‘The Dose Makes the Poison’

Dr Clifford Elcombe

University of Dundeeand

CXR Biosciences

Father of Modern Toxicology Father of Modern Toxicology PARACELSUS — — 1564

“All things are poisonous, only the dose makes it non-poisonous.”(Dose alone determines toxicity)

Dose

THE KEY CONCEPT in Toxicology

3

• Toxicology is arguably the oldest scientific discipline, as the earliest humans had to recognize which plants were safe to eat.

• Approximately 100,000 chemicals currently in use worldwide, 500 new chemicals enter the market- place annually.

• 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.

aniseapplesbananasbrocollibrussel sproutscabbagecarrotscauliflowercelerycinnamonclovescocoacomfrey teafennelgrapefruit juice

honey dew melonhorseradishkalemushroomsmustardorange juiceparselyparsnipspeachesblack pepperpineapplesradishesraspberriestarragonturnips

A Selection of Natural Carcinogens

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…….

AND Spinach.

Hazard and Risk

• Hazard – the potential for harm– Intrinsic property of the chemical

• Risk – Risk is the chance (probability) that harm will

actually occur– Hazard x exposure (dose and time)

ALL Interactions between

Chemicals and Biological Systems follow a

Dose-Response Relationship

Dose-Response Relationship

• The quantitative relationship between the concentration of a xenobiotic in the body and the magnitude of the biological effect it produces.

• The magnitude of the effect of a xenobiotic is a function of the amount of xenobiotic a person is exposed to (i.e., “The Dose Makes the Poison”).

Dose Concepts

• The magnitude of the toxic response is proportional to the concentration (how much) of the chemical at the target site.

• The concentration of a chemical at the target site is proportional to the dose.

• Four important processes control the amount of a chemical that reaches the target site.

– Absorption

– Tissue distribution

– Metabolism

– Excretion

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)

Dose-Response Relationship“The Dose Makes the Poison”

An

ima

ls S

lee

pin

g (

%)

Phenobarbital (mg/kg) Log Scale

An

ima

ls K

ille

d (

%)

ED50LD50

Effective Dose Lethal Dose100

60

80

40

20

100

60

80

40

20

10 20 30 50 1001 2 3 5 7 10

Linearised Model

110 100 1,000 10,000 100,000

1

10

100

1,000

10,000

100,000

1,000,000

Dose (ppm in diet)

Ris

k p

er 1

,000

,000

VSD ("virtually safe dose")

Metabolic Saturation!

Concentration Analogies

one automobile in bumper-to-bumper traffic from Cleveland to San Francisco

one minute in two years

One Part Per Million is :

one 4 inch hamburger in a chain of hamburgers circling the earth at the equator two-and-a-half times (4x10 9 inches)

one second of time in 32 years

Concentration Analogies

One Part Per Billion is :

Which Results in the Largest Exposure?

• 1000 ng/mL

• 1 g/mL

• 1 ppm

• 1000 ppb

Resources

A Journalist's Handbook on Environmental Risk Assessment

http://ruby.fgcu.edu/Courses/Twimberley/IDS3920/main.html

http://www.agius.com/hew/resource/hazard.htm