Principles of
Toxicology :
The Study of Poisons
PM Dr Mohd Khan Ayob
PPSKTM, FST
Universiti Kebangsaan Malaysia
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To know scope and definition
of toxicology,
Describe how toxicologist
work and manage toxicants,
To know basic principles of
toxicology.
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Introduction
Are all substances toxic?
YES! Look at these:
Sugar has an LD50 of 30,000 mg/kg
Ethanol has an LD50 of 13,700 mg/kg
Table salt has an LD50 of 3,750 mg/kg
Water has an LD50 of slightly greater than
80,000 mg/kg
Synthetic does not mean toxic or poisonous
Natural does not mean safe or even low risk
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LD50:
LD50:
The amount
amount (dose)
(dose) of
of aa
The
chemical which
which
chemical
produces death
death in
in 50%
50%
produces
of aa population
population of
of test
test
of
animals to
to which
which it
it is
is
animals
administered by
by any
any of
of
administered
variety of
of methods.
methods.
aa variety
Normally expressed
expressed as
as
Normally
milligrams of
of
milligrams
substance per
per kilogram
kilogram
substance
of
of
animal body
body weight
weight
animal
(mg/kg)
(mg/kg)
Do 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.
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Did you know that....(in the USA)
About
4 million toxic exposures
annually
Fewer than 1% of overdose patients
that reach the hospital result in fatality
But 13-35% mortality if arrive in deep
coma
One
fourth of suicide attempts are
via drugs
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Leading causes of pharmaceutical
death
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Analgesics
Tricyclic antidepressants
Sedative/hypnotics
Stimulants and street
drugs
Cardiovascular drugs
Alcohols
Toxicology, an old field
Toxicology is arguably the oldest scientific discipline,
as the earliest humans had to recognize which plants
were safe to eat.
Yes!
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No!
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Humans are exposed to chemicals both
deliberately and inadvertently.
Most exposure of humans to chemicals is via naturally
occurring compounds consumed in the diet from food
plants.
Chemicals are natural, biological, or synthetic in
origin
Natural (food, metals, minerals)
Biological (toxins from bacteria)
Syntheticmanufactured through chemical processes
Approximately 100,000 chemicals are currently
in use worldwide. 500 new formulations enter
the marketplace annually.
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What is Toxicology?
Old definition: the basic science of poisons
New Definition: the study of the adverse
effects of chemical agents on biological
systems
The ultimate goal is to increase our
understanding of how chemicals affect
human health.
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Toxicology - Terminologies
What is toxicology? The study of the effects of
poisons.
Poison = Toxicant , Toxin and/or Xenobiotic
Poisonous substances (Toxins) are produced by
plants, animals, or bacteria.
Phytotoxins
Zootoxins
Bacteriotoxins
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What is a Toxicant?
The term toxicant refers to toxic substances produced by or are by-products of human-made
activities.
Heavy Metals
Solvents and Vapours
Radiation and Radioactive Materials
Dioxin/Furans
Pesticides
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What is a Xenobiotic
*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.
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# What is Toxic?
This
term relates to poisonous or
deadly effects on the body by
inhalation (breathing),
ingestion (eating), or
absorption, or by
direct contact with a chemical.
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# What is a Toxic Symptom?
Any
feeling or sign indicating the
presence of a poison in the system.
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# What are Toxic Effects?
The health effects that occur due to
exposure to a toxic substance; also
known as a poisonous effect on the
body.
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# What is Toxicity?
the
degree to which a substance is
poisonous or can cause injury.
The toxicity depends on a variety of
factors:
dose, duration and route of exposure, shape
and structure of the chemical itself, and
individual human factors.
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# What is Selective Toxicity?
A toxic
chemical that produces injury to
one kind of living matter without
harming another form of life, even
though the two may co-exist.
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Toxicology
The
science that deals with harmful or
adverse effects of toxcicants (chemicals) on
living organisms and assesses the
probability (risk) of their occurrence.
The interface of chemistry and biology.
Toxicology: toxicosis or disease effect
VS
Pharmacology: therapeutic effect
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1. Toxicant/ Toxin/ Poison/ Hazard
any agent capable of producing a
deleterious response in a biological system
2. Adverse/Toxic effects
any unwanted change (damage) from an
organisms normal state
dependent upon the concentration of active
compound at the target site (receptor)for a
sufficient time.
3. Living organism
cellular target sites/ storage depots and
enzymes
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COMMON TOXICOLOGY
QUESTIONS
1. What is a poison?
2. Where dose it come from? (exposure Q)
3. How does it get into living organism?
(exposure Q)
4. What does it do to living organism?
(mechanism Q)
5. How can we treat/prevent this toxicity?
(clinical Q)
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Classification of Toxic Agents
Heavy
Metals
Solvents and Vapours
Radiation and Radioactive Materials
Dioxin/Furans
Pesticides
Plant Toxins
Animal Toxins
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Subcategories of Toxic Substance
Classifications
Effect on target organs (liver, kidney, hematopoietic
system),
Use (pesticide, solvent, food additive),
Source of the agent (animal and plant toxins),
Effects (cancer mutation, liver injury),
Physical state (gas, dust, liquid),
Labeling requirements (explosive, flammable, oxidizer),
Chemistry (aromatic amine, halogenated hydrocarbon), or
Poisoning potential (extremely toxic, very toxic, slightly
toxic)
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General Classifications of Interest
to Communities
Air
pollutants
Occupation-related
Acute and chronic poisons
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The science of Toxicology helps people
make
informed decisions and balance
RISKS vs. BENEFITS
The study found
the highest levels
of pesticide
residues in
peaches, apples,
pears.
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AND Spinach.
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The Scope of Toxicology
Toxicology related closely to
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Pharmacology,
Biochemistry,
Molecular biology,
Chemistry,
Epidemiology,
Pathology,
Genetics,
Public Health,
Medicine,
etc.
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Sub-disciplines of Toxicology
Environmental
Toxicology
Occupational (Industrial) Toxicology
Food & Nutritional Toxicology
Clinical Toxicology
Forensic Toxicology
Descriptive Toxicology
Mechanistic Toxicology
Regulatory Toxicology
Analytical Toxicology
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Environmental Toxicology
Studies chemicals that are contaminants
of food, water, soil, or the air.
Deals with toxic substances that enter
the waterways, such as lakes, streams,
rivers and oceans.
Fact: Most common problems include
water-borne bacteria and viruses,
waste heat from electrical plants,
radioactive wastes, sewage, and
industrial pollution.
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Occupational (Industrial)
Toxicology
Protects workers from toxic substances and
makes their work environment safe.
Fact: Occupational diseases caused by industrial chemicals
account for an estimated 50,000 to 70,000 deaths and
350,000 new cases of illness each year in the United States.
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Food Toxicology
Food toxicology is the study of the nature, properties,
effects, and detection of toxic substances in food, and
their disease manifestation in humans.
deals with substances found in food (contaminants) that
might be harmful to those who consume sufficient
quantities of the food containing such substances.
Involves delivering a safe and edible supply of food to the
consumer.
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Food Toxicology
Food
contaminanats:
Environmental pollutants
the air, water and soil, such as the case with toxic
metals, PCBs (Polychlorinated Biphenyls) and dioxins,
Various chemicals (intentionally used)
pesticides, animal drugs, antibiotics and other
agrochemicals
food additives.
Toxins
Plant, animal and microbial toxins
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Food Toxicology
human exposure to toxic chemicals and nutritional imbalances are
currently known or suspected to be responsible for promoting or
causing
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cancer,
kidney and liver dysfunction,
hormonal imbalance,
immune system suppression,
musculoskeletal disease,
birth defects,
premature births,
impeded nervous and sensory system development,
reproductive disorders,
mental health problems,
cardiovascular diseases,
genitor-urinary disease,
old-age dementia, and
learning disabilities.
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Nutritional Toxicology
Nutritional toxicology is the study of the
nutritional aspects of toxicology.
targets the interrelations that toxicants or
toxins have with nutrients in the diet, which
affect nutritional status and prevent against
the adverse effects of toxicants or toxins
Eg: antinutrient substances
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Clinical Toxicology
Is
concerned with diseases and illnesses
associated with short term or long term
exposure to toxic chemicals.
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Forensic Toxicology
Helps
to establish cause and
effect relationships between
exposure to a drug or
chemical and the toxic or
lethal effects that result.
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Descriptive Toxicology
Is
concerned with
gathering toxicological
information from animal
experimentation.
These type of experiments
are used to establish the
chemical dosage that
would cause illness and
death.
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Mechanistic Toxicology
Makes
observations on how toxic
substances cause their effects.
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Analytical Toxicology
Identifies
the toxicant through analysis of
body fluids, stomach content, excrement,
skin, or suspected containers.
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Regulatory Toxicology
Gathers
and evaluates existing
toxicological information to establish
concentration-based standards of safe
exposure.
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Regulatory Toxicology
Use data from descriptive and mechanistic
toxicology to perform risk assessments.
Concerned with meeting requirements
of regulatory agencies.
Industry/government interactions.
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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)
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What Do Toxicologists Do?
Mechanistic toxicologists study how a chemical
causes toxic effects by investigating its absorption,
distribution, metabolism and excretion (ADME). 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.
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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.
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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.
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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 .
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Principles of Toxicology
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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).
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The Dose
Swiss
physician
Paracelsus (1493-1541)
All substances are poisons: there is
none which is not a poison. The right
dose differentiates a poison from a
remedy.
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The Dose Makes the Poison!
An apparently non-toxic 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)
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Dose
Determines Whether a Chemical Will Be
Beneficial or Poisonous
Beneficial Dose
Toxic Dose
Aspirin
300 1,000 mg
1,000 30,000 mg
Vitamin A
5000 units/day
50,000 units/day
Oxygen
20% (Air)
50 80% (Air)
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LD50 Comparison
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Exposure Concepts
Exposure
means Contact with a hazard.
Hazard is a chemical substance, physical agent,
or biological agent that can harm the health of
people
Different
toxic responses may arise from
different:
Routes of exposure.
Frequencies (how often) of exposure.
Duration (how long) of exposure (acute vs.
chronic).
Concentration of exposure (how much) the DOSE
Risk = Hazard x Expos
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Route of Exposure
Ingestion (water and food)
Absorption (through skin)
Injection (bite, puncture, or cut)
Inhalation (air)
People can protect themselves by
blocking these routes of exposure.
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Major Routes of Toxicant Entry
Ingestion via the gastro-intestinal [GI] tract
Inhalation via the lungs
Dermal via the skin
Other Parenteral (non-intestinal) routes:
Intravenous (IV) direct injection into a vein
Intraperitoneal (IP) injection into the peritoneal cavity
Subcutaneous (SC) injection between the skin and the muscle
Intramuscular (IM) injection directly into the muscle
Intradermal injection into the dermis
Occupational Exposures Inhalation, Dermal
Accidental / Suicide Exposures Ingestion
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Route of Exposure
Ingestions account for 79% of exposures
7% dermal
6% ophthalmologic
5% inhalations
3% stings and bites
0.3% injection
Typical Effectiveness of Route of
Exposure:
iv > inhale > ip > im > ingest > topical
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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
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Sources of Exposure
Exposure to chemicals may come from
many sources:
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Environmental
Occupational
Therapeutic
Dietary
Accidental
Deliberate
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Mechanisms of Toxicity
The term toxicity is used to describe the nature of
adverse effects produced and the conditions
necessary for their production.
Before toxicity can develop, a substance must come
into contact with a body surface such as skin, eye or
mucus of the alimentary or respiratory tract an
exposure.
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Mechanisms of Toxic Effects
Adverse effects can occur at the level of the
molecule, cell, organ, or organism
Molecular level: chemical can interact with: Proteins /
Lipids / DNA
Cellular level: chemical can
interfere with receptor-ligand binding
interfere with membrane function
interfere with cellular energy production
bind to biomolecules
agitate homeostasis
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Mechanisms of Toxicity
1.
2.
3.
4.
5.
6.
7.
Interfere with O2 transport or tissue utilization of
oxygen (example cyanide, CO)
Affect CNS (example cocaine, sedatives)
Affect ANS (example organophosphates)
Affect lungs (example paraquat)
Affect cardiovascular system (example TCA, Ca++
channel blockers)
Direct local damage (example acids, bases)
Delayed effects on liver or kidneys (example
acetaminophen, metals)
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Types of toxic effect
A wide variety of effects due to various toxicants:
Allergic agents: itching, rashes, sneezing, watery eyes.
Asphyxiants: cause displacement of oxygen and thus
suffocation.
Irritants: cause pulmonary edema (fluid in the lungs) when
inhaled at high concentrations and rashes when spilled onto
the skin.
Necrotic agents cause cell death.
Carcinogens, mutagens and teratogens: Cancer, mutations,
and deformed embryos result from chronic exposure to low
levels
Systemic poisons can have an adverse effect on the whole
body when taken internally.
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Adverse Effects
Not all organs are affected equally
greater susceptibility of the target organ
higher concentration of active compound
Liver: high blood flow, oxidative reactions
Kidney: high blood flow, concentrates
chemicals
Lung: high blood flow, site of exposure
Neurons: oxygen dependent, irreversible
damage
Myocardium: oxygen dependent
Bone marrow, intestinal mucosa: rapid
divide
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Ultimatum of Toxic Effects
Death - arsenic,
cyanide
Organ Damage ozone, lead
Mutagenesis - UV light
Carcinogenesis benzene, asbestos
Teratogenesis thalidomide
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Perception vs. Reality
Perception:
Pollution is a significant contributor to cancer
and that cancer rates are soaring.
Reality:
Life expectancy increasing in industrialized
countries.
Cancer (non-smoking) death rates steady or
going down.
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Cancer Death Rates - Male
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Cancer Death Rates - Female
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Perception vs. Reality
Perception
High dose animal cancer tests tell us the
significant cancer risks for humans.
Reality
Half of all chemicals-natural or synthetictested in standard animal cancer tests have
turned out to be carcinogenic.
Near toxic doses-the maximum tolerated dose,
can cause chronic cell wounding or mitosis
risk for cancer.
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Perception vs. Reality
Perception
Human exposures to carcinogens and other
toxins are nearly all due to synthetic
chemicals.
Reality
Amount of synthetic pesticide residues in
plant foods is insignificant compared to the
amount of natural plant pesticides.
5-10,000 natural pesticides consumed, totaling
1500 mg/day.
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Perception vs. Reality
Perception
Synthetic toxins pose greater carcinogenic
hazards than natural toxins.
Reality
Proportion of natural chemicals that is
carcinogenic when tested in both rats and
mice is the same as for synthetic chemicalsroughly half.
All chemicals are toxic at some dose.
99.9% of chemicals ingested are natural.
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Perception vs. Reality
Perception
Toxicology of man-made chemicals is different
from that of natural chemicals.
Reality
Humans have many general, natural defenses
that make us well buffered against normal
exposures to toxins, both natural and
synthetic.
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Perception vs. Reality
Perception
Correlation implies causation.
Reality
No persuasive evidence from either
epidemiology or toxicology that pollution is a
significant cause of cancer for the general
population.
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Perceptions About Chemicals
What
drives our perceptions?
Involves subjective judgments.
Are chemicals bad?
Natural vs. synthetic
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Natural Carcinogens in Coffee
Acetaldehyde
Benzaldehyde
Benzene
Benzofuran
Benzo[a]pyrene
Caffeic acid
Catechol
1,2,5,6
Dibenzanthracene
Ethanol
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Ethylbenzene
Formaldehyde
Furan
Furfural
Hydrogen peroxide
Hydroquinone
Limonine
Styrene
Toluene
Xylene
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Toxicology helps create a safer
world ...
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.
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.
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The End
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