Introduction to Toxicology

A Brief Introduction to the

Concepts of Toxicology

We Will Be Using

Throughout This Course

By Dr Tajdar H Khan

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.

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 ?

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

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.

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

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

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

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)

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.

History

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.

Toxicology Terms

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

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

Units Used to Measure

Chemicals

in the Environment

• PPM – Parts per million

• PPB – Parts per billion

• PPT – Parts per trillion

A simple cube 1 cubic meter

in

volume

1m

1m

1m

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

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

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

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

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

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

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

Important Relationship

For water at STP (standard temperature

[23oC] and pressure [15 psi])

1 cc = 1ml = 1g

Which means that

1 liter of water = 1 kg

1 mg / kg = 1 ppm

1mm3 / liter = 1 ppm

1 mg / liter = 1 ppm

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

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

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

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)

Primary Routes of Exposure

to Pesticides

There are three primary routes by which

organisms are exposed to pesticides

Oral

Dermal

Inhalation

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

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

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)

Duration of Exposure

Three terms are commonly used to

describe the duration of dose(s)

Acute

Chronic

Subchronic

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”

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”

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”

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

Words again

Safe

Low Risk

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

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)

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”

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”

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

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

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

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

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

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

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

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.

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

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