Chemical Hormesis

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Chemical Hormesis

• Monty L. Herr, PhD, CIH

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ParacelsusWhat is it that is not poison? All
things are poison and none without poison. Only
the dose determines that a thing is not poison.
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Dose-ResponseNoncarcinogenic Effects

• Threshold Response
• Can determine a no-effect level

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Dose-Response Curve
Threshold Response Case
100

o
o
o
Toxic Response Probability
NOAEL
0,0
Dose or Exposure
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Dose-ResponseCarcinogenic Effects

• Nonthreshold response
• No dose is risk free

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Dose-Response Curve
Zero Threshold Linear Response Case
100

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

o
o
o
Toxic Response Probability
0,0
Dose or Exposure
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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
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Ed Calabrese

• Environmental Health Sciences Department
• University of Massachusetts
• Coworker Linda Baldwin

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Chemical Hormesis

• BELLE Biological Effects of Low Level Exposures
• http//www.belleonline.com/
• Low-dose stimulation/high-dose inhibition -
  Arndt-Schultz Law

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February 13, 2003

• Dangerous levels of toxins miscalculated
• Potential pollutants and poisons may be
  beneficial in low doses.

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

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• September 2003
• HORMESIS
• Nietzsche's Toxicology
• Whatever doesn't kill you might make you stronger

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October 17, 2003

• HORMESISSipping From a Poisoned Chalice

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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.
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• December 19, 2003
• Scientists Revisit Idea That a Little Poison
  Could Be Beneficial
• By Sue Begley

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• Knight Ridder papers
• 27 February 2004
• Hormesis TheoryTiny Bits of Toxins Do Affect
  People
• By Seth Borenstein

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• 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

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

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HORMESIS

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

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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

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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.

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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
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Females





Males

METHANOL
FRUIT FLY LONGEVITY
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Males

Females

GAMMA RAYS
MOUSE LUNG ADENOMAS
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Testosterone









Luteinizing hormone

Alcohol and Rat Serum Levels
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Effects of metals on phagocytosis in the clam,
Mya arenaria, hemocytes
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(No Transcript)
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CADMIUM AND RAT TESTICULAR CANCER






Source Waalkes, 1988
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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

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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

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Results of initial screening organized by test
model

• Percent
• Bacteria 9.3
• Protozoa 3.0
• Fungi 6.4
• Plants 34.9
• Animals 46.3

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Generalizability of Hormesis

• Numerous species
• Broad range of chemical classes
• Broad range of biological endpoints

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PERSPECTIVE 1

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

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PERSPECTIVE 2

• HORMESIS Based on Perspective 1 it should be
  considered as a real concept in the biological
  sciences

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PERSPECTIVE 3

• HORMESIS IS GENERALIZABLE
• Across biological models
• Across endpoints measured
• Across Chemical Classes/Physical Agents

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PERSPECTIVE 4

• Based on Perspective 3, HORMESIS is
  evolutionarily based, with broad potential
  implications

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PERSPECTIVE 5

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

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PERSPECTIVE 6

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

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PERSPECTIVE 7

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

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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.

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PERSPECTIVE 9

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

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PERSPECTIVE 10

• 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 11

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

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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

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Hormesis Curve