Reevaluation
of the Fundament
Dose-Response
Relationship
A new databasesuggests that the U-shaped,ratherthan
the sigmoidal, curvepredominates
EdwardJ. CalabreseandLindaA. Baldwin
The
shapeof the dose-response
curve for toxic substances has
been the topic of an enormous
debate that began several decades
ago and continues today (Calabrese
1978). The argument centers on
whether there is a threshold below
which no adverse effects would be
expected or whether the dose-response relationship is linear, with
risk being proportional to dose
(Bingham 1971, Hatch 1971, 1972,
Oser 1971, Dinman 1972, Stokinger
1972, Stopps 1974, Albert and
Altshuler 1976). The principal public health implication is that if a
threshold response were assumed to
exist, exposures below that level
would be safe (i.e., no effect). However, if there were no thresholds of
response, then the potential for a
risk could be expected regardless of
how low the exposures were.
Despite the apparently striking
differences between these two competing theories of dose-response relationships, both have become accepted within the scientific and
regulatory communities. The threshold theory has been principally applied to assessing risk from exposure
whereas the
to noncarcinogens,
EdwardJ. Calabrese(e-mail:edwardc@
schoolph.umass.edu) is a professor of
Toxicology and Linda A. Baldwin (email: [email protected])is
a research associate in the Department
of Environmental Health Sciences,
School of Public Health and Health Sciences at the University of Massachusetts, Amherst, MA 01002.
? 1999
AmericanInstituteof BiologicalSciences.
September1999
The U-shaped response
in toxicological and
pharmacological
experiments is highly
generalizable, being
independent of phylum,
chemical class, and
biological endpoint
nonthreshold (i.e., linear) approach
has been used for carcinogens. Consequently, with respect to carcinogens, the issue of what is an acceptable risk has arisen because the linear
approach assumes the potential for
risk at all exposures, and zero exposure is not possible to achieve.
The problem with such risk estimations, especially for carcinogens,
is that they are typically based on the
effects of exposing animals (usually
rodents) to very high doses of the
compounds, often four to five orders
of magnitude beyond normal human
experience, with the results then being extrapolated via one of a variety
to biomathematical models to low
doses estimated to cause risks in the
one-in-a-million
zone (Calabrese
1978, 1983). This exercise of estimating human responses from rodent models is not inappropriate in
theory because animal models may
provide acceptable qualitative predictions of human responses. How-
ever, regulatory agencies such as the
Environmental Protection Agency
(EPA) and the Food and Drug Administration have used the animal
studies and biostatistical models to
provide apparent estimates of human
risk even though the predictions are
essentially unverifiable, often inconsistent with human experience, and
extremely costly to implement within
risk management decisions.
As this brief synopsis of the risk
assessment dilemma since the 1970s
indicates, it has become necessary to
better understand how biological
systems respond to low levels of a
wide range of carcinogenic and noncarcinogenic stressor agents. Although this reexamination of the biological effects of low-level exposures
to chemicals and radiation has taken
many forms, one unmistakable conclusion is that most, if not all, biological systems have both constitutive and inducible adaptive response
mechanisms that help to defend the
organism from a wide range of stressor agents. These adaptive response
mechanisms include, for example,
stress protein responses, DNA repair
mechanisms, and cell and tissue repair mechanisms (Hart and Frome
1996). It is further known that it is
the interplay of these adaptive mechanisms with external stressor agents
that determines the shape of the doseresponse curve. That is, individuals
or species with limited adaptive capacities succumb to lower doses of
stressor agents than organisms or
species with better adaptive mechanisms. Thus, adaptive mechanisms
help account for both inter-individual
725
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is collaborating with JSTOR to digitize, preserve, and extend access to
BioScience
®
www.jstor.org
Figure 1. U-shaped
dose-response curves.
(a)Generalformof a Ushaped dose-response
curveshowingresponse
relative to a reference
level (i.e., control
value),with a regionof
apparentimprovement
(e.g., reductionin dysfunction) as well as a
region of toxic or adverseeffects.(b) Reciprocal of the samecurve
showinga regionof apparent enhancement
(e.g., increase above
normal level of function) as well as a region
of toxic or adverseeffects. From Davis and
Svendsgaard(1992).
SI
I
(a)
•-
O
-
R
-
--
-
REFERENCE LEVEL
/
-
-D
C
2
ADVERSE EFFECTS
APPARENT IMPROVEMENT
0
20
40
60
80
100
Dose
Dose
I
.
I
I
I
o.
DOSE REGIONOF
APPARENT ENHANCEMENT
"II_
DOSE REGION OF
ADVERSE EFFECTS
C
and interspecies variation in response to
a
toxic substances.
it
is
also
S0
However,
to
-•U
important
recognize that adaptive
responses may be affected by the dose of
the stressor agents.
For example, high
(
(b)
doses of stressor
agents may saturate
0
20
40
100
60
80
normal detoxificaDose
tion pathways, making them at least temporarily nonfunctional. Furthermore, over a broad range of doses. Accordmost biological systems operate within ing to this evolutionary expectation
an optimal zone of responsiveness,
(Parsons in press), the shape of the
typically at low levels of exposure, dose-response curve would be either
that is maintained by an integrated a U or an inverted U, depending on
series of biochemical pathways.
the biological response measured
It is within this concept of under- (Figure 1). For example, when the
standing how organisms respond to response refers to endpoints such as
low-level stressor agents and what growth, longevity, and fecundity, the
roles constitutive and inducible de- dose-response curve displays a stimufense mechanisms play that a new lation or increase in response at low
theory of the dose-response relation- doses compared to the control, folship has emerged that challenges and lowed by inhibition of the stimuenhances both the linear and thresh- lated response at higher doses (i.e.,
old theories of dose-response rela- the shape of the dose-response curve
tionships. From careful reexamination is an inverted U; Figure ib). When
of current theories of organismal, the response at low doses is to diminphysiological, cellular, and molecu- ish effects such as mutations, backlar defense mechanisms has emerged ground cancer, or disease incidence
the evolutionary expectation that compared to the control, then the
dose-response relationships should dose-response curve is U-shaped
neither be simply linear nor show a (Figure la).
threshold effect but should rather
At low levels of biological stress,
reflect the underlying capacity for organisms would be expected not
systems to adapt to the effects of only to repair limited stressor-inphysical and chemical stressor agents duced damage, but also to modestly
0
D=
SI
Il
I
lI
ai
726
i
.
I
overcompensate such repair activities,
thereby assuring adequate repair until
homeostasis is reestablished. During
this modest overcompensation response phase, the organism would
not only eliminate the low-level
stress-induced damage but also reduce background stress or damage
more effectively than before stressor
exposure. At the low end of the doseresponse curve, therefore, a dip below that of the controls (i.e., a net
reduction in damage below that in
the unexposed control) would be observed. However, as the dose increases, it would eventually reach a
level at which the capacity to overcompensate would be overwhelmed,
and net toxicity would ensue (i.e., a
response threshold would be exceeded). This modest overcompensation response should be observed
with both carcinogens and noncarcinogens. In this article, we use
the term hormesis (from the Greek
word "to excite") to refer to the
phenomenon of stimulatory effects
observed at low doses of toxic substances. These low-dose stimulatory
effects (i.e., hormesis) should not be
confused with the physiological and
biochemical mechanisms that may
account for the phenomenon (e.g.,
the adaptive and homeostatic mechanisms described above).
In this article, we present evidence
of U-shaped dose-response relationships. We then reevaluate the fundamental dose-response relationship
within the context of U-shaped doseresponse curves. Finally, we discuss
the impact of implementing changes
in how society and the scientific community regard the phenomenon of
hormesis.
U-shaped dose-response
curves
U-shaped dose-response relationships at low doses have often been
reported in the peer-reviewed literature. Numerous well-designed and
replicable findings of such responses
were reported in the late nineteenth
and early twentieth centuries by
highly respected researchers (for review, see Calabrese and Baldwin
1999a). However, some early and
influential advocates of the U-shaped
dose-response theory became closely
linked with the proponents of the
BioScience Vol. 49 No. 9
medical practice of homeopathy; as
a result, the theory became more of
an attempt to explain the actions of
homeopathic therapiesthan a broad
biological hypothesis. In fact, although the original scientific credit
for reportingsuchlow-dose U-shaped
responses goes to Hugo Schulz, of
the University of Greifswald, Germany, in the late 1880s, Schulz also
created a major problem for the
broad acceptance of his theory by
becomingclosely associated with the
homeopathic physician Rudolph
Arndt in proclaiming that his findingsprovidedhomeopathy'sexplanatory principle (i.e., that any disease
state can be correctedby vanishingly
small doses of substances that at
higher doses produce symptoms of
the disease).
The U-shaped dose-response
theory soon became known as the
Arndt-Schulz Law. However, because of its association with homeopathy, the Arndt-SchulzLaw came
under serious attack by dominant
medically oriented scientists (Clark
1937) and suffered the same fate as
homeopathy in the early twentieth
century-that is, it became a highly
marginalized and often discredited
theory. In addition, there was difficulty in replicating the reported Ushaped responses because of the
modest nature of the response and
weaknessesin the study designs (e.g.,
inadequate numbers of doses tested
and inadequate sample sizes). The
combination of weak response and
poor study design did not bode well
for a fledgling theory whose practical relevance was not clear. However, because the issue of low-dose
exposure has come to dominate current risk assessment practices, understanding the nature of the
hormesis phenomenon is a matter of
when low-dose responsesof a "paradoxical" naturewere observedin the
target organisms of the toxin (i.e.,
low doses produced a response opposite of that produced by higher
doses), attention was quickly reoriented to high-dose issues of obvious
practicality. In fact, even though
nearlyall majormicrobiologicaltexts
of the mid-twentieth century (Salle
1939, Clifton 1957, Thimann 1963,
Lamanna and Mallette 1965) acknowledged the fact that low doses
of disinfectants stimulated the
growth of bacteria, the emphasis remained on the "real" issue of defining the bacteriostatic and bacteriocidal effects observed at high
disinfectant doses.
Despite numerous challenges and
the lack of broad acceptance of the
Arndt-SchulzLaw,investigatorscontinued to report U-shaped dose responses, and by 1943 mycologists at
the University of Idaho, unaware of
the Arndt-SchulzLaw, identifiedthe
same phenomenon and renamed it
"hormesis" (Southam and Erhlich
1943). To this day, both terms are
used interchangeablyto describe Ushapeddose responses.However, because of the close association of
modern toxicology with traditional
medicine, and because of the extremehistoricaltension betweentraditional medicine and homeopathy,
the Arndt-SchulzLaw/hormesisphenomenon has never achieved recognition and legitimate biological hypothesis status despite its occasional
support by noteworthy individuals
(Luckey1980, 1991, Stebbing1981,
Sugaharaet al. 1992, Kondo 1993).
Perhapsthe most importantphilosophical concept emergingfrom the
study of the historical foundations
of hormesis is how a phenomenon
substantially initiated by powerful
considerable importance.
Acceptance of the Arndt-Schulz
Law was also hindered by the fact
that toxicology of the first half of the
twentieth century focused predominately on high-dose phenomena. In
fact, toxicology continues to focus
on high doses even as we approach
the twenty-first century! In the early
twentieth century, for example, research involving microbial disinfection and pest eradication centered
on the application of high doses to
achieve these desired goals. Even
leaders in the field, including several
Nobel prize winners and their students, with consistent data replication, could have become marginalized
within the scientific community. Although the reasons for this marginalized status are complex, involving
political, social, scientific, and personal factors, the fact that it occurred in open Western scientific
society should raise great concern
over the process by which scientific
research is conducted and reported
(for a detailed review of the histori-
September1999
cal foundations of hormesis and its
marginalization, see Calabrese and
Baldwin 1999a, 1999b).
Creationof an
hormesisdatabase
In 1996, we set forth to comprehensively evaluatethe hormesisphenomenon-that is, to determinewhether
the fundamental dose response includes a U shapeat the low end of the
dose-response curve-via the use of
rigorous, a priori objective criteria
that included information on study
design, magnitude of response, statistical significance, and reproducibility of findings (Calabrese and
Baldwin 1997). To date, we have
evaluated several thousand articles
that addresslow-dose effects of various chemicals and have found more
than 1300 that display hormesis according to our criteria. Of particular
note is the finding that the U-shaped
response in toxicological and pharmacological experiments is highly
generalizable, being independent of
phylum, chemical class, and biological endpoint (Figure 2). Hormetic
effects are seen in organisms from
bacteria to humans and are caused
by a vast array of chemicals, including relatively innocuous agents as
well as some highly toxic substances
(e.g., heavy metals such as lead, cadmium, and mercury,and unintended
industrial byproducts, such as dioxin). The range of endpoints affected is also extensive and includes
growth, a wide variety of behaviors
(e.g., learning, eating, and survival),
longevity, reproduction, and incidence of birth defects and diseases
such as cancer.
Figure 2 shows some examples of
dose-response relationships that are
consistent with the hormesis phenomenon; these examples were selected to demonstrate broad-based
generalizability of the phenomenon.
However, the application of the
quantitative scoring system (i.e., the
criteria described in Calabrese and
Baldwin 1997, which assign a score
that shows the degree to which the
data conform to the U-shaped doseresponse curve based on study design, response, and reproducibility
criteria) to these 24 examples reveal
that only one (Figure 2a) received a
high evidence score. Of the rest, one
727
160
140
a
(P < 0.01)
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140
-- -- --
8-------
8 100
g so
4020
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PENICILLIN+
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0.001 1 0.004 1 0.008
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0.002
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MERCURY+
FUNGI GERMINATION
g
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15
60 125 250 500
Phenobarbital (ppm in diet)
30
2
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Mercury concentration (ppm)
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30
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os-so 050+
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+
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AMPHIPOD FECUNDITY
CYANOBACTERIA
PHOTOSYNTHESIS z
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GROWTH
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80
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1.5
1.9
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9.2
Figure2. Representativeexamplesof dose-responsecurveswith the scoresand evidenceof hormesis.Data from:(a) Calabreseand
Brown 1994, (g) Nutman and Roberts1962, (h) Davis and Hidu 1969, (i) Reish and Carr1978, (j)Joy 1990, (k) Gaurand Singh
(q) Laughlinet al. 1989, (r)Morse and Zareh 1991, (s) Broerseet al. 1982, (t) Parsons1981, (u) Stebbing1981, (v) Liuet al. 1987,
of statistialsignificance;absenceof statisticalsignificancedenotesstudiesthat did not performstatisticalanalyseson theirdata,with
(Figure 2c) received a moderate to
high score, two (Figures 2g and 2o)
received a moderate score, eight received a low to moderate score (Figures 2d, 2e, 2h, 21, 2p, 2v, 2w, and
2x), and 12 received a low score
(Figures 2b, 2f, 2i, 2j, 2k, 2m, 2n, 2q,
2r, 2s, 2t, and 2u).
Overall, our assessment of the
characteristics of the U-shaped doseresponse relationship indicates considerable range and diversity with
728
respect to patterns of the stimulatory dose, magnitude of stimulatory
response, and relationship of the
maximum stimulatory response to
the "no observedadverseeffectlevel"
(NOAEL; Calabrese and Baldwin
1998a). Many U-shaped dose-response relationshipsconform to a Ushaped curve displaying a 10- to 20fold stimulatory range, a maximum
stimulatoryresponsethat is 30-60%
greaterthan the control, and a maxi-
mum stimulatoryresponseoccurring
at a dose four- to fivefold below the
NOAEL. However, other U-shaped
dose-responserelationshipsarestrikingly different (Calabreseand Baldwin 1998a). For example, in some
cases the rangeof stimulation is over
several orders of magnitude of dose,
and the maximum stimulatory response approaches 10-fold. Recognition that U-shaped dose-response
curves can vary widely suggests that
BioScience Vol. 49 No. 9
160
140
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10
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IMMUNE
RESPONSE
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: 40-
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15
140
-----------
--
10
+ (P < 0.05)
160
SW
80
5
Copper(ug/L)
(P < 0.05)
*
140
120
100
.r
0.5
Ethanolconcentration(%)
V
.
0
40-
+
DIMETHOATE
MITEFECUNDITY
SODIUMARSENITE+
HUMANKERATINOCYTE
PROLIFERATION a'. 20
0-
0
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0.7
Howe 1976, (b) Holdway and Sprague1979, (c) Kitanoet al. 1998, (d) BerandMoskwa 1951, (e) Milleret al. 1945, (f) Kitchenand
1990, (1)Connelland Airey1982, (m)Downs and Frankowski1982, (n) Hodjat 1971, (o) Bodaret al. 1988, (p) Broerseet al. 1982,
(w) Germolecet al. 1996, and (x) Folker-Hansenet al. 1996. Theasterisksindicatestatisticallysignificantdata;P valuesindicatelevel
the exception of (f), in which the lowest responsewas not statisticallydifferentfrom the control.
the area of hormetic dose-response
relationships, including their possible
risk assessment implications, is considerably more complex than previously assumed.
Although many types of endpoints
have been assessed in the hormesis
database, two that are of broad interest are effects on reproductive
processes and cancer. A substantial
body of work indicates that both
endpoints display apparent hormetic
September 1999
relationships.With respect to reproduction, evidence of chemical
hormesis was observed in experiments with arachnids (mites; Hueck
et al. 1952, Rodriguez et al. 1957,
Folker-Hansen et al. 1996), crustaceans (daphnids; Elnabarawy et al.
1986, Bodar et al. 1988), insects
(Johansson 1947, Kuenen 1958,
Sutherlandet al. 1967, Hodjat 1971,
Gordon and McEwen 1984, Lowery
and Sears 1986a, 1986b, Morse and
Zareh 1991), hydrozoans (hydra;
Browne and Davis 1977, Stebbing
1981), annelids (polychaete worms;
Reish and Carr 1978), and rodents
(Daston et al. 1991, Calabrese and
Baldwin 1993). The range of endpoints showing low-dose enhancement typically included offspring
number, egg production, basal follicle number, maternal weight, implant number, and live fetuses per
litter. Examples of hormetic effects
729
in these studies have been reported
most often with heavy metals, insecticides, and radiation.
Recognition of the occurrence of
low-dose stimulation of reproductive output may be useful for providing insight into the cause of insect
outbreaks. Ecologists and applied
entomologists have long recognized
that insect outbreaks often occur after pesticide applications. Although
these outbreaks have often been attributed to elimination of predator
or competitive species, field and laboratory data support the hypothesis
that hormetic-like physiological
stimulation is responsible (Morse
1998). When hormesis as a concept
is viewed not simply in biological
terms, the question of whether it is
beneficial or not is often contextual.
For example, in the case above,
hormesis would be beneficial to the
insects (i.e., increased fecundity) but
harmful to the plants damaged by
the insects.
The extension of the hormetic
phenomenon into the field of carcinogenesis has also been explored
(Calabrese and Baldwin 1998b). In
the case of cancer, hormesis is reflected by a decrease in disease incidence at low doses compared to the
control (or background) incidence.
This reduced response can be seen
only in studies of animal models that
exhibit a relatively high background
incidence of cancer, which provides
the possibility of observing a response
that is less than the control response
(e.g., see Figures 2c, 2f, 2m, 2p, and
2s). Recently, we have identified a
number of investigations that provide evidence of hormesis for various stages (i.e., initiation, promotion, and progression) of the process
of carcinogenesis (Calabrese and
Baldwin 1998b). Such examples include studies assessing the effects of
chemicals (e.g., dioxin; Kociba et al.
1978) and radiation (Broerse et al.
1978, 1982, 1987) on mammary tumors in selected rat strains, the effects of hydrocarbons on pulmonary
tumors in mice (O'Gara et al. 1965,
Nesnow et al. 1994, Prahalad et al.
1997), and the effects of heavy metals (e.g., cadmium) on testicular cancer in rats (Waalkes et al. 1988). The
key feature in all such studies is the
need for a high background tumor
incidence and a study design suffi730
ciently powerful to permit the
hormetic hypothesis to be assessed.
Nevertheless, the search for experimental studies that assess the
relationship of hormesis to carcinogenesis is difficult, principally because assessing hormetic responses
has not been the explicit goal of the
investigators. In fact, of the nearly
two dozen articles in our database
that display evidence of hormesis in
animal cancer studies, none was derived from investigator hypotheses
to evaluate whether the dose-response relationship for various carcinogenesis endpoints displayed
hormesis. Hormesis was posited only
once the investigation had reached
the interpretative phase.
Even though evidence of hormesis
in assessing carcinogenesis has been
based on the study of animals with
high background incidences of cancer, there is no reason to believe that
the mechanisms accounting for the
hormesis phenomenon occur only
when the control incidence is elevated. The possibility that hormesis
also occurs in strains with low background incidence of cancer is of great
significance because such strains are
often used in dose-response studies.
In cases in which the controls display
low or no disease incidence, it is not
possible to detect low-dose reductions in the endpoint measured (e.g.,
cancer incidence) compared to the
control. At low doses, the disease
incidence will be similar to the control incidence, and a change in the
dose-response relationship will not
be apparent until an increased incidence is observed at a higher dose
(i.e., the dose-response curve will
exhibit a threshold response). Adaptive mechanisms (e.g., DNA repair)
may still be induced (i.e., stimulated)
by low doses, but they will be unable
to be reflected as a reduction in disease incidence.
observed. In fact, as important as it
is to identify examples of the hormesis
phenomenon, it is equally important
to understand the basis for why
hormesis may not be observed. Examining both questions is necessary
if hormesis is to be applied in testing
protocols or exploited in matters related to system optimization or
therapeutics.
One reason for the absence of
hormesis, as discussed above, is the
use of controls that display a negligible cancer or disease incidence
background response, which prevents the detection of a reduction in
this incidence. Other principal reasons for the absence of evidence for
hormesis are inadequate study design, including either insufficient
doses and/or dose spacing in the lowdose zone; selection of an endpoint
that has high background variability
along with a modest low-dose stimulation; lack of measurements over
time, preventing documentation of
the process of initial disruption in
homeostasis, the overcompensation
response, and the subsequent reestablishment of homeostasis; and differential capacities of biological systems to display hormesis, which can
affect the maximum response.
In fact, a principal methodological reason for the limited impact of
hormesis on the field of toxicology is
the inadequate number of low doses
in study designs. The ultimate goal
of the hazard assessment protocols
of US regulatory agencies is to define
the NOAEL, which essentially specifies the transition between no effect
and toxicity and therefore provides
an estimate of the threshold. However, the key issue in hormesis is that
there is significant biological activity below the traditional NOAEL.
Why hormesis is not
always seen
While hormesis remains to be accepted as a credible phenomenon in
the toxicology community, the availability of the extensive hormesis database and the broadening experimental and general scientific interest
in low-dose effects are likely to have
a significant impact on how hormesis
is regarded. If the hormesis phenomenon continues to receive serious attention, it will have the capacity to
Even though we have carried out a
comprehensive search of the toxicological and pharmacological literature for examples of hormesis and
have found this phenomenon to be
quite common and broadly generalizable, there are numerous instances
in which evidence of hormesis is not
Societal significance
of hormesis
BioScience Vol. 49 No. 9
affect many aspects of toxicology,
regulatory science, and risk assessment. Although it may be premature
to focus extensively on the implications of hormesis, a brief listing is
worthwhile.
* How chemicals and drugs are evaluated may have to be changed. Emphasis on high-dose response analyses would have to be expanded to
include the lower-dose (i.e., subNOAEL) region.
* How risk is estimated will need to
be improved and made more realistic. The hormesis phenomenon suggests that current procedures used
by regulatory agencies to estimate
the risks of both carcinogens and
noncarcinogens need considerable
modification and perhaps significant
overhauling.
* Risk communication practices
would need to recognize the improvement in scientists' understanding of
the dose-response relationship. Such
recognition of the acceptance of
hormesis is likely to be quite challenging for regulatory and public
health agencies because their past
and current approaches for assessing risks would need to be changed.
* The health criteria for all current
environmental standards may need
to be reassessed in light of the
hormesis phenomenon.
* The implications for hazardous
waste cleanup are likely to be affected by the acceptance of the
hormetic hypothesis. In most cases,
the hormesis phenomenon is likely
to conclude that the prior risks were
substantially overestimated. Such a
determination may also affect past
court decisions concerning the
cleanup of waste sites.
* The hormesis phenomenon may be
used in providing a foundation for
improved understandings of bacterial infestations and insect outbreaks.
* The hormesis phenomenon is intimately linked with various theories
of optimization of performance and
may be used to enhance worker performance and personal well-being.
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