Environmental Health Institute - July, 2006

University of Rochester Medical Center

Introduction to Toxicology

Dina Markowitz, Ph.D.

Director, Center for Science Education & Outreach
Department of Environmental Medicine
University of Rochester
 What is Toxicology?

Toxicology is the study of how

toxicants cause adverse effects
on living organisms.
 Toxicology Terms to Know

Toxicant (Poison):
A chemical capable of producing a
harmful reaction in a living organism.

Adverse effect:
Any change that interferes with an
organism’s normal functioning.
 What is a Poison?

All substances are poisons;

there is none that is not a poison.
The right dose
differentiates a poison and a remedy.

Paracelsus (1493-1541)
 Examples of Toxicants:
Chemicals that can Cause Harm

Prenatal alcohol abuse

→ fetal alcohol syndrome

www.betterendings.org/
FASD/facts/nationalgeo.htm

Mercury in fish
→ brain damage
 Examples of Toxicants:
Chemicals that can Cause Harm

Lead in paint
→ brain damage

Dioxin poisoning
→ facial scarring (chloracne)

www.seco.noaa.gov
 What amount causes harm?

Some chemicals are good in small amounts,

but toxic in large amounts

Example: botulinum toxin

Small amount →
Large amount →
 What amount causes harm?

Some chemicals are good in small amounts,

but toxic in large amounts

Example: botulinum toxin

Small amount → prevents wrinkles (BOTOX)

Large amount → paralysis, death
 Dose

• Dose refers to the amount of a toxicant

entering the body
• Dose is measured as milligrams of toxicant
per kilogram of body weight = mg/kg

Example: 100 mg caffeine

• 50 kg adult (110 pounds)
dose = 100 mg/50kg = 2 mg/kg
• 10 kg baby (22 pounds)
dose = 100 mg/10 kg = 10 mg/kg
 Effects of Amount on Dose

Increasing the amount

of chemical for the
same size of organism

Dose increases
 Effects of Size on Dose

A smaller size of
organism with the same
amount of chemical

Dose increases
What factors determine the dose
of a toxicant that causes harm?

?
 What factors determine the dose
of a toxicant that causes harm?

• The concentration of the toxicant

• The chemical properties of the toxicant
• The number of times of exposure (frequency)
• The length of time of exposure (duration)
• How it gets into the body (exposure pathway)
 Response:
an abnormal change in an organism

Depending on the toxicant, dose, and route

of exposure, the response can be:
• local (effects part of the organism) or
systemic (effects the whole organism)
• reversible or irreversible
• immediate or delayed
 Dose-Response Relationship:
As the dose increases, the percent of
individuals who respond increases
% of Individuals Responding

100

75

50

25

0
0 10 20 30 40 50 60 70 80 90 100

Dose (mg/kg body weight)

 Dose-Response Relationship:
As the dose increases, the percent of
individuals who respond increases

All individuals
% of Individuals Responding

100 respond at a dose

of 100 mg/kg
75

50
Half of individuals
respond at a dose of
25 43 mg/kg

0
0 10 20 30 40 50 60 70 80 90 100

Dose (mg/kg body weight)

 Glasses of Wine: Dose-Response

100

75
% of people
who have 50
Half of people
difficulty have difficulty
walking 25 walking after 4.5
glasses of wine
0
0 1 2 3 4 5 6 7 8
Glasses of Wine
 Glasses of Wine: Dose-Response

100

75
% of people
who have 50
Half of people
difficulty have difficulty
walking 25 walking after 4.5
glasses of wine
0
Why don’t all
people respond 0 1 2 3 4 5 6 7 8
the same? Glasses of Wine
 Different individuals can show a greater
or lesser response to the same toxicant

What factors can cause a difference in response?

?
 Different individuals can show a greater
or lesser response to the same toxicant

What factors can cause a difference in response?

• Age - young or old
• Gender - male or female
• Genetic differences – different genes
• Nutrition
• Health – previous or current diseases
• Exposure to other toxicants – previous or current
 LD50

The dose of toxicant which is deadly to

50% of the population
 Which has the highest LD50?
Which has the lowest LD50?

Toxicant LD50 (mg/kg)

Ethyl alcohol
Salt (sodium chloride)
Iron (Ferrous sulfate)
Morphine
Mothballs (paradichlorobenzene)
Aspirin
DDT
Cyanide
Nicotine
Black Widow Spider venom
Rattle Snake venom
Tetrodotoxin (from fish)
Dioxin (TCDD)
Botulinum Toxin
 Which has the highest LD50?
Which has the lowest LD50?

Toxicant LD50 (mg/kg)

Ethyl alcohol 10,000
Salt (sodium chloride) 4,000
Iron (Ferrous sulfate) 1,500
Morphine 900
Mothballs (paradichlorobenzene) 500
Aspirin 250
DDT 250
Cyanide 10
Nicotine 1
Black Widow Spider venom 0.55
Rattle Snake venom 0.24
Tetrodotoxin (from fish) 0.01
Dioxin (TCDD) 0.001
Botulinum Toxin 0.00001
 Frequency of Exposure

Number of times of exposure Time in between exposure

(Number of glasses of wine) (Time between each glass
of wine)

or
or
 Duration of Exposure:
How long the exposure lasted

Acute < 24hr 1 high dose

Subacute 1 month repeated exposures
Subchronic 1-3months repeated low dose
Chronic > 3months repeated low dose

The amount of toxicant can build up in body over time and:

• Can move to different organs (example - lead)
• Can overwhelm the bodies’ ability to repair damage
and remove the toxicant (example - radiation)
 Routes of Exposure

Skin
(dermal)

Lung Oral
(inhalation) (gut)

Injection
 Routes of Exposure

Which is the Skin

worst? (dermal)

Lung Oral
(inhalation) (gut)

Injection
 Distribution: Where the toxicant
accumulates in the body

• Fat soluble
• Water soluble
• Bone
• Muscle
 Not all organs are affected
equally by a toxicant

Target organs:
higher concentration of toxicant
→ more adverse effects
• Liver
• Kidney
• Lung
• Neurons
• Heart muscle
• Bone marrow
• Intestines
• Sperm/eggs
 Target Organs: Mechanisms of Action

• Adverse effects can occur

at the level of the:
 Molecule
 Cell
 Organ
 Organism

• Toxicant can interact with:

 Proteins
 Lipids
 DNA
 Metabolism of Toxicants

• How the body breaks down a toxicant

 Using enzymes in the body
• What the toxicant turns into
 Water-soluble toxicants are easier to
excrete
• How fast does this occur
 Can take hours, days, weeks or years
 Half-life:
How long it takes for ½ to go away

14
12
10
8
Concentration
of toxicant in 6
blood 4
(microgram/ml) 2
0
0 1 2 3 4 5 6 7 8 9 10 11
Time (hours)
 Half-life:
How long it takes for ½ to go away

14
12
10
8
Concentration Half life is 4 hours
of toxicant in 6
blood 4
(microgram/ml) 2
0
0 1 2 3 4 5 6 7 8 9 10 11
Time (hours)
 Risk Assessment

Risk: The probability or likelihood that

exposure to a particular toxicant at a
specific concentration or dose may
cause an adverse effect.

Risk Assessment: The process used to

estimate the likelihood that humans will
be adversely affected by a chemical or
physical agent under a specific set of
conditions.
 Risk Assessment

An estimate of the likelihood that exposure to a

toxicant may cause harm

Toxicity Exposure
Assessment Assessment

Risk Assessment
 Toxicity Assessment

• Toxicity testing:
 Determines the hazard which a substance
may present to humans
 Exposure limits are established
• If exposure to the substance is kept below
the exposure limit, the risk from the
substance is considered to be acceptable.
 Exposure Assessment

Must evaluate potential for exposure to a

substance:
 Where do you encounter it?
 How often will you encounter it?
 How might it enter the body?
 How long does it remain in the body?
 Risk Assessment

Must take into account the possible

harmful effects of the toxicant on
many individual people
Risk is only part of the picture
 Choices

As part of our society, you must make decisions

which assess risks, benefits, and potential
trade-offs.
• Thalidomide: Leprosy treatment vs. birth
defects
• Pesticides: Mosquito abatement vs. toxicity
• Sunlight: Vitamin D and skin cancer
 Tradeoffs

Plan to reduce risks to take advantage of the

benefits offered by use of a particular
‘product.’
– Sunlight: Vitamin D and skin cancer
 Precautionary Principle

If the consequences of an action are unknown, but

judged to have some potential for negative
consequences, then it is better to avoid that action.

“Better safe than sorry.”