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Chemical Hormesis
Monty L. Herr, PhD, CIH
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.”
Dose-ResponseNoncarcinogenic Effects
Threshold ResponseCan determine a no-effect level
Dose-Response Curve
100%
ToxicResponse
Probability
Dose or Exposure0,0
o
o
NOAEL
o
Threshold Response Case
Dose-ResponseCarcinogenic Effects
• Nonthreshold response
• No dose is risk free
Dose-Response Curve
100%
ToxicResponse
Probability
Dose or Exposure0,0
o
o
o
Zero Threshold
Zero Threshold Linear Response Case
Dose-Response Curve
100%
ToxicResponse
Probability
Dose or Exposure
0,0
o
o
o
Non-Linear Response Case - Hormesis
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
Ed Calabrese
• Environmental Health Sciences Department
• University of Massachusetts
• Coworker: Linda Baldwin
Chemical Hormesis
• BELLE: Biological Effects of Low Level Exposures
• http://www.belleonline.com/
• Low-dose stimulation/high-dose inhibition - Arndt-Schultz Law
February 13, 2003
Dangerous levels of toxins miscalculated
Potential pollutants and poisons may be beneficial in low doses.
•
June 9, 2003
A Little Poison Can Be Good For You
The received wisdom about toxins and radiation may be all wet.
• September 2003
HORMESIS:
Nietzsche's Toxicology
• Whatever doesn't kill you might make you stronger
October 17, 2003
• HORMESIS:Sipping From a Poisoned Chalice
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.
December 19, 2003
Scientists Revisit Idea That a Little Poison Could Be Beneficial
By Sue Begley
•
• Knight Ridder papers• 27 February 2004• Hormesis Theory:
Tiny Bits of Toxins Do Affect People
• By Seth Borenstein
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
U.S. News and World ReportOctober 18, 2004
“Is There a Tonic in the Toxin?”
HORMESIS
• DEFINITION:– Dose response phenomenon characterized by a low
dose stimulation and a high dose inhibition.
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
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.
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
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
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
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
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
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
***
*
**
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
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
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
Results of initial screening organized by test model
Percent
Bacteria 9.3
Protozoa 3.0
Fungi 6.4
Plants 34.9
Animals 46.3
Generalizability of Hormesis
• Numerous species
• Broad range of chemical classes
• Broad range of biological endpoints
PERSPECTIVE # 1
• HORMESIS: a concept with much supportive experimental evidence that is reproducible
PERSPECTIVE # 2
• HORMESIS: Based on Perspective # 1 it should be considered as a real concept in the biological sciences
PERSPECTIVE # 3
• HORMESIS IS GENERALIZABLE– Across biological models– Across endpoints measured– Across Chemical Classes/Physical Agents
PERSPECTIVE # 4
• Based on Perspective # 3, HORMESIS is evolutionarily based, with broad potential implications
PERSPECTIVE # 5
• HORMESIS: very common in toxicological/pharmacological literature, making it a central concept
PERSPECTIVE # 6
• HORMESIS: a normal component of the traditional dose response, being graphically contiguous with the NO(A)EL.
PERSPECTIVE # 7
• HORMESIS: readily definable quantitative features, that are broadly generalizable, making it reasonably predictable.
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.
PERSPECTIVE # 9
• HORMESIS: no single hormetic mechanism; there appears to be a common underlying biological strategy underlying such phenomena.
PERSPECTIVE # 10
• HORMESIS: important implications for toxicology, risk assessment, risk communication, cost-benefit assessments, clinical medicine, drug development and numerous other areas
PERSPECTIVE # 11
• HORMESIS: should become the object of formal evaluation by leading advisory bodies such as the National Academy of Sciences
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
Hormesis Curve