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Chemical Hormesis

Chemical Hormesis. Monty L. Herr, PhD, CIH. 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.”. Dose-Response Noncarcinogenic Effects. Threshold Response Can determine a no-effect level.

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Chemical Hormesis

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  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

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

  18. 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

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

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

  21. 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

  22. 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.

  23. 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

  24. Females Males METHANOL + FRUIT FLY LONGEVITY

  25. Males Females GAMMA RAYS + MOUSE LUNG ADENOMAS

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

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

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

  29. 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

  30. 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

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

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

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

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

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

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

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

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

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

  40. 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.

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

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

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

  44. 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

  45. Hormesis Curve

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