chemical hormesis monty l. herr, phd, cih. paracelsus what is it that is not poison? all things are...
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Chemical Hormesis
Monty L. Herr, PhD, CIH
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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.”
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Dose-ResponseNoncarcinogenic Effects
Threshold ResponseCan determine a no-effect level
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Dose-Response Curve
100%
ToxicResponse
Probability
Dose or Exposure0,0
o
o
NOAEL
o
Threshold Response Case
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Dose-ResponseCarcinogenic Effects
• Nonthreshold response
• No dose is risk free
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Dose-Response Curve
100%
ToxicResponse
Probability
Dose or Exposure0,0
o
o
o
Zero Threshold
Zero Threshold Linear Response Case
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Dose-Response Curve
100%
ToxicResponse
Probability
Dose or Exposure
0,0
o
o
o
Non-Linear Response Case - Hormesis
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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
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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
• HORMESIS:Sipping 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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•
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• Knight Ridder papers• 27 February 2004• Hormesis Theory:
Tiny Bits of Toxins Do Affect People
• By Seth Borenstein
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April 5, 2004
LOW-DOSE EFFECTSDebate 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 ReportOctober 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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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
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0
20
40
60
80
100
120
140
0 0.25 0.5 1 2 4 8
Methanol (%)
Lo
ng
evi
ty (
% c
on
tro
l)
METHANOL +FRUIT FLY LONGEVITY
Females
Males
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0
20
40
60
80
100
120
140
0 10 25 50 100 150 200 300
Gamma ray dose (rad)
Inci
de
nce
(%
co
ntr
ol)
GAMMA RAYS +MOUSE LUNG ADENOMAS
Males
Females
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020
406080
100120140160
180200220
240260
0 0.5 0.75 1 1.25 1.5 2 2.5 3
Alcohol (g/kg)
Se
rum
leve
l (%
co
ntr
ol)
*
Alcohol andRat Serum Levels
*
*Testosterone
Luteinizing hormone
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020406080
100120140160180200220240260
0 1E-09 1E-08 1E-07 1E-06 1E-05 1E-04 0.001
Metal Concentration (M)
Ph
ag
ocy
tosi
s A
ctiv
ity (
% c
on
tro
l)
HgCl2
MethHgCl
CdCl2
ZnCl2
Effects of metals on phagocytosis in the clam, Mya arenaria,
hemocytes
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0
20
40
60
80
100
120
140
160
0 0.01 0.1 1 10 40 80
Cadmium (uM)
Nitr
ate
redu
ctas
e (%
con
trol
)*
Cadmium andAquatic Plant (H. verticillata)
Nitrate Reductase Activity
**
* *
In vivo
In vitro
***
*
**
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0
50
100
150
200
250
300
350
400
450
500
0 1 2.5 5 10 20 40
Cadmium chloride (uM/kg)
Tu
mo
r in
cid
en
ce (
% c
on
tro
l)
Source: Waalkes, 1988
CADMIUM AND RAT TESTICULAR CANCER
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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/pharmacological 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