Biological Effects of

Low Level Exposures

A Publication of the Northeast Regional Environmental Public Health Center, University of Massachusetts, School of Public Health, Amherst, MA 01003
Vol. 13 No. 2 Part I, September 2005, ISSN 1092-4736

BIOMEDICAL IMPLICATIONS OF
HORMESIS – PART 1

INTRODUCTION
While the hormesis concept has often been
assessed within the context of its risk
assessment implications, it is becoming
more widely recognized that will also have
at least as large and significant an
impact on the biomedical sciences. Con-
sequently, this issue of the BELLE News-
letter is devoted to an exploration of some
of the biomedical implications of hormesis.
Since we believe that these articles repre-
sent only the so-called tip of the iceberg in
terms of biomedical implications of
hormesis, we hope that this issue will
encourage others to explore their areas of
investigation. It is our hope that im-
proved knowledge of the dose response and
their interactions with adaptive mecha-
nisms will enable researchers to explore
and find practical ways to enhance the
health of patients and entire populations.
The present contributions not only provide
detailed and integrative information on
this topic but also often point the direction
where important developments are likely.
TABLE OF CONTENTS
INTRODUCTION: BIOMEDICAL IMPLICATIONS OF
HORMESIS – PART1 Edward Calabrese...............................1
SHOULD WE EXPLORE THE CLINICAL UTILITY OF
HORMESIS? Wayne B. Jonas................................................2
THE MANAGED IMMUNE SYSTEM: PROTECTING THE
WOMB TO DELAY THE TOMB Rodney R. Dietert and
Michael S. Piepenbrink..........................................................7
LOW-DOSE RADIATION AND ITS CLINICAL IMPLICA-
TIONS: DIABETES Guan-Jun Wang, Xiao-Kun Li,
Kazuo Sakai and Lu Cai.....................................................12
BREAST CANCER, CHEMOTHERAPY AND HORMESIS
Lorne J. Brandes.................................................................22
NONLINEARITY IN BIOLOGY, TOXICOLOGY AND
MEDICINE JOURNAL.....................................................28
INTERNATIONAL HORMESIS SOCIETY .......................28
IHS APPLICATION FOR MEMBERSHIP..........................29
ADVISORY COMMITTEE................................................31
 hormesis with the fringe medical system called homeopa-
SHOULD WE thy, the powerful effects of pharmacology at high doses,
and the disastrous effects of early, unscientific attempts
EXPLORE THE to clinically apply radiation hormesis.

CLINICAL UTILITY Use and Definitions of Hormesis in Toxicology

OF HORMESIS? The term hormesis was coined by two toxicologists in

Wayne B. Jonas, MD
Director, Samueli Institute for Information Biology
1700 Diagonal Road
Suite 400
Alexandria, Virginia 22314
Phone: 703-299-4800
Fax: 703-535-6752
Email: wjonas@siib.org
John A. Ives, PhD
Samueli Institute for Information Biology
1700 Diagonal Road
Suite 400
Alexandria, Virginia 22314
Phone: 703-299-4800
Fax: 703-535-6752
Email: jives@siib.org
ABSTRACT
The idea that low-dose adaptive effects as described in
hormesis can be used clinically has been discussed for
hundreds if not thousands of years. Paracelsus famous
adage that “the dose makes the poison” and the common
folk saying that one can be cured by “the hair of the dog
that bit you” speak to this idea. So why has so little
research been done on the possible clinical utility of
hormesis? What areas of clinical hormesis seem to be the
most promising to explore? This article examines these
concepts and proposes some initial areas of research
where the possible utility of hormeiss might be investi-
gated.
WHY HAS CLINICAL HORMESIS NOT
BEEN DEVELOPED?
Given the growing literature on hormesis and its poten-
tially wide clinical utility, why has research on the clinical
effects of hormetic dose-responses not been more
extensively explored? We propose that a number of
obstacles to the investigation of clinical hormesis have
prevented its development. These include an almost
exclusive use of the term in toxicology, the inaccurate
definition of hormesis in its early years, the association of
1943 and its discussion has, until recently, remained as a
small discussion in the toxicology literature. 1 Its implica-
tions remain focused mostly around environmental risk
assessment. Only recently has the term been used in a
standard textbook of pharmacology, yet most pharma-
cologists we speak to are not familiar with the term. The
initial definitions of hormesis revolved around stimula-
tory effects of low-doses of toxins often emphasizing an
apparent positive rather than adaptive, nature of sub-
stances that were normally associated with adverse
effects. 2 This was interpreted by some skeptics as an
attempt to push the beneficial nature of the area rather
than more precisely define and understand the science.
When Ed Calabrese and Linda Baldwin, two toxicolo-
gists, began to show that hormetic dose-responses were
widespread outside the field of toxiciology the discussion
began to take on a more interdisciplinary nature, with
the recent creation of the professional association the
International Hormesis Society. 3 Still, few physicians or
clinical investigators are involved in this Society or the
field.
Association with Homeopathy
In contrast to toxicologists’ failure to discuss the clinical
implications of hormesis, practitioners of the fringe
medical system called homeopathy were more than
willing to use the concept in an attempt to justify their
practice. Schulz, one of the first to describe the
hormetic phenomenon believed he had discovered the
underlying mechanism of homeopathy. This further
contaminated any discussion of possible clinical use of
the concept. 2 Homeopaths were ousted from main-
stream medicine and often fought with conventional
practitioners. In addition, they held to the irrational
claim that dilutions beyond Avogadro’s number still had
effects. 4 Some of their drugs were eventually found
useful in conventional medicine, although at higher
doses. Instead of clearly differentiating the study of
clinical hormesis from homeopathy, however, many in
the field of hormesis avoided the concept all together,
refusing to discuss or explore any clinical applications.
This is unfortunate since the rising use of complemen-
tary and alternative medicine has created an increased
interest in the low-dose effects of chemicals in foods,
herbs, and homeopathic substances as well as other
stimulatory interventions such as exercise and psycho-
therapy. 5, 6 Hormesis may offer insights into the mecha-
nisms of some of these therapies. For example, it is
possible that the reported effects from ultra-high dilu-
tions in homeopathy are due to hormetic dose-responses

2 BELLE Newsletter
secondary to the borosilicate contaminants derived from
the glass in which these preparations are made. Most
homeopathic medicines are made in glass and significant
amounts of borosilicates contaminate their solutions. 7
Silicates are often bioactive. Thus, a likely explanation
for the reported effects in homeopathy is secondary
silicate contamination.
The Power of Pharmacology
It was around the same time the phenomenon of
hormesis was being explored in toxicology, that the
powerful effects of high dose pharmacology was being
demonstrated and widely used. These discoveries over-
shadowed any interest in the clinical effects of low doses.
Antibiotics, anesthetics, analgesics and chemotherapeu-
tic agents produced such dramatic effects that the almost
exclusive focus in pharmacology was on the discovery of
new therapeutic agents and agents with lower toxicity,
not the potential use of low-doses of drugs. At the same
time, misguided attempts to apply radiation hormesis
resulted in disaster. When Eben Byers, a millionaire
promoter of a radioactive “longevity tonic” called
Radithor, died of radiation poisoning in 1932, the idea of
clinical applications of hormesis took another hit, since
he had promoted the tonic as scientifically proven
because of hormesis. 8
RESEARCH ON THE POSSIBLE
CLINICAL UTILITY OF HORMESIS
There is a growing literature on exploring the possible
utility of hormetic dose-response effects. Ed Calabrese
and Linda Baldwin have summarized several areas of
hormesis that may have clinical implications and applica-
tions. Alzheimer’s, bone remineralization, tumor growth
and revascularization, hair growth, and viral infections
all have evidence of hormesis as an approach to treat-
ment. 9 A recent special issue in Critical Reviews in Toxicol-
ogy focused on hormetic dose-response relationships in
immunology including its use in bacterial and viral
disease, lupus, Grave’s disease, acute respiratory diseases,
and cancer. 10 Hormetic dose-response relationships may
be the basis for treatment outside toxicology in areas of
psychology and stress management. 11
There may be wide potential for clinical applications of
hormesis. It is now well established that low-doses of
toxic and infectious agents often stimulate growth, repair
and protective processes in cells, animals and humans.
These effects are found to occur with a number of
toxins, drugs, viral, and bacterial agents including
environmental toxins and those used for chemical,
biological, nuclear and radiation [CBRN] terrorist
purposes. 12 Hormetic responses occur in various cell
lines, tissues, animal and plant species and humans and
have been observed after exposure to low levels of toxic
chemicals 3, 13, including heavy metals 14, infectious agents
Vol. 13, No. 2 Part I, September 2005
, as well as ionizing radiation 16 and in trauma. 17, 18
15
Exposure to low-level stressors can induce both general
and specific protective effects. Studies have demon-
strated this occurs from exposure to ischemia, heat,
hydrogen peroxide, nicotine, oxygen radicals, alcohol,
heavy metals (e.g., cadmium, arsenic, lead), cytotoxic
and carcinogenic agents used for chemotherapy (e.g.,
adriamycin, cisplatinum), interleukin-1 (and other
cytokines), gram-negative organisms and other stressors.
3, 18, 19
Reduced mortality as well as reduced cellular and
organ damage has been found in brain, liver, kidney,
lung, muscle, and in a number of isolated cell lines. Is it
possible to use such low-dose exposures to rapidly induce
protective and therapeutic effects to toxic exposures and
stresses without causing harm? 20 Protective effects can
occur well below the no observable adverse effect level
(NOAEL). Could hormesis offer an alternative approach
for the mitigation of a number of toxic and infectious
agents but with potentially wider application, safety and
flexibility than current vaccine and anti-toxin ap-
proaches?
There are a number of examples whereby exposure to
sub-toxic doses of otherwise toxic compounds confers
protection and treatment against higher toxic doses of
the same or similar harmful compounds. 20 We call this
concept Rapid Induction of Protective Tolerance
(RIPT). RIPT occurs by inducing a stimulatory effect on
cell repair, tolerance and protective processes. One
challenge in the study of this area is that significant
clinical effects would likely arise from a coordinated
whole organism response of inherent [self-derived]
healing and defense processes that are complex to
investigate. The clinical value of hormesis may be most
evident if multiple, redundant mechanisms are induced.
21, 9
Many cellular protective mechanisms are distinct from
immune stimulation, like that produced by vaccines, yet
immune mechanisms may enhance and extend a RIPT
effect. 10 If true, this would allow rapid use of hormesis in
a wide variety of situations including terrorism, environ-
mental toxicity, drug toxicity, cancer and emerging
infections such as influenza, SARS and Avian flu.
RECENT RESEARCH ON POTENTIAL
APPLICATIONS OF HORMESIS
We have been investigating the potential protective
effects of low level exposure using a number of toxins in
a variety of studies. Our program on protective and
treatment effects examines the biological effects of low
level exposures to physical, chemical, and biological
agents as a simple method for modulating the adverse
effects from exposure to higher doses of the same toxins.
22
The method could be applicable to self-treatment of
toxin exposure by soldiers on the battlefield and for
protecting civilian populations from terrorist
3
attack as well as in other biomedical areas. Potential
areas of application in need of further investigation
include the following.
Terrorism and Biowarfare Protection
There is evidence that rapid induction of protective
tolerance (RIPT) against biowarfare and terrorists agents
may be feasible. 23 An early double-blind clinical study of
the biowarfare agent mustard gas demonstrated that low-
dose mustard gas and similar blistering agents reduced
damage to mustard in humans. 24 Little research on the
concept followed, however. We recently did a compre-
hensive, systematic review of the CBRN literature for
studies examining the stimulatory and protective effects
for the top 10 CBRN terrorist agents. 25 The area is rarely
investigated, but most studies that specifically looked for
stimulatory or protective effects, found them, including
with the potent neurotoxins soman and sarin. Jonas and
Dillner 15 investigated whether low-dose preparations of
infected tissue given to mice could induce protection
against a higher infectious challenge by the same organ-
ism. Their data demonstrated that these preparations
consistently increase mean survival time and decrease
the mortality from Francisella tualrensis infection, a top
biowarfare threat agent.
Brain Injury
Recently, Jonas, Tortella and Ives 17, 18, 26, 27 have shown that
RIPT can be used to reduce brain injury after trauma.
Low dose glutamate [the primary toxin released during
brain injury] reduces core brain damage by 40% in
animal brain injury models. By complexing glutamate
with low-dose silica particles its effectiveness was mark-
edly enhanced through induction of several classes of
proteins. 18 28 Importantly, brain damage was reduced
even when low dose glutamate/silica was administered
after the trauma providing evidence that the RIPT
concept may be a useful approach for both prevention
and treatment in brain injury and stroke. The combina-
tion of a low-dose toxin with silica appears to be a key
mechanism for enhancement of the effects of various
toxic agents when given at low-dose and through the
stimulation of protective proteins. As mentioned above,
silica-toxin complexes may also provide a rational
explanation for the reported effects of homeopathy
rather than unplausible explanations such as “memory
in water.”
Environmental Toxins and Cancer
The RIPT approach may also help mitigate the effects of
environmental toxins such as arsenic, mercury and
cadmium. We conducted a meta-analysis of the literature
on the low-dose protective effects of environmental
toxins of various types. 29, 30 Significant protective effects
were demonstrated in repeated studies with arsenic and
mercury, two of the most important environmental
4 BELLE Newsletter
toxins worldwide. Low dose arsenic and mercury en-
hanced toxin excretion up to 40% and reduced mortality
to lethal doses by 19%. These findings have recently
been confirmed by others 31. Similar work with cadmium
is reported in several studies. 32, 33 As with CBRN and
brain injury agents, the rapid induction of protective
proteins appears to be an important mechanism. Van
Wijk demonstrated that specific patterns of heat shock
proteins [hsp] predicted cross protection to a variety of
environmental toxins. 22 We have shown in our laborato-
ries that non-toxic, low-dose cadmium exposure rapidly
stimulates specific methallothienien production [a
protective protein] and its mRNA signal, which can be
maintained for weeks 32 with no adverse effects on cell
growth, replication, function or mortality. Subsequent
exposure of the same cells to higher doses of cadmium
showed delayed transformation into cancer usually
produced by cadmium. Thus, a “window of protection”
to specific agents can be turned on and off for weeks at a
time apparently without harm.
Emerging Infections
Many infectious viral and bacterial organisms rapidly
mutate and evolve into either more virulent or drug-
resistant forms. With increasingly mobile world popula-
tions and wide use of anti-viral and anti-bacterial drugs
the stage is set for an accelerated emergence of more
virulent viruses that are resistant to treatment. Examples
include SARS, Avian flu, influenza, tuberculosis and
malaria. The possible emergence of Avian flu in Vietnam
further highlights the urgent need for alternative
approaches to protection and treatment. For over a
hundred years certain physicians have claimed, with no
scientific evidence, that low-dose preparations of such
agents can protect and mitigate the effects of infectious
disease 34. Veterinarians routinely use such agents to
induce herd immunity in agriculture. However, there is a
paucity of research and the reports from scientific
studies are mixed. 35, 36 Several double-blind trials on the
prevention and treatment of influenza appear to support
such claims and call for further investigation. 37 As
mentioned previously, these effects may be due to the
immunostimulatory effects produced by silica and glass
contaminates in the preparations. Other recent research
has demonstrated that a reduced dose of influenza
vaccine can be as effective as higher doses when properly
administered. 38 More research investigating the possibil-
ity of using a RIPT approach to emerging infections is
needed.
Research is required on the low dose induction of the
body’s protective mechanisms to explore the possible use
of RIPT on the battlefield, against bioterrorism, and for
other purposes. The major challenges in the study of
RIPT include: 1) the need for a sound mechanistic basis
for the study of low-dose stimulation, 2) difficulty in
optimizing low-dose effects, and 3) the failure to exam-
ine the entire dose-response range for various toxins. 30
RIPT research could produce an internal “cellular
bioshield” against toxins.
PROPOSED AREAS OF STUDY FOR THE
CLINICAL UTILITY OF HORMESIS
We propose that a research effort to investigate the
clinical utility of hormesis be developed and focus on the
following areas.
Toxins. Examination of the protective effects and
cellular mechanisms of low-doses in cellular
systems using several types of cell stressors (tox-
ins). An initial focus might be toxins with high
terrorist potential, including botulinum toxin,
cyanide, paraoxon, cadmium, arsenic, con-G and
ricin.
Viruses. Both tissue culture and animal models
should be investigated in an effort to develop low
dose approaches against viral agents including
influenza and emerging infectious agents such as
Avian flu.
Brain injury. Protection against brain injury due to
ischemia and neurotransmitter poisoning should
be investigated using glutamate and low doses of
silica. Proteometric and immunostaining methods
could be used to elucidate molecular mecha-
nisms.
Cancer. Studies that will screen a variety of chemicals
for their potential protective effects against cancer
in animal and tissue culture models are needed.
Effective substances would be further studied
using genomic and proteometric methods to
elucidate mechanisms.
In addition, areas that may involve hormetic dose-
responses should be explored.
These include:
Food and Diet. Are the salutogenic effects of low-
calorie diets a hormetic response? If so, what
chemicals in foods might account for these
effects? This area would examine the value of
therapeutic food from the hormetic perspective. 39
Exercise. Are the salutogenic effects of exercise due
to hormesis? If so, we should explore the genomic
and proteomic markers that correlate with this
effect so as to individualize the amount of exercise
optimal for each individual.
Herbs. Many herbal preparations use low-doses of
multiple substances to achieve their effects. Are
these effects hormetic in nature?
Homeopathy. Notwithstanding the criticism of
homeopathy above, many homeopathic sub-
stances are not given in ultra-low doses. These
substances may produce hormetic effects at low-
doses like herbal preparations.
Stress management. Many stress management
Vol. 13, No. 2 Part I, September 2005
programs involve the application of small inter-
mittent “doses” of stressful stimulation as an
effective method for inducing increased tolerance
to stress. Calabrese and others have suggested this
may represent a clinical hormetic application. 11
The clinical utility of hormesis is a vast, largely un-
charted area, yet the potential clinical implications of
low-dose effects are great. These areas should be investi-
gated using rigorous scientific methods in both basic
and clinical studies.
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THE MANAGED
IMMUNE SYSTEM:
PROTECTING THE
WOMB TO DELAY
THE TOMB
Rodney R. Dietert and Michael S. Piepenbrink
Department of Microbiology and Immunology
College of Veterinary Medicine
Cornell University
Ithaca, NY 14853
Phone: 607 253-4015
Fax: 607 253-3384
Email: rrd1@cornell.edu
Key Words: Immune balance, Skewed responses,
Perinatal development, Environmental management
ABSTRACT
It is likely to come as a surprise to most lay audiences
that much of our safety net for ensuring protection
against the adverse effects of chemicals in the environ-
ment or drugs is based on evaluations performed largely
using adult animals. Of course in the case of drugs,
clinical trials are also required, but again this usually
means testing for unanticipated and undesired side
effects on adult human populations. Certainly, multi-
generation studies are performed to test chemical safety
levels, but these usually require chemicals or drugs to
induce profound teratogenic (disruption of early
development) or reproductive alterations to trigger a
concern. The potential jeopardy lies with more subtle
effects of chemicals on non-adults that could neverthe-
less adversely impact health. So in extrapolating safety
data derived largely from adults, we have presumed to
understand and fully accept the spectrum of risks to
non-adults.
Yet, where the human experiment has been carried out
on the largest scale, as in the case of fetal exposure to
alcohol or environmental tobacco smoke, we know that
the fetus is particularly sensitive (1-3). The effects of
these agents on the fetus are not fully predicted based
on similar adult exposures, nor do they have identical
consequences in terms of dose response and persistence
of effects. The bottom line is that the amount of alcohol
Vol. 13, No. 2 Part I, September 2005
required for adverse effects on a young adult woman is
much different than the amount that can impact the
fetus if exposure occurs during specific vulnerable
periods of gestation. So does this mean we have taken
this lesson to heart?
As a society, we expend countless dollars, Euros, etc. on
various micronutrients, dietary supplements and nutri-
tive compounds that we hope will encourage our im-
mune systems to perform better against the latest viral or
bacterial infection crossing our path at that time. But
this “pop a pill-immediately lose the ill” approach to
better health masks a broader issue concerning optimum
immune health over the course of a lifetime, a course
most of us hope is long indeed. The question must be
raised whether the science is now in place or at least
accumulating to encourage a more comprehensive and
lasting approach to managing the immune system with
the individual and our most sensitive sub-populations in
mind.
The recent comprehensive review of hormesis and the
immune system (4) suggests that it is not simply life-stage
based immunotoxicity where there is a need to improve
our understanding and predictability of outcome.
Indeed, understanding immunomodulatory exposures
and the range of doses that impact the immune system
by age and gender is the broader goal. This article will
discuss the possible benefits arising from early attention
to immune health and the application of fundamental
developmental immunology to the neonatal, adolescent,
adult and geriatric stages of life.
Immune Balance
Over a lifetime of health challenges, we face the need to
mount robust immune responses against a variety of
infectious agents and potential cancer cells. We are
presented with wildly different classes of viruses, bacte-
ria, parasites and tumor cells each with their own host
defense challenges. Additionally, it is important to
respond to vaccinations with effective, immediate
responses and robust immunological memory to ensure
adequate long-term protection. To meet such challenges,
it is helpful to have effective immune balance among the
distinct segments of the immune system that afford
protection against different categories of disease-induc-
ing agents. Today’s infection is not necessarily
tomorrow’s health challenge
While immune balance is a potential paradigm to
promote life-long health, historically, it has not been on
the radar screen. This is particularly evident when one
realizes that drugs and herbs promising immune en-
hancement may not be the universal panacea desired
either in the individual or across a population. Certainly
a better understanding of dose-response toxicity,
hormetic responses and genetic variation must be paired
with intended immunomodulation. Immune enhanced
7
relief from viral infections in one person might mean
increased risk of autoimmune reactions in another. So
“enhancement” is not necessarily effective balance and
enhancement for one person may mean disease for
another.
The Paradigm Shift: Immune Skewing vs. Immunosup-
pression
Historically, immunotoxicologists focused on profound
generalized immunosuppression as the primary concern.
It was relatively easy to identify toxicants that at relevant
doses caused atrophy of the thymus or significant
population loss within the spleen. With the increased
incidence of atopy, asthma, and certain autoimmune
diseases in recent years, researchers are now focused on
targeted immunosuppression and targeted immune-
mediated damage resulting from autoimmune or inflam-
matory responses. Changes associated with these
different health risks can be subtle involving little to no
loss of immune cells or histopathological alterations to
immune tissues. The goal then is to avoid imbalance and
either the lack of certain required responses or the
promotion of responses that are undesirable and might
compromise host tissue integrity. But emphasizing
immune balance as the ultimate goal requires a different
mind set and potentially new approaches for immune
assessment. It also requires the recognition that across a
heterogeneous human population, individuals start at
different places on an immune balance curve based on
genetic heterogeneity. Therefore, the one-recipe-for-all
approach has obvious pitfalls and should immediately be
viewed with considerable skepticism.
The importance of immune balance and the potential
mechanistic bases for skewing were discussed in several
recent reviews (5,6). The precise mechanisms and
pathways for controlling T helper 1 (Th1) vs. T helper 2
(Th2) responses among dendritic cells and T lympho-
cytes are still the subjects of active ongoing research.
One thing is very clear from these reviews. While it is
challenging to dissect all of the components influencing
immune balance in a fully matured adult, it is a com-
pletely different set of issues to consider immune bal-
ance within a moving target, as is the case with the
developing immune system. The following section
illustrates this point as well as the important windows of
opportunity or, in some cases, vulnerability that appear
to exist.
The Immune Maturation Dilemma
The developing fetus presents a remarkable paradox in
terms of immune cell differentiation, functional develop-
ment, and tissue integrity (i.e. homeostatic) consider-
ations. For example, the T cell system needs to mature
efficiently to meet the challenges presented by the
neonatal environment at birth; but during the course of
maturation, the potential for maternal-fetal allogeneic
8 BELLE Newsletter
reactions must be minimized. One hallmark of preg-
nancy is a strong skewing toward Th2 cytokines, which
enables the survival of the fetus in the genetically-
dissimilar (i.e. allogeneic) maternal environment (7).
Placental trophoblasts seem to help determine the Th2
nature of the maternal-fetal interface. When these cells
express Th1 cytokines and receptors such as interferon-
gamma and its receptor, there is an increased risk of
preeclampsia, a pregnancy complication also called
toxemia and characterized by high blood pressure,
swelling, and fever (8). Using a rodent model, Sefrioui et
al. (9) showed that the Th1 vs. Th2 cytokine pattern in
utero was critical in determining whether tolerance or
immunity developed. Leibnitz (10) recently discussed
the fact that, at birth, humans have a T cell system that is
reduced in Th1 functional capacity. This is the capacity
that is necessary for effective anti-viral defense but also
promotes tissue/organ rejection. Aggressive Th1 func-
tion, in utero, would jeopardize maternal-fetal compatibil-
ity and increase the risk of pregnancy complications.
Evidence for the reduced Th1 capacity of newborns is
reflected in the fact that the neonate is severely reduced
in the production of interferon-gamma, the hallmark
Th1 cytokine (11). For the neonate to thrive, develop-
ment of Th1 must proceed at a rapid pace shortly after
birth. Transplantation studies suggest that the newborn
is far more accepting of transplants than a child six
months or more of age because it is essentially Th1
deficient compared to an adult (12).
All of this leads to the conclusion that the late fetus and
early newborn have a highly skewed immune capacity
compared with the final balance that will be obtained in
most juveniles and adults. In effect, desired immune
balance will only exist in the newborn if and when the
Th1 capacity matures effectively. Clearly, our attention
needs to be directed at those environmental factors (e.g.
diet, toxicants, infections, and vaccinations) and the
relevant doses that allow the fetus to thrive but also
promote much needed Th1 maturation immediately
following birth. Conversely, we need to identify factors
and dose ranges that have the capacity to delay and/or
impair neonatal Th1 function.
Windows of Opportunity/Vulnerability
Given that the late fetus and early newborn lacks the
desired immune balance necessary to meet later life
disease challenges, this represents a window in which
attention to environment and immune maturation is
likely to reap life long rewards. Delayed or impaired
Th1 maturation would be expected to leave the indi-
vidual with a potentially life-long immune imbalance. In
contrast, promotion of optimum Th1 capacity immedi-
ately after birth would increase the likelihood of effective
viral vaccine responses, reduce the risk of childhood
asthma and atopy and potentially influence the risk of
later life cancer. Considering the major differences
between the adult and fetal immune systems and the
different strategies needed to achieve immune balance
in each, it is hardly surprising that adult safety data have
only minimal application to the fetal/early neonatal life
stage. The inherently skewed immune system of the
fetus and newborn provides an ideal opportunity for
direct evaluation of environmental conditions that
promote effective juvenile immune balance vs. those that
interfere with this outcome. However, to accomplish this
we will need directly applicable dose response data
including knowledge of potential hormetic responses
rather than information extrapolated from the adult
immune system.
Furthermore, the opportunity to truly manage the
immune system may best be directed toward the early
(non-adult) stages of development. Developmental
immunotoxicity results, to date, suggest that in utero and
early neonatal effects tend to be more persistent than
those induced in adults (13). So the idea that one
should attempt late-life corrections to an unbalanced
immune system (skewed at birth) when adult health
problems arise may be too little too late. The early-
managed immune system is simply the most efficient and
cost effective approach in terms of a reducing a lifetime
of health care costs.
Early Environment-Later Life Disease?
One question surrounding the concept of increased
sensitivity of the developing immune system to environ-
mental modulation is the question of evidence for actual
impact on human health. Because non-teratogenic
immune changes would result in a greater risk of disease,
the challenge is to look at epidemiological patterns in
human disease in concert with mechanistic animal
studies. Altered patterns of disease associated with
immunomodulation is a matter of discerning population
shifts imposed on an already existing incidence of
disease. Perhaps the most readily accessible examples
concern the increased incidence in asthma, atopy and
certain autoimmune diseases. For this mini-review,
disease consideration will be restricted to childhood
asthma.
According to a recent Pew Foundation report (14), the
incident of asthma in industrialized counties has in-
creased dramatically in recent decades. This has resulted
in a significant public health cost. In 2002, there were
approximately 16 million adolescents with asthma (15).
The impact of the increase has been dramatic. For
example, there were 14 million missed school days in
1996 up from 6.6 million in 1980 (16). The environmen-
tal causes for this increase are certainly multi-factorial
and involving various toxins, infectious agents, and air-
born pollutants, the latter that can exacerbate symptoms.
However, there is one common theme in terms of the
type of immunomodulatory change contributing to
increased incidence. That change is a shift in immune
balance toward a Th2 bias (17). In fact, Anderson (17)
Vol. 13, No. 2 Part I, September 2005
argues that it is the retention of the fetal immune
imbalance that is the hallmark of early asthma. The
tenet has also been advanced by Bousquest et al. (18)
who discuss the likelihood that fetal-expressed genes
promoting Th2 may continue to be inappropriately
expressed in some neonates increasing the risk of
asthma. Additionally, maternal immune responses
during pregnancy appear to have the potential to help
shape the subsequent Th profile of the neonate (19).
One perinatal indicator of subsequent risk of asthma
appears to be the serum immunoglobulin E levels of
cord blood at birth (20).
In the newborn, those environmental factors that
promote strong early life Th1 responses tend to be
protective against childhood asthma while those that
impair effective Th1 maturation seem to contribute to
elevated incidence of the disease. Several studies from
Europe have indicated that exposure of the newborn to
barnyard environments (including endotoxin-laden
bacteria) was highly protective against childhood asthma
(21,22). These results are compatible with the concept
that stimulating Th1 cytokines and responses at key
periods of early development can help effective immune
balance to be achieved. On the reverse side of this
equation, exposure to environmental contaminants that
impair Th1 functional development could leave adoles-
cents with an increased risk of asthma. Based on their
immunotoxic effect, certain heavy metals such as lead
would be candidates to promote the risk of asthma via
the persistent Th2 bias they can create (23-26).
Dietary intake, both maternally and in the neonate, is
important in immune balance. Early malnourishment
seems to allow Th2 polarization to be maintained (27).
Vitamin A deficiency can also contribute to Th2 skewing
(28). In contrast, consumption of dietary nucleic acids
appears to skew the profile toward Th1 (29). Glu-
tathione levels in antigen presenting cells seem to help
steer responses toward Th1 or Th2. Depletion of
glutathione depresses Th1 responses skewing the re-
sponse in favor of Th2 (30).
Genetics can also play a role overlaying the environmen-
tal exposure issue. Among farming-family children, the
genotype of an important cell surface receptor for
immune signaling, Toll-like receptor-2 (TLR-2), influ-
enced the risk of asthma (31). Another factor influenc-
ing Th1/Th2 balance as well as risk of asthma appears to
be the cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene
and its polymorphisms in the human population (32).
This suggests that segments of the human population are
likely to respond differently when exposed to specific
environmental risk factors based on the genetics of the
immune cell signaling as well as their inherited immune
balance capacities. Such genotype-by-environment
interactions indicate the challenges in conducting
appropriate analyses that have the statistical power to
assess changes within sub-populations. Futhermore, it
9
suggests the importance of employing animal models
that can mimic potentially vulnerable human sub-
populations. Given this genetic heterogeneity, we should
not expect positive or adverse risk factors to shift more
than a segment of the human population across an
immune balance boundary associated with clinical
symptomology.
In summary, early onset asthma has increased in inci-
dence with environmental factors playing a major role in
this increase. Current evidence involving infectious
agents, environmental toxins, dietary factors and genetic
polymorphism can be placed within a unified immuno-
logical concept. It suggests that managing the fetal and
neonatal immune system to reduce persistence of the
fetal (Th2-skewed) immune phenotype and to promote
rapid and effective Th1 maturation has the potential to
significantly reduce the risk of asthma across the popula-
tion.
Hormesis and the Managed Immune System
The recent review of hormesis and the immune system
by Calabrese (4) has important implications for the
managed immune system. This review summarized
several key points. First, the numerous examples of
hormesis pertaining to immune responses indicates the
importance of identifying beneficial and adverse effects
associated with different portions of dose-response
curves. Rather than blanket labeling environmental
factors as beneficial or adverse in terms of immune
management, we need to tailor effective and beneficial
doses to each individual (based on genotype). The
second message from this review is that virtually all of the
hormesis examples described in the literature are
restricted to the adult immune system or adult-derived
cells examined in vitro. This does not mean that
hormesis is not key to the developing immune system.
Rather, it reflects the extreme dearth of comprehensive
dose response comparisons that exist for different
windows of immune development. If we err by univer-
sally applying adult safety results to the fetus, then we
also must be cautious about applying hormetic dose
range across age groups. Obviously, direct age-based
data are needed to optimally manage the early immune
system.
CONCLUSIONS
Attention to the early immune system and those environ-
mental factors and dose ranges that promote effective
immune balance is a cost-effective approach to reducing
later life disease risk and health care costs. Application
of adult safety data is severely limited for this purpose.
Instead, the use of direct exposure information leading
to timely and effective neonatal T helper 1 maturation
appears key to long-term immune balance. While focus
on the early immune system has not been a traditional
safety approach, it seems clear that this is when an
10 BELLE Newsletter
immune imprint becomes established; one that impacts
greatly on postnatal health and well being.
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11
 ABSTRACT
LOW-DOSE
RADIATION AND ITS Induction of hormesis and adaptive response by low-dose
radiation (LDR) has been extensively indicated. Adaptive

CLINICAL response induced by LDR was not only resistant to

damage caused by subsequently high-dose radiation, but
also cross resistant to other non-radiation challenges
IMPLICATIONS: such as chemicals. Mechanisms by which LDR induces
the preventive effect on radiation- or chemical-induced
DIABETES tissue damage include induced or up-regulated expres-
sion of protective proteins such as heat shock proteins
and antioxidants. Since oxidative damage to tissues is a
major pathogenesis of many human diseases including
Guan-Jun Wang 1, Xiao-Kun Li 2, Kazuo Sakai 3 and Lu diabetes, this review will summarize available data with
Cai 1,2,4,* an emphasis on the preventive effect of LDR on the
development of diabetes and the therapeutic effect of
LDR on diabetic cardiovascular complications. The
1
Department of Hematology and Oncology available data indicated that pre-exposure of mice to
The First University Hospital LDR reduced the incidence of alloxan-induced diabetes,
Jilin University Medical College and also delayed the onset of hyperglycemia in diabetes-
prone non-obese diabetic mice. Experiments with
Changchun 130021
animals indicated the therapeutic effect of low-intensity
P.R. China or power laser (LIL or LPL) radiation on skin wound
healing, which has stimulated clinical use of LIL to cure
2
Department of Biopharmacy skin ulcer in diabetic patients. Mechanisms by which
LDR prevents diabetes, though they are unclear now,
Collage of Pharmacy
may include the induction of pancreatic antioxidants to
and Biopharmaceutical Research & Development Center prevent β cells from oxidative damage and immuno-
Jinan University modulation to preserve pancreatic function. For LIL
Guangzhou 510080 therapeutic effects on diabetic wound healing, mecha-
nisms may include its antioxidant action, immuno-
P.R. China
modulation, cell-proliferation stimulation as well as
improvement of systemic and wound-regional microcir-
3
Low Dose Radiation Research Center culation. Therefore, although there are only a few
Central Research Institute of Electric Power Industry studies indicating LDR prevention of the development of
diabetes, many studies have demonstrated LDR, specifi-
2-11-1 Iwado-Kita, Kome
cally LIL, therapeutic effectiveness of diabetic wound
Tokyo, 201-8511 healing. These preliminary results encourage further
assessment of the clinical implications of LDR to diabe-
4
Departments of Medicine, Pharmacology and tes-related areas.
Toxicology,
Key words: Low-dose radiation, hormesis, adaptive
and Radiation Oncology response, diabetes, diabetic complications
the University of Louisville School of Medicine
Louisville 40202
INTRODUCTION
USA

Low-dose radiation (LDR)-induced hormesis has been

Corresponding author at Department of Medicine
extensively studied for the last two decades (Luckey
University of Louisville 1982). It includes stimulation of DNA, RNA, and protein
511 South Floyd Street synthesis as well as DNA repair activity, increase in
MDR 533, Louisville cellular antioxidant capacity, prolongation of life span
and activation of immune functions (Cai 1999; Calabrese
KY 40202
2002; Calabrese and Baldwin 2003). These cellular
Phone: 502-852-5215 hormetic effects contribute to a protection of cells in
Fax: 502-852-6904 vitro or in vivo against gene mutation, DNA damage, and
Email: Lcai1@hotmail.com chromosome aberrations caused by subsequent radiation
or toxic chemicals, which was called an adaptive re-

12 BELLE Newsletter
sponse (Olivieri et al., 1984; Cai and Liu 1990; Cai et al.,
1994; Cai and Jiang 1995; Cai and Wang 1995; Cai and
Cherian 1996).
Since extensive scientific evidence shows the stimulation
of immunological function, antioxidant activity and DNA
repair ability, an important issue is whether LDR-induced
hormesis or adaptive response can be manipulated for
medical and other benefits, as discussed six years ago in a
special issue of Belle 1999 (Cai et al., 1999) and ad-
dressed recently by Dr. Calabrese and his associates
(Calabrese and Baldwin 2002; Calabrese 2004). In
clinical implication, LDR has been introduced as an
effective therapy of non-Hodgkin's lymphoma (Richaud
et al., 1998; Kennerdell et al., 1999; Girinsky et al., 2001).
For instance, in the study by Richaud et al., (1998), most
patients treated by LDR showed efficient response, in
particular for follicular lymphoma. They lived without
any acute nonlymphoblastic leukemia or myelodysplasic
syndrome with a median follow-up of 88 months. Al-
though they did not discuss any issues related to LDR-
induced adaptive response or hormesis for the mecha-
nism of this beneficial effect, this could not exclude the
role of LDR hormesis in immunity and adaptive response
in the hematopoietic tolerance in this efficient treat-
ment. In addition, since Alzheimer's disease (AD) is
related to oxidative damage to neurons leading to cell
loss and LDR enhances brain antioxidant activity
(Kojima et al., 1999; Yamaoka et al., 2002), whether LDR-
enhanced activity of antioxidants in brain could protect
brain cells from oxidative damage to prevent AD has
been discussed. Human epidemiological study showed a
low incidence (4.39%, 25/570) of AD in the population
of high natural radiation background area as compared
to that (4.95%, 25/505) of control population (Wei et al.,
1996). Therefore, the similar mechanisms of LDR-
induced hormesis and adaptive response may be also
clinically implicated for prevention or therapy of other
disorders.
Diabetes mellitus has dramatically increased globally, and
affects 18 millions of Americans (Bardsley and Want
2004). Type 1 diabetes is a lack of insulin production and
Type 2 diabetes is predominantly due to resistance to the
effects of insulin. Both Type 1 and Type 2 have the same
long-term complications including skin ulcer (Bardsley
and Want 2004). Type 1 diabetes occurs because the
insulin-producing cells of the pancreas (called β cells)
are destroyed by the body's own immune system for
unknown reasons. There are other people who develop
a condition similar to type 1 diabetes - characterized by
destruction of the β cells but without autoimmune
reaction, as the streptozotocin (STZ)- or alloxan (ALX)-
induced diabetes in animal models (Shafrir 1990). Type
2 diabetes is the most common form of diabetes, and its
cause is more complex. In type 2 diabetes, high blood
glucose arises despite an initial abundance of the hor-
mone insulin. With progression of the disease they can
develop a deficiency of insulin similar to people with
Vol. 13, No. 2 Part I, September 2005
type 1 diabetes.
Oxidative stress is now known to be involved in almost of
all pathological states of pancreatic β-cells either in Type
1 or Type 2 diabetes (Shafrir 1990; Haskins et al., 2003).
Oxidative stress is characterized by increased production
of reactive oxygen or nitrogen species (ROS or RNS)
such as superoxide, hydrogen peroxide, nitric oxide and
peroxynitrite and/or decreased concentrations of
antioxidants and antioxidant enzymes including glu-
tathione (GSH), vitamin E, ascorbate, glutathione
peroxidase (Gpx), superoxide dismutases (SOD), and
catalase. The β cell destruction by ROS and/or RNS,
whether induced by STZ or ALX given exogenously or
elicited by cytokines, is a process that occurs through
both apoptotic and necrotic mechanisms. After diabetes
onset, the secondary oxidative stress caused by diabetic
hyperglycemia, hyperlipidemia and even inflammation
also play a critical role for most diabetic complications
(Rosen et al., 2000; Cai and Kang 2001).
Therefore, this review assessed the available data with
emphasis on: (1) Effects of LDR on the development of
diabetes; (2) Effects of LDR on diabetic complications;
and (3) Possible mechanisms by which LDR prevents the
development of diabetes and diabetic complications.
Finally, the clinical diabetes-related implications of LDR
are discussed.
EFFECTS OF LDR ON THE
DEVELOPMENT OF DIABETES
Takehara et al. (1995) performed the first investigation
of the effects of LDR on ALX-induced diabetes in the rat
model. ALX caused a significant degranulation of β cells
in the pancreas along with an increase in fasting blood
glucose. These changes were significantly prevented by
LDR. The preventive effect of LDR on the development
of diabetes was further supported by subsequent experi-
ments (Yamaoka et al., 1996; Takahashi et al., 2000; Sakai
et al., 2004). These studies indicate the following fea-
tures:
LDR prevented ALX-induced diabetes in a rat model and
also in a spontaneously developed non-obese diabetic
(NOD) mouse model (Takehara et al., 1995; Takahashi et
al., 2000). LDR which induced the protection against the
development of diabetes could be acute exposure
(Takehara et al., 1995; Takahashi et al., 2000) and also be
chronic exposure (Sakai et al., 2004). For acute exposure
with gamma rays, among doses of 0.25, 0.5, 1.0 and 2.0
Gy used, only exposure to 0.5 Gy provided the significant
protection against ALX-induced diabetes (Takehara et
al., 1995). There was no significant difference for use of
one or two doses of 0.5 Gy gamma-rays in the protective
effect against the development of diabetes (Takahashi et
al., 2000). However, the time interval between LDR and
diabetes onset seems an important factor to determine
13
the protective effect against the development of diabetes.
As shown in Figure 1, non-LDR treated NOD mice
developed diabetes starting at 15 wks of age (panel A)
and the incidence of diabetes was 60% (panel B), while
LDR treated NOD mice at 12, 13 or 14 wks of age
developed diabetes starting at 3 to 7 wks later and also
showed low incidence of diabetes. The most effective
protection was noted in the group of mice irradiated by
LDR at 13 wk of age.
The decreased blood glucose and increased plasma
insulin suggest a protection of LDR against β-cell dam-
age in NOD diabetic mice (Takahashi et al., 2000).
Examination of β cells performed for the untreated
NOD mice and LDR-treated mice (irradiated at 13 weeks
of age) showed a significant increase in apoptotic β cell
death in the pancreases of untreated NOD mice was
evident, but not in the LDR-treated NOD mice. This
observation is keeping with other studies indicating that
apoptosis of pancreatic β cells are responsible for the
development of diabetes in NOD mice (Kurrer et al.,
1997; Nakayama et al., 2002).
In addition to the protective effect of LDR against the
development of diabetes, LDR was found to provide a
therapeutic effect on diabetic hyperglycemia. Recently
Sakai et al. (2004) investigated the effects of chronic LDR
on C57BL/KsJ-db/db mice with Type 2 diabetes. These
mice develop Type 2 diabetes by 10 weeks of age, due to
obesity, and are characterized by hyperinsulinemia. A
group of 10-week old female mice was irradiated for life
at dose rate of 0.7 mGy/hr. The urine glucose levels of
all of the mice were strongly positive at the beginning of
the irradiation. In the LDR-treated diabetic mice,
however, a decrease in the urine glucose level was
observed in three mice, one in the 35th week, one in the
52nd week and one in the 80th week. No recovery from
the diabetes was observed in the 12 mice of non-LDR-
irradiated diabetic group. These preliminary results
suggest that LDR provides a therapeutic effect on
diabetes.
EFFECTS OF LDR ON DIABETIC
COMPLICATIONS
The major pathogenic cause for various diabetic compli-
cations is attributed to diabetes-overproduced ROS/RNS
and diabetes-impaired antioxidants in tissues (Rosen et
al., 2000; Cai and Kang 2001). Whether LDR is able to
prevent or cure various complications of diabetes
mellitus is a very interesting issue. Although there was no
study directly using low-dose ionizing radiation, there
were several studies using low levels of non-ionizing
irradiation such as laser radiation and magnetic field.
Ionizing radiation
In an early study by Yamaoka and Komoto (1996),
indications for treatment at the Misasa Hot Spring, a
14 BELLE Newsletter
radon producing radioactive spring, diabetes patients
along with other patients with pain and hypertension
were noted. The hot-spring treatment with radon was
found to significantly improve the vasodilation and
alleviated diabetic symptoms. In the animal studies by
Takahashi et al. (2000) and Sakai et al. (2004), LDR not
only decreased the incidence and percentage of develop-
ing diabetic mice, but also enhanced the surviving rate
of these type 1 and type 2 diabetic animals. For instance,
at the age of 90 weeks animal survival was 75 % in the
LDR-treated NOD mice and only 40 % in the non-LDR-
treated NOD mice. Mortality was delayed and the
healthy appearance was prolonged in the irradiated mice
by about 20-30 weeks compared with non-LDR-treated
NOD mice. For the study using chronic LDR, survival
rates of both LDR-treated and non-LDR-treated diabetic
mice were 100% at 30 weeks of age (these mice devel-
oped diabetes at 10 weeks of age), but 33% in LDR-
treated diabetic mice and 0% in non-LDR-treated
diabetic mice at 120 weeks of age (Sakai et al., 2004).
Although these indications are not direct parameters of
diabetic complications, these indications may result from
the protective effects of LDR against diabetes-initiated
various complications.
Non-ionizing radiation
Low-intensity or –power laser (LIL or LPL) radiation has
been extensively used for therapy of diabetic patients. In
recent years, LIL has gained considerable recognition
and importance among treatment modalities for various
medical problems including wound repair processes,
musculoskeletal complications and pain control (Reddy
2003). In diabetic conditions, LIL successfully enhanced
wound healing, tensile strength and systemic or local
microcirculation in the diabetic animal models (Stadler
et al., 2001; Reddy 2003; Byrnes et al., 2004; Kawalec et
al., 2004) and diabetic patients (Schindl et al.,
1997,1998,1999a,b,2002; Zinman et al., 2004).
Although different kinds of lasers have been used for this
therapy, the efficient therapy depends on the wavelength
of the electromagnetic radiation (Stadler et al., 2001;
Reddy 2003; Kawadec et al., 2004). For instance, the
ability of photostimulation to promote healing of
impaired wounds using a Ga-As laser in rats with STZ-
induced diabetes was compared with the effects of a He-
Ne laser. Reddy (2003) found that the He-Ne laser
appears to be superior to the Ga-As laser in promoting
wound healing in diabetic animal models.
Low-power electromagnetic field was also used for a
therapeutic purpose. Chebotar'ova and Chebotar'ov HIe
(2003) investigate the effectiveness of combinations of
low-power electromagnetic therapy and low-power
variable magnetic field on the clinical-
electroneuromyography in 12 patients with diabetic
polyneuropathies. Exposure to both provided significant
decreases in neurological deficit and required insulin
daily dose and significant increases in nerve conduction hyperglycemia and complications in diabetic patients
velocity, the muscle compound action potentials (muscle who received radon hot spring, Yamaoka et al (2004b)
power) and peripheral outflow in some patients. found that the radon therapy enhanced the antioxidant
functions, such as the activities of SOD and catalase,
POSSIBLE MECHANISMS FOR LDR along with inhibition of lipid peroxidation and total
PREVENTIVE AND THERAPEUTIC cholesterol produced in the body, although the therapy
EFFECTS also increased the levels of plasma insulin and glucose-6-
phosphate dehydrogenase. This study further supports
LDR-enhanced endogenous antioxidant activity
the concept that LDR protects against diabetes and its
complications probably through induction of antioxi-
Oxidative stress is the critical factor responsible for
dants.
diabetic onset and complications, while antioxidants can
prevent both diabetic onset and complications (Cai and
LDR-modulated immune function
Kang 2001; Rosen et al., 2001). Development of diabetes
induced either by T cell-mediated inflammatory autoim-
Type 1 diabetes loses the ability to produce insulin due
mune reaction or chemicals such as STZ and ALX is
to the destruction of the insulin-producing β cells in the
largely attributed to ROS and RNS formation leading to
pancreas. The β cells are targets of an autoimmune
β-cell destruction (Fig. 2). In addition, low concentra-
attack during which the diabetic's own immune cells,
tions of antioxidants exists in animal pancreatic islets
especially the T cells, recognize unique proteins in the β
also make it vulnerable to oxidative damage (Lenzen et
cells as foreign and go about ridding the β cells from the
al., 1996; Tiedge et al., 1997). There is evidence indicat-
pancreas. Like other autoimmune diseases, type 1
ing that up-regulation of SOD made mice resistant to
diabetes can be caused by defects in the primitive cells
diabetes development (Kubisch et al., 1997).
that are the precursor cells of the blood and immune
Thioredoxin (Trx), a redox (reduction/oxidation)-
system called hematopoietic stem cells (HSC). HSCs are
active protein, protects cells from oxidative stress.
capable of producing the entire set of cells that com-
Transgenic mice with specific expression of Trx in
prises the immune system, as well as red blood cells and
pancreatic islets showed a significantly lower incidence of
platelets. To support of the importance of normal
spontaneously developed and STZ-induced diabetes as
hematopoietic system for maintaining a normal immune
compared to their wild-type counterparts (Hotta et al.,
function to avoid the development of type 1 diabetes,
1998).
bone marrow transplantation was shown to halt autoim-
mune processes and reverse the damage caused by
LDR significantly increases endogenous antioxidants in
autoimmune cells in NOD mice (Li et al., 1996; Chilton
different tissues including liver, spleen, brain and testes
et al., 2004; Nikolic et al., 2004). We have demonstrated
(Yamaoko et al., 1991,1998,1999,2002,2004a; Kojima et
that LDR can stimulate HSC proliferation and mobilizes
al., 1998,1999; Zhang et al., 1998). The activation and/or
HSCs into peripheral circulation (Li et al., 2004). This
induction of antioxidants include SOD, GSH, Gpx,
HSC stimulating and mobilizing effect of LDR may be
glutathione reductase (GR), catalase and Trx. In these
one of the mechanisms to maintain a normal immune
tissues, the increased antioxidants by LDR significantly
function to avoid the development of Type 1 diabetes
prevents tissue damage from various oxidative stresses,
such as in the case of NOD mice (Takahashi et al., 2000).
for instance, cardon tetrachloride-induced liver damage
(Kojima et al., 1998; Yamaoka et al., 2004a), 1-methyl-4-
Ina and Sakai (2004) have shown the possibility for LDR
phenyl-1,2,3,6-tetrahydropyrine- or Fe-NTA-induced
to ameliorate severe autoimmune diseases. In their
brain damage (Kojima et al., 1999; Yamaoka et al., 2002),
experiment, chronic low-dose-rate γ irradiation at 0.35 or
and radiation-induced testis damage (Zhang et al.,
1.2 mGy/h was found to significantly prolong the life
1998). In studies by Takehara et al. (1995) and Takhashi
span of MRL-lpr/lpr mice carrying a deletion in the
et al. (2000), LDR (0.5 Gy) also significantly increases
apoptosis-regulating Fas gene that markedly shortens life
the SOD activity in the pancreas of non-diabetic mice.
due to severe autoimmune disease. Immunological
The activity of pancreatic SOD in ALX-induced or NOD
modifications were indicated by a significant increase of
diabetic mice was significantly decreased, but this
CD8+ T cells and a significant decrease of CD3+ CD45R/
decrease could be prevented by LDR. In addition, in
B220+ as well as CD45R/B220+ CD40+ cells, along with
ALX-induced diabetic mice, plasma and pancreatic lipid
amelioration of total-body lymphadenopathy, splenom-
peroxide levels were also significantly increased, but not
egaly, proteinuria, and kidney and brain syndromes. In
in LDR-irradiated diabetic mice (Takehara et al. 1995).
another clinical study in which an attenuation of diabetic
These results suggest that the increased antioxidant
hyperglycemia and complications were observed in the
capacity of pancreases by LDR is one of the major
diabetic patients received radon hot spring (Yamaoka et
mechanisms to prevent ALX-induced or spontaneously
al., 2004b), radon-got spring significantly increased
developed diabetes (Fig. 2).
patient’s immune response such as enhanced concanava-
lin A-induced mitogen response. Therefore, LDR-
For the mechanisms of the attenuation of diabetic
modulated immune function may be one of the mecha-

Vol. 13, No. 2 Part I, September 2005 15

nisms underlying LDR prevention of type 1 diabetes (Fig.
2).
Multiple mechanisms involved in LIL improvement of
diabetic wound healing
The mechanisms discussed above are predominantly for
the preventive or therapeutic action of low-dose ionizing
radiation. However, we do not exclude their roles in the
therapeutic effect of LIL on diabetic wound healing
since LIL acts as similar function in certain aspects
(Wilden and Karthein 1998). Small amount of ROS/
RNS generation is one of the factors responsible for
LDR- induced hormesis and adaptive response (Cai
1999; Cai et al., 1999). Exposure of cells to LIL also
generates certain amounts of ROS/RNS (Callaghan et
al., 1996; Vladimirov et al. 2004), which may stimulate
adaptive mechanisms, shown by increased antioxidant
activities (Karageuzyan et al., 1998; Fujimaki et al., 2003;
Kao and Sheen 2003).
Besides antioxidant action of LIL, the directly stimulat-
ing cell proliferation and procollagen synthesis through
activation of signaling pathways are also important
mechanisms for the diabetic wound healing (Duan et al.,
2001; Pereira et al., 2002; Schindl et al., 2003; Vinck et al.,
2003). Whether stimulating HSCs by LIL is also involved
in the enhancing effect on diabetic wound healing
remains unclear; however, direct exposure of wound
tissues to growth factors promoted wound healing
processes of diabetic animals (Galeano et al., 2004a,b),
and basic fibroblast growth factor was found to be
increased in the wound tissue of diabetic rats in response
to LIL (Byrnes et al., 2004).
A specific mechanism for LIL to enhance diabetic wound
healing may be the improvement of systemic and wound
regional microcirculation (Schindl et al., 1998,2002). For
instance, in the patients with diabetic microangiopathy
receiving a single LIL irradiation, skin blood circulation,
by means of temperature recordings detected by infrared
thermography, significantly increased as compared to
non-LIL treated diabetic patients.
PROSPEROUS REMAKERS
Radiation is known to have significant effects on living
organisms dependent on the dose received. At high
doses, radiation destroys cells in tissue. At low doses, on
the other hand, radiation is no longer considered to be
as harmful as once thought. Hormesis and adaptive
response of cells or tissues in response to LDR were
extensively documented (Luckey 1982; Cai 1999; Cai et
al., 1999; Calabrese 2002; Calabrese and Baldwin 2002).
However, debates for the induction and importance of
hormetic effects and adaptive responses still exist, in
particular for the risk of LDR in genetic instability and
carcinogenesis (Johansson 2003; Poumadere 2003;
16 BELLE Newsletter
Calabrese 2004). Among the several issues raised in these
debates, one is how the adaptive response or hormesis
interacts with the bystander effect in determining
biological responses at low doses of radiation and the
shape of the dose-response relationship (Zhou et al.,
2003). Although the epidemiological and experimental
studies remain not strong enough to change the current
policy of radiation safety, the phenomenon of LDR-
induced hormesis and adaptive response could not be
negative. Definitively large epidemiological studies and
more detail experimental studies with new and accurate
techniques remain required before determining whether
the current linear non-threshold model needs to be
changed.
However, clinical application of LDR is a different
situation. The targets of clinical application with LDR
would be mainly patients with various disorders. It is
clear that none of the medications used in clinics is
absolutely non-toxic. Therefore, evaluation of LDR for its
clinical application should be also realistic and parallel
as evaluation of other new medications. If LDR can play
a critical approach in prevention or therapy of certain
disorders, such as diabetes, we should not ignore it.
This short review collected the available data demonstrat-
ing possible implications for the prevention of diabetes
development and therapy of diabetic complications.
These preliminary results showed that pre-exposure of
animals to LDR significantly prevented ALX-induced or
spontaneously developed diabetes. Although there was
no experiments of using low-dose ionizing radiation to
cure any diabetic complications, clinical observation
implied a therapeutic effect of low-dose radon on
diabetic complications in the patients. More importantly,
effective therapeutic effect of LIL on skin wound healing
of diabetic subjects has attracted the attention of investi-
gators and clinicians. Although exact mechanisms by
which LDR prevents the development of diabetes and
provides the therapeutic effect on diabetic complication
remain largely unknown, several possibilities may be
included, such as the increase in antioxidants, immuno-
modulation, HSC stimulation and peripheral mobiliza-
tion, stimulation of target cells and improvement of
systemic and wound-regional microcirculation as out-
lined in Figure 2. Therefore, further experiments on this
topic remain required, and we believe that LDR implica-
tions in diabetes-related areas is an important area of
research.
ACKNOWLEDGEMENTS
The work cited in this review is supported in part by
research grants from Philip Morris USA, Inc. and
American Diabetes Association to LC.
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19
 Figure 1. LDR prevention of the development of diabetes in NOD mice. Pane A represents the time point at which
the first mouse from the groups treated with LDR (0.5 Gy) at 12, 13 or 14 weeks (w) of age and without LDR (control
group) spontaneously developed diabetes (hyperglycemia). Results indicate that the first mouse developed diabetes is
at 22 weeks of age in the group of mice with LDR at 13 weeks of age (13 w), which is 7 weeks later than that(15 weeks
of age) in control group. Panel B represents the incidence of diabetic mice in different groups. Results indicate that
10 % of mice with LDR at 13 weeks of age (13 w) developed diabetes at 24 weeks of age, which is much lower than
those in the control and other LDR-treated groups. Figures were made by the authors, based on the results from the
study by Takahashi et al. (2000).

20 BELLE Newsletter
Figure 2. Outlines of the possible mechanisms underlying LDR’s protective effect against the development of diabetes
and therapeutic effect on diabetic complications. IR: ionizing radiation; NIR: non-ionizing radiation. Solid line and
dash line indicate the increasing and decreasing effect, respectively.

Vol. 13, No. 2 Part I, September 2005 21


BREAST CANCER,
CHEMOTHERAPY
AND HORMESIS
Lorne J. Brandes, MD
Departments of Medicine
and Pharmacology/Therapeutics
University of Manitoba
and Section of Hematology/Oncology
CancerCare Manitoba
675 McDermot Avenue
Winnipeg MB R3E0V9
Canada
Phone: 204-787-2139
Fax: 204-786-0196
Email: brandes@cc.umanitoba.ca
ABSTRACT
N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine
(DPPE; tesmilifene) is a novel antihistaminic and
chemopotentiating agent that has a hormetic effect on
DNA synthesis in MCF-7 human breast cancer cells in
vitro and stimulates the growth of experimental tumors
in rodents. In a prospectively randomized phase three
trial (NCIC MA.19), 152 patients who were co-adminis-
tered DPPE and doxorubicin survived 50% longer
(P<0.03) than 153 patients who were administered the
same dose and schedule of doxorubicin alone. At
clinically relevant in vitro concentrations that do not
inhibit the P-glycoprotein (P-gp) pump, DPPE selectively
sensitizes cancer cells that express the multiple drug
resistance (MDR+) phenotype, making them more
susceptible to the cytotoxic effects of chemotherapeutic
agents, including anthracyclines and taxanes. Based on
its previously demonstrated interaction with histamine at
CYP3A4, a P450 that metabolizes arachidonic acid, and
its induction of high levels of PGI2 in the gut of rodents,
modulation by DPPE of the intracellular concentration
of arachidonate products, such as
hydroxyeicosatetraeinoic acids (HETEs), implicated in
increased cancer cell proliferation and metastasis, is
postulated.
I. Treatment of metastatic breast cancer (MBC)
Historically, the systemic treatment of metastatic breast
cancer (MBC) has been predicated on achieving a
cytotoxic effect to shrink tumors [1]. Anti-hormonal
therapies, such as tamoxifen and aromatase inhibitors,
22 BELLE Newsletter
are generally preferred in the treatment of estrogen-
receptor (ER)-positive breast cancer in the metastatic
setting, especially in older women [2]. The use of
chemotherapy is reserved for the approximately fifty
percent of pre- or post-menopausal women who have
more aggressive tumors that are generally not hormon-
ally-responsive, or in cases where anti-hormonal agents
fail to control the disease.
II. Chemotherapy and survival in MBC
Despite the availability of highly potent cytotoxic drugs,
including anthracycline derivatives (doxorubicin and
epirubicin) [3] and taxanes (paclitaxel and docetaxel)
[4], significant improvement in survival is rarely ob-
served in metastatic breast cancer, even though major
tumor responses (shrinkage of 50% or more in size) and
an increase in the time to progression (TTP; the period
from starting on treatment until disease progression) are
often observed. A minority of patients with aggressive
breast cancer whose tumors overexpress type 2 human
epidermal growth factor (Her-2) [5], benefit from the
addition of the specific Her-2 antibody, trastuzumab
(Herceptin), to taxane therapy, resulting in increased (≤
25%) survival [6].
III. Increased survival in MBC when DPPE is co-adminis-
tered with doxorubicin
In a prospective randomized international phase three
study (MA.19) conducted by the National Cancer
Institute of Canada Clinical Trials Group, 152 women
with metastatic breast cancer who received the combina-
tion of doxorubicin and the experimental
chemopotentiating drug, N,N-diethyl-2-[4-
(phenylmethyl) phenoxy] ethanamine (DPPE;
tesmilifene), survived 50% longer than 153 women who
received the same dose and schedule of doxorubicin
alone (23.6 months vs. 15.6 months, respectively; p<0.03)
[7]. Contrary to earlier phase two studies [8,9], the
overall survival benefit in DPPE-treated patients resulted
despite the absence of an improvement in tumor re-
sponse rates or TTP.
An independently conducted sub-group analysis (unpub-
lished) revealed that a significant survival benefit of the
DPPE/doxorubicin combination occurred mainly in
patients with a short (≤ 36 months) disease-free interval
(DFI; the time from diagnosis to disease recurrence) and
those with ER-negative tumors, both surrogates for
aggressive disease [10]. Recent in vitro studies (unpub-
lished) suggest a selective chemopotentiating effect of
clinically relevant concentrations of DPPE on cancer
cells expressing the multiple drug resistant (MDR+)
phenotype, common in aggressive cancer [11].
Based on the results of MA.19, a confirmatory phase
three international study (YMB 1002-02) in 700 women
with metastatic breast cancer is currently comparing the
combination of DPPE, epirubicin and cyclophosphamide
to the same dose and schedule of epirubicin and cyclo-
phosphamide alone in patients with DFI ≤ 36 months,
stratified for ER status (positive or negative). The
primary endpoint of this new pivotal study is survival;
secondary endpoints are TTP, response rates and quality
of life. Accrual is expected to be completed by late 2005,
with survival outcome known as early as late 2006.
IV. Pharmacology of DPPE
A. DPPE binding to “antiestrogen binding sites” on P450
enzymes
Although its mechanism(s) of action remain to be fully
elucidated, the pharmacological profile of DPPE may
provide important clues to its chemopotentiating action.
A diphenylmethane derivative that resembles tamoxifen,
DPPE lacks the stilbene bridge and third phenyl ring
necessary to bind the ER [12]. The drug was synthesized
in an effort to determine a biological role for
antiestrogen binding sites (AEBS) that also bind
tamoxifen [13]. As opposed to the ER, which is located
primarily in the nucleus in breast and uterine tissue, the
AEBS is located in the microsomal fraction, derived from
endoplasmic reticulum, and is found in most tissues,
although most abundantly in liver [14]. Because
tamoxifen binds to both sites, an assessment of a putative
role for AEBS in its antiestrogenic/antitumor action
could only be discerned with a selective agent.
Radioligand binding studies revealed DPPE does not
bind to the ER in rat uterine cytosol, but is equipotent to
tamoxifen to bind the AEBS in rat liver microsomes [12].
DPPE also antagonizes the uterotropic effects of exog-
enous estrogen in vivo, suggesting a role for AEBS in the
antiestrogenic action of tamoxifen [15]. Spectral analysis
assessing DPPE binding to purified human isozymes
ultimately led to the determination that the AEBS
represents the “substrate” site on certain microsomal
cytochromes P450, including CYP3A4, CYP2D6 and
CYP1A1 [16].
The 3A4 isozyme is important in the metabolism of
arachidonic acid, lipids, hormones and many drugs [17],
including antineoplastic agents such as taxanes, vinca
alkyloids, etoposide and cyclophosphamide/
ifosphamide. Substrates for CYP3A4 are usually also
substrates for the co-regulated P-glycoprotein (P-gp)
membrane pump [18]. When overexpressed in cancer
cells, P-gp contributes to multiple drug resistance [19].
High (50µM) concentrations of DPPE have been shown
to inhibit P-gp in vitro, overcoming drug resistance to
paclitaxel [20].
B. Histamine and proliferation: Interactive binding of
DPPE and histamine at P450
The structure of DPPE is also similar to H1-antihista-
Vol. 13, No. 2 Part I, September 2005
mines such as diphenhydramine and hydroxyzine, but is
much weaker than these agents in classical assays of H1-
activity that measure antagonism of histamine-induced
muscle contraction [21]. In contrast, DPPE competes
more strongly than conventional H1 and H2 antagonists
for the binding of 3H-histamine to microsomal AEBS/
P450, an interaction that correlates with cytotoxicity to
breast cancer cells in vitro [22]. Histamine binding to
AEBS/P450 results from its affinity for the heme iron
moiety of the enzymes [16]. Through binding to the
P450 substrate site, “AEBS” ligands such as DPPE,
tamoxifen and many other arylalkylamines [23] sterically
hinder histamine binding to the heme iron.
A role for intracellular histamine in promoting normal
and malignant growth was originally proposed by
Kahlson and Rosengren [24]. P450 enzymes are also
important regulators of cell function, including prolif-
eration [25], and may be overexpressed in malignant
cells of breast origin [26]. We have recently identified an
in situ histamine/P450 complex in rat liver microsomes
[27], and amplified upon Kahlson’s original hypothesis
with the suggestion that histamine may modulate growth
by regulating the catalytic activity of various P450s
[16,27].
At non-cytotoxic concentrations that correlate with its
inhibition of 3H-histamine binding to P450, DPPE
inhibits DNA synthesis in mitogen stimulated normal
spleen cells in vitro [28]. In contrast, DPPE exerts a
hormetic (biphasic) effect on DNA synthesis in trans-
formed and malignant cells, killing them at high concen-
trations in vitro [28]. DPPE stimulates tumor growth in
mice (L5178Y lymphoma) and rats (DMBA-induced
mammary carcinoma) [29]. Correlating with this find-
ing, systemic administration of DPPE markedly increases
inflammation and mitosis in rat skin painted with the
tumor promoting phorbol ester, PMA [29].
C. L-histidinol and DPPE: Dissimilar agents with similar
effects on histamine binding, DNA synthesis,
cytoprotection and chemopotentiation
Warrington [30] showed that L-histidinol, the alcohol
precursor to histidine (that, in turn, may be converted to
histamine by histidine decarboxylase) [31], potentiates
chemotherapy to effect cures in experimental murine
tumors, while protecting the bone marrow. In collabora-
tive studies with Warrington [28], L-histidinol was
demonstrated to compete for 3H- histamine binding in
microsomes, to inhibit DNA synthesis in normal mitogen
stimulated spleen cells and to have a biphasic effect on
DNA synthesis in transformed and malignant cells. Like
L-histidinol, DPPE was observed to protect the bone
marrow of mice from high doses of daunorubicin and 5-
fluorouracil, while increasing tumor-free survival in mice
administered doxorubicin [28]. In addition to its
protection of the bone marrow, a cytoprotective effect of
DPPE in the gut of rats exposed to cold-restraint stress
23
has been linked to the induction of a 10-fold increase in
levels of prostacyclin (PGI2) [32].
V. DPPE sensitization of MDR+ cells appears to be
independent of P-gp inhibition
At clinically relevant concentrations (3-5 µM), signifi-
cantly lower than those required to inhibit the P-gp [33],
DPPE appears to selectively potentiate chemotherapy
drugs in MDR+ cells in vitro. This finding suggests some
alternative, possibly novel, mechanism by which DPPE
overcomes drug resistance. Warrington previously
reported a similar profile for L-histidinol in overcoming
MDR [34].
VI. Hormetic effect on DNA synthesis and
chemopotentiation by DPPE may be linked to the
modulation of arachidonate metabolism
The observation that DPPE causes (i) low-concentration
stimulation and high-concentration inhibition of DNA
synthesis in MCF-7 breast cancer cells in vitro; (ii)
stimulation of inflammation and mitotic activity in
phorbol-painted skin [29];
(iii) growth-stimulation of rodent tumors; and (iv)
induction of high levels of PGI2 in the gut [32], raises the
possibility that, like its cytoprotective effects,
chemopotentiation by DPPE may be linked to its interac-
tion with P450s and/or lipoxygenases involved in
arachidonate metabolism. An interaction with these
enzymes might result in an increase or decrease in
cellular levels of various lipids and eicosanoids that,
depending on their concentration, stimulate or inhibit
DNA synthesis.
That only cells expressing the MDR+ phenotype appear
to be sensitized to chemotherapy by DPPE could be
linked to their increased turnover of arachidonate. For
example, aggressive cancers with increased metastatic
potential appear to have significantly higher levels of
prostaglandins [35]. Thus, co-administration of DPPE
may “set up” high grade MDR+ cells for killing, not by
inhibiting the P-gp, but by causing further significant
perturbations (up or down) in certain eicosanoids.
Candidates might include hydroxyeicosatetraenoic acids
(HETEs). High levels of 5- and 12-(S)-HETE are impli-
cated in increased mitosis and tumor aggressivity [36],
while inhibition of their synthesis leads to apoptosis of
breast cancer cells [37]. Thus, the hormetic effect of
DPPE on DNA synthesis in transformed and malignant
cells, possibly important to its chemopotentiation, may
be mediated indirectly by the modulation of HETEs or
other lipid/eicosanoid products that stimulate/inhibit
cell division and affect cell survival.
CONCLUSION
Validation of a survival benefit with the addition of DPPE
to epirubicin and cyclophosphamide will have important
24 BELLE Newsletter
implications for the treatment of humans with aggressive
forms of breast cancer. Chemopotentiation of other
antineoplastic drugs by DPPE in patients with various
refractory cancers has been reported [33], including
cyclophosphamide in patients with androgen-indepen-
dent prostate cancer [38]. These findings raise the hope
that DPPE may have the potential to increase survival in
many types of chemotherapy-responsive cancer.
Statement of potential conflict of interest:
Dr. Brandes is the inventor of DPPE (tesmilifene) and
could benefit financially from its successful commercial-
ization. DPPE is licensed by the University of Manitoba
to YM Biosciences, Mississauga, ON.
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26 BELLE Newsletter
Vol. 13, No. 2 Part I, September 2005 27
 NONLINEARITY IN BIOLOGY, TOXICOLOGY AND MEDICINE JOURNAL
Starting January 2005 the journal NON-LINEAR-
ITY: Biology, Toxicology and Medicine
(www.nonlinearity.net), now entering its third year,
will be editorially directed by BELLE, published and
owned by the University of Massachusetts/Amherst.
The consolidation of all journal activities under the
auspices of BELLE is designed to enhance both the
visibility and leadership role of BELLE in the area
of low dose biological effects as well as to facilitate
an improved promotion of the journal and a more
direct interaction amongst contributing authors,
BELLE and the scientific community.
NONLINEARITY in Biology, Toxicology and
INTERNATIONAL HORMESIS SOCIETY
GOAL
A growing number of scientists, including
toxicologists, pharmacologists, biostatisticians,
epidemiologists, occupational and environmental
medical researchers and others have begun to
display considerable interest in the topic of
hormesis, a dose response phenomenon character-
ized by a low dose stimulation and a high dose
inhibition. While there are many professional
societies that have a general interest in dose re-
sponse relationships, none explicitly is devoted to
the topic of understanding the nature of the dose
response in general and hormesis in particular. The
diversity of professional societies that may consider
dose response issues, including hormesis, is nonethe-
less quite broad ranging from the agricultural to the
biomedical and clinical sciences. However, nearly
without exception, these societies tend to be strongly
organized around professional advancement and not
focused on specific scientific concepts. This makes
the issue of hormesis one of diffuse interest across a
broad range of professions. The present situation
represents a major obstacle for the integrated
assessment of the dose response in general and
hormesis in particular. In order to provide intellec-
tual and research leadership on the topic of
hormesis, a new professional association has been
created called the International Hormesis Society
(IHS).
The Society will be dedicated to the enhance-
ment, exchange and dissemination of ongoing
global research efforts in the field of hormesis. In
addition, the Society will also strongly encourage the
assessment of the implications of hormesis for such
diverse fields as toxicology, risk assessment, risk
28 BELLE Newsletter
Medicine has an internationally recognized edito-
rial board, a strong peer-review process, with all
final manuscript decisions on publication made by
Associate Editors with recognized excellence in
their respective areas. A listing of the papers pub-
lished in NONLINEARITY: Biology, Toxicology and
Medicine over the past two years can be found on
the journal website. We invite you to subscribe to
the journal as well as becoming a contributor via
the submission of relevance manuscripts. To
subscribe to the journal please visit the journal
website (www.nonlinearity.net) and follow the
directions for subscription.
communication, medicine, numerous areas of
biomedical research, and all other biological disci-
plines including relevant engineering domains
dealing with the dose response.
LOCATION
The International Hormesis Society will be
administered by BELLE, School of Public Health &
Health Sciences at the University of Massachusetts at
Amherst.
MEMBERSHIP
The IHS is a professional society designed to
enhance understanding of the nature of the dose
response and its implications for science and society.
Those individuals with a professional interest in
these areas will be eligible for membership. Appli-
cants for membership must complete the attached
membership application form. Corporate member-
ships would be $1000.00 (U.S.) per year while Indi-
vidual membership dues will be $125.00 (U.S.) per
year. Student memberships are encouraged with an
annual dues set at $10.00. Applications should be
mailed to the BELLE Office, Environmental Health
Sciences Program, Morrill I, Room N344, University
of Massachusetts, Amherst, MA, 01003.
As part of IHS membership, each corporate and
individual member will receive a subscription to the
journal Nonlinearity in Biology, Toxicology and
Medicine, which is a peer-reviewed quarterly journal.
In addition, there will be a Society Newsletter devel-
oped for the membership. There will also be an
annual conference to which all society members will
receive a reduction in registration fees.
 INTERNATIONAL HORMESIS SOCIETY
Application for Membership
Application for the following membership category (mark only one):

Corporate Membership
$1,000.00/year

Individual Membership
$125.00/year
Retiree Membership
$75.00/year
Student Membership
$10.00/year

Please type or print in ink only

Last Name: ____________________________________ Middle Initial(s): ________

First Name: ____________________________________ Date of Birth: ___________

Title: __________________________________________________________________

Address: _______________________________________________________________________
Organization
____________________________________________________________
Department
____________________________________________________________
Street/P.O. Box
____________________________________________________________
City State
____________________________________________________________
Postal Code Country
_______________/________________/__________________
Telephone: country code area code number
_______________/________________/__________________
Fax: country code area code number
____________________________________________________________
E-mail

Payment (check one credit card type):

American Express
MasterCard
Visa
Discover
Check made to UMass.-IHS

_____________________________________________ __________________________________
Account Number Expiration Date

Completed application forms should be mailed to:

BELLE Office
Environmental Health Sciences Program
Morrill I, Room N344
University of Massachusetts
Amherst, MA 01003

Telephone: 413-545-3164
Fax: 413-545-4692
E-mail: belle@schoolph.umass.edu

Signature of Applicant Date

Vol. 13, No. 2 Part I, September 2005 29

30 BELLE Newsletter
ADVISORY A. Wallace Hayes, Ph.D. University of Mainz-Institute of Toxicol-
COMMITTEE Andover, MA ogy
Mainz, Federal Republic of Germany
CHAIRMAN Wayne Jonas, M.D.
Samueli Institute Wim F. Passchier, Ph.D.
Edward J. Calabrese, Ph.D. Health Council of the Netherlands
University of Massachusetts, Amherst John G. Keller, Ph.D. Rijswijk, The Netherlands
Olney, MD
Konrad Rydzynski, M.D., Ph.D.
Roger O. McClellan, D.V.M. Nofer Institute of Occupational Medi-
COMMITTEE MEMBERS Albuquerque, NM cine
Lodz, Poland
James Robert Beall, Ph.D. Myron Pollycove, M.D.
Jefferson, MD North Bethesda, MD Masami Watanabe, Ph.D.
Nagasaki University
Michael P. Bolger, Ph.D. Stephen M. Roberts, Ph.D. Nagasaki, Japan
U.S. FDA University of Florida

Joseph Borzelleca, Ph.D. Harry Salem, Ph.D.

Medical College of Virginia U.S. Army BELLE OFFICE
Northeast Regional Environmental
James S. Bus, Ph.D. Donald E. Stevenson, Ph.D. Public Health Center, University of
Dow Chemical Company Dermigen, Inc. Massachusetts, Amherst, MA 01003
Tel: 413-545-3164
Ralph R. Cook, M.D. David G. Thomassen, Ph.D. Fax: 413-545-4692
Midland, MI U.S. Department of Energy Email: belle@schoolph.umass.edu
Web: www.belleonline.com
J. Michael Davis, Ph.D.
U.S. EPA
INTERNATIONAL MEMBERS
Christopher DeRosa
ATSDR John Ashby, Ph.D.
Zeneca Central Toxicity Laboratory
David J. Doolittle, Ph.D. Macclesfield Cheshire, United Kingdom
R.J. Reynold Tobacco Company
Sadao Hattori, Ph.D.
Max Eisenberg, Ph.D. Central Research Institute of Electric
Baltimore, MD Power
Tokyo, Japan
William Farland, Ph.D.
U.S. EPA Zbigniew Jaworoski, Ph.D.
Central Laboratory for Radiological
William F. Greenlee, Ph.D. Protection
CIIT Warszawa, Poland

Ron W. Hart, Ph.D. Shu-Zheng Liu, M.D.

NCTR, Director Emeritus Norman Bethune University of Medical
Sciences
Changchun, China
Franz Oesch, Ph.D.

Vol. 13, No. 2 Part I, September 2005 31

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32 BELLE Newsletter