A Brief Introduction to the Concepts of Toxicology We Will … · A Brief Introduction to the...
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Introduction to Toxicology
A Brief Introduction to the
Concepts of Toxicology
We Will Be Using
Throughout This Course
By Dr Tajdar H Khan
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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.
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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.
You Know ?
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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 (Vada’s)includes
notes on poisons and antidotes.
50-100 A.D. - Greek physicians classified over
600 plant, animal, and mineral poisons.
Anno Domini (AD or A.D.) and Before Christ (BC or B.C.)
History
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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, Spanish Jewry of his time
Poisons and Their Antidotes The Hemlock is a member of the great order Umbelliferae, the same family of plants to which the parsley, fennel, parsnip
and carrot belong. Every part of this plant, especially the fresh leaves and fruit, contains a volatile, oily alkaloid, which
is so poisonous that a few drops prove fatal to a small animal.
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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.”
History
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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).
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Lethal Doses
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.
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
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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
Italian physician
Ramazzini (1713) published
“De Morbis Artificum”
(Diseases of Workers)
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Spanish physician Orfila (1815) established toxicology as
a distinct scientific discipline.
History
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20th Century
Paul Ehrlich –developed staining procedures to observe cell and tissues and pioneered the understanding of how toxicants influence living organisms.
History
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20th Century
Rachel Carson - alarmed public
about dangers of pesticides
in the environment.
History
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Toxicity - The adverse effects
that a chemical
may produce.
Dose - The amount of a
chemical that gains
access to the body.
Toxicology Terms
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Exposure – Contact providing
opportunity of
obtaining a
poisonous dose.
Hazard – The likelihood that the
toxicity will be
expressed.
Toxicology Terms
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Threshold Effects for Dose
Is there such a thing as
a „safe‟ dose??
Agent A
Agent B
Dose
Res
ponse
“NOEL”
(No Observable Effect Level)
Dose-Response
Relationships
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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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Exposure Concepts
Different toxic responses may arise from
different:
– Routes of exposure.
– Frequencies of exposure.
– Duration of exposure (acute vs. chronic).
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Routes of Environmental Exposure
Ingestion (water and food)
Absorption (through skin)
Injection (bite, puncture, or cut)
Inhalation (air)
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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.
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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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Units Used to Measure
Chemicals
in the Environment
• PPM – Parts per million
• PPB – Parts per billion
• PPT – Parts per trillion
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A simple cube 1 cubic meter
in
volume
1m
1m
1m
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Is formed of 1,000,000 cubes,
1 cubic centimeter each
100cm
100cm
100cm
100cm x 100cm
x 100cm =
1,000,000cc
In 1 m3 block
1cc = 1ppm
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One part per million is
• 1 inch in 16 miles
• 1 minute in two years
• 1 cent in $10,000
• 1 ounce of salt in 31 tons of potato
chips
• 1 bad apple in 2,000 barrels of apples
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Divide each 1cc block into
1,000 blocks 0.1cm on a side
1cm
1cm
1cm
0.1cm x 0.1cm x
0.1cm =
0.001cm3
In 1 m3 block
0.001cm3 =
0.001cc or
1ppb
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One part per billion is
• 1 inch in 16,000 miles
• 1 second in 32 years
• 1 cent in $10,000,000
• 1 pinch of salt in 10 tons of potato chips
• 1 lob in 1,200,000 tennis matches
• 1 bad apple in 2,000,000 barrels of
apples
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And divide each 0.1cc block
into 1,000 blocks 0.01cm
on a side
0.1cm
0.1cm
0.1cm
0.01cm x 0.01cm
x 0.01cm =
0.000001cm3
In 1 m3 block
.000,000,001m3 =
0.000,001cc or
1ppt
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One part per trillion is
• 1 postage stamp in the area of the city of
Dallas
• 1 inch in 16 million miles (more than 600
times around the earth)
• 1 second in 320 centuries
• 1 flea on 360 million elephants
• 1 grain of sugar in an Olympic sized pool
• 1 bad apple in 2 billion barrels
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Important Concept
• On the left side of the decimal point ( . )
– 1 trillion is bigger than 1 billion
– 1 billion is bigger than 1 million
– 1 million is bigger than 1 thousand…
• On the right side of the decimal point ( . )
– 1 part per trillion is smaller than 1 part per billion
– 1 part per billion is smaller than 1 part per million
– 1 part per million is smaller than 1 part per
thousand
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Important Relationship
For water at STP (standard temperature
[23oC] and pressure [15 psi])
1 cc = 1ml = 1g
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Which means that
1 liter of water = 1 kg
1 mg / kg = 1 ppm
1mm3 / liter = 1 ppm
1 mg / liter = 1 ppm
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Measures of Toxicity
• Toxicity of chemicals is determined in the
laboratory
• The normal procedure is to expose test
animals
– By ingestion, application to the skin, by inhalation,
gavage, or some other method which introduces
the material into the body, or
– By placing the test material in the water or air of
the test animals’ environment
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Measures of Toxicity
• Toxicity is measured as clinical “endpoints”
which include
– Mortality (death)
– Teratogenicity (ability to cause birth defects)
– Carcinogenicity (ability to cause cancer), and,
– Mutagenicity (ability to cause heritible change in
the DNA)
• At this time we will discuss 2 measures of
mortality – the LD50 and the LC50
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Measures of Toxicity:
The Median Lethal Dose
LD50
The amount (dose) of a chemical which produces death in 50% of a population of test animals to which it is administered by any of a
variety of methods
mg/kg
Normally expressed as milligrams of substance per kilogram of animal body weight
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Measures of Toxicity:
The Median Lethal
Concentration
LC50
The concentration of a chemical in an environment (generally air or water) which
produces death in 50% of an exposed population of test animals in a specified time
frame
mg/L
Normally expressed as milligrams of substance per liter of air or water (or as ppm)
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Primary Routes of Exposure
to Pesticides
There are three primary routes by which
organisms are exposed to pesticides
Oral
Dermal
Inhalation
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Primary Routes of Exposure:
Oral Exposure
Any exposure to pesticide which occurs when
the chemical is taken in through the mouth
and passes through the gastrointestinal tract
During oral exposure, although carried within
the body, the pesticide is still outside of the
body cavity
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Primary Routes of Exposure:
Dermal Exposure
Exposure of the skin to a pesticide
Most common route of human exposure
With proper hygiene this type of exposure is generally not serious unless there is a specific, rapid toxicological effect (often eye effects) which is of concern
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Primary Routes of Exposure:
Inhalation Exposure Occurs when a pesticide is breathed into the
lungs through the nose or mouth
Significant route of exposure for aquatic organisms
Not of toxicological concern until it crosses from the lung into the body (unless the chemical is corrosive)
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Duration of Exposure
Three terms are commonly used to
describe the duration of dose(s)
Acute
Chronic
Subchronic
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Duration of Exposure:
Acute Exposure
Application of a single or short-term (generally less than a day) dosing by a chemical
If toxic symptoms are expressed, they are referred to as symptoms of “acute toxicity”
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Duration of Exposure:
Chronic Exposure
Expression of toxic symptoms only after
repeated exposure to a chemical in doses
regularly applied to the organism for a time
greater than half of its life-expectancy
If toxic symptoms are expressed, they are
referred to as symptoms of “chronic toxicity”
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Duration of Exposure:
Subchronic Exposure
Toxic symptoms are expressed after repeated applications for a timeframe less than half the life expectancy of the organism – but more often than a single dose or multiple doses applied for only a short time
If toxic symptoms are expressed, they are referred to as symptoms of “subchronic toxicity”
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Remember –
• For pesticides – less is more when
dealing with toxicity
• The less you need to cause a toxic
effect – the more toxic the substance is
• Thus an LD50 of 25 mg/kg is more toxic
than is one of 7,000 mg/kg
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Words again
Safe
Low Risk
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Signal Words
The relative acute toxicity of a pesticide is reflected on the label in the form of a “signal
word”
The (toxicologically) appropriate signal word MUST appear on every pesticide label
The three possible signal words are
CAUTION
WARNING
DANGER
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Signal Words:
CAUTION “Caution” reflects the lowest degree of relative
toxicity
All pesticides with an LD50 of greater than 500
mg/kg must display this word on their label
Actually includes two groups of pesticides –
those classed by the EPA as “Relatively
nontoxic (>5,000 mg/kg) and those classed
as “slightly toxic” (500 – 5,000 mg/kg)
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Signal Words:
WARNING
“Warning” reflects an intermediate degree of relative toxicity
All pesticides with an LD50 of greater than 50 and less than 500 mg/kg must display this word on their label
Pesticides in this category are classed as “moderately toxic”
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Signal Words:
DANGER
“Danger” reflects the highest degree of relative
toxicity
All pesticides with an LD50 of less than 50
mg/kg must display this word on their label
Pesticides here are classed as “highly toxic”
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POISON!!!
• Legally defined term – not just anything you
don’t like
• Any pesticide with an LD50 of 50 mg/kg or less
• Labels must reflect this classification
• Label must have the signal word “DANGER” plus the word “POISON”
• Label also must display the skull and crossbones icon
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Relative toxicity
• Organisms can’t differentiate between
“natural” and “synthetic” chemicals
• “Synthetic” does not mean toxic or poisonous
• “Natural” does not mean safe or even low risk
• Chemicals must be evaluated in their
biological context of behavior in organisms
• Mode of action, not source, is the concern of
toxicologists and informed users of pesticides
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Relative toxicity
• Most herbicides act on biological pathways
not present in humans
• Those approved for use in the Region (much
more about these later!!) have LD50s of 50
mg/kg or greater – they have intermediate or
relatively low toxicity
• Some of the insecticides used are highly
toxic
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Relative toxicity
• Some examples of pesticides and other
chemicals are given to show relative risk of
pesticides in the environment in which we live
• This is NOT to trivialize the pesticides
• Always treat them with caution and respect
• But, have a realistic recognition of their
relative risk in a world of risks
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Relative toxicity:
Insecticides
• TCDD (Dioxin) 0.1 mg/kg
• Parathion 13.0 mg/kg
• Nicotine 50.0 mg/kg
• Carbaryl 270.0 mg.kg
• Malathion 370.0 mg/kg
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Relative Toxicity:
Herbicides and Additives mg/kg
Paraquat 95
2,4-D 375
2,4-DP 532
Triclopyr 630
Tebuthiuron 644
Dicamba 757
Hexazinone 1,690
Glyphosate 4,320
mg/kg
Limonene 5,000
Clopyralid >5,000
Sulfometuron Met.. >5,000
Imazapyr >5,000
Diesel oil 7,380
Picloram 8,200
Fosamine am.. 24,400
Kerosene 28,000
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Relative Toxicity:
Comparative information Highly toxic chemicals
0 – 50 mg/kg range
(taste 1 teaspoonful)
mg/kg
• Botulinus toxin 0.00001
• Dioxin 0.1
• Parathion 13.0
• Strychnine 30.0
• Nicotine 50.0
Moderately toxic chemicals
50- - 500 mg/kg range
(teaspoonful 1 ounce)
mg/kg
• Paraquat 95
• Caffeine 200
• Carbaryl 270
• Malathion 370
• 2,4-D 375
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Relative Toxicity
Comparative Information Slightly toxic chemicals
500 – 5,000 mg/kg range
(1 ounce 1 pint)
mg/kg
• 2,4-DP 532
• Triclpoyr 630
• Tebuthiuron 644
• Dicamba 757
mg/kg
• Formaldehyde 800
• Hexazinone 1,690
• Asprin 1,700
• Vitamin B3 1,700
• Household bleach 2,000
• Table salt 3,750
• Glyphosate 4,320
etc.
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Relative Toxicity:
Are all substances toxic?
YES!
All are toxic to some quantifiable degree
Sugar has an LD50 of 30,000 mg/kg
The foresters favorite – ethanol has an LD50
of only 13,700 mg/kg
Even water has a recognized LD50 of slightly
greater than 80,000 mg/kg
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Relative Toxicity:
The Last Word Pesticides are chemicals introduced into the
environment to perform a function
The source of a chemical (synthetic vs. natural) is irrelevant when considering its toxicity
Pesticides should be treated with care and proper respect – but so should household cleaners, gasoline and kerosene, bleaches, paints and all other chemicals