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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.

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Presentation on theme: "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."— Presentation transcript:

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-Response Noncarcinogenic Effects Threshold Response Can determine a no-effect level

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

5 Dose-Response Carcinogenic Effects Nonthreshold response No dose is risk free

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

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

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

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

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

25 METHANOL + FRUIT FLY LONGEVITY Females Males

26 GAMMA RAYS + MOUSE LUNG ADENOMAS Males Females

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

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

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30 Source: Waalkes, 1988 CADMIUM AND RAT TESTICULAR CANCER

31 Results of initial screening organized by agent AgentPercent Alcohol and metabolites6.2 Antibiotics7.9 Auxin related4.6 Hydrocarbons3.4 Metals29.6 Herbicides7.2 Insecticides6.1 Fungicides1.5 Pesticides2.9 Miscellaneous30.6

32 Results of initial screen organized by endpoint Percent Growth62.2 Metabolic Effects 15.2 Longevity5.2 Survival5.7 Reproduction5.7 Miscellaneous5.8

33 Results of initial screening organized by test model Percent Bacteria9.3 Protozoa3.0 Fungi6.4 Plants34.9 Animals46.3

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


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