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

1. Environmental Health Institute - July, 2006University of Rochester Medical Center Introduction to Toxicology Dina Markowitz, Ph.D. Director, Center for Science Education & Outreach Department of Environmental Medicine University of Rochester

2. What is Toxicology? Toxicology is the study of how toxicants cause adverse effects on living organisms.

3. 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.

4. 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)

5. Examples of Toxicants: Chemicals that can Cause Harm Prenatal alcohol abuse → fetal alcohol syndrome Mercury in fish → brain damage www.betterendings.org/FASD/facts/nationalgeo.htm

6. Examples of Toxicants:Chemicals that can Cause Harm Lead in paint → brain damage Dioxin poisoning → facial scarring (chloracne) www.seco.noaa.gov

7. What amount causes harm? Some chemicals are good in small amounts, but toxic in large amountsExample: botulinum toxinSmall amount → Large amount →

8. What amount causes harm? Some chemicals are good in small amounts, but toxic in large amountsExample: botulinum toxinSmall amount → prevents wrinkles (BOTOX)Large amount → paralysis, death

9. 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

10. Effects of Amount on Dose Increasing the amount of chemical for the same size of organism Dose increases

11. Effects of Size on Dose A smaller size of organism with the same amount of chemical Dose increases

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

13. 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)

14. 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

15. Dose-Response Relationship:As the dose increases, the percent of individuals who respond increases 100 75 50 % of Individuals Responding 25 0 0 10 20 30 40 50 60 70 80 90 100 Dose (mg/kg body weight)

16. Dose-Response Relationship:As the dose increases, the percent of individuals who respond increases All individuals respond at a dose of 100 mg/kg 100 75 50 % of Individuals Responding Half of individuals respond at a dose of 43 mg/kg 25 0 0 10 20 30 40 50 60 70 80 90 100 Dose (mg/kg body weight)

17. Glasses of Wine: Dose-Response 100 75 % of people who have difficulty walking 50 Half of people have difficulty walking after 4.5 glasses of wine 25 0 0 1 2 3 4 5 6 7 8 Glasses of Wine

18. Glasses of Wine: Dose-Response 100 75 % of people who have difficulty walking 50 Half of people have difficulty walking after 4.5 glasses of wine 25 0 Why don’t all people respond the same? 0 1 2 3 4 5 6 7 8 Glasses of Wine

19. Different individuals can show a greater or lesser response to the same toxicant • What factors can cause a difference in response? ?

20. 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

21. LD50 The dose of toxicant which is deadly to 50% of the population

22. 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

23. 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

24. Frequency of Exposure Number of times of exposure (Number of glasses of wine) Time in between exposure (Time between each glass of wine) or or

25. Duration of Exposure: How long the exposure lasted Acute< 24hr 1 high dose Subacute 1 month repeated exposures Subchronic1-3months 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)

26. Routes of Exposure Skin (dermal) Oral (gut) Lung (inhalation) Injection

27. Routes of Exposure Skin (dermal) Which is the worst? Oral (gut) Lung (inhalation) Injection

28. Distribution: Where the toxicant accumulates in the body Fat soluble Water soluble Bone Muscle

29. 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

30. 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

31. 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

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

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

34. 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.

35. Risk Assessment An estimate of the likelihood that exposure to a toxicant may cause harm Toxicity Assessment Exposure Assessment Risk Assessment

36. 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.

37. 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?

38. Risk Assessment Must take into account the possible harmful effects of the toxicant on many individual people

39. Risk is only part of the picture

40. 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

41. Tradeoffs Plan to reduce risks to take advantage of the benefits offered by use of a particular ‘product.’ • Sunlight: Vitamin D and skin cancer

42. 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.”