‘The Dose Makes the Poison’

1. ‘The Dose Makes the Poison’ Dr Clifford Elcombe University of Dundee and CXR Biosciences

2. Dose THE KEY CONCEPT in Toxicology Father of Modern Toxicology PARACELSUS — 1564 “All things are poisonous, only the dose makes it non-poisonous.” (Dose alone determines toxicity)

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, 500new 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.

4. A Selection of Natural Carcinogens anise apples bananas brocolli brussel sprouts cabbage carrots cauliflower celery cinnamon cloves cocoa comfrey tea fennel grapefruit juice honey dew melon horseradish kale mushrooms mustard orange juice parsely parsnips peaches black pepper pineapples radishes raspberries tarragon turnips

5. 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.

6. 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)

7. ALL Interactions between Chemicals and Biological Systems follow a Dose-Response Relationship

8. 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”).

9. 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

10. 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)

11. Effective Dose Lethal Dose 100 100 80 80 60 AnimalsKilled (%) Animals Sleeping (%) 60 LD50 ED50 40 40 20 20 1 2 3 5 7 10 10 20 30 50 100 Phenobarbital(mg/kg) Log Scale Dose-Response Relationship“The Dose Makes the Poison”

12. Linearised Model 1,000,000 100,000 10,000 1,000 Risk per 1,000,000 100 10 1 1 100 1,000 10,000 100,000 10 Dose (ppm in diet) VSD ("virtually safe dose")

13. Metabolic Saturation!

14. Concentration Analogies • one automobile in bumper-to-bumper traffic from Cleveland to San Francisco • one minute in two years • One Part Per Million is :

15. Concentration Analogies • One Part Per Billion 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

16. Which Results in the Largest Exposure? • 1000 ng/mL • 1 mg/mL • 1 ppm • 1000 ppb

17. 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