Toxicology of High Priority Substances

1. Toxicology of High Priority Substances Robert Burr MD Robert Burr MD

2. Part 1: Principles Part 2: Metals Part 3: Dioxin and TCE Robert Burr MD

3. Toxicology of High Priority Substances Part 1: Principles Robert Burr MD

4. Toxicology • “Science of poisons” • Toxin = Poison • Toxin = Chemical that has an adverse effect on a living system. • Mechanism & Effects • Potency • Control • Treatment Robert Burr MD

5. “Dose Makes the Poison” • The amount of a chemical to which a living system is exposed is critical to the expressed toxic response. • Each chemical has its own “dose-response” relationship. • Potency is not defined by any particular response, but by the amount required to produce a specific toxic response. Robert Burr MD

6. 100% Response 0% Dose More potent Less Potent Robert Burr MD

7. Dose-Response Curve • “Sigmoid” curve • Defined in term of a specific response • Requires a specific effect to look for… • Terminology • No Observed Effect Level (NOEL) • No Observed Adverse Effect Level (NOAEL) • LD50/ED50 • Often little or no human data Robert Burr MD

8. 100% Response 0% Dose LD50 ED50 NOEL NOAEL Robert Burr MD

9. Toxic Response - Factors • Dose • Specific effect(s) • Mechanism • Target cells/tissues • Route of exposure • Duration • Individual susceptibility • Age, genetics, other exposures, illness, etc. Robert Burr MD

10. Important Point • What we see and what the person feels are effects at the level of function of an whole organ or system, not the specific toxic response at the level of the cell or tissue. Robert Burr MD

11. Toxic Responses - Mechanism • Cytotoxic (cell injury) • “Physiologic” (disrupt normal functions) • Allergenic (asthma, dermatitis) • Mutagenic • Carcinogenic • Teratogenic • Toxins often act through more than one mechanism Robert Burr MD

12. Cytotoxic Responses: Cell Injury Robert Burr MD

13. Cells Can’t Just Stop • Important to remember that active cell processes are required to maintain the cells in a functional state. • If the processes fall below a critical level, the cell will enter a period of functional decline and eventually reach a state from which they cannot recover. • In the most active cells, this state can be reached in a few minutes. Robert Burr MD

14. Spectrum of Cell Injury Acute Chronic Organ failure Acute severe illness - death Reduced organ function Acute moderate-severe illness Injury with inflammation Mild-moderate reversible illness Fibrosis and progressive loss of function Dose Apoptosis (no inflammation) None Reduced function Minor functional disturbance None None Robert Burr MD

15. Normal Cirrhosis Acute Hepatitis Robert Burr MD

16. Normal (almost) Chronic Acute Robert Burr MD

17. Duration of Exposure • Acute toxic exposure • Presents as acute symptoms • Carcinogenesis unusual • Full recovery possible • Chronic toxic exposure • Insidious • Presents as chronic, irreversible injury • Cirrhosis, emphysema, cancer Robert Burr MD

18. Physiologic Responses Robert Burr MD

19. Allergenic Responses Robert Burr MD

20. Mutagenic Responses Robert Burr MD

21. DNA Robert Burr MD

22. Mutations Robert Burr MD

23. Robert Burr MD

24. Mutations and Cancer Robert Burr MD

25. Carcinogenic Responses Robert Burr MD

26. Teratogenic Responses Robert Burr MD

27. Human Development Robert Burr MD

28. Critical Stages Robert Burr MD

29. Robert Burr MD

30. Target Cells and Tissues • Direct contact: lungs, skin • Active sites of metabolism and biotransformation: liver • Concentration and excretion: liver, kidney • Critical susceptibility: brain, heart Robert Burr MD

31. 100% Response 0% Dose Robert Burr MD

32. Common Chemical Health Effects • Eye irritation • Skin irritation and rash • Respiratory irritation and cough • Reactive airways disease • Allergic reactions (requires more than one exposure) Robert Burr MD

33. Sources of Exposure • >100,000 commercial chemicals • Several thousand new each year • Limited data on almost all • Know very little about mixtures (e.g., smoke). • We know most about acute effects of common chemicals at high doses. • Drugs are most extensively tested. Robert Burr MD

34. How Do We Know Something is Toxic? • The association of exposure and illness must be recognized (and accepted). • May cause acute illness on exposure • Exposure markedly increases the risk of something unique and rare • Illness consistent with experimental data Robert Burr MD

35. Things that get in the way • Exposure increases the risk of a common illness. • Limited opportunity to make associations • Structure of the medical industry • Mobile workforce • Complex exposure histories • Resistance to the recognition of compensable illnesses Robert Burr MD

36. ? Robert Burr MD

37. Break Robert Burr MD