Hormesis: What it Means for Toxicology, the Environment and Public Health

1. Hormesis: What it Means for Toxicology, the Environment and Public Health Edward J. Calabrese, Ph.D Environmental Health Sciences School of Public Health University of Massachusetts

2. Overview • How I Became Involved with Hormesis • Hormesis:Toxicological Foundations • Examples of Hormetic Responses • Comparison with Threshold Model • Hormesis and Risk Assessment

3. Hormesis Definition: • Dose response phenomenon characterized by a low dose stimulation and a high dose inhibition. • Generally similar quantitative features with respect to amplitude and range of the stimulatory response. • May be directly induced or the result of compensatory biological processes following an initial disruption in homeostasis.

4. HORMESIS Interpretation: • Issue of beneficial/harmful effects should not be part of the definition of hormesis. • This assessment should be reserved for a subsequent evaluation of the biological and ecological context of the response.

5. A Response B Response Dose • The most common form of the hormetic dose-response curve depicting low-dose • stimulatory and high-dose inhibitory responses, the - or inverted U-shaped curve. • The hormetic dose-response curve depicting low-dose reduction and high-dose • enhancement of adverse effects, the J- or U-shaped curve.

6. Hormesis and Evaluative Criteria Assessing the Dose-Response Continuum: • LOAEL-defining the toxic phase of the dose response • NOAEL (or BMD)-defining the approximate threshold • Below NOAEL (or BMD) doses-number and range • Concurrent Control

7. Hormesis and Assessment Criteria Dose Response Patterns Statistical Significance Replication of Findings

8. Evidence of Hormesis General Summary: • Hormesis databases: thousands of dose responses indicative of hormesis • Hormesis is a very general phenomenon: independent of model, endpoint and agent • Frequency of hormesis: far more frequent than threshold model in fair head-to-head comparisons

9. Dose Response Features Stimulation Amplitude: • Modest • 30-60% Greater Than Control • Usually Not More Than 100% Greater Than The Control

10. Stimulatory Range ~75 % - Within 20-Fold of NOAEL ~20% - >20<1000-Fold of NOAEL ~<2% - > 1000-Fold of NOAEL

11. 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

12. Hormetic Mechanisms Many studies have provided mechanistic explanations to account for observed hormesis responses; Each mechanism is unique to the model, tissue, endpoint and agent Some general examples: Often existence of opposing receptors

13. Methanol and Fruit Fly Longevity

14. Gamma Rays and Mouse Lung Adenomas

15. Transforming Growth Factor-Beta and Human Lung Fibroblasts

16. Effects of Acute Ethanol on Overall Social Activity of Adolescent Rats Tested on Postnatal Day 30

17. * * * * * * * Effect of X-rays on the Root Length of Carnation Cuttings *

19. * * Effect on Growth of Salt Marsh Grass

20. Comparative Dose Response Relationships for the Pain Threshold for Vocalization

21. * * * * * * * Effect of Different Doses of Morphine on PTZ-induced Seizure Threshold

22. * * * Alcohol and Rat Serum Levels

23. * * * MCPA + OAT SHOOT GROWTH

24. Effects of Metals on Phagocytosis in the Clam, Mya arenaria, hemocytes

26. Effect of Sodium Arsenate on PHA-treated Bovine Lymphocytes

28. * * * Effect of Gamma Rays on the Life Span of Female House Crickets * * * *

29. * * * * Effect of Acridine on the Number of Broods per Daphnid * *

30. Effect of Mistletoe Lectin on Human Tumors in Culture

31. Effects of Ten Estradiol A-ring Metabolites on Endothelial Cells from Human Umbilical Veins

32. Effect of Plumbagin on Human Granulocyte Phagocytosis

33. Effect of Tin (II) on MTT Conversion in C6 Glioma Cells

34. * * * * * Number of Open Arm Entries in the Elevated Plus Maze in Male C57BL/6 Mice Treated with DHEA *

35. * * * The Effects of Allixin on the Survival of Primary Cultured Hippocampal Neurons from Embryonic (E18) Wistar Rats *

36. * * * * * The Effects of Methyl Mercury on Viability as Measured by Mitochondrial Dehydrogenase Activity in the D407 Cell Line *

37. Effects of the Disinfectant Byproduct MX on the Occurrence of DNA Damage in the Comet Assay Using Rat Liver Epithelial Cell Line WB-F344

38. Effects of n-Hexane on DNA Damage in Human Lymphocytes in the Comet Assay

39. Effects of As2O5 on Total Chromosomal Aberrations in Human Leukocytes

40. Effects of X-rays on Chromosomal Aberrations (i.e., Dicentrics) in Human Lymphocytes (pooled results of four donors and six laboratories)

41. Effect of DDT on Liver Foci Formation in Male F344 Rats

42. Bladder Tumor Incidence Adjusted for Time in ED01 Megamouse Study

43. Hormetic or Threshold Which Dose Response Is More Common?

44. The Threshold Model Prediction: Random Bounce Below the Threshold as Practically Defined by the NOA(E)L or BMD

45. The Hormesis Model • Predicts that responses to doses in the below toxic threshold zone should be non-randomly distributed • The non-randomness should be reflected in the frequency of responses above and below the control value and in the magnitude of the deviation from the control

46. Hypothesis Evaluation Dose-Response Evaluation Criteria Entry Criteria: Estimate a LO(A)EL Estimate a NO(A)EL or BMD One or more doses below NO(A)EL or BMD

47. Testing Threshold Model Predictions Three Separate Database Evaluations: • Toxicological Literature - multiple models/endpoints - reviewed 21,000 articles with entry criteria to yield 800 dose responses • Yeast Cell Strains - 13 strains/2,200-57,000 dose responses-cell proliferation • E. coli – approximately 2,000 chemicals tested over 11 concentrations - cell proliferation

48. 100 90 Threshold ModelPredictedMean 80 70 60 Mean Cumulative Percent of Chemicals 50 PredictionInterval 95% 40 30 20 10 -10 0 10 30 40 50 60 70 -20 20 Percent Difference From Control Growth

49. 100 BMD10.0 90 BMD 7.5 80 70 BMD 5.0 BMD 2.5 60 Cumulative Percent of Chemicals 50 40 30 20 10 0 -20 -10 0 10 20 30 40 50 60 70 80 Percent Difference From Control Growth

50. Threshold Model Inconsistencies • Below threshold responses do not provide evidence of random bounce • Non-random responses clearly predominate • The non-random responses discredit the Threshold Dose Response Model • Findings are consistent with the Hormetic Dose Response Model