settings.

Forensic toxicologists can help to determine the possible

effects of agents on behavior (e.g., alcohol on driving
ability), and also assist in determining the cause of death in
individuals who may have suffered from intoxication by
chemical or physical agents.

Toxicogenomics
In the new millennium, advances in toxicology are leading to
additional and refined uses of toxicology.
Understanding the genetic basis of responses to chemical
and physical exposures can help to predict which individuals
will respond best, and with the least side effects, to
particular pharmaceutical agents and also to predict which

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individuals will be most at risk from specific occupational
and environmental exposures.

This new area of study, known as toxicogenomics, will

provide the opportunity for a more customized approach to
individual health.
Nanotoxicology
The prefix, nano, implying a billionth of an amount, has
been appropriated for nanotechnology, the science of
extremely small materials. An increasing number of
consumer and other products are now made of nanoscale
substances. The corresponding study of the safety and
potential hazards of nanoparticles and nanotubules is known
as nanotoxicology.

Many nanomaterials are initially formed from nanoparticles

which can produce aerosols and colloidal suspensions. As
such they can readily be inhaled, ingested, or potentially
absorbed through the skin.
Although our knowledge of the toxic activity of these very
small particles is scant, we can, and often do, use ultrafine
particles as models of nanoparticulate behavior. Studies to
date have indicated that ultrafine particles are more toxic on
a mass for mass basis than their larger counterparts.
Moreover, ultrafine particles have been shown to penetrate
the skin and translocate from the respiratory system to
other locations in the body.

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Although nanotechnology promises major advances in the
fields of physics, electronics, chemistry, and medicine,
workers in nanotechnology industries often face exposure to
unknown levels of nanoparticulates with unique sizes,
shapes, and activities. Hence, research aimed at defining
the potential toxicity of these particulates is needed as are
effective monitoring and surveillance techniques and
adequate protective equipment.

1. Socrates (470-399 B.C.): Tried and convicted of

corrupting the youth sentenced to death.
Most celebrated poisoning victim.

Executed by poison hemlock.

Active principle: coniine.

2. Cleopatra: conducted numerous experiments with

poisons effects amusement
- Ended taking her own life with the aid of a
serpent asp
Short cut HISTORY OF TOXICOLOGY
Throughout the ages, toxicological science has provided
information that has shaped and guided society.
I.

Antiquity & Early history: referred to as ancient

history covers the period from the founding of
modern civilization in Mesopotamia, around 3500
BCE, to the start of the Middle Ages.

3. Evil Wind: Mazuku pocket of oxygen poor air (CO2

odorless asphyxiation)
II. Middle Ages: AKA The Dark Ages, roughly refers to
the time between the fall of Ancient Rome in the 5 th
Century until to the European Renaissance and
cultural rebirth beginning around the 14th century.
15th Century Europe: Italians
poisoning into an art form

Knew of human and animal poisons

life.....

developed

Poisoning became a normal hazard of

Search for an acceptable diet unfortunate outcome

Categorized and studied poisons

1. Venice's "Council of Ten" (City Council)

Royal "tasters"

Put out poisoning contracts on political enemies.

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Council transactions: detailed records with name of

victim, contractor, type and amount of poison given,
results

2. Borgia: prominent family who practiced "applied

toxicology"
Cesare, Lucretia and others.

Killed husbands, wives, lovers, political opponents,

churchmen.

3. Black Death or Bubonic Plague: bacterial disease

spread by rodents that wiped out around 1/3 of
Europes population (nearly 25 million) in the mid
14th century.
-

A pandemic

Little Ice Age

III. Early Modern: spans the time from the

Renaissance, beginning around the 14th century, to
the Industrial Revolution, which began in the 18 th
century in some parts of the world.

Killed political enemies for hire....

Documented signs and symptoms.

3. Paracelsus
full
name:
Philippus
Aurelius
Theophastrus Bombastus von Hohenheim-Paracelsus
(1493-1514) FATHER OF TOXICOLOGY
Instrumental in logical development of toxicology as
science.

Developed concept of "dose".

Action as a result of chemical entity -- toxicon.

4. Orfila (1787-1853) Spaniard--personal physician to

Louis XVIII
"The FOUNDER of Modern Toxicology"

Developed toxicology into a science.

Compiled chemical and biological information on
most known poisons.

Proposed the necessity of chemical analysis to prove

cause-and-effect.

1. Fowlers Solution: Potassium Arsenite 1786 1936

general tonic
- Some say Charles Darwin used it often
- Malaria, chorea and syphilis

5. Christian Hahnemann: founded HOMEOPATHIC

MEDICINE

2. Catherine de Medici (1519-1589)

Wife of Henry II of France, mother of three French
kings, ruler of France.

IV. Modern: generally referred to as the period from the

Industrial Revolution of the 18th Century to the end of
World War II.
Analytical methods developed for As, Hg and
miscellaneous alkaloids

Early "experimental toxicologist".

Poisoned poor and sick street people under guise of

"feeding" and assistance".

V.

Organic chemistry makes giant advances

Post Modern: stretches from World War II to the
Present.

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1. Love Canal: named after the late 18th century
entrepreneur William T. Love
2. Minamata, Japan
3. Thalidomide
MAJOR DRIVING FORCES FOR THE RECENT EXPANSION
& DEVELOPMENT OF THE SCIENTIFIC BASIS AND
PRACTICE OF TOXICOLOGY
1. Exponential increase in the number of synthetically
produced industrial chemicals
2. Major increase in the number and nature of new
drugs, pharmaceutical preparations, tissue
implantable materials and medical devices.
3. Increase in the number and types of pesticides &
other substances used in agriculture and the food
industry.
4. Mandatory testing and regulation of chemicals used
commercially, domestically & medically.
5. Enhanced public awareness of potential adverse
effects from xenobiotics (non naturally occurring) to
man, animals and the environment.
6. Litigation, principally as a consequence of
occupational related illness unrecognized or poorly
documented product safety concerns (including
drugs) and environmental harm.
SCOPE OF TOXICOLOGY

WHAT DO TOXICOLOGISTS STUDY?

Toxicology has become a science that builds on and uses
knowledge developed in other related medical sciences,
such as physiology, biochemistry, pathology, pharmacology,
medicine, and epidemiology, to name only a few. Given its
broad and diverse nature, toxicology is also a science where
a number of areas of specialization have evolved as a result
of the different applications of toxicological information that
exist within society today. It might be argued, however, that
the professional activities of all toxicologists fall into three
main
areas
of
endeavor:
descriptive
toxicology,
research/mechanistic toxicology, and applied toxicology.
Descriptive toxicologists are scientists whose work
focuses on the toxicity testing of chemicals. This work is
done primarily at commercial and governmental toxicity
testing laboratories, and the studies performed at these
facilities are designed to generate basic toxicity information
that can be used to identify the various organ toxicities
(hazards) that the test agent is capable of inducing under a
wide range of exposure conditions. A thorough descriptive
toxicological analysis would identify all possible acute and
chronic toxicities, including the genotoxic, reproductive,
teratogenic (developmental), and carcinogenic potential of
the test agent. It would also identify important metabolites
of the chemical that are generated as the body attempts to
break down and eliminate the chemical, as well as analyze
the manner in which the chemical is absorbed into the body,
distributed throughout the body and appropriate dose
response test data are generated for those toxicities of
greatest concern during the completion of the descriptive
studies so that the relative safety of any given exposure or
dose level that humans might typically encounter can be
determined.

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Basic research or mechanistic toxicologists are scientists
who study the chemical or agent in depth for the purpose of
gaining an understanding of how the chemical or agent
initiates those biochemical or physiological changes within
the cell or tissue that result in the toxicity (adverse effect).
They identify the critical biological processes within the
organism that must be affected by the chemical to produce
the toxic properties that are ultimately observed. Or, to
state it another way, the goal of mechanistic studies is to
understand the specific biological reactions (i.e., the
adverse chain of events) within the affected organism that
ultimately result in the toxicity under investigation. These
experiments may be performed at the molecular,
biochemical, cellular, or tissue level of the affected
organism, and thus incorporate and apply the knowledge of
a number of many other related scientific disciplines within
the biological and medical sciences (e.g., physiology,
biochemistry, genetics, molecular biology). Mechanistic
studies ultimately are the bridge of knowledge that connects
functional
observations
made
during
descriptive
toxicological studies to the extrapolations of doseresponse
information that is used as the basis of risk assessment and
exposure guideline development (e.g., occupational health
guidelines or governmental regulations) by applied
toxicologists.
Applied toxicologists are scientists concerned with the
use of chemicals in a real world or non laboratory setting.
For example, one goal of applied toxicologists is to control
the use of the chemical in a manner that limits the probable
human exposure level to one in which the dose any
individual might receive is a safe one. Toxicologists who
work in this area of toxicology, whether they work for a state
or federal agency, a company, or as consultants, use
descriptive and mechanistic toxicity studies to develop
some identifiable measure of the safe dose of the chemical.

The process wherebyaccumulated by various tissues and

organs, and then ultimately excreted from the body.
Hopefully, this safe dose or level of exposure is derived is
generally referred to as the area of risk assessment.
Divisions of Toxicology
1. DESCRIPTIVE TOXICOLOGY
- Concerned directly with toxicity testing which
provides information for safety evaluation and
regulatory requirements.
- Toxicity in animals evaluate the risk posed to
humans and environment
- Hypothesis generation mechanistic toxicology
- Risk assessment regulatory toxicology
2. MECHANISTIC TOXICOLOGY
- Concerned in identifying and understanding the
cellular, biochemical and molecular mechanisms
by which chemicals exert toxic effects on living
organisms.
- Risk assessment regulatory toxicology useful
in demonstrating that an adverse outcome
observed in animals is relevant to humans.
- Examples: Thalidomide, 6 mercaptopurine,
organophosphates, saccharin
- Advent of molecular biology and genomics tools
that explore exactly how humans may differ from
laboratory animals.
3. REGULATORY
TOXICOLOGY(industry
and
government setting)
- Responsible for deciding on the basis of data
provided
by
descriptive
and
mechanistic
toxicologists, whether a drug or another chemical
poses a sufficiently low risk to be marketed for a
stated purpose.
- FDA, EPA, OSHA
- Deciphers and analyzes toxicological data for risk
estimation.

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-

Solvent vapor thresholds in industry.

Sign and symptom management.

Safe level for human drugs.

Emergency care--home poisoning.

Safe level of heavy metals in water.

Poison control antidotes and regimens

Safe levels of pesticides.

2. Forensic Toxicology: (Medical Examiners office)

hybrid of analytical chemistry and fundamental
toxicological principles
Medical-legal aspects of poisonings.

Identification and quantification of poisons.

Establish relationship between tissue residual level

and probable cause of death.

3. Industrial Toxicology:
Estimation of worker safety based on 8 hr work day,
40 hr work week....

Graphical representation of the interconnections between different

areas of toxicology.

Some specialty areas (subdivisions) of Toxicology:

1. Clinical Toxicology: (hospital setting)

Involve
physicians/individuals
who
received
specialized training in emergency medicine and
poison management

Deal with emergencies such

poisonings, attempted suicides.

Compound identification and quantification.

as

overdoses,

Engineering of safety measures.

Air sampling, worker sampling.

4. Environmental Toxicology:
Effects of compounds on water, wildlife.

Movement of chemicals in the environment--soil, air,

water.

Residual life of chemicals in the environment.

Impacts of toxic substances on population dynamics

in an ecosystem.

One View
On earth creatures shall be seen who are constantly
killing one another. Their wickedness shall be
limitless; their violence shall destroy the worlds vast
forests; and even after they have been sated, they

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shall in no wise suspend their desire to spread
carnage, tribulations, and banishment among all
living beings. Their overreaching pride shall impel
them to lift themselves toward heaven. Nothing shall
remain on earth, or under the earth, or in the water,
that shall not be hunted down and slain, and what is
in one country, dragged away into another; and their
bodies shall become the tomb and the thoroughfare
for all living things they have ruinedThe fertile
earth, following the law of growth, will eventually
lose the water hidden in her breast, and this water,
passing the through the cold and rarified air, will be
forced to end in the element of fire. Then the surface
of the earth will be burned, and that will be the end
of all terrestrial nature.
Leonardo Da Vinci, 1452-1519
5. Biochemical and Molecular Toxicology:
Determining mode of action of chemicals at the
molecular level mechanisms by which toxicants
modulate cell growth and differentiation and cells
response to toxicants at the level of the gene.

Effect of chemicals on DNA, cancer genes.

6. Product development Toxicology: (Corporate

setting)
Service and preclinical toxicology for product
development.

Evaluation of full toxic

destined for drug use.

Establish safe doses for people.

potential

of

chemicals

7. Genetic Toxicology

Assesses the effects of chemical on the DNA and on

the genetic processes of the living cells

8. Developmental Toxicology

Encompasses the study of pharmacokinetics,

pharmacodynamics, pathogenesis and outcomes
following exposure to agents or conditions leading to
abnormal development.

Examples:
structural
malformations,
growth
retardation, functional malformation and death.

Within applied toxicology a number of subspecialties occur.

These are: forensic toxicology, clinical toxicology,
environmental toxicology, and occupational toxicology.
Forensic toxicology is that unique combination of
analytical
chemistry,
pharmacology,
and
toxicology
concerned with the medical and legal aspects of drugs and
poisons; it is concerned with the determination of which
chemicals are present and responsible in exposure
situations of abuse, overdose, poisoning, and death that
become of interest to the police, medical examiners, and
coroners. Clinical toxicology specializes in ways to treat
poisoned individuals and focuses on determining and
understanding the toxic effects of medicines and simple
over-the-counter (nonprescription) drugs. Environmental
toxicology is the subdiscipline concerned with those
chemical exposure situations found in our general living

Page 17 of 62
environment. These exposures may stem from the
agricultural application of chemicals (e.g., pesticides, growth
regulators, fertilizers), the release of chemicals during
modern-day living (e.g., chemicals released by household
products), regulated and unintentional industrial discharges
into air or waterways (e.g., spills, stack emissions, NPDES
discharges, etc.), and various nonpoint emission sources
(e.g., the combustion byproducts of cars). This specialty
largely focuses on those chemical exposures referred to as
environmental contamination or pollution. Within this area
there may be even further subspecialization (e.g.,
ecotoxicology, aquatic toxicology, mammalian toxicology,
avian toxicology). Occupational toxicology is the
subdiscipline concerned with the chemical exposures and
diseases found in the workplace.

The basic principle that governs toxicology was first stated

by Paracelsus about 500 years ago. In his words:

Regardless of the specialization within toxicology, or the

types of toxicities of major interest to the toxicologist,
essentially every toxicologist performs one or both of the
two basic functions of toxicology, which are to (1) examine
the nature of the adverse effects produced by a chemical or
physical agent (hazard identification function) and (2)
assess the probability of these toxicities occurring under
specific conditions of exposure (risk assessment function).
Ultimately, the goal and basic purpose of toxicology is to
understand the toxic properties of a chemical so that these
adverse effects can be prevented by the development of
appropriate handling or exposure guidelines.

What is "Dose"?

BASIC PRINCIPLES OF TOXICOLOGY

Determining Toxicity
The Dose Makes the Poison

"All substances are poisons; there are none which is not a

poison. The right dose differentiates a poison and a remedy."
This is a very powerful principle since it lays out the
fundamental challenge of all toxicological research - to
determine the doses at which specific agents cause adverse
effects on living things.
It is also important as a counterbalance to the popular idea
that agents can be divided into those that are poisons or
"toxic" agents, and those that are not. All agents are toxic; it
is only the degree and type of toxicity that differ from one
agent to another.

To understand this principle, it is important to first define

dose. The dose of a chemical or physical agent is the
amount of that agent that comes into contact with a living
organism or some part of a living organism. The type of
dose most familiar to the average person is that associated
with medicines.
For example, a physician may prescribe a dose of 10
milligrams once each day. However, hidden within this
amount is the concept that dose really represents the
amount of agent per unit (e.g., kilogram) of body weight.
When physicians decide on a prescribed dose, they take into
account the weight of the individual receiving the
medication. A heavier person, for example, may require a
greater dose to achieve the same effect that a lesser dose
would have on a lighter person.

Page 18 of 62
the job. One hundred aspirins taken all together will likely
result in toxic effects.

In toxicology, it is common for the dose to be explicitly

expressed in terms of body weight and, often, in terms of
time as well. Thus, the dose may be given as 10 milligrams
per kilogram of body weight (10 mg/kg) or even 10
milligrams per kilogram of body weight per day (10
mg/kg/day). This latter dose given to a person weighing 70
kilograms, for example, would result in a total dose of 700
mg (70 x 10) over the course of a day.

In
addition to
the somewhat different ways of expressing dose, there are
different kinds of doses that can be important
toxicologically.
For example, dose can refer to the amount of a substance to
which an individual or population is exposed. This definition
is generally applied in cases of occupational and
environmental exposures.

One should also keep in mind that medications are

chemicals designed for positive effects, but at the right
dose. Thus a baby aspirin tablet may not cure an adult of a
headache, while two ordinary aspirins are more likely to do

In the experimental situation, the dose to which animals are

exposed is known as the administered dose. Dose can also
be defined as the amount absorbed into the organism, also
known as the internal dose. This definition reflects the idea
that only the amount that is absorbed is available to cause
harm at sites in the body distant from the site at which the
agent makes contact with the individual.
As toxicological knowledge grew more sophisticated, it
became possible to define dose in yet other ways that better

Page 19 of 62
reflect the connection between dose and effect. One
example is the target organ dose or the amount that
reaches the site(s) at which the adverse effects occur. This
is also known as the biologically effective dose.
It is always important to note that the extent and nature of
adverse effects, for a given agent, may vary, dependent
upon the dose and route of exposure. Major routes of
exposure include ingestion, inhalation or skin contact
(dermal).
Effects are also dependent upon the age and sex of the
exposed individual, as well as other characteristics of this
individual, including underlying disease, nutritional status,
and history of previous exposures.
In addition, the time course and duration of the dose
administration or exposure are important variables. A single
large dose given all at once is likely to have quite a different
impact than the same total dose given in small amounts
over a long period of time.
Also, the spacing between doses given over long periods of
time can be critical in determining whether or not adverse
effects will occur.

Public interpretation of dose and effect, frequently fueled by

media sensationalism, may fail to take into account all the
variables affecting dose. Unless this is done, however,
reaching conclusions about a chemical's or product's toxicity
is purely speculative.
"All substances are poisons; there are none which is not a
poison. The right dose differentiates a poison and a remedy."
The original German statement, "Alle Dinge sind Gift und
nichts ist ohne Gift; allein die Dosis macht, dass ein Ding
kein Gift ist," is sometimes summarized and translated as
"The dose makes the poison." This is a good starting point,
but really not as simple as it sounds.

Page 20 of 62
So, while the basic principle expressed so eloquently by
Paracelsus governs the practice of toxicology, it is important
to understand that applying this principle is difficult and
requires an appreciation of all of the factors that influence
responses to a given dose and all of the ways that dose may
be defined. All too often, conclusions about dose and effect
are made without consideration for these issues and such
conclusions should be carefully scrutinized before they are
accepted.
Thus, dose entails many variables, and the ultimate extent
of its effects is closely entwined with the route of exposure.
To summarize, the variables which must be taken into
account in making a full determination of the consequences
of dose include:

Subject Variability (Health Status) - Whether any preexisting health conditions, such as asthma, diabetes,
or hypertension, may affect susceptibility to an
agent.

Route of Exposure - The way in which the person is

exposed. The three most common routes of exposure
are ingestion, inhalation and skin contact.

Later modules will consider how toxicity (of which dose is

one attribute) together with extent of exposure determines
risk.
Which of the following does not affect toxicity?
a. Whether the agent is inhaled or ingested
b. Whether the exposed organism is male or female
c. Whether the agent is synthetic or naturally occurring
d. Whether the exposure is continuous or sporadic
e. Whether the exposed organism is a child or an adult

Dose Amount - A measure of the magnitude of the

dose.
Dose Frequency - How often exposure occurs, e.g.,
daily, weekly, five days out of seven, etc.
Dose Duration - Over how long a total period of time
dose exposure occur, e.g., a week, a month, a year, a
lifetime.
Subject
Variability
(Natural)
Individual
characteristics such as age, sex, body weight, ethnic
background, and genetics.

The correct answer is "Option C. The toxicity of an agent

does not depend on its source."
How is Dose Measured?
Depending on the situation, measuring dose can be a
straightforward process or a very cumbersome one.
The best setting in which to accurately measure dose is the
laboratory, where the conditions can be controlled.
When doing research on experimental animals, it is possible
to present them every day with food and/or water

Page 21 of 62
containing exactly the same amount of the agent being
tested.

them with general information about human behavior (e.g.,

amount of food or water consumed each day).

Using measures of the amount ingested, it is possible to

fairly accurately calculate the total amount of the agent the
animal is exposed to each day, and thus the daily dose.

Because of the lack of appropriate data, these dose

estimates are often quite uncertain; the fewer the data, the
greater the degree of uncertainty.
Additional complexity is involved in real world exposures to
multiple chemicals, especially at the same time. Consider,
for example, the exposure of the population in the vicinity of
the 9/11 World Trade Center disaster.

At the other extreme, measuring the doses to which

individual humans are exposed in their everyday
environment is much more difficult.
The amount of a particular agent ingested is likely to vary
from day to day and measures of the concentration of the
agent in the media of interest (e.g., air or water), are
unlikely to be available on a daily basis.

In this case, it is only possible to estimate the doses to

which
individuals
are
exposed
using
whatever
environmental measurements are available and combining

Measuring the absorbed dose is more difficult than

quantitating the exposure dose since it requires information
about the way that different animals absorb agents through
various routes of exposure (e.g., inhalation, dermal
absorption) and under differing conditions. For example,
absorption through a young male rat's skin might be very
different from the dose delivered through drinking water in
an aged female monkey.

Page 22 of 62
The most difficult dose to quantitate is the target organ
dose or biologically effective dose (e.g., the dose that
actually reaches the liver) since this generally cannot be
directly measured. To make such measurements in animals
generally requires invasive procedures that could alter the
response of the organism, while to make such
measurements in humans would be unethical.

Thus, target organ doses are usually calculated using

information about the distribution and fate of the agent in
the organism.
This information can be gathered from studies on the
amounts of an agent that are absorbed, excreted, stored
and freely circulating in an organism.

Information about absorption is collected through laboratory

experiments, generally performed on a limited number of
animals. Because of ethical and other considerations, such
laboratory studies are typically performed on rodents and
rarely on humans. As a result, there is a level of uncertainty
in extrapolating the effects of absorbed dose from
laboratory animal studies to humans.

Often this type of information is not available or is

incomplete so that it is difficult to calculate target organ
doses with confidence, even in organisms which have been
extensively studied (e.g., rodents). Estimation of the target
organ dose is much more difficult in humans since the
needed information is generally even less available.
Which type of dose is most relevant for determining the
toxicity of and agent?
a. Administered dose
b. Absorbed dose

Page 23 of 62
c. Target organ dose
d. None of the above
The correct answer is "Option C. Target organ dose. This is
the dose at the site at which toxicity occurs so it is the most
relevant for assessing the relationship between dose and
effect."
Dose-Effect and Dose-Response
Since the basic question in toxicology is how dose is related
to toxicity, most toxicology studies are designed to
investigate how living creatures react as doses vary
incrementally, from low to high levels. In studies on
experimental animals, different groups of animals are
administered, or exposed to, different daily doses.

observed, examinations of effects on these organs are

generally done during autopsy after studies are completed.
Researchers are developing exciting new ways to assess
effects in living animals, including techniques such as
Magnetic Resonance Imaging (MRI), ultrasound, Positron
Emission Tomography (PET), and optical imaging. In the
latter, biolumenescing genes are inserted into the genetic
material of animals and detection of light indicates
functioning of certain biological pathways.
The data are then plotted on a graph that shows the dose on
one axis and the response or effects on the other.

Then, at various intervals, the animals are examined for the

presence or absence of effects. These effects may be
behavioral changes, alterations in the compositions of body
tissues or fluids (e.g., blood, serum, urine), or structural
changes in parts of the organism.

In a typical dose-response graph, the dose is plotted against

the number or proportion of animals exhibiting a particular
response.
For a long time, death was the response of choice for
assessing short term (acute) toxicity, and the toxicology
literature contains many citations listing such lethal doses of
assorted agents for a variety of laboratory animals.

Since examination of internal organs requires invasive

procedures that can have an impact on the effects

In most cases, the dose that is lethal to 50% of the exposed

animals (LD50) is the value that is published.

Page 24 of 62
Although LD50 values are widespread in the scientific
literature and still used and useful, concerns over animal
welfare and the development of more technically
sophisticated tools have led to other approaches for
assessing toxicity.
On the other hand, dose-effect comparisons can be depicted
in graphs, charts, or tables which plot dose against the
degree of response (i.e., the severity of the effects). Thus, a
low dose may cause no effects, a higher dose, limited
effects, a still higher dose, serious outcomes, and, at a high
enough dose, death.
A common real world scenario that illustrates this type of
dose-effect relationship is the sequence of events that can
occur as a result of human alcohol consumption.

While the alcohol example in the preceding slide illustrates

the dose-effect relationship for a short term (acute)
exposure, dose-effect relationships are also commonly used
for assessing long term (chronic) effects.
When used to characterize chronic toxicity for chemicals
that do not cause cancer, the dose-effect relationship in
laboratory animals exposed over long periods of time is
examined to determine the highest dose at which no
observable adverse effect is seen (NOAEL) or the lowest
dose at which an adverse effect is observed (LOAEL).
This single value on the curve is then extrapolated to
humans to estimate the maximum exposures that are likely
to be without adverse effect. Making this assessment often
requires judgment because there may be subtle distinctions
between normal variation and an adverse effect.

In this case, a low consumption does not result in

observable effects but increasing amounts of alcohol lead to
increasingly severe symptoms including incoordination and
unconsciousness, and sometimes even death.

Note: The Y-axis in dose-response curves does not always

measure the same effect. Earlier we saw a curve where
lethality was the parameter under consideration as the dose
(X-axis) was increased. In this generic graph, though, the
response, still measured as a percentage, may represent
various effects
BASIC TOXICOLOGY TERMINOLOGY
Toxic having the characteristic
undesirable or adverse health effect.

of

producing

an

Page 25 of 62
Toxicity any toxic (adverse) effect that a chemical or
physical agent might produce within a livingorganism.

Subacute exposure resembles acute exposure except that

the exposure duration is greater, from

Toxicology the science that deals with the study of the

adverse effects (toxicities) chemicals or
physical agents may produce in living organisms under
specific conditions of exposure. It is a science that attempts
to qualitatively identify all the hazards (i.e., organ toxicities)
associated with a substance, as well as to quantitatively
determine the exposure conditions under which those
hazards/toxicities are induced. Toxicology is the science that
experimentally investigates the occurrence, nature,
incidence, mechanism, and risk factors for the adverse
effects of toxic substances.

Subchronic exposure exposures repeated or spread over

an intermediate time range. For animal testing, this time
range is generally considered to be 13 months.
Chronic exposure exposures (either repeated or
continuous) over a long (greater than 3 months) period of
time. With animal testing this exposure often continues for
the majority of the experimental animals life, and within
occupational settings it is generally considered to be for a
number of years.

Exposure to cause an adverse effect, a toxicant must first

come in contact with an organism. The means by which an
organism comes in contact with the substance is the route
of exposure (e.g., in the air, water, soil, food, medication) for
that chemical.

Acute toxicity an adverse or undesirable effect that is

manifested within a relatively short time interval ranging
from almost immediately to within several days following
exposure (or dosing). An example would be chemical
asphyxiation from exposure to a high concentration of
carbon monoxide (CO).

Dose the total amount of a toxicant administered to an

organism at specific time intervals. The quantity can be
further defined in terms of quantity per unit body weight or
per body surface area.

Chronic toxicity a permanent or lasting adverse effect that

is manifested after exposure to a toxicant. An example
would be the development of silicosis following a long-term
exposure to silica in workplaces such as foundries.

Internal/absorbed dose the actual quantity of a toxicant

that is absorbed into the organism and distributed
systemically throughout the body.

Local toxicity an adverse or undesirable effect that is

manifested at the toxicants site of contact with the
organism. Examples include an acids ability to cause
burning of the eyes, upper respiratory tract irritation, and
skin burns.

Delivered/effective/target organ dose the amount of

toxicant reaching the organ (known as the target organ) that
is adversely affected by the toxicant.
Acute exposure exposure over a brief period of time
(generally less than 24 h). Often it is considered to be a
single exposure (or dose) but may consist of repeated
exposures within a short time period.

Systemic toxicity an adverse or undesirable effect that

can be seen throughout the organism or in an organ with
selective vulnerability distant from the point of entry of the
toxicant (i.e., toxicant requires absorption and distribution
within the organism to produce the toxic effect). Examples
would be adverse effects on the kidney or central nervous
system resulting from the chronic ingestion of mercury.

Page 26 of 62

Reversible toxicity an adverse or undesirable effect that

can be reversed once exposure is stopped. Reversibility of
toxicity depends on a number of factors, including the
extent of exposure (time and amount of toxicant) and the
ability of the affected tissue to repair or regenerate. An
example
includes
hepatic
toxicity
from
acute
acetaminophen exposure and liver regeneration.
Delayed or latent toxicity an adverse or undesirable effect
appearing long after the initiation and/or cessation of
exposure to the toxicant. An example is cervical cancer
during adulthood resulting from in utero exposure to
diethylstilbestrol (DES).
Allergic reaction a reaction to a toxicant caused by an
altered state of the normal immune response. The outcome
of the exposure can be immediate (anaphylaxis) or delayed
(cell-mediated).
Idiosyncratic reaction a response to a toxicant occurring at
exposure levels much lower than those generally required to
cause the same effect in most individuals within the
population. This response is genetically determined, and a
good example would be sensitivity to nitrates due to
deficiency in NADH (reduced-form nicotinamide adenine
dinucleotide phosphate)methemoglobinreductase.
Mechanism of toxicity the necessary biologic interactions
by which a toxicant exerts its toxic effect on an organism.
An example is carbon monoxide (CO) asphyxiation due to
the binding of CO to hemoglobin, thus preventing the
transport of oxygen within the blood.
Toxicant any substance that causes a harmful (or adverse)
effect when in contact with a living organism at a sufficiently
high concentration.
Toxin any toxicant produced by an organism (floral or
faunal, including bacteria); that is, naturally produced

toxicants. An example would be the pyrethrins, which are

natural pesticides produced by pyrethrum flowers (i.e.,
certain chrysanthemums) that serve as the model for the
man made insecticide class pyrethroids.
Hazard the qualitative nature of the adverse or
undesirable effect (i.e., the type of adverse effect) resulting
from exposure to a particular toxicant or physical agent. For
example, asphyxiation is the hazard from acute exposures
to carbon monoxide (CO).
Safety the measure or mathematical probability that a
specific exposure situation or dose will not produce a toxic
effect.
Risk the measure or probability that a specific exposure
situation or dose will produce a toxic effect.
Risk assessment the process by which the potential (or
probability of) adverse health effects of exposure are
characterized.

Page 27 of 62
A toxic agent is anything that can produce an adverse
biological effect. It may be chemical, physical, or biological
in form. For example, toxic agents may be chemical (such as
cyanide), physical (such as radiation) and biological (such as
snake venom).

Toxic substances may be organic or inorganic in composition

A distinction is made for diseases due to biological

organisms. Those organisms that invade and multiply within
the organism and produce their effects by biological activity
are not classified as toxic agents. An example of this is a
virus that damages cell membranes resulting in cell death.
If the invading organisms excrete chemicals which are the
basis for toxicity, the excreted substances are known as
biological toxins. The organisms in this case are referred
to as toxic organisms. An example is tetanus. Tetanus is
caused by a bacterium, Clostridium tetani. The bacteria C.
tetani itself does not cause disease by invading and
destroying cells. Rather, it is a toxin that is excreted by the
bacteria that travels to the nervous system (a neurotoxin)
that produces the disease.
A toxic substance is simply a material which has toxic
properties. It may be a discrete toxic chemical or a mixture
of toxic chemicals. For example, lead chromate, asbestos,
and gasoline are all toxic substances. Lead chromate is a
discrete toxic chemical. Asbestos is a toxic material that
does not consist of an exact chemical composition but a
variety of fibers and minerals. Gasoline is also a toxic
substance rather than a toxic chemical in that it contains a
mixture of many chemicals. Toxic substances may not
always have a constant composition. For example, the
composition of gasoline varies with octane level,
manufacturer, time of season, etc.

Toxic substances may be systemic toxins or organ

toxins.
A systemic toxin is one that affects the entire body or
many organs rather than a specific site. For example,
potassium cyanide is a systemic toxicant in that it affects
virtually every cell and organ in the body by interfering with
the cell's ability to utilize oxygen.
Toxicants may also affect only specific tissues or organs
while not producing damage to the body as a whole. These
specific sites are known as the target organs or target
tissues.
Benzene is a specific organ toxin in that it is
primarily toxic to the blood-forming tissues.
Lead is also a specific organ toxin; however, it has
three target organs (central nervous system,
kidney, and hematopoietic system).

Page 28 of 62
A toxicant may affect a specific type of tissue (such as
connective tissue) that is present in several organs. The
toxic site is then referred to as the target tissue.
There are many types of cells in the body and they can be
classified in several ways.

10 mg DDT per day for 90 days

There are numerous types of doses, e.g., exposure dose,
absorbed dose, administered dose and total dose.

basic structure (e.g., cuboidal cells)

tissue type (e.g., hepatocytes of the liver)
germinal cells (e.g., ova and sperm)
somatic cells (e.g., non-reproductive cells of the body)

Germ cells are those cells that are involved in the

reproductive process and can give rise to a new organism.
They have only a single set of chromosomes peculiar to a
specific sex. Male germ cells give rise to sperm and female
germ cells develop into ova. Toxicity to germ cells can cause
effects on the developing fetus (such as birth defects,
abortions).
Somatic cells are all body cells except the reproductive
germ cells. They have two sets (or pairs) of chromosomes.
Toxicity to somatic cells causes a variety of toxic effects to
the exposed individual (such as dermatitis, death, and
cancer).
Dose by definition is the amount of a substance
administered at one time. However, other parameters are
needed to characterize the exposure to xenobiotics. The
most important are the number of doses, frequency, and
total time period of the treatment.
For example:
650 mg Tylenol as a single dose
500 mg Penicillin every 8 hours for 10 days

Fractionating a total dose usually decreases the

probability that the total dose will cause toxicity. The reason
for this is that the body often can repair the effect of each
subtoxic dose if sufficient time passes before receiving the
next dose. In such a case, the total dose, harmful if received
all at once, is non-toxic when administered over a period of
time. For example, 30 mg of strychnine swallowed at one
time could be fatal to an adult whereas 3 mg of strychnine
swallowed each day for ten days would not be fatal.
The units used in toxicology are basically the same as those
used in medicine. The gram is the standard unit. However,
most exposures will be smaller quantities and thus the
milligram (mg) is commonly used. For example, the
common adult dose of Tylenol is 650 milligrams.
The clinical and toxic effects of a dose must be related to
age and body size. For example, 650 mg is the adult dose of
Tylenol. That would be quite toxic to young children, and
thus Children's Tylenol tablets contain only 80 mg. A better
means to allow for comparison of effectiveness and toxicity
is the amount of a substance administered on a body weight

Page 29 of 62
basis. A common dose measurement is mg/kg which stands
for mg of substance per kg of body weight.
Another important aspect is the time over which the dose is
administered. This is especially important for exposures of
several days or for chronic exposures. The commonly used
time unit is one day and thus, the usual dosage unit is
mg/kg/day.

establishes the lowest dose where an induced effect occurs

- the threshold effect
determines the rate at which injury builds up - the slope for
the dose response.

Since some xenobiotics are toxic in much smaller quantities

than the milligram, smaller fractions of the gram are used,
such as microgram (g). Other units are shown below:
Environmental exposure units are expressed as the
amount of a xenobiotic in a unit of the media.
mg/liter (mg/l) for liquids
mg/gram (mg/g) for solids
mg/cubic meter (mg/m3) for air

Smaller units are used as needed, e.g., g/ml. Other

commonly used dose units for substances in media are parts
per million (ppm), parts per billion (ppb) and parts per
trillion (ppt).

Within a population, the majority of responses to a toxicant

are similar; however, a wide variance of responses may be
encountered, some individuals are susceptible and others
resistant. As demonstrated above, a graph of the individual
responses can be depicted as a bell-shaped standard
distribution curve.

Dose Response The dose-response relationship is a

fundamental and essential concept in toxicology. It
correlates exposures and the spectrum of induced effects.
Generally, the higher the dose, the more severe the
response. The dose-response relationship is based on
observed data from experimental animal, human clinical, or
cell studies.
Knowledge of the dose-response relationship:
establishes causality that the chemical has in fact induced
the observed effects

Dose responses are commonly presented as mean + 1 S.D.

Page 30 of 62
(standard deviation), which incorporates 68% of the
individuals. The variance may also be presented as two
standard deviations, which incorporates 95% of the
responses. A large standard deviation indicates great
variability of response. For example, a response of 15+8 mg
indicates considerably more variability than 15+2 mg.

The dose-response curve normally takes the form of a

sigmoid curve. It conforms to a smooth curve as close as
possible to the individual data points. For most effects, small
doses are not toxic. The point at which toxicity first appears
is known as the threshold dose level. From that point, the
curve increases with higher dose levels. In the hypothetical
curve above, no toxicity occurs at 10 mg whereas at 35 mg
100% of the individuals experience toxic effects.
A threshold for toxic effects occurs at the point where the
body's ability to detoxify a xenobiotic or repair toxic injury
has been exceeded. For most organs there is a reserve
capacity so that loss of some organ function does not cause
decreased performance. For example, the development of
cirrhosis in the liver may not result in a clinical effect until
over 50% of the liver has been replaced by fibrous tissue.

Knowledge of the shape and slope of the dose-response

curve is extremely important in predicting the toxicity of a
substance at specific dose levels. Major differences among
toxicants may exist not only in the point at which the
threshold is reached but also in the percent of population
responding per unit change in dose (i.e., the slope). As
illustrated above, Toxicant A has a higher threshold but a
steeper slope than Toxicant B.
Dose Estimates of Toxic Effects (LD, EC, TD)
Dose-response curves are used to derive dose estimates of
chemical substances. A common dose estimate for acute
toxicity is the LD50 (Lethal Dose 50%). This is a statistically
derived dose at which 50% of the individuals will be
expected to die. The figure below illustrates how an LD50 of
20 mg is derived.

Page 31 of 62

Toxic Doses (TDs) are utilized to indicate doses that cause

adverse toxic effects. The usual dose estimates are listed
below:

Other dose estimates also may be used. LD0 represents the

dose at which no individuals are expected to die. This is just
below the threshold for lethality. LD10 refers to the dose at
which 10% of the individuals will die.
For inhalation toxicity, air concentrations are used for
exposure values. Thus, the LC50 is utilized which stands for
Lethal Concentration 50%, the calculated concentration of a
gas lethal to 50% of a group. Occasionally LC0 and LC10 are
also used.
Effective Doses (EDs) are used to indicate the
effectiveness of a substance. Normally, effective dose refers
to a beneficial effect (relief of pain). It might also stand for a
harmful effect (paralysis). Thus the specific endpoint must
be indicated. The usual terms are:

The knowledge of the effective and toxic dose levels

aides the toxicologist and clinician in determining the

Page 32 of 62
relative safety of pharmaceuticals. As shown above, two
dose-response curves are presented for the same drug, one
for effectiveness and the other for toxicity. In this case, a
dose that is 50-75% effective does not cause toxicity
whereas a 90% effective dose may result in a small amount
of toxicity.
Therapeutic Index and Margin of Safety
The Therapeutic Index (TI) is used to compare the
therapeutically effective dose to the toxic dose. The TI is a
statement of relative safety of a drug. It is the ratio of the
dose producing toxicity to the dose needed to produce the
desired therapeutic response. The common method used to
derive the TI is to use the 50% dose-response points. For
example, if the LD50 is 200 and the ED50 is 20 mg, the TI
would be 10 (200/20). A clinician would consider a drug
safer if it had a TI of 10 than if it had a TI of 3.
The use of the ED50 and LD50 doses to derive the TI may
be misleading as to safety, depending on the slope of the
dose-response curves for therapeutic and lethal effects. To
overcome this deficiency, toxicologists often use another
term to denote the safety of a drug - the Margin of Safety
(MOS).
The MOS is usually calculated as the ratio of the dose that
is just within the lethal range (LD01) to the dose that is 99%
effective (ED99). The MOS = LD01/ED99. A physician must
use caution in prescribing a drug in which the MOS is less
than 1.

Due to differences in slopes and threshold doses, low doses

may be effective without producing toxicity. Although more
patients may benefit from higher doses, this is offset by the
probability that toxicity or death will occur. The relationship
between the Effective Dose response and the Toxic Dose
response is illustrated above.

Page 33 of 62
Knowledge of the slope is important in comparing the
toxicity of various substances. For some toxicants a small
increase in dose causes a large increase in response
(toxicant A, steep slope). For other toxicants a much larger
increase in dose is required to cause the same increase in
response (toxicant B, shallow slope).
NOAEL and LOAEL
Two terms often encountered are No Observed Adverse
Effect Level (NOAEL) and Low Observed Adverse
Effect Level (LOAEL). They are the actual data points
from human clinical or experimental animal studies.

imply toxic or harmful effects and may be used to describe

beneficial effects of chemicals as well.
The NOAEL, LOAEL, NOEL, and LOEL have great importance
in the conduct of risk assessments.
Toxic Effects
Toxicity is complex with many influencing factors; dosage is
the most important. Xenobiotics cause many types of
toxicity by a variety of mechanisms. Some chemicals are
themselves toxic. Others must be metabolized (chemically
changed within the body) before they cause toxicity.
Many xenobiotics distribute in the body and often affect only
specific target organs. Others, however, can damage any
cell or tissue that they contact. The target organs that are
affected may vary depending on dosage and route of
exposure. For example, the target for a chemical after acute
exposure may be the nervous system, but after chronic
exposure the liver.
Toxicity can result from adverse cellular, biochemical,
or macromolecular changes. Examples are:
cell replacement, such as fibrosis
damage to an enzyme system
disruption of protein synthesis
production of reactive chemicals in cells
DNA damage

Sometimes the terms No Observed Effect Level (NOEL)

and Lowest Observed Effect Level (LOEL) may also be
found in the literature. NOELs and LOELs do not necessarily

Some xenobiotics may also act indirectly by:

modification of an essential biochemical function
interference with nutrition

Page 34 of 62

alteration of a physiological mechanism

Systemic Toxic Effects
Toxic effects are generally categorized according to the site
of the toxic effect. In some cases, the effect may occur at
only one site. This site is referred to as the specific target
organ. In other cases, toxic effects may occur at multiple
sites. This is referred as systemic toxicity.
Following are types of systemic toxicity:

Subchronic toxicity results from repeated exposure for

several weeks or months. This is a common human
exposure
pattern
for
some
pharmaceuticals
and
environmental
agents.
Examples
are:
Ingestion of coumadin tablets (blood thinners) for several
weeks as a treatment for venous thrombosis can cause
internal bleeding.
Workplace exposure to lead over a period of several weeks
can result in anemia.

Acute Toxicity
Subchronic Toxicity
Chronic Toxicity
Carcinogenicity
Developmental Toxicity
Genetic Toxicity (somatic cells)
Acute Toxicity
Acute toxicity occurs almost immediately (hours/days) after
an exposure. An acute exposure is usually a single dose
or a series of doses received within a 24 hour period. Death
is a major concern in cases of acute exposures. Examples
are:
In 1989, 5,000 people died and 30,000 were permanently
disabled due to exposure to methyl isocyanate from an
industrial accident in India.
Many people die each year from inhaling carbon monoxide
from faulty heaters.
Non-lethal acute effects may also occur, e.g., convulsions
and respiratory irritation.
Subchronic Toxicity

Chronic Toxicity
Chronic toxicity represents cumulative damage to specific
organ systems and takes many months or years to become
a recognizable clinical disease. Damage due to subclinical
individual exposures may go unnoticed. With repeated
exposures or long-term continual exposure, the damage
from these subclinical exposures slowly builds-up
(cumulative damage) until the damage exceeds the
threshold for chronic toxicity. Ultimately, the damage
becomes so severe that the organ can no longer function
normally and a variety of chronic toxic effects may result.
Examples of chronic toxic affects are:
cirrhosis in alcoholics who have ingested ethanol for
several years
chronic kidney disease in workmen with several years
exposure
to
lead
chronic bronchitis in long-term cigarette smokers
pulmonary fibrosis in coal miners (black lung disease)
Carcinogenicity
Carcinogenicity is a complex multistage process of abnormal
cell growth and differentiation which can lead to cancer. At
least two stages are recognized. They are initiation in
which a normal cell undergoes irreversible changes and
promotion in which initiated cells are stimulated to

Page 35 of 62
progress to cancer.
promoters.

Chemicals can act as initiators or

The initial neoplastic transformation results from the

mutation of the cellular genes that control normal cell
functions. The mutation may lead to abnormal cell growth.
It may involve loss of suppresser genes that usually restrict
abnormal cell growth. Many other factors are involved (e.g.,
growth factors, immune suppression, and hormones).
A tumor (neoplasm) is simply an uncontrolled growth of
cells. Benign tumors grow at the site of origin; do not
invade adjacent tissues or metastasize; and generally are
treatable. Malignant tumors (cancer) invade adjacent
tissues or migrate to distant sites (metastasis). They are
more difficult to treat and often cause death.
Developmental Toxicity
Developmental Toxicity pertains to adverse toxic effects to
the developing embryo or fetus. This can result from
toxicant exposure to either parent before conception or to
the mother and her developing embryo-fetus. The three
basic types of developmental toxicity are:

development. A chemical might also induce a mutation in a

parent's germ cell which is transmitted to the fertilized
ovum. Some mutated fertilized ova develop into abnormal
embryos.
Genetic Toxicity
Genetic Toxicity results from damage to DNA and altered
genetic
expression.
This
process
is
known
as
mutagenesis. The genetic change is referred to as a
mutation and the agent causing the change as a
mutagen. There are three types of genetic change:

If the mutation occurs in a germ cell the effect is heritable.

There is no effect on the exposed person; rather the effect is
passed on to future generations. If the mutation occurs in a
somatic cell, it can cause altered cell growth (e.g. cancer)
or cell death (e.g. teratogenesis) in the exposed person.
Factors Influencing Toxicity
The toxicity of a substance depends on the following:
form and innate chemical activity
dosage, especially dose-time relationship
exposure route
species

Chemicals cause developmental toxicity by two methods.

They can act directly on cells of the embryo causing cell
death or cell damage, leading to abnormal organ

age
sex
ability to be absorbed

Page 36 of 62

metabolism
distribution within the body
excretion
presence of other chemicals
The form of a substance may have a profound impact on its
toxicity especially for metallic elements. For example, the
toxicity of mercury vapor differs greatly from methyl
mercury. Another example is chromium. Cr3+ is relatively
nontoxic whereas Cr6+ causes skin or nasal corrosion and
lung cancer.
The innate chemical activity of substances also varies
greatly. Some can quickly damage cells causing immediate
cell death. Others slowly interfere only with a cell's function.
For example:

hydrogen cyanide binds to cytochrome oxidase

resulting in cellular hypoxia and rapid death
nicotine binds to cholinergic receptors in the CNS
altering nerve conduction and inducing gradual onset
of paralysis

The dosage is the most important and critical factor in

determining if a substance will be an acute or a chronic
toxicant. Virtually all chemicals can be acute toxicants if
sufficiently large doses are administered. Often the toxic
mechanisms and target organs are different for acute and
chronic toxicity. Examples are:

Exposure route is important in determining toxicity. Some

chemicals may be highly toxic by one route but not by
others. Two major reasons are differences in absorption and
distribution within the body. For example:

ingested chemicals, when absorbed from the

intestine, distribute first to the liver and may be
immediately
detoxified

inhaled toxicants immediately enter the general

blood circulation and can distribute throughout the
body prior to being detoxified by the liver

Frequently there are different target organs for different

routes of exposure.
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. For example, rats cannot vomit
and expel toxicants before they are absorbed or cause
severe irritation, whereas humans and dogs are capable of
vomiting.
Selective toxicity refers to species differences in toxicity
between two species simultaneously exposed. This is the
basis for the effectiveness of pesticides and drugs.
Examples are:

Page 37 of 62
An insecticide is lethal to insects but relatively nontoxic to
animals
antibiotics are selectively toxic to microorganisms while
virtually nontoxic to humans

Age may be important in determining the response to

toxicants. Some chemicals are more toxic to infants or the
elderly than to young adults.
For example:
Parathion
is
more
toxic
to
young
animals
nitrosamines are more carcinogenic to newborn or young
animals
Although uncommon, toxic responses can vary depending
on sex. Examples are:
male rats are 10 times more sensitive than females
to liver damage from DDT
female rats are twice as sensitive to parathion as
male rats
The ability to be absorbed is essential for systemic
toxicity to occur. Some chemicals are readily absorbed and
others poorly absorbed. For example, nearly all alcohols are
readily absorbed when ingested, whereas there is virtually
no absorption for most polymers. The rates and extent of
absorption may vary greatly depending on the form of the
chemical and the route of exposure.
For example:

ethanol is readily absorbed from the gastrointestinal

tract but poorly absorbed through the skin
organic mercury is readily absorbed from the
gastrointestinal tract; inorganic lead sulfate is not

Metabolism, also known as biotransformation, is a major

factor in determining toxicity. The products of metabolism
are known as metabolites. There are two types of
metabolism
detoxification
and
bioactivation.
Detoxification is the process by which a xenobiotic is
converted to a less toxic form. This is a natural defense
mechanism of the organism. Generally the detoxification
process converts lipid-soluble compounds to polar
compounds. Bioactivation is the process by which a
xenobiotic may be converted to more reactive or toxic
forms.
The distribution of toxicants and toxic metabolites
throughout the body ultimately determines the sites where
toxicity occurs. A major determinant of whether or not a
toxicant will damage cells is its lipid solubility. If a toxicant is
lipid-soluble it readily penetrates cell membranes. Many
toxicants are stored in the body. Fat tissue, liver, kidney, and
bone are the most common storage depots. Blood serves as
the main avenue for distribution. Lymph also distributes
some materials.
The site and rate of excretion is another major factor
affecting the toxicity of a xenobiotic. The kidney is the
primary excretory organ, followed by the gastrointestinal
tract, and the lungs (for gases). Xenobiotics may also be
excreted in sweat, tears, and milk.
A large volume of blood serum is filtered through the kidney.
Lipid-soluble toxicants are reabsorbed and concentrated in
kidney cells. Impaired kidney function causes slower
elimination of toxicants and increases their toxic potential.
The presence of other chemicals may decrease toxicity
(antagonism), add to toxicity (additivity), or increase
toxicity (synergism or potentiation) of some xenobiotics.
For example:

Page 38 of 62

alcohol may enhance the effect of many

antihistamines and sedatives
antidotes function by antagonizing the toxicity of a
poison
(atropine
counteracts
poisoning
by
organophosphate insecticides)

Chemical Interactions
Humans are normally exposed to several chemicals at one
time rather than to an individual chemical. Medical
treatment and environment exposure generally consists of
multiple exposures.
Examples are:

Xenobiotics administered or received simultaneously may

act independently of each other. However, in many cases,
the presence of one chemical may drastically affect the
response to another chemical. The toxicity of a combination
of chemicals may be less or it may be more than would be
predicted from the known effects of each individual
chemical. The effect that one chemical has on the toxic
effect of another chemical is known as an interaction.
Types of Interactions
There are four basic types of interactions. Each is based on
the expected effects caused by the individual chemicals.The
types of interactions are:

hospital patients on the average receive 6 drugs

daily
home influenza treatment consists of aspirin,
antihistamines,
and
cough
syrup
taken
simultaneously

drinking water may contain small amounts of

pesticides, heavy metals, solvents, and other organic
chemicals

air often contains mixtures of hundreds of chemicals

such as automobile exhaust and cigarette smoke

gasoline vapor at service stations is a mixture of 4050 chemicals

Normally, the toxicity of a specific chemical is determined

by the study of animals exposed to only one chemical.
Toxicity testing of mixtures is rarely conducted since it is
usually impossible to predict the possible combinations of
chemicals that will be present in multiple-chemical
exposures.

This table quantitatively illustrates the percent of the

population affected by individual exposure to chemical A
and chemical B as well as exposure to the combination of
chemical A and chemical B. It also gives the specific type of
interaction:

Page 39 of 62
insecticide formulation containing both is equivalent
to the sum of the hepatotoxicity of each.
Antagonism
Antagonism is often a desirable effect in toxicology and is
the basis for most antidotes. Examples include:

The interactions described can be categorized by their

chemical or biological mechanisms as follows:

chemical reactions between chemicals

modifications in absorption, metabolism, or excretion

reactions at binding sites and receptors

physiological changes

Additivity
Additivity is the most common type of drug interaction.
Examples of chemical or drug additivity reactions are:

Potentiation
Potentiation occurs when a chemical that does not have a
specific toxic effect makes another chemical more toxic.
Examples
are:

Two central nervous system (CNS) depressants taken

at the same time, a tranquilizer and alcohol, often
cause depression equal to the sum of that caused by
each drug.
Organophosphate insecticides interfere with nerve
conduction. The toxicity of the combination of two
organophosphate insecticides is equal to the sum of
the toxicity of each.

The hepatotoxicity of carbon tetrachloride is greatly

enhanced by the presence of isopropanol. Such exposure
may
occur
in
the
workplace.

Chlorinated insecticides and halogenated solvents

both produce liver toxicity. The hepatotoxicity of an

Synergism
Synergism

Normally, warfarin (a widely used anticoagulant in cardiac

disease) is bound to plasma albumin so that only 2% of the
warfarin is active. Drugs which compete for binding sites on
albumin increase the level of free warfarin to 4% causing
fatal hemorrhage.

can

have

serious

health

effects.

With

Page 40 of 62
synergism, exposure to a chemical may drastically increase
the effect of another chemical. Examples are:

Exposure to both cigarette smoke and radon results

in a significantly greater risk for lung cancer than the
sum of the risks of each.
The combination of exposure to asbestos and
cigarette smoke results in a significantly greater risk
for lung cancer than the sum of the risks of each.
The hepatotoxicity of a combination of ethanol and
carbon tetrachloride is much greater than the sum of
the hepatotoxicity of each.

Different types of interactions can occur at different target

sites for the same combination of two chemicals. For
example, chlorinated insecticides and halogenated solvents
(which are often used together in insecticide formulations)
can produce liver toxicity with the interaction being additive.
The same combination of chemicals produces a different
type of interaction on the central nervous system.
Chlorinated insecticides stimulate the central nervous
system whereas halogenated solvents cause depression of
the nervous system. The effect of simultaneous exposure is
an antagonistic interaction.
What is Toxicokinetics?
Toxicokinetics is essentially the study of "how a substance
gets into the body and what happens to it in the body".
Four processes are involved in toxicokinetics.

The study of the kinetics (movement) of chemicals was

originally conducted with pharmaceuticals and thus the term
pharmacokinetics became commonly used. In addition,
toxicology studies were initially conducted with drugs.
However, the science of toxicology has evolved to include
environmental and occupational chemicals as well as drugs.

Toxicokinetics is thus the appropriate term for

the study of the kinetics of all toxic substances.
Frequently the terms toxicokinetics, pharmacokinetics, or
disposition may be found in the literature to have the same
meaning. Disposition is often used in place of

toxicokinetics to describe the time-course of

movement of chemicals through the body (that is,
how does the body dispose of a xenobiotic?).
The disposition of a toxicant along with its' biological
reactivity are the factors that determine the severity
of toxicity that results when a xenobiotic enters the
body. Specific aspects of disposition of greatest importance
are:
duration and concentration of substance at the portal of entry

Page 41 of 62

rate and amount that can be absorbed

distribution in the body and concentration at specific body sites
efficiency of biotransformation and nature of the metabolites
the ability of the substance or it's metabolites to pass through cell membranes and
come into contact with specific cell components (e.g., DNA).
the amount and duration of storage of the substance (or it's metabolites)
tissues
the rate and sites of excretion
Examples of how toxicokinetics of a substance can influence
its toxicity:
Absorption. A highly-toxic substance, which is poorly absorbed, may be no more of a
hazard than a substance of low toxicity that is highly absorbed.
Biotransformation. Two substances with equal toxicity and absorption may differ in
hazard depending on the nature of their biotransformation. A substance biotransformed
into a more toxic metabolite (bioactivated) is a greater hazard than a substance that is
biotransformed into a less toxic metabolite (detoxified).
Absorption, distribution, biotransformation, and elimination
are inter-related processes as illustrated in the following
figure.
Absorption is the process whereby toxicants gain entrance
into the body. Ingested and inhaled materials are still
considered outside the body until they cross the cellular
barriers of the gastrointestinal tract or respiratory system.
To exert an effect on internal organs it must be absorbed,
although local toxicity, such as irritation, may occur.
Absorption varies greatly with specific chemicals and the

Page 42 of 62
route of exposure. For skin, oral or respiratory exposure, the
exposure dose (outside dose) is only a fraction of the
absorbed dose (internal dose). For substances injected or
implanted directly into the body, exposure dose is the same
as
the
absorbed
or
internal
dose.
Several factors affect the likelihood that a xenobiotic will be
absorbed. The most important are:
route of exposure
concentration of the substance at the site of contact

Other routes of exposure - used primarily for specific

medical purposes:

chemical and physical properties of the substance

The relative roles of concentration and properties of the
substance vary with the route of exposure. In some cases, a
high percentage of a substance may not be absorbed from
one route whereas a low amount may be absorbed via
another route. For example, very little DDT powder will
penetrate the skin whereas a high percentage will be
absorbed when it is swallowed. Due to such route-specific
differences in absorption, xenobiotics are often ranked for
hazard in accordance with the route of exposure. A
substance may be categorized as relatively non-toxic by one
route and highly toxic via another route.
The primary routes of exposure by which xenobiotics can
gain entry into the body are:

For a xenobiotic to enter the body (as well as move within,

and leave the body) it must pass across cell membranes
(cell walls). Cell membranes are formidable barriers and a
major body defense that prevents foreign invaders or

Page 43 of 62
substances from gaining entry into body tissues. Normally,
cells in solid tissues (such as skin or mucous membranes of
the lung or intestine) are so tightly compacted that
substances can not pass between them. This requires that
the xenobiotic have the ability to penetrate cell
membranes. It must cross several membranes in order to
go
from
one
area
of
the
body
to
another.
In essence, for a substance to move through one cell
requires that it first move across the cell membrane into the
cell, pass across the cell, and then cross the cell membrane
again in order to leave the cell. This is true whether the
cells are in the skin, the lining of a blood vessel, or an
internal organ (e.g., liver). In many cases, in order for a
substance to reach the site of toxic action, it must pass
through
several
membrane
barriers.
As illustrated in the diagram below, a foreign chemical will
pass through several membranes before it comes into
contact with and can damage the nucleus of a liver cell.

Cell membranes(often referred to as plasma membranes)

surround all body cells and are basically similar in structure.
They consist of two layers of phospholipid molecules
arranged like a sandwich, referred to as a "phospholipid
bilayer".
Each phospholipid molecule consists of a
phosphate head and a lipid tail. The phosphate head is
polar, that is it is hydrophilic (attracted to water). In

Page 44 of 62
contrast, the lipid tail is lipophilic (attracted to lipid-soluble
substances).
The two phospholipid layers are oriented on opposing sides
of the membrane so that they are approximate mirror
images of each other. The polar heads face outward and the
lipid tails inward in the membrane sandwich.

Some toxicants move across a membrane barrier with

relative ease while others find it difficult or impossible.
Those that can cross the membrane, do so by one of two
general methods, passive transfer or facilitated
transport.
The cell membrane is tightly packed with these phospholipid
molecules interspersed with various proteins and cholesterol
molecules. Some proteins span across the entire membrane
providing for the formation of aqueous channels or pores.
A typical cell membrane structure is illustrated below.

Passive transfer consists of simple diffusion(or osmotic

filtration) and is "passive" in that there is no cellular energy
or assistance required.
Some toxicants can not simply diffuse across the membrane
but require assistance or facilitated by specialized transport
mechanisms. The primary types of specialized transport
mechanisms are:
facilitated diffusion
active transport

Page 45 of 62

endocytosis (phagocytosis and pinocytosis)

Passive transfer is the most common way that xenobiotics
cross cell membranes. Two factors determine the rate of
passive transfer:

Exceptions are membranes of capillaries and kidney

glomeruli which have relatively large pores (about 40) that
allow molecules up to a molecular weight of about 50,000
(molecules slightly smaller than albumen which has a
molecular weight of 60,000) to pass through.

The illustration below demonstrates the passive diffusion

and filtration
of xenobiotics through a typical cell
difference in concentrations of the substance on opposite sides
of the membrane
membrane.
(substance moves from a region of high concentration to
one having a lower
concentration. Diffusion will continue until the concentration is equal on both sides of
the membrane)
ability of the substance to move either through the small pores in the membrane or the
lipophilic interior of the membrane

Properties of the chemical substance that affect its' ability

for passive transfer are:
lipid solubility
molecular size
degree of ionization
Substances with high lipid solubility readily diffuse through
the phospholipid membrane. Small water-soluble molecules
can pass across a membrane through the aqueous pores,
along with normal intracellular water flow.
Large water-soluble molecules usually can not make it
through the small pores, although some may diffuse through
the lipid portion of the membrane, but at a slow rate. In
general, highly ionized chemicals have low lipid solubility
and pass with difficulty through the lipid membrane.
Most aqueous pores are about 4 in size and allow
chemicals of molecular weight 100-200 to pass through.

Facilitated diffusion is similar to simple diffusion in that it

does not require energy and follows a concentration
gradient. The difference is that it is a carrier-mediated
transport mechanism. The results are similar to passive
transport but faster and capable of moving larger molecules

Page 46 of 62
that have difficulty diffusing through the membrane without
a carrier. Examples are the transport of sugar and amino
acids
into
RBCs
and
the
CNS.

Some substances are unable to move with diffusion, unable

to dissolve in the lipid layer, and are too large to pass
through the aqueous channels. For some of these
substances, active transport processes exist in which
movement through the membrane may be against the
concentration gradient, that is, from low to higher
concentrations.
Cellular
energy
from
adenosine
triphosphate (ADP) is required in order to accomplish this.
The transported substance can move from one side of the
membrane to the other side by this energy process. Active
transport is important in the transport of xenobiotics into the
liver, kidney, and central nervous system and for
maintenance of electrolyte and nutrient balance.
In the following figure, the sodium and potassium ions are
moving against concentration gradient with the help of the

ADP

sodium-potassium

pump.

Many large molecules and particles can not enter cells via
passive or active mechanisms. However, some may still
enter
by
a
process
known
as
endocytosis.
In endocytosis, the cell surrounds the substance with a
section of its cell wall. This engulfed substance and section
of membrane then separates from the membrane and
moves into the interior of the cell. The two main forms of
endocytosis are phagocytosis and pinocytosis.
In phagocytosis(cell eating), large particles suspended in

Page 47 of 62
the extracellular fluid are engulfed and either transported
into cells or are destroyed within the cell. This is a very
important process for lung phagocytes and certain liver and
spleen cells. Pinocytosis(cell drinking) is a similar process
but involves the engulfing of liquids or very small particles
that are in suspension within the extracellular fluid.
The illustration below demonstrates endocytosis membrane
transport.

How fast is a chemical distributed?

Why do some chemicals stay in the body for a long time whereas othe
quickly?
When a chemical is absorbed it passes through cell linings of
the absorbing organ (skin, lung, or gastrointestinal tract)
into the interstitial fluid(fluid surrounding cells) of that
organ. Interstitial fluid represents about 15% of the total
body weight. The other body fluids are the intracellular
fluid(fluid inside cells), about 40% of the total body weight
and blood plasma which accounts for about 8% of the
body weight. However, the body fluids are not isolated but
represent one large pool. The interstitial and intracellular
fluids, in contrast to fast moving blood, remain in place with
certain components (e.g., water and electrolytes) moving
slowly into and out of cells. A chemical, while immersed in
the interstitial fluid, is not mechanically transported as it is
in
blood.
A toxicant can leave the interstitial fluid by:
entering local tissue cells
entering blood capillaries and the blood circulatory system
entering the lymphatic system

Distribution is the process whereby an absorbed chemical

moves away from the site of absorption to other areas of the
body. In this section we will answer the following questions:
How do chemicals move through the body?
Does distribution vary with the route of exposure?
Is a chemical distributed evenly to all organs or tissues?

If the toxicant gains entrance into the blood plasma, it

travels along with the blood, either in a bound or unbound
form. Blood moves rapidly through the body via the
cardiovascular circulatory system. In contrast, lymph moves
slowly through the lymphatic system. The major distribution
of an absorbed chemical is by blood with only minor
distribution by lymph. Since virtually all tissues have a
blood supply, all organs and tissues of the body are
potentially
exposed
to
the
absorbed
chemical.

Page 48 of 62
Distribution of a chemical to body cells and tissues requires
that the toxicant penetrate a series of cell membranes. It
must first penetrate the cells of the capillaries (small blood
vessels) and later the cells of the target organs. The factors
previously described pertaining to passage across
membranes apply to these other cell membranes as well.
For example, concentration gradient, molecular weight, lipid
solubility, and polarity are important, with the smaller,
nonpolar toxicants, in high concentrations, most likely to
gain entrance.

undergo rapid storage, biotransformation, or elimination.

Toxicologists determine the VD of a toxicant in order to know
how extensively a toxicant is distributed in the body fluids.
The volume of distribution can be calculated by the formula:

The distribution of a xenobiotic is greatly affected by

whether it binds to plasma protein. Some toxicants may
bind to these plasma proteins (especially albumin), which
"removes" the toxicant from potential cell interaction.
Within the circulating blood, the non-bound (free) portion is
in equilibrium with the bound portion. However, only the
free substance is available to pass through the capillary
membranes. Thus, those substances that are extensively
bound are limited in terms of equilibrium and distribution
throughout the body. Protein-binding in the plasma greatly
affects distribution, prolongs the half-life within the body,
and
affects
the
dose
threshold
for
toxicity.

The volume of distribution may provide useful estimates as

to how extensive the toxicant is distributed in the body. For
example, a very high apparent VD may indicate that the
toxicant has distributed to a particular tissue or storage area
such as adipose tissue. In addition, the body burden for a
toxicant can be estimated from knowledge of the V D by using
the formula:

The plasma level of a xenobiotic is important since it

generally reflects the concentration of the toxicant at the
site of action. The passive diffusion of the toxicant into or
out of these body fluids will be determined mainly by the
toxicant's concentration gradient. The total volume of body
fluids in which a toxicant is distributed is known as the
apparent volume of distribution (VD ). The VD is
expressed in liters.
If a toxicant is distributed only in the plasma fluid, a high V D
results; however, if a toxicant is distributed in all sites
(blood plasma, interstitial and intracellular fluids) there is
greater dilution and a lower VD will result. Binding in effect
reduces the concentration of "free" toxicants in the plasma
or VD. The VD can be further affected by toxicants that

Once a chemical is in the blood stream it may be:

Excreted
Stored
biotransformed into different chemicals (metabolites)
its metabolites may be excreted or stored

the chemical or its metabolites may interact or bind with cellular comp

Page 49 of 62

Most chemicals undergo some biotransformation. The

degree with which various chemicals are biotransformed
and the degree with which the parent chemical and its'
metabolites are stored or excreted varies with the nature of
the exposure (dose level, frequency and route of exposure).
Biotransformation is the process whereby a substance is
changed from one chemical to another (transformed) by a
chemical reaction within the body. Metabolism or
metabolic transformations are terms frequently used for
the biotransformation process. However, metabolism is
sometimes not specific for the transformation process but
may
include
other
phases
of
toxicokinetics.
Biotransformation is vital to survival in that it transforms
absorbed nutrients (food, oxygen, etc.) into substances
required
for
normal
body
functions.
For
some
pharmaceuticals, it is a metabolite that is therapeutic and
not
the
absorbed
drug.
For
example,
phenoxybenzamine(Dibenzyline), a drug given to relieve
hypertension, is biotransformed into a metabolite, which is
the active agent. Biotransformation also serves as an
important defense mechanism in that toxic xenobiotics and
body wastes are converted into less harmful substances and
substances that can be excreted from the body.
If you recall, toxicants that are lipophilic, non-polar, and of
low molecular weight are readily absorbed through the cell
membranes of the skin, GI tract, and lung. These same
chemical and physical properties control the distribution of a
chemical throughout the body and it's penetration into
tissue cells. Lipophilic toxicants are hard for the body to
eliminate and can accumulate to hazardous levels.

However, most lipophilic toxicants can be transformed into

hydrophilic metabolites that are less likely to pass through
membranes of critical cells. Hydrophilic chemicals are
easier for the body to eliminate than lipophilic substances.
Biotransformation is thus a key body defense mechanism.
Fortunately, the human body has a well-developed capacity
to biotransform most xenobiotics as well as body wastes.
An example of a body waste that must be eliminated is
hemoglobin, the oxygen-carrying iron-protein complex in red
blood cells. Hemoglobin is released during the normal
destruction of red blood cells. Under normal conditions
hemoglobin is initially biotransformed to bilirubin, one of a
number of hemoglobin metabolites. Bilirubin is toxic to the
brain of newborns and, if present in high concentrations,
may cause irreversible brain injury. Biotransformation of the
lipophilic bilirubin molecule in the liver results in the
production of water-soluble (hydrophilic) metabolites
excreted into bile and eliminated via the feces.
The biotransformation process is not perfect. When
biotransformation results in metabolites of lower toxicity,
the process is known as detoxification. In many cases,
however, the metabolites are more toxic than the parent
substance. This is known as bioactivation. Occasionally,
biotransformation can produce an unusually reactive
metabolite that may interact with cellular macromolecules
(e.g., DNA). This can lead to a very serious health effect, for
example, cancer or birth defects. An example is the
biotransformation of vinyl chloride to vinyl chloride epoxide,
which covalently binds to DNA and RNA, a step leading to
cancer of the liver.
Elimination from the body is very important in determining
the potential toxicity of a xenobiotic. When a toxic

Page 50 of 62
xenobiotic (or its metabolites) is rapidly eliminated from the
body, it is less likely that they will be able to concentrate in
and damage critical cells. The terms excretion and
elimination are frequently used to describe the same
process whereby a substance leaves the body. Elimination,
however, is sometimes used in a broader sense and includes
the removal of the absorbed xenobiotic by metabolism as
well as excretion. Excretion, as used here, pertains to the
elimination or ejection of the xenobiotic and it's metabolites
by
specific
excretory
organs.
Except for the lung, polar (hydrophilic) substances have a
definite advantage over lipid-soluble toxicants as regards
elimination from the body. Chemicals must again pass
through membranes in order to leave the body, and the
same chemical and physical properties that governed
passage across other membranes applies to excretory
organs
as
well.
Toxicants or their metabolites can be eliminated from the
body by several routes. The main routes of excretion are via
urine, feces, and exhaled air. Thus, the primary organ
systems involved in excretion are the urinary system,
gastrointestinal system and respiratory system. A few other
avenues for elimination exist but they are relatively
unimportant, except in exceptional circumstances.
Risk Assessment
For many years the terminology and methods used in
human risk or hazard assessment were not consistent. This
led to confusion among scientists and the public. In 1983,
the National Academy of Sciences (NAS) published standard
terminology and concepts for risk assessments.

The following terms are routinely used in risk assessments:

Four basic steps in the risk assessment process as defined

by
the
NAS
are:

Page 51 of 62

Risk management decisions follow the identification and

quantification of risk which are determined by risk
assessments. During the regulatory process, risk managers
may request that additional risk assessments be conducted
to justify the risk management decisions. As indicated in
the figure above, the risk assessment and risk management
processes are intimately related.
This section will describe only the risk assessment process.
Risk assessments may be conducted for individual
chemicals or for complex mixtures of chemicals. In cases of
complex mixtures, such as hazardous waste sites, the
process of risk assessment itself becomes quite complex.
This complexity results from:

Conducting scientifically sound risk assessments is of great

national importance. An error in undercalculating risk
probabilities could lead to overexposure of the population.
On the other hand, an overcalculation of risk could result in
unwarranted costs to the public. As illustrated above, the
cost to clean-up a hazardous waste site varies greatly with
the degree of clean-up required which is determined by risk
assessments.

Introduction
simultaneous exposure to many substances with the potential for numerous chemical
and biological interactions
In order to understand how toxins cause a harmful change in
exposures by multiple media and pathways (e.g., via water, air, organs,
and soil)tissues, cells, or biochemicals, it is first necessary to
have knowledge of normal physiology and anatomy. In the
exposure to a wide array of organisms with differing susceptibilities
initial section, we present an overview of normal physiology,
adults, humans, animals, environmental organisms)
especially as related to the normal body components and

Page 52 of 62
how they function. While we indicate how some xenobiotics
can damage the different body components, detailed
examples of toxic cellular and biochemical reactions will be
covered in later sections.
The body is immensely complex with numerous
components, all which perform precise functions necessary
for the body to maintain health and well being. Malfunction
of any component can result in a breakdown of a portion of
the body, commonly referred to as disease. Toxins can
damage an organ or organ system so that it can not function
properly, leading to death or sickness of the organism (for
example, liver or kidney failure). However, in nearly all
cases, the toxin actually exerts its harmful effect directly on
specific cells or biochemicals within the affected organ.
These cell and chemical changes in turn cause the tissue or
organ
to
malfunction.
Most toxins are usually specific in their toxic damage to
particular tissues or organs, referred to as the "target
tissues" or "target organs". Toxic effects may in fact affect
only a specific type of cell or biochemical reaction. For
example, the toxic effect of carbon monoxide is due to its'
binding to a specific molecule (hemoglobin) of a specific cell
(red blood cell). Another example of a highly specific effect
is that of organophosphate toxins, which inhibit an enzyme
(acetylcholine esterase), responsible for modulating
neurotransmission
at
nerve
endings.
On the other hand, the effect of some toxins may be
generalized and potentially damage all cells and thus all
tissues and all organs. An example is the production of free
radicals by whole body radiation. Radiation interacts with
cellular water to produce highly reactive free radicals that
can damage cellular components. The result can be a range

of effects from death of the cell, to cell malfunction, and

failure of normal division (e.g., cancer). An example of a
multi-organ chemical toxin is lead, which damages several
types of cells, including kidney cells, nerve cells, and red
blood cells.
The body is a remarkable complex living machine consisting
of trillions of cells and multitudes of biochemical reactions.
Each cell has a specific function and they work in concert to
promote the health and vitality of the organism. The
number and types of toxic reactions is likewise very large.
While this tutorial can not possibly present all these types of
cellular and biochemical toxic reactions, it is our goal to
provide an overview of the primary toxic mechanisms with a
few examples that illustrate these mechanisms. It is
important to understand that changes at one level in the
body can affect homeostasis at several other levels.
The understanding of the cellular and chemical toxicity is
growing rapidly and there is already extensive literature in
that regard. A listing of all the excellent books pertaining to
this subject is beyond the scope of this tutorial. While other
references were occasionally consulted, the textbooks listed
below have served as the primary resources for this tutorial.
Homeostasis
Homeostasis is the ability of the body to maintain relative
stability and function even though drastic changes may take
place in the external environment or in one portion of the
body. Homeostasis is maintained by a series of control
mechanisms, some functioning at the organ or tissue level
and others centrally controlled.
The major central
homeostatic controls are the nervous and endocrine
systems.

Page 53 of 62

We are continually challenged by physical and mental

stresses, injury, and disease, any which can interfere with
homeostasis. When the body loses its homeostasis, it may
plunge out of control, into dysfunction, illness, and even
death. Homeostasis at the tissue, organ, organ system, and
organism levels reflects the combined and coordinated
actions of many cells. Each cell contributes to maintaining
homeostasis.
To maintain homeostasis, the body reacts to an abnormal
change (induced by a toxin, biological organism, or other
stress) and makes certain adjustments to counter the
change (a defense mechanism). The primary components
responsible for the maintenance of homeostasis are:

An example of a homeostatic mechanism can be illustrated

by the body's reaction to a toxin that causes anemia and
hypoxia (low tissue oxygen)(See illustration). Erythropoiesis
(production of red blood cells) is controlled primarily by the
hormone, erythropoietin. Hypoxia (the stimulus) interacts
with the heme protein (the receptor) that signals the kidney
to produce erythropoietin (the effector). This, in turn,
stimulates the bone marrow to increase red blood cells and

Page 54 of 62
hemoglobin, raising the ability of the blood to transport
oxygen and thus raise the tissue oxygen levels in the blood
and other tissues. This rise in tissue oxygen levels serves to
suppress further erythropoietin synthesis (feed back
mechanism). In this example, it can be seen that cells and
chemicals interact to produce changes that can either
perturb homeostasis or restore homeostasis. In this
example, toxins that damage the kidney can interfere with
production of erythropoietin or toxins that damage the bone
marrow can prevent the production of red blood cells. This
interferes with the homeostatic mechanism described
resulting
in
anemia.

Page 55 of 62
Adaptation
This section discusses cellular effects. However, cell and
chemical effects can not be conveniently separated as cells
are constructed of a variety of chemicals of diverse types.
Specific intracellular chemical changes may be manifest as
changes in the cell, either its appearance or function.
Indeed, the actual mechanisms leading to cell damage are
usually biochemical in nature.
To maintain homeostasis, cells and tissues
constantly adapt to changes in the tissue environment

attempt to respond to external stimuli so as to cope with new demands

are usually capable of an amazing degree of cellular adaptability

adaptability may be beneficial in nature (physiological) or detrimental (

Examples of physiological adaptation are:

an increase in skeletal muscle cells in athletes due to exercise and inc

demand

the increase in number and size of epithelial cells in breasts of wom

endocrine stimulation during pregnancy.
When these cells or tissues are damaged, the body attempts
to adapt and repair or limit the harmful effects. Often the
adaptive changes result in cells or organs that can not
function normally.
This imperfect adaptation is a
pathological
change.
Examples of pathological adaptations are:
Change from ciliated columnar epithelium to non-ciliated squamous

Page 56 of 62
trachea and bronchi of cigarette smokers. The replacement nutrition,
of squamous
a reduced
epithelium
blood flow to the tissue, and natural
can better withstand the irritation of the cigarette smoke. However,
aging.theAn
loss
example
of cilia and
of atrophy is the decrease in size of
mucous secretions of columnar epithelium diminish the tracheo-bronchial
muscles and muscle
defensecells in persons whose legs are
mechanisms.
paralyzed, in a cast, or infrequently used (e.g., bed-ridden
patients).
Replacement of normal liver cells by fibrotic cells in chronic alcoholics
cirrhosis of the liver). A severely cirrhotic liver is incapableHypertrophy
of normal metabolism,
is an increase in size of individual cells.
maintenance of nutrition, and detoxification of xenobiotics.
This frequently results in an increase in the size of a tissue
or organ. When cells hypertrophy, components of the cell
increase in numbers with increased functional capacity to
If the change is minor, cellular adaptation may result and
meeting increased cell needs. Hypertrophy generally occurs
healing with a return to normal. When damage is very
in situations where the organ or tissue can not adapt to an
severe, the result may be cell death or permanent functional
increased demand by formation of more cells. This is
incapacitation.
commonly seen in cardiac and skeletal muscle cells, which
do not divide to form more cells. Common causes for
Cellular adaptation to toxic agents is of three basic types:
hypertrophy are increased work or stress placed on an organ
or hormonal stimulation. An example of hypertrophy is the
Increase in cell activity
compensatory increase in the size of cells in one kidney
after the other kidney has been removed or is in a diseased
state.
Decrease in cell activity
is an increase in the number of cells in a
Alteration in cell morphology (structure and appearance) or cellHyperplasia
function
tissue. This generally results in an enlargement of tissue
mass and organ size. It occurs only in tissues capable of
mitosis such as the epithelium of skin, intestine, and
Specific Types of Cellular Adaptations
glands. Some cells do not divide and thus can not undergo
hyperplasia, for example, nerve and muscle cells.
Atrophy is a decrease in the size of cells. If a sufficient
Hyperplasia is often a compensatory measure to meet an
number of cells are involved, the tissue or organ may also
increase in body demands. Hyperplasia is a frequent
decrease in size. When cells atrophy, they have:
response to toxic agents and damage to tissues such as
wounds or trauma. In wound healing, hyperplasia of
reduced oxygen needs
connective tissue (e.g., fibroblasts and blood vessels)
contributes to the wound repair. In many cases, when the
reduced protein synthesis
toxic stress is removed, the tissue returns to normal.
Hyperplasia may result from hormonal stimulation, for
decrease in number and size of the organelles.
example, breast and uterine enlargement due to increased
estrogen
production
during
pregnancy.
The most common causes of atrophy are: reduced use of the
cells, lack of hormonal or nerve stimulation, decrease in

Metaplasia is the conversion from one type of mature cell

Page 57 of 62
to another type of mature cell. It is a cellular replacement
process. A metaplastic response often occurs with chronic
irritation and inflammation. This results in a tissue more
resistant to the external stress as the replacement cells are
capable of survival under circumstances in which the
original cell type could not survive. The cellular changes,
however, usually result in a loss of function, which was
performed by the original cells that were lost and replaced.
Examples of metaplasia are:

example of dysplasia is the atypical cervical cells that

precede cervical cancer. Routine examination of cervical
cells is a routine screening test for dysplasia and possible
early stage cervical cancer (Papanicolaou test). Cancer
occurs in at the site of Barrett's syndrome and in the bronchi
of
chronic
smokers
(bronchogenic
squamous
cell
carcinoma).

Anaplasia refers to cells that are undifferentiated. They

have irregular nuclei and cell structure with numerous
The common condition in which a person suffers from chronic reflux of acid from the
mitotic figures. Anaplasia is frequently associated with
stomach into the esophagus (Gastroeosphageal Reflux Disease)
malignancies
esophageal cells (squamous epithelium) are sensitive to the refluxed
acid andand
die. serves as one criterion for grading the
aggressiveness
of a cancer. For example, an anaplastic
are replaced with the columnar cells of the stomach that are resistant
to the stomach's
carcinoma is one in which the cell appearance has changed
acidity. This pathological condition is known as "Barrett's syndrome".
from the highly-differentiated cell of origin to a cell type
The change in the cells of the trachea and bronchi of chroniclacking
cigarette
thesmokers
normal from
characteristics of the original cell. In
ciliated columnar epithelium to non-ciliated stratified squamousgeneral,
epithelium.
anaplastic cells have lost the normal cellular
metaplasia frequently are also sites for neoplastic transformations.
controls, which regulate division and differentiation.
cells lack the defense mechanism performed by the cilia in movement of particles up
and out of the trachea.
Neoplasia is basically a new growth of tissue and is
commonly
referred
to as a tumor. There are two types of
With cirrhosis of the liver, which is a common condition of chronic
alcoholics,
the normal
functional hepatic cells are replaced by nonfunctional fibrous tissue.
neoplasia, benign and malignant. Malignant neoplasias are
cancers. Since cancer is such an important and complex
medical problem, a separate section is devoted to cancer.
Dysplasia is a condition of abnormal cell changes or
deranged cell growth in which the cells are structurally
changed in size, shape, and appearance from the original
cell type. Cellular organelles also become abnormal. A
common feature of dysplastic cells is that the nuclei are
larger than normal and the dysplastic cells have a mitotic
rate higher than the predecessor normal cells. Causes of
dysplasia include chronic irritation and infection. In many
cases, the dysplasia can be reversed if the stress is removed
and normal cells return. In other cases, dysplasia may be
permanent or represent a precancerous change. An

Page 58 of 62
as to whether or not the disease develops e.g.the
development of cancer (carcinogenesis) or some
forms of developmental damage to the foetus
(teratogenesis)
Irritant effects:

detergents may remove fat from the skin and cause

dermatitis
cement dust being alkaline may irritate the skin, or
cause more severe damage (chromates within
cement may also cause sensitisation and allergic
dermatitis).
respiratory irritation may be caused
concentrations of formaldehyde vapour

by

low

More serious inflammation:

Toxicodynamics
- or what poisons may do to the body
A note on terminology:
Acute effects refer to the short term consequences
of exposure
Chronic effects relate to a much longer time scale,
while sub-acute are in between acute and chronic)

Some effects may be dose related - the higher the

exposure the worse it gets e.g. irritant effects on the
skin, asthma, asbestosis
Other effects are 'all or none' and for a given
exposure there is an element of chance (stochastic)

more toxic agnets and/or higher exposures may be

associated with damage resulting in inflammation for
example of terminal bronchioles and alveoli leading
to a chemical pneumonitis and pulmonary oedema
(e.g. from nitrogen dioxide NO2)

Corrosive effects:

severe local effects by contact e.g. caustics such as

sodium hydroxide, or acids such as sulphuric, nitric
or hydrochloric acid.

Narcotic and anesthetic effects:

fat soluble solvents will behave as anaesthetics and

cause
drowsiness,
nausea,
headache,

Page 59 of 62
unconsciousness and death e.g. vapours from
organic solvents such as ether or trichlorethylene
Asphyxiation:
Various gases can cause asphyxia by interfering with
oxygen transport. Examples: Carbon monoxide,
Hydrogen cyanide, Hydrogen sulphide. Carbon
monoxide is present wherever there is incomplete
combustion of carbon compounds. It is odourless,
and will react with haemoglobin (Hb) to form COHb
which cannot carry oxygen..Hydrogen sulphide might
initially be detected by its smell at low
concentrations but it paralyses the sense of smell
and can effectively become odourless. Hydrogen
cyanide: in the form of its salts sodium and
potassium cyanide is used in many industries and
the organic cyaniden acrylonitrile (vinyl cyanide) is
used in the rubber industry. Absorption can also
occur through the skin. At low concentrations these
gases poison cytochromes and cause the rapid onset
of headache, dizziness, vomiting and confusion. At
high concentrations they are very rapidly lethal.

Cardiovascular effects include arrhythmias e.g.

caused by trichloroethane or by carbon disulphide

A very specific effect of exposure to some poisons

such as the organophosphate insecticides (e.g.
malathion,
parathion)
relates
to
their
anticholinesterase effect. Synaptic transmission from
a nerve cell to another cell such as a muscle cell in
many situations relies on acetyl choline. The enzyme
acetylcholinesterase in nerve endings catalyses the
hydrolysis of acetylcholine to choline and acetylCoA,
thus determining a very short action of acetylcholine.
Organophosphate and carbamate pesticides inhibit
acetylcholinesterase and lead to accumulation of
acetylcholine at sites of neuromuscular transmission
causing weakness of muscles, and paralysis including
of respiration.

Endocrine mimicking agents can act as endocrine

disrupters

Sensitizers:
These provoke an immune response (sensitization) resulting
in asthma, rhinitis, allergic dermatitis e.g. diisocyanates,
glutaraldehyde, nickel

Other effects on specific organs:

You may wish to refer to another resource on specific organ
damage, but here are some other points:
'Heavy' metals e.g. Pb (lead) Cd (Cadmium) and Hg
(mercury) have a propensity to bind sulphur and
indeed in nature in the earth's crust are often found
as sulphides. they tend to bind to sulphydryl groups
-SH in enzymes and other proteins and cause
damage in various parts of the body
The lungs are often the subject of damage
e.gparaquat poisoning

Carcinogens:
e.g. vinyl chloride causes hepatic haemangiosarcomas,
benzene is a genotoxic carcinogen. Occupational exposures
to high concentrations of benzene have shown to increase
the likelihood of an individual developing leukaemia; the
added risk incurred as a result of being exposed to 1 ug/m 3
of benzene for a lifetime is about 4 X 10-6.
Other effects on DNA:

Page 60 of 62

Mutagenic effects: inherited defects by DNA

damage e.g. alkylating agents such as
mechlorethamine
Teratogenic:
Damage
to
foetus,
not
necessarily damaging the mother e.g methyl
nitro nitroso-guanidine (MNNG).

rate; may be mistaken for other diseases. Often difficult to

determine cause-and-effect unless in laboratory....

asbestos-caused cancer may be delayed 20-30

years....

acute exposure may result in either acute or

chronic effects....

Characteristics of Exposure and Effect....

Exposure:
1. Acute: exposure for a duration of less than 24 hr;
often a single exposure...
2. Subacute: generally refers to repeated exposure for a
month or less.
3. Subchronic:
months.

exposure duration from between 1-3

4. Chronic: exposure often greater than 3 months.

Usually continual daily dietary exposure. For animal studies,
often for a lifetime of the animal.
Effect: the toxic effects observed following single or
repeated exposure to a chemical are often quite different...
1. Acute Effects: rapidly developing, reaching a
maximum with severe symptoms.
(exposure to high doses of CN- will kill within a few
minutes..... )

(acute exposure to asbestos may lead to

cancer....)
chronic exposure may result in either chronic
or acute effects...
(chroniclead exposure may lead to subacute or acute
symptoms....)
4. Accumulative Effects: occurs two ways...
accumulation of toxin: exposure to heavy metals
(lead, mercury) that have long half-lives result in
disease due to metal accumulation....

accumulation of effect: low level exposure to

organophosphate pesticides depresses acetylcholine
esterases to a point where symptoms occur....

5. Delayed Effects: effect may occur only after long

exposure; agent cannot be found in blood or tissues.
Damage to system alreadydone....
radiation sickness
Classification of toxicants....

2. Subacute Effects: symptoms generally not as severe,

but toxic effects often same as acute....

In toxicology, compounds are classified various ways, by one

or more of the following classes:

3. Chronic Effects: progresses at a slow and varying

Classification by....

Page 61 of 62
Use: pesticides (atrazine), solvents (benzene), food
additives (nutrasweet)
Effects: carcinogen (benzo-a-pyrene), mutagen
(methylnitrosamine), hepatotoxicant (CHCl3)....
Physical state: oxidant (ozone), gas (CO2), dust (Fe2O3),
liquid (H2O)....
Chemistry: aromatic amine(aniline), halogenated
hydrocarbon (methylene chloride)....
Mechanism: cholinesterase inhibitor (malathion),
methemoglobin producer (nitrite)....
Target Organ Toxicity: many toxins do not produce
general effects but are specific to only a few organs......

1. Central nervous system

2. Circulatory system (blood, blood-forming system)
3. Visceral organs (liver, kidneys, lung)
4. Muscle and Bone

Possible mechanisms of tissue sensitivity: i.e., why

are toxins often selective to tissues?

vinyl chloride: liver cancer

asbestos: mesothelioma

paraquat: lung toxicity

cadmium: kidney toxicity

Target organs are often not the site of the highest

concentration of a chemical....
Lead concentrates in bone, but its effects are
mainly seen in soft tissues, such as liver, kidney
and blood cells....

Target organs most frequently affected by toxicants:

DDT accumulates in adipose tissue (fat stores), but

produces no effects there...it is primarily a central
nervous system toxin....

preferential accumulation: toxicant may

accumulate in only certain tissues, and cause toxicity
there....
Cd in kidney, paraquat in lung
selective metabolic activation: enzymes needed
to convert a compound to the active form may be
present in highest quantities in a particular
organ..CCl4, nitrosamines in liver

characteristics of tissue repair: some tissues

may be protected from toxicity by actively repairing
toxic damage; some tissues may be susceptible
because they lack sufficient repair capabilities...
nitrosamines in liver

specific receptors and/or functions: toxicant

may interact with receptors in a given tissue....

curare: a receptor-specific neuromuscular

blocker used in dart poisons

Page 62 of 62

Physiological sensitivity: the nervous system is

extremely sensitive to agents that block utilization of
oxygen....

nitrite: oxidizes hemoglobin

(methemoglobinemia)
cyanide: inhibits cytochrome oxidase (cells
not able to utilize oxygen)
barbiturates: interfere with sensors for
oxygen and carbon dioxide content inblood....