Chemical Hormesis

1. Chemical Hormesis Monty L. Herr, PhD, CIH

2. Paracelsus“What is it that is not poison? All things are poison and none without poison. Only the dose determines that a thing is not poison.”

3. Dose-ResponseNoncarcinogenic Effects • Threshold Response • Can determine a no-effect level

4. Dose-Response Curve Threshold Response Case 100% o o o Toxic Response Probability NOAEL 0,0 Dose or Exposure

5. Dose-ResponseCarcinogenic Effects • Nonthreshold response • No dose is risk free

6. Dose-Response Curve Zero Threshold Linear Response Case 100% o o o Toxic Response Probability Zero Threshold 0,0 Dose or Exposure

7. Dose-Response Curve Non-Linear Response Case - Hormesis 100% o o o Toxic Response Probability 0,0 Dose or Exposure

8. Hormesis Curve Maximum response (averages 130-160% of control) Distance to NOAEL (averages 5-fold) NOAEL Control Hormetic Zone (averages 10- to 20-fold) Increasing Dose Dose-response curve depicting the quantitative features of hormesis

9. Ed Calabrese • Environmental Health Sciences Department • University of Massachusetts • Coworker: Linda Baldwin

10. Chemical Hormesis • BELLE: Biological Effects of Low Level Exposures • http://www.belleonline.com/ • Low-dose stimulation/high-dose inhibition - Arndt-Schultz Law

11. February 13, 2003 Dangerous levels of toxins miscalculated Potential pollutants and poisons may be beneficial in low doses.

12. June 9, 2003 A Little Poison Can Be Good For You The received wisdom about toxins and radiation may be all wet.

13. September 2003 HORMESIS: Nietzsche's Toxicology • Whatever doesn't kill you might make you stronger

14. October 17, 2003 • HORMESIS:Sipping From a Poisoned Chalice

15. December 12, 2003 A scientist finds benefit in small doses of toxins AMHERST -- Edward J. Calabrese, a gray-haired man who works in a rundown office surrounded by documents on highly toxic chemicals, has an explosive idea.

16. December 19, 2003 Scientists Revisit Idea That a Little Poison Could Be Beneficial By Sue Begley

18. Knight Ridder papers • 27 February 2004 • Hormesis Theory:Tiny Bits of Toxins Do Affect People • By Seth Borenstein

19. April 5, 2004 LOW-DOSE EFFECTS Debate expands on how to extrapolate data from high-dose tests for environmental contaminants. By Cheryl Hogue, pp. 50-54

20. U.S. News and World Report October 18, 2004 “Is There a Tonic in the Toxin?”

21. HORMESIS • DEFINITION: • Dose response phenomenon characterized by a low dose stimulation and a high dose inhibition.

22. Criteria used to judge data for evidence of hormesis • The magnitude of the low dose stimulatory response • The number of doses establishing the reliability of the beta-curve • Statistical power • The reproducibility of the findings

23. To evaluate high conformity to the J-curve • Establishment of an endpoint-specific lowest observed effect level (LOEL) and no-observed-effect level (NOEL) • expected to have  2 doses below the NOEL.

24. Hormesis Curve Maximum response (averages 130-160% of control) Distance to NOAEL (averages 5-fold) NOAEL Control Hormetic Zone (averages 10- to 20-fold) Increasing Dose Dose-response curve depicting the quantitative features of hormesis

25. Females Males METHANOL + FRUIT FLY LONGEVITY

26. Males Females GAMMA RAYS + MOUSE LUNG ADENOMAS

27. * Testosterone * * Luteinizing hormone Alcohol and Rat Serum Levels

28. Effects of metals on phagocytosis in the clam, Mya arenaria, hemocytes

30. CADMIUM AND RAT TESTICULAR CANCER Source: Waalkes, 1988

31. Results of initial screening organized by agent • Agent Percent • Alcohol and metabolites 6.2 • Antibiotics 7.9 • Auxin related 4.6 • Hydrocarbons 3.4 • Metals 29.6 • Herbicides 7.2 • Insecticides 6.1 • Fungicides 1.5 • Pesticides 2.9 • Miscellaneous 30.6

32. Results of initial screen organized by endpoint Percent • Growth 62.2 • Metabolic Effects 15.2 • Longevity 5.2 • Survival 5.7 • Reproduction 5.7 • Miscellaneous 5.8

33. Results of initial screening organized by test model Percent Bacteria 9.3 Protozoa 3.0 Fungi 6.4 Plants 34.9 Animals 46.3

34. Generalizability of Hormesis • Numerous species • Broad range of chemical classes • Broad range of biological endpoints

35. PERSPECTIVE # 1 • HORMESIS: a concept with much supportive experimental evidence that is reproducible

36. PERSPECTIVE # 2 • HORMESIS: Based on Perspective # 1 it should be considered as a real concept in the biological sciences

37. PERSPECTIVE # 3 • HORMESIS IS GENERALIZABLE • Across biological models • Across endpoints measured • Across Chemical Classes/Physical Agents

38. PERSPECTIVE # 4 • Based on Perspective # 3, HORMESIS is evolutionarily based, with broad potential implications

39. PERSPECTIVE # 5 • HORMESIS: very common in toxicological/pharmacological literature, making it a central concept

40. PERSPECTIVE # 6 • HORMESIS: a normal component of the traditional dose response, being graphically contiguous with the NO(A)EL.

41. PERSPECTIVE # 7 • HORMESIS: readily definable quantitative features, that are broadly generalizable, making it reasonably predictable.

42. PERSPECTIVE # 8 • HORMESIS: far more common than the threshold dose response in fair, head to head comparisons; • this would make the hormetic model the most dominant in toxicology.

43. PERSPECTIVE # 9 • HORMESIS: no single hormetic mechanism; there appears to be a common underlying biological strategy underlying such phenomena.

44. PERSPECTIVE # 10 • HORMESIS: important implications for toxicology, risk assessment, risk communication, cost-benefit assessments, clinical medicine, drug development and numerous other areas

45. PERSPECTIVE # 11 • HORMESIS: should become the object of formal evaluation by leading advisory bodies such as the National Academy of Sciences

46. Estimate of articles showing hormesis • Total number of toxicology articles published since 1900 500,000 • 2% of the total number employed 6 or more doses 10,000 • 10% of articles have 3 doses  NOEL 1000 • 90% have 3 doses within 2 orders of magnitude of NOEL 900

47. Hormesis Curve