[ RadSafe ] Challenging Dose-Response Dogma (and not just from radiation)

[John Jacobus]

I did not know there was an LNT for liver cancers from
carcinogens.  Sorry the figures did not come out, but
they have been shown before


-------------
THE SCIENTIST

Volume 19 | Issue 3 | Page 22 | Feb. 14, 2005

Vision
Challenging Dose-Response Dogma

Hormesis presents a good model for toxicological risk
assessment – and it's not homeopathy 
| By Edward J. Calabrese 

The central pillar upon which toxicological
assessments are built is the dose-response
relationship. 

[Courtesy of Edward J. Calabrese FIGURE 1.  Stylized
curves that illustrate the linear, threshold, and
hormetic dose-response models for carcinogens.]


The central pillar upon which toxicological
assessments are built is the dose-response
relationship. But reliance on theoretical prediction
models for dose response creates a wolf-crying
atmosphere that generates fear and superfluous costs
to the public. A better alternative exists, however. A
rich vein of data supports hormetic dose-response
modeling, which allows for the observation that some
toxins, in small amounts, confer benefits rather than
harm.

Having been relegated for years to the toxicological
waste heap by misconception and inertia, hormesis is
regaining respect, and I believe that such modeling
will replace the outmoded standards in toxicology and
may ultimately influence most areas of biological
research.1 

Since the consolidation of toxicological and
pharmacological conceptual thinking in the 1930's, the
overwhelmingly accepted dose-response model has been
the threshold model, which assumes that toxins must
exceed a certain concentration in tissues before they
induce toxic effects. The threshold model has been
used to establish public health-based exposure
standards for the long-recognized toxins, such as
cadmium, lead, and mercury. Below the threshold dose,
no toxicity risk is assumed. And to protect against
the possibility that humans are more susceptible to
toxic effects than mice, rats, and other animal
models, safety factors, typically in the 100-fold
range, have been introduced.2 

The only major institutional challenge to this
dose-response framework deals with carcinogens. US
governmental agencies decided that carcinogens should
be assumed to act in a linear or no-threshold (LNT)
manner, suggesting that there is no safe level of
exposure (Figure 1). From this, the Environmental
Protection Agency, the Food and Drug Administration,
and other regulatory and health agencies developed the
concept of acceptable risk. That is, any exposure to a
carcinogen, no matter how small – even as low as a
single exposure on one day – posed some cancer risks.1


Throughout the past several decades, US regulatory
agencies and those of many foreign countries have
followed the dictates of these two dose-response
models when establishing community and occupational
exposure standards. The scientific problem with such
predictions of cancer risk is that they are, for all
intents and purposes, theoretical, and therefore
incapable of being verified either in animal or
epidemiological investigations. These predictions
become bad policy when such educated guesses are shown
to be both far off the mark and enormously expensive
to society.

For example, cancer risk assessments based on LNT
modeling predict that millions of US citizens will die
each year of liver cancer due to chemical carcinogens
in the environment, yet less than 20,000 die of this
disease from all causes. In addition, LNT modeling has
resulted in huge expenditures for emissions-control
technology and remediation activities.

THE HORMETIC CHALLENGE The hormetic dose response
challenges such long-standing toxicological
dose-response model mindsets. Hormetic dose responses
are biphasic, displaying either an inverted U- or
J-shape depending on the endpoint measured (Figure 1).
It's generally recognized, for example, that adults
who consume a glass of wine most days have reduced
risk to cardiovascular disease compared to
nondrinkers, while excessive consumption increases
such risks. This type of J-shaped dose response is now
known to be quite common in toxicology and
pharmacology, being seen with many dozens of
chemicals, and for hundreds of important endpoints
such as cancer risks, longevity, growth, performance
on various types of intelligence tests, and more.3 

Comprehensive assessments of the literature have shown
the hormetic model to be biologically more fundamental
than either major dose-response rival, more common in
valid head-to-head comparisons, and generalizable
across biological model, endpoint measured, and the
chemical class or physical agents studied. Based on
these conclusions I have argued that the hormetic
dose-response model should replace both the threshold
and linear models as the default model in risk
assessments for noncarcinogens and carcinogens.2
Further, the hormetic dose response should be
considered not just the dominant model in toxicology
but also in the broader domain of the biomedical
sciences including immunology, cancer cell biology,
neuroscience, and all other fields that rely upon
dose-response relationships.

Ultimately, the challenge that the hormetic model
presents to the biomedical communities, including
toxicology, is nothing less than a scientific
revolution. It changes the understanding of how
biological systems deal with low levels of
chemical/physical agents. It should alter how studies
assessing the dose response should be designed with
respect to the number, size, and spacing of such
doses, and the distribution of subjects within these
and other frameworks. It should cause regulators to
reevaluate how risk assessments are conducted, and how
medical dosing should be optimized.

The hormesis concept also changes the way society
might think about contaminants and drugs. A toxicant
that enhances tumor formation at high doses may affect
a reduction in tumor incidence at lower doses. For
example, in studies with the rat model used by the US
National Toxicology Program, DDT has been reliably
demonstrated to reduce tumor incidence significantly
below that of the control group at low doses while
being a carcinogen at higher doses (Figure 2).4 

This information is common within the Hormesis
Database that we've developed at the University of
Massachusetts.5 Such accumulated data from the
peer-reviewed biomedical literature provide a
challenge to the scientific and regulatory communities
concerning how these data should be integrated into
political, regulatory, and educational activities. The
challenge extends to pharmaceuticals such as antitumor
drugs. At high concentrations they inhibit tumor
growth, while at lower concentrations stimulation of
tumor growth may occur. Such possibilities have
important implications dealing with not only drug
design and testing but also for clinical management of
cancer.

[Courtesy of Edward J. Calabrese FIGURE 2.  Effect of
DDT on number of GST P-positive foci in F344 rat
livers in two bioassays assessing different but
slightly overlapping doses of carcinogen. As the dose
decreases the J-shaped dose-response becomes evident.
Also note difference in scale between the two graphs.
(Based on T. Sukata et al., Int J Cancer, 99:112–8,
2002).]

TOXICOLOGICAL BLUNDERS Why the hormetic dose response
has been either unknown or ignored within the
biomedical and toxicological communities is a
significant issue. Its absence from the toxicological
literature during the past century resulted from a
complex set of interacting factors. On the scientific
side, the principal reason is that hormesis can be
difficult to detect because the magnitude of the
stimulation is modest, being only about 30%-60%
greater than control at maximum. This modest response
could readily be dismissed as normal variation unless
the experimental design has a sufficient number of
properly spaced doses. But since toxicology has long
been a high-dose/few-doses discipline, based on the
overriding belief in the threshold model, it does not
usually explore possible hormetic responses.

Now institutionalized within the EPA and FDA,
industrial and academic researchers have little
incentive to explore beyond the high-dose/few-doses
paradigm. In addition, researchers seek out animal
models that display low background disease incidence
for statistical reasons (i.e., to keep sample size
low). But hormetic levels cannot be observed within a
negligible background.

On the political side, the hormesis concept,
immediately upon its discovery in the 1880s, became
closely but incorrectly associated with the medical
practice of homeopathy, becoming a victim of
collateral damage in a long-standing and intensely
bitter confrontation with traditional medicine. While
hormetic effects are generally seen in the 10-4 to
10-9molar concentration range, homeopathy is often
practiced at concentrations far below 10-18 M.
Nonetheless, intellectual field leaders in
pharmacology, such as the eminent scholar and
researcher Alfred J. Clark of the University of
Edinburgh, delivered powerful, convincing, and
unrelenting criticisms of the hormesis concept (then
called the Arndt-Schulz law) just as the dose-response
concept was being consolidated in scientific,
biostatistical, and governmental circles, leaving the
hormesis concept in a marginalized status at best (see
his Handbook of Pharmacology, 1937).

Since toxicology had its origins in pharmacology, and
pharmacology was central to traditional medicine, it
was only natural that the rejection of the
Arndt-Schulz law (and the hormesis concept) would
become part of the toxicological mantra that led the
field.

HORMESIS REEMERGES Despite the broad array of
obstacles it confronted, hormesis has emerged from its
dormant, and at times ridiculed past, to claim a place
at the toxicological table of dose-response mechanisms
– as seen with its inclusion in major texts including
Hayes' Principles and Methods of Toxicology and
Casarett and Doull's Essentials of Toxicology.
Furthermore it challenges for that pristine seat, the
default model upon which most decisions fall back in
risk-assessment.

While most interest in the hormetic model has focused
on its application to environmental risk assessment,
especially for carcinogens, it will have enormous
implications for the biomedical sciences and clinical
medicine. In the world of clinical medicine the
hormetic zone may be that component of the dose
response to either avoid, such as in tumor, microbe,
or viral stimulation, or to seek out, such as in
enhancing cognition, sexual performance, hair growth,
or cardiovascular health. In an ironic twist, the
increased recognition, acceptance, and use of hormesis
within the biomedical research and clinical medicine
domains may prove to be the equivalent of a
toxicological Trojan Horse, which will lead to its
eventual acceptance in environmental risk assessment.

Edward J. Calabrese is a professor of toxicology at
the University of Massachusetts, School of Public
Health, Amherst. He has researched extensively in the
area of host factors affecting susceptibility to
pollutants, and he has authored more than 10 books,
including Principles of Animal Extrapolation,
Ecogenetics, and Nutrition and Environmental Health,
vols. I and II. 

He can be contacted at edwardc at schoolph.umass.edu. 

References 
1. EJ Calabrese, LA Baldwin  "Toxicology rethinks its
central belief – Hormesis demands a reappraisal of the
way risks are assessed," Nature 2003,  421: 691-2.
[PubMed Abstract][Publisher Full Text] 

2. EJ Calabrese  "Hormesis: from marginalization to
mainstream. A case for hormesis as the default
dose-response model in risk assessment," Toxicol Appl
Pharm 2004,  197: 125-36. [Publisher Full Text]  

3. EJ Calabrese, LA Baldwin  "Hormesis: U-shaped
dose-response and their centrality in toxicology,"
Trends Pharmacol Sci 2001,  22: 285-91. [PubMed
Abstract][Publisher Full Text] 

4. T Sukata et al,  "Detailed low-dose study of 1,1-B
IS(p-chlorophenyl)-2,2,2-trichloroethane
carcinogenesis suggests the possibility of a hormetic
effect," Int J Cancer 2002,  99: 112-8. [PubMed
Abstract][Publisher Full Text] 

5. EJ Calabrese, R Blain  "The hormesis database: an
overview," Toxicol Appl Pharm 2005, in press.

=====
+++++++++++++++++++
"Baltimore is actually a very safe city if you are not involved in the drug trade."
DR. PETER BEILENSON, the city's health commissioner.

-- John
John Jacobus, MS
Certified Health Physicist
e-mail:  crispy_bird at yahoo.com

__________________________________________________
Do You Yahoo!?
Tired of spam?  Yahoo! Mail has the best spam protection around 
http://mail.yahoo.com