Introduction to Toxicology

Larry Johnson
Partnership for Environmental Education
and Rural health (PEER)
Texas A & M University
 Toxicology
What is toxicology? The study of the effects of poisons.
Poisonous substances are produced by plants, animals, or bacteria.

Phytotoxins
Zootoxins
Bacteriotoxins

Toxicant - the specific poisonous chemical.

Xenobiotic - man-made substance and/or produced by but not normally

found in the body.
 Introduction
Toxicology is arguably the oldest scientific discipline, as the
earliest humans had to recognize which plants were safe
to eat.

Most exposure of humans to chemicals is via naturally

occurring compounds consumed from food plants.
Humans are exposed to chemicals both inadvertently and
deliberately.
 You Know ?
92% of all poisonings happen at home.

The household products implicated in most

poisonings are: cleaning solutions, fuels,
medicines, and other materials such as glue
and cosmetics.

Certain animals secrete a xenobiotic poison

called venom, usually injected with a bite or
a sting, and others animals harbor infectious
bacteria.

Some household plants are poisonous to

humans and animals.
 History
2700 B.C. - Chinese journals: plant and
fish poisons

1900-1200 B.C. - Egyptian documents

that had directions for collection, preparation, and
administration of more than 800 medicinal and poisonous recipes.

800 B.C. - India - Hindu medicine includes

notes on poisons and antidotes.

50-100 A.D. - Greek physicians classified over

600 plant, animal, and mineral poisons.
 History
50- 400 A.D. - Romans used poisons for
executions and assassinations.

The philosopher, Socrates, was executed

using hemlock for teaching radical
ideas to youths.

Avicenna (A.D. 980-1036) Islamic authority on

poisons and antidotes.

1200 A.D. - Spanish rabbi Maimonides writes

first-aid book for poisonings,
Poisons and Their Antidotes
 History
Swiss physician Paracelsus (1493-
1541) credited with being
“the father of modern toxicology.”

“All substances are poisons: there is

none which is not a poison. The
right dose differentiates a poison
from a remedy.”
 The Dose Makes the Poison

An apparently nontoxic chemical

can be toxic at high doses. (Too
much of a good thing can be
bad).

Highly toxic chemicals can be life

saving when given in appropriate
doses. (Poisons are not harmful
at a sufficiently low dose).
 Lethal Doses
Approximate Lethal Doses of Common Chemicals
(Calculated for a 160 lb. human from data on rats)

Chemical Lethal Dose

Sugar (sucrose) 3 quarts
Alcohol (ethyl alcohol) 3 quarts
Salt (sodium chloride) 1 quart
Herbicide (2, 4-D) one half cup
Arsenic (arsenic acid) 1-2 teaspoons
Nicotine one half teaspoon
Food poison (botulism) microscopic
Source: Marczewski, A.E., and Kamrin, M. Toxicology for the citizen, Retrieved August 17, 2000
from the World Wide Web: www.iet.msu.edu/toxconcepts/toxconcepts.htm.
 History

Italian physician
Ramazzini (1713) published
“De Morbis Artificum”
(Diseases of Workers)
describing "asthma" in bakers, miners, farmers, gilders,
tinsmiths, glass-workers, tanners, millers, grain-sifters,
stonecutters, ragmen, runners, riders, porters, and
professors. Ramazzini outlined health hazards of the dusts,
fumes, or gases that such workers inhaled. The bakers and
horse riders described by Ramazzini would today probably
be diagnosed as suffering from allergen-induced asthma.
The lung diseases suffered by most of the other workers
would now be classified as "pneumoconiosis," a group of
dust-related chronic diseases.
 History

Spanish physician Orfila (1815) established

toxicology as
a distinct scientific discipline.
 History
20th Century

Paul Ehrlich –developed staining procedures to observe

cell and tissues and pioneered the understanding of how
toxicants influence living organisms.
 History
20th Century

Rachel Carson - alarmed public

about dangers of pesticides
in the environment.
 Occupational and
Environmental Toxicology
Environmental toxicants (air
and water pollutants) are
substances harmful to the
environment and to humans.
Environmental toxicants are both natural and
man made.

Public perception that man-made ones are more serious than

natural ones - Reality: both
are serious.
5,000,000 yearly deaths worldwide due
to bacterial toxicants (Salmonella, E. coli)
 Occupational and
Environmental Toxicology
Many examples of diseases associated with specific
occupations were recorded in antiquity, but they were
not considered serious because the health of the
workers was not a societal concern.

- Paracelsus - Miner’s Disease (1533)

- Hill & Pott (1761 &1775)
- Radium dial painters, “aniline dye” workers (1900)
- Shoe salesmen (1950s)
- Industrial chemical workers (1940-present)
 Occupational and
Environmental Toxicology
- Paracelsus - Miner’s Disease (1533) came from
inhaling metal vapors, foundation for the field of chemotherapy.

- Hill (1761) linked tobacco (snuff)

to cancer.

- Pott (1775) linked scrotal cancer

and soot (benzo(a)pyrene) in
chimney sweeps.
 Occupational and
Environmental Toxicology
- Radium dial painters,
“aniline dye” workers (1900)
painters licked their brushes
to pull it to a point.

- Shoe salesmen (1950s)

shoe-fitting fluoroscopes:
radiation of feet in shoes
of children and repeated
exposure for salesmen.
 Occupational and
Environmental Toxicology
- Industrial chemical workers
(1940-present)

Workers typically are exposed to

a greater number of carcinogens
for longer periods of time.
Occupations with high risk of cancer :
Health care workers, pharmaceutical and
laboratory workers, refinery workers, rubber
workers, furniture makers, and pesticide workers.
Modern Toxicology
1961 - Society of Toxicology

1970s - EPA, FDA, and NIOSH

 Toxicology Terms

Toxicity - The adverse effects

that a chemical
may produce.

Dose - The amount of a

chemical that gains
access to the body.
 Toxicology Terms

Exposure – Contact providing

opportunity of
obtaining a
poisonous dose.

Hazard – The likelihood that the

toxicity will be
expressed.
 Threshold Effects for Dose
Dose-Response
Relationships Is there such a thing
as a ‘safe’ dose??

Agent A
Response

Agent B

“NOEL”
(No Observable Effect Level)

Dose
 Fundamental Rules of
Toxicology

Exposure must first occur for the chemical to present a risk.

The magnitude of risk is proportional to both the potency of

the chemical and the extent of exposure.

“The dose makes the poison” (amount of chemical at the

target site determines toxicity).
 Exposure Concepts

Different toxic responses may arise from

different:

– Routes of exposure.

– Frequencies of exposure.

– Duration of exposure (acute vs. chronic).

Routes of Environmental
Exposure

Ingestion (water and food)

Absorption (through skin)
Injection (bite, puncture, or cut)
Inhalation (air)
 Chemicals, Chemicals
Everywhere
Everything in the environment is made of chemicals. Both
naturally occurring and synthetic substances are chemical in
nature.
People are exposed to chemicals by
eating or swallowing them,breathing
them, or absorbing them through the
skin or mucosa.

People can protect themselves by

blocking these routes of exposure.
 Duration & Frequency of
Exposure
Duration and frequency are also important
components of exposure and contribute to dose.

Acute exposure - less than 24 hours; usually entails a

single exposure

Repeated exposures are classified as:

– Subacute - repeated for up to 30 days
– Subchronic - repeated for 30-90 days
– Chronic -repeated for over 90 days
 Exposure Concepts
Exposure to chemicals may come from many sources:

– Environmental
– Occupational
– Therapeutic
– Dietary
– Accidental
– Deliberate
Children & Poisons
 Individual Responses Can Be
Different
The variety of responses among organisms that get the
same dose of chemical is due to individual susceptibility.
Dose and individual susceptibility play roles in all situations
involving chemicals, including those making medicine and
caffeine.
 Introduction to Xenobiotics
*Recall: Foreign chemicals are
synthesized within the body are termed
xenobiotics (Gr.Xenos meaning
“strange”)*

• Xenobiotics may be naturally

occurring chemicals produced by
plants, microorganisms, or animals
(including humans).

• Xenobiotics may also be synthetic chemicals produced by

humans.

Poisons are xenobiotics, but not all xenobiotics are poisonous.

How Does the Body Prevent the
Actions of Xenobiotics ?
1) Redistribution
2) Excretion – (primarily water soluble compounds)
- kidney and liver
3) Metabolism – the major mechanism for terminating
xenobiotic activity, and is frequently the single most
important determinant of the duration and intensity of
toxic responses to a xenobiotic.
- LIVER, kidney, lung, GI, and others

Note: 1) and 2) are highly dependent upon 3)

 Xenobiotics at Work
TOXICOKINETICS

Xenobiotic

Excretion
General Scheme of Xenobiotic Metabolism

Lipophilic Hydrophilic
(parent compound) (metabolite)

Metabolism 1) Decrease biological activity

2) Increase excretability

Phase I Phase II Metabolites

Metabolites
(oxidative) (synthetic)
size
Bioactivation polarity ionization
Detoxification
Detoxification functionality water solubility
Increase excretability
 How Xenobiotics Cause
Toxicity
Some xenobiotics cause toxicity by disrupting normal cell functions:

– Bind and damage proteins (structural, enzymes)

– Bind and damage DNA (mutations)

– Bind and damage lipids

– React in the cell with oxygen to form

“free radicals” which damage lipid, protein,
and DNA
 Types of Toxic Effects
Death - arsenic, cyanide

Organ Damage - ozone, lead

Mutagenesis - UV light

Carcinogenesis - benzene, asbestos

Teratogenesis - thalidomide
Target Organ Toxicity

Central Nervous System – lead

Immune System - isocyanates
Liver - ethanol, acetaminophen
Respiratory Tract - tobacco smoke,
asbestos, ozone
Eye - UV light (sunlight)
Kidney - metals
Skin - UV light, gold, nickel
Reproductive System –
dibromochloropropane
Mechanistic Toxicology

How do chemicals cause their toxic effects?

 What Do Toxicologists Do?
Most toxicologists work to develop a
mechanistic understanding of how
chemicals affect living systems:
– Develop safer chemical products
– Develop safer drugs
– Determine risks for chemical
exposures
– Develop treatments for chemical
exposures
– Teach ( e.g. other toxicologists,
graduate students, and youth)
 What Do Toxicologists Do?
Mechanistic toxicologists study how a chemical
causes toxic effects by investigating its absorption,
distribution, and excretion. They often work in
academic settings or private industries and develop
antidotes.

Descriptive toxicologists evaluate the toxicity of

drugs, foods, and other products. They often perform
experiments in a pharmaceutical or academic setting.

Clinical toxicologists usually are physicians or

veterinarians interested in the prevention, diagnosis,
and treatment of poisoning cases. They have
specialized training in emergency medicine and
poison management.
What Do Toxicologists Do?
Forensic toxicologists study the application of toxicology to
the law. They uses chemical analysis to determine the
cause and circumstances of death in a postmortem investigation.

?
Environmental toxicologists study the
effects of pollutants on organisms, populations, ecosystems,
and the biosphere.

Regulatory toxicologists use scientific data to decide how to

protect humans and animals from excessive risk.
Government bureaus such as the FDA and EPA employ this type
of toxicologist.
 Regulatory Toxicology
Use data from descriptive and mechanistic toxicology to
perform risk assessments.

Concerned with meeting requirements of

regulatory agencies.

Industry/government interactions.
 Review
Toxicology is the science that studies the harmful effects of
overexposure to drugs, environmental contaminants, and
naturally occurring substances found in food, water, air, and soil.
– Main objectives are to establish safe doses and determine
mechanisms of biologic action of chemical substances.
A career in toxicology involves evaluating the harmful effects and
mechanisms of action of chemicals in people, other animals, and
all other living things in the environment.
– This work may be carried out in government, private industry
and consulting firms, or universities and other research
settings.
Toxicologists routinely use many sophisticated tools to
determine how chemicals are harmful.
(e.g.) computer simulations, computer chips, molecular
biology, cultured cells, and genetically-engineered laboratory
animals .
 What Is the Risk?
People can make some choices about chemical exposure;
however, some exposure is controlled at a level other than
an individual one. Collective groups of people, such as
communities and governments, seek to control chemical
exposure on a community or global level.
Animals in
Research
“Virtually every medical
achievement of the last
century has depended
directly or indirectly on
research in animals.”
U.S. Public Health
Service
 Summary
Toxicology is a fascinating science that
makes biology and chemistry interesting
and relevant.

Understanding HOW (i.e. mechanism)

something produces a toxic effect can lead to new ways of
preventing or treating chemically-related diseases. Animal
use in research is essential for medical progress.

Many diseases are the result of an interaction between our

genetics (individual variability) and chemicals in our
environment.

Toxicology provides an interesting and exciting way to apply

science to important problems of social, environmental,
and public health significance.
 Toxicology or
Environmental Health
Science is a “hook”
to interest
your students
in science
and
nonscience
curricula.
 Hook
The science of toxicology provides a fantastic pedagogical
opportunity to do true ‘interdisciplinary’ teaching, to make
relevant many of the exciting biological discoveries that
occur everyday.

Whether it is exploring the wonders

of the biology of DNA and heredity,
or the more mundane aspects of
acid-base chemistry, or the ethical,
legal, and social implications of
genetic testing for common
diseases such as cancer or
Alzheimer's -
 Hook
or the global ecological implications of species extinction;
or social risks and benefits of genetically modified foods -
or diagnosing the cause of the Mad Hatter’s strange behavior in Lewis
Carol’s ‘Alice in Wonderland’ (mercury poisoning)-
or the fall of the Roman Empire (lead poisoning),

toxicology and environmental health

science provide an interesting
“hook” to make the subject matter
– what ever it may be –

interesting and relevant to your

students.
 Your Role

NIEHS, SOT, and PEER feels the responsibility to help educate

the next generation of citizens to better understand the world
around them, and especially to understand how chemicals –
man-made or natural – present both risks and benefits to
society.

Of course, everything we eat, drink, breathe, touch, or use is

made of chemicals, so the task is LARGE!

We hope to make the science of toxicology ‘less obscure’ to the

public.
 Your Role

Risk is a part of everyday life, and one’s decisions as to the

‘acceptability’ of a particular risk is influenced by
knowledge and experience.

While we can’t do much about the ‘experience part’, we

can try to increase the public’s knowledge about the
risks and benefits of all things chemical.

You play a critical role in this effort, and we can’t do it

without YOU.
The power of EDUCATION
National Institute of Texas Rural Systemic
Environmental Health Initiative
Sciences

Partnership for The Center for

Environmental Environmental and
Education and Rural Rural Health
Health

College of Education, College of Veterinary

Texas A&M Medicine at Texas
University A&M University