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

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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

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Overview

• How I Became Involved with Hormesis
• HormesisToxicological 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.

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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.

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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.

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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

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Hormesis and Assessment Criteria

• Dose Response Patterns
• Statistical Significance
• Replication of Findings

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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

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Dose Response Features

• Stimulation Amplitude
• Modest
• 30-60 Greater Than Control
• Usually Not More Than 100 Greater Than The
  Control

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Stimulatory Range

• 75 - Within 20-Fold of NOAEL
• 20 - gt20lt1000-Fold of NOAEL
• lt2 - gt 1000-Fold of NOAEL

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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
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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

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Methanol and Fruit Fly Longevity
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Gamma Rays and Mouse Lung Adenomas
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Transforming Growth Factor-Beta and Human Lung
Fibroblasts
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Effects of Acute Ethanol on Overall Social
Activity of Adolescent Rats Tested on Postnatal
Day 30
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Effect of X-rays on the Root Length of Carnation
Cuttings

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Effect on Growth of Salt Marsh Grass
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Comparative Dose Response Relationships for the
Pain Threshold for Vocalization
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Effect of Different Doses of Morphine on
PTZ-induced Seizure Threshold

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Alcohol and Rat Serum Levels
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MCPA
OAT SHOOT GROWTH
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Effects of Metals on Phagocytosis in the Clam,
Mya arenaria, hemocytes
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Effect of Sodium Arsenate on PHA-treated Bovine
Lymphocytes
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Effect of Gamma Rays on the Life Span of Female
House Crickets




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Effect of Acridine on the Number of Broods per
Daphnid


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Effect of Mistletoe Lectin on Human Tumors in
Culture
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Effects of Ten Estradiol A-ring Metabolites on
Endothelial Cells from Human Umbilical Veins
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Effect of Plumbagin on Human Granulocyte
Phagocytosis
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Effect of Tin (II) on MTT Conversion in C6 Glioma
Cells
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Number of Open Arm Entries in the Elevated Plus
Maze in Male C57BL/6 Mice Treated with DHEA

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

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

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Effects of the Disinfectant Byproduct MX on the
Occurrence of DNA Damage in the Comet Assay Using
Rat Liver Epithelial Cell Line WB-F344
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Effects of n-Hexane on DNA Damage in Human
Lymphocytes in the Comet Assay






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Effects of As2O5 on Total Chromosomal Aberrations
in Human Leukocytes






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






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Effect of DDT on Liver Foci Formation in Male
F344 Rats







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Bladder Tumor Incidence Adjusted for Time in
ED01 Megamouse Study







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Hormetic or Threshold

• Which Dose Response Is More Common?

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The Threshold Model

• Prediction Random Bounce Below the Threshold as
  Practically Defined by the NOA(E)L or BMD

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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

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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

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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

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100
90
Threshold Model Predicted Mean
80
70
60
Mean
Cumulative Percent of Chemicals
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Prediction Interval 95
40
30
20
10
0
10
30
40
50
60
70
-10
20
-20
Percent Difference From Control Growth
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100
BMD 10.0
90
BMD 7.5
80
70
BMD 5.0
BMD 2.5
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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
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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

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Why Has Toxicology Missed Hormesis?

• Modest Response - could be normal variation
• Emphasis on High Doses - need to define the NOAEL
  and LOAEL
• Use of only few doses

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Why is Hormesis Important?

• It will change how toxicologists,
  pharmacologists, risk assessors, and physicians
  do their jobs
• It will change the risk communication message

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Hypothesis Testing

• Expands Dose Response Spectrum
• Creates New Categories of Questions

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Study Design

• Number of Doses/Concentrations
• Spacing of Doses/Concentrations
• Temporal Features
• Key feature in recognizing the compensatory
  nature of the hormetic dose response

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Implications of New Design Considerations

• Additional Costs For
• Extra Doses
• Multiple Temporal Evaluations
• Enhanced Need for Replication

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Possible Adjustments

• Less than lifetime studies/different endpoints
• Less expensive models cell culture,
  invertebrates, fish, etc.
• increases sample size for statistical power

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Endpoint Selection

• Background Incidence
• Low Background Disease Incidence Precludes
  Ability to Detect Possible Hormetic Response

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Biomathematical Modeling

• Implications for Cancer Risk Assessment
• Models flexibility to fit observed data
• Models not constrained to always be linearly
  decreasing at low doses
• Low Dose Risk Characterization include
  likelihood of below background risks
• Uncertainty Characterization include both upper
  and lower bounds.

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Environmental

• Re-Defining Hazard Assessment
• Re-Defining Dose Response Default
• Re-Evaluation of Risk Assessment Practices
• Harmonization Cancer and Non-Cancer
• Cost-Benefit Re-Assessment

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Therapeutics

• Cognitive Dysfunction
• Immune Stimulation
• Anti-Tumor
• Anti-Viral
• Anti-Bacterial

• Angiogenesis
• Cytokine/Hospital Infections
• Hair Growth
• Molecular Designs

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Life Style

• Exercise
• Alcohol Consumption
• Stress

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Perspective 1

• The Threshold Dose Response Model fails to make
  accurate predictions in the below threshold zone

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Perspective 2

• The Threshold Dose Response Model has been
  significantly out-competed by the Hormetic Dose
  Response Model in multiple, independent
  comparisons

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Perspective 3

• There is little toxicological justification for
  the continued use of the threshold dose response
  to estimate below threshold responses

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Perspective 4

• Given Perspectives 1-3, there is no basis to use
  the threshold dose response model in risk
  assessment practices. This has significant
  implications for current standards based on the
  threshold model and future risk assessment
  practices

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Perspective 5

• HORMESIS a concept with much supportive
  experimental evidence that is reproducible

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Perspective 6

• HORMESIS Based on Perspective 5 it should be
  considered as a real concept in the biological
  sciences

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Perspective 7

• HORMESIS is Generalizable
• Across Biological Models
• Across Endpoints Measured
• Across Chemical Class/Physical Agents

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Perspective 8

• Based on Perspective 7, HORMESIS is
  evolutionarily based, with broad potential
  implications

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Perspective 9

• HORMESIS very common in toxicological/pharmacolo
  gical literature, making it a central concept

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Perspective 10

• HORMESIS a normal component of the traditional
  dose response, being graphically contiguous with
  the NO(A)EL

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Perspective 11

• HORMESIS readily definable quantitative
  features, that are broadly generalizable, making
  it reasonably predictable

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Perspective 12

• 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

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Perspective 13

• The low dose hormetic stimulatory response is a
  manifestation of biological performance and
  estimates biological plasticity in the effected
  systems

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Perspective 14

• HORMESIS no single specific hormetic mechanism
  there appears to be a common biological strategy
  underlying such phenomena

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Perspective 15

• HORMESIS important implications for toxicology,
  risk assessment, risk communication, cost-benefit
  assessments, clinical medicine, drug development
  and numerous other areas

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Perspective 16

• HORMESIS Should Become the Default Model in Risk
  Assessment Why?
• More Common By Far Than Other Models
• Can Be Validated or Discredited with Testing
• Generalizable by Biological Model, Endpoint and
  Chemical Class

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Perspective 17

• HORMESIS should become the object of formal
  evaluation by leading advisory bodies such as the
  National Academy of Sciences