Environmental Health Institute - July, 2006University of Rochester Medical Center

Introduction to Toxicology

What is Toxicology?

Toxicology is the study of how

toxins cause adverse effects on

living organisms.

Toxicology Terms to Know

toxins (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 toxins: Chemicals that can Cause Harm

Mercury in fish→ brain damage

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

Prenatal alcohol abuse→ fetal alcohol syndrome

Examples of toxins:Chemicals that can Cause Harm

Dioxin poisoning→ facial scarring (chloracne)

Lead in paint → brain damage

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

Name the toxins that may be present in each scene

10

11

12

13

                                                                                                                                         

                                        

Dose

• Dose refers to the amount of a toxins entering the body

• Dose is measured as milligrams of toxins 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

Examples

• A woman who weighs 80 kg took 3 aspirin pills. Each pill contains 300 mg of aspirin. What is the dose the woman took?

Examples

• A man who weighs 130 kg took the same number of pills of aspirin. What is the dose the man took?

Example

• How can each person have taken the same number of pills but each be given the same dose?

Example

• If a child ingest a poison a parent will call poison control (a government hotline that instructs parents of what to do in these types of situations). What information will poison control need from the parent?

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

?

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

• The concentration of the toxins

• The chemical properties of the toxins

• The number of times of exposure (frequency)

• The length of time of exposure (duration)

• How it gets into the body (exposure pathway)

Concentration

• The dose• Some doses have a mild affect and

some have a severe or even deadly affect

Chemical Properties

• Some toxins are easily absorbed by the blood stream while others are not

• Some toxins react with chemicals in our body more easily– Example: hemoglobin bonds very

quickly to carbon dioxide

Frequency of Exposure

Number of times of exposure

(Number of glasses of wine)

Time in between exposure

(Time between each glass of wine)

oror

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 toxins 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 toxins (example - radiation)

Length of exposure

• A man works in a lab and is exposed to very low amounts of benzene vapors over a 20 year period

Length of exposure

• A gardener spills a large quantity of pesticides while working in the shed. She cleans up the mess but is exposed to large amounts of the vapor from the chemicals

Length of exposure

• A volunteer working at ground zero was exposed to mercury over a 4 week period.

Routes of Exposure

Skin (dermal)

Lung (inhalation)

Oral (gut)

Which is the

worst?

Inhalation

1. cause damage to a)mucous membranes b)Throatc)lungs 2. pass through the lungs into the circulatory system to affect other areas of the body*3. Can be fatal

oral

1. Most toxins are poorly absorbed from the intestines into the blood stream.

2. severe damage lining of the mouth, throat, and gastrointestinal tract

3. Can cause death in some cases

Dermal (skin)

1. If the toxin is extremely hazardous may pass through the skin and cause serious or even fatal poisoning

2. Mostly results inflammation, burning, blistering, and complete destruction of the skin

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, 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 the measure of mortality – the LD50

LD50

The dose of toxins which is deadly to 50% of the population

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/kgNormally expressed as milligrams of substance per kilogram of animal body

weight

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

6

Dose (mg/kg body weight)

0

25

50

75

100

0 10 20 30 40 50 60 70 80 90 100

% o

f D

ea

ths

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

Dose (mg/kg body weight)

0

25

50

75

100

0 10 20 30 40 50 60 70 80 90 100

All individuals respond at a dose of 100 mg/kg

Half of deaths were at a dose of 43 mg/kg %

of

De

ath

s

Glasses of Wine: Dose-Response

0

25

50

75

100

0 1 2 3 4 5 6 7 8

Glasses of Wine

% of people who have difficulty walking

Half of people have difficulty walking after 4.5 glasses of wine

Glasses of Wine: Dose-Response

0

25

50

75

100

0 1 2 3 4 5 6 7 8

Glasses of Wine

% of people who have difficulty walking

Half of people have difficulty walking after 4.5 glasses of wine

Why don’t all people

respond the same?

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

What factors can cause a difference in response?

?

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 toxins – previous or current

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

Which has the highest LD50?

Which has the lowest LD50?

toxins LD50 (mg/kg)Ethyl alcohol 10,000Salt (sodium chloride) 4,000Iron (Ferrous sulfate) 1,500Morphine 900Mothballs (paradichlorobenzene) 500Aspirin 250DDT 250Cyanide 10Nicotine 1Black Widow Spider venom 0.55Rattle Snake venom 0.24Tetrodotoxin (from fish) 0.01Dioxin (TCDD) 0.001Botulinum Toxin 0.00001

Remember –

• 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

Which is more toxic?

• Alcohol• Morphine• Nicotine

Why?

• A 75 kg person consumes 25 mg of tetradotoxin while eating puffer fish. Is this dose dangerous? Explain why or why not?

• Each black widow spider releases 2.0 mg of venom with each bite. How many bites would each person below need in order to have a 50% chance of death?

a)75 kg maleb)50 kg femalec)10 kg baby

How toxic is it?

Safe

Low Risk

Signal Words

The relative acute toxicity of a chemical is reflected on the label in the form of a “signal word”

The (toxicologically) appropriate signal word MUST appear on every chemcial label

The three possible signal words areCAUTIONWARNINGDANGER

Signal Words:CAUTION

“Caution” reflects the lowest degree of relative toxicity

All chemicals with an LD50 of greater than 500- ~5000 mg/kg must display this word on their package

Signal Words:WARNING

“Warning” reflects an intermediate degree of relative toxicity

All chemicals with an LD50 of greater than 50 and less than 500 mg/kg must display this word on their label

Chemicals in this category are classed as “moderately toxic”

Signal Words:DANGER

“Danger” reflects the highest degree of relative toxicity

All chemicals with an LD50 of less than 50

mg/kg must display this word on their label

chemicals here are classed as “highly toxic”

POISON!!!

• Legally defined term – not just anything you don’t like

• Any chemcial 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

Distribution: Where the toxins accumulates in the body

• Fat soluble

• Water soluble

• Bone

• Muscle

Metabolism of toxins

• How the body breaks down a toxins

Using enzymes in the body

• Where the toxin builds up

Water-soluble toxins are easier to excrete

• How fast does the breakdown of the toxin take

Can take hours, days, weeks or years

Half-life: How long it takes for ½ to go away

Concentration of toxins in

blood

(microgram/ml)

02

46

810

1214

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

Concentration of toxins in

blood

(microgram/ml)

02

46

810

1214

0 1 2 3 4 5 6 7 8 9 10 11

Time (hours)

Half life is 4 hours

• Which type of toxin most likely has the shortest half life?

a)Water soluble toxin

b)Fat soluble toxin

c)Toxin that accumulates in the bones

d)Toxin that accumulates in the muscles

Why?

Risk Assessment

Risk: The probability or likelihood that exposure to a particular toxins 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

Risk Assessment

Toxicity Assessment

Exposure Assessment

An estimate of the likelihood that exposure to a toxins may cause harm

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:

1. What is the chemical properties?

2. How often will you encounter it?

3. How might it enter the body?

4. How long does it remain in the body?

Risk Assessment

Must take into account the possible harmful effects of the toxins 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.”

Identifying Risks

To identify possible risks from exposure to a particular toxins, scientists use simple plants or animals, rather than humans, as test subjects.

Bioassay

A procedure that uses living organisms to determine the toxicity of a chemical.

1. Expose living organisms to different concentrations of a potential toxins

2. Observe the effects on the organisms’ behavior and survival

3. Determine if, or at what concentration, a chemical has harmful effects

Model Organisms

• What type of model organism would you use to determine effects to humans?

• What other kinds of organisms might be used for bioassays?

Units Used to Measure Chemicals

in the Environment

• PPM – Parts per million

• PPB – Parts per billion

• PPT – Parts per trillion

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

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

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

ppm to %

ppm X 100 = %

1,000,000

• Example: What is the percent concentration of a 5000 ppm solution?

% to ppm

% concentration X 10,000 = ppm

Example: What is the part per million of a 4.5 % solution?

4.5 X 10,000 = 45,000 ppm

Grams of solute to ppm

Gram of solute X 1,000,000 = ppm

Grams of solvent

• Example: 50 grams of sodium chloride was dissolved in 500 grams of water. What is the ppm of sodium chloride in solution?

• Example: 90 grams of sucrose was placed in 750 mL of water. What is the ppm of sucrose in solution?

• A student wanted to make up a 5.0 % solution of nicotine. How should he/she do this?

• 1st step: change percent to ppm

• 2nd step:

Determine the grams of solute

* You determine the volume of solvent

ppm X grams of solvent = grams of solute

1,000,000