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Chemical Hormesis Monty L. Herr, PhD, CIH.

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Presentation on theme: "Chemical Hormesis Monty L. Herr, PhD, CIH."— Presentation transcript:

1 Chemical Hormesis Monty L. Herr, PhD, CIH

2 Paracelsus “What is it that is not poison
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 Threshold Response Case
Dose-Response Curve Threshold Response Case 100% o o o Toxic Response Probability As a result, a range of exposure exists from zero to some finite value that can be tolerated by the organism with essentially no adverse effects. In developing a toxicity value for evaluating noncarcinogenic effects, the approach is to identify the upper bound of this tolerance range (i.e., the maximum subthreshold level). In dose-response experiments, an exposure level at which there are no statistically or biologically significant increases in the frequency or severity of adverse effects between the exposed population and its appropriate control is called the no-observed-adverse-effects level (NOAEL). Some effects may be produced at this level, but are not considered to be adverse, nor precursors to specific adverse effects. Because variability exists in the human population, attempts are made to identify a subthreshold level protective of sensitive individuals in the population. For most chemicals, this level can only be estimated. NOAEL 0,0 Dose or Exposure

5 Dose-Response Carcinogenic Effects
Nonthreshold response No dose is risk free Carcinogenesis is generally assumed to be a nonthreshold phenomenon. For carcinogens, a small number of molecular events are assumed to evoke changes in a single cell that can lead to uncontrolled cellular proliferation and to disease. It is assumed that there is essentially no level of exposure that does not pose a finite probability, however small, of generating a carcinogenic response. No dose is assumed to be risk-free. For carcinogenic effects, a two-part evaluation process is used in which the substance first is assigned a weight-of-evidence classification, and then a slope factor is calculated.

6 Zero Threshold Linear Response Case
Dose-Response Curve Zero Threshold Linear Response Case 100% o o o Toxic Response Probability As a result, a range of exposure exists from zero to some finite value that can be tolerated by the organism with essentially no adverse effects. In developing a toxicity value for evaluating noncarcinogenic effects, the approach is to identify the upper bound of this tolerance range (i.e., the maximum subthreshold level). In dose-response experiments, an exposure level at which there are no statistically or biologically significant increases in the frequency or severity of adverse effects between the exposed population and its appropriate control is called the no-observed-adverse-effects level (NOAEL). Some effects may be produced at this level, but are not considered to be adverse, nor precursors to specific adverse effects. Because variability exists in the human population, attempts are made to identify a subthreshold level protective of sensitive individuals in the population. For most chemicals, this level can only be estimated. Zero Threshold 0,0 Dose or Exposure

7 Non-Linear Response Case - Hormesis
Dose-Response Curve Non-Linear Response Case - Hormesis 100% o o o Toxic Response Probability As a result, a range of exposure exists from zero to some finite value that can be tolerated by the organism with essentially no adverse effects. In developing a toxicity value for evaluating noncarcinogenic effects, the approach is to identify the upper bound of this tolerance range (i.e., the maximum subthreshold level). In dose-response experiments, an exposure level at which there are no statistically or biologically significant increases in the frequency or severity of adverse effects between the exposed population and its appropriate control is called the no-observed-adverse-effects level (NOAEL). Some effects may be produced at this level, but are not considered to be adverse, nor precursors to specific adverse effects. Because variability exists in the human population, attempts are made to identify a subthreshold level protective of sensitive individuals in the population. For most chemicals, this level can only be estimated. 0,0 Dose or Exposure

8 (averages 130-160% of control)
Hormesis Curve Maximum response (averages % 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
Low-dose stimulation/high-dose inhibition - Arndt-Schultz Law

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

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

13 Nietzsche's Toxicology
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 A scientist finds benefit in small doses of toxins
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 Scientists Revisit Idea That a Little Poison Could Be Beneficial
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 LOW-DOSE EFFECTS April 5, 2004
Debate expands on how to extrapolate data from high-dose tests for environmental contaminants. By Cheryl Hogue, pp

20 U.S. News and World Report “Is There a Tonic in the Toxin?”
October 18, 2004 “Is There a Tonic in the Toxin?” In the October 18 issue of US News and World Report, there was a two-page article entitled “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 (averages 130-160% of control)
Hormesis Curve Maximum response (averages % 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
Doses showing a stimulatory response in the low dose zone did not achieve statistical significance. Source: Brousseau, P., Pellerin, J., Morin, Y., Cyr, D., Blakley, B., Boermans, H., and Founier, M. (2000). Flow cytometry as a tool to monitor the disturbance of phagocytosis in the clam Mya arenari hemocytes following in vitro exposure to heavy metals. Toxicology, 142:

29

30 CADMIUM AND RAT TESTICULAR CANCER
SETAC NLDR Source: Waalkes, 1988

31 Results of initial screening organized by agent
Agent Percent Alcohol and metabolites 6.2 Antibiotics Auxin related Hydrocarbons Metals Herbicides Insecticides Fungicides Pesticides Miscellaneous

32 Results of initial screen organized by endpoint
Percent Growth 62.2 Metabolic Effects 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


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