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