Adoption of Linear No-Threshold Model Violated Basic Scientific Principles and Was Harmful
Commentary published in Archives of Toxicology in Feb 2014.
The final
publication is available at:
http://rd.springer.com/article/10.1007/s00204-014-1208-8/fulltext.html
Letter from Mohan Doss
regarding Edward Calabrese's paper „How the US National Academy of Sciences
misled the world community on cancer risk assessment: new findings challenge
historical foundations of the linear dose response" (Arch Toxicol (2013)
87:2063-2081) and the Letter from Ralph J Cicerone (Arch Toxicol (2014)
88:171-172)
Mohan Doss
Diagnostic Imaging, Fox Chase
Cancer Center,
Philadelphia, PA, 19111
Mohan.Doss@fccc.edu
I
am writing with regard to the Letter to the Editor from the President of
National Academy of Sciences (NAS) Ralph J. Cicerone (Cicerone and Crowley 2013) regarding Professor Edward Calabrese’s recent article
in Archives of Toxicology (Calabrese 2013), which was critical of Hermann J. Muller’s claim in
his Nobel Prize lecture (Muller 1946) that there is "no escape from the conclusion
that there is no threshold
dose" for radiation-induced mutations in drosophila.
The
claim of “no” threshold by Muller was an extremely strong one, since “no”
threshold meant that even an infinitesimal amount of radiation dose would result
in increased mutations. Hence, such a claim should not have been made unless
experiments had been performed at the lowest possible radiation dose, i.e. for
a single gamma ray photon absorbed in a fruit fly, and the results had shown
increased mutations. Whereas this may be considered as too stringent a
requirement for making the claim of “no” threshold dose, the acceptance of the
concept has led to concerns about even a single x-ray photon, as indicated in
the statement “There is no reason to believe that even a single x-ray photon
could not result in a base change leading to a mutation that could cause cancer
or a hereditary defect” in the textbook “Radiobiology for the Radiologist” (Hall and Giaccia 2006) (p. 136). There is indeed concern among a majority of
radiologists about the potential harm to patients from X-rays based on the
concept of no threshold dose, as determined in a recent survey (Pandharipande et al. 2013).
Thus,
the requirement to show increased mutations from the absorption of a single ray
of radiation prior to making a “no” threshold dose claim is indeed a reasonable
one. In the absence of such experimental
data, the claim should have been less definitive with regard to the absence of
a dose threshold, e.g. a valid conclusion would have been that “there is a low
threshold dose for increased mutations”, specifying the lowest dose for which
increased mutations had been observed. The claim of “no” threshold dose was
not a scientifically justifiable statement as there was no evidence for it. In
addition, considering Muller was cognizant of the results from Caspari and
Stern’s manuscript demonstrating a significant dose threshold (Calabrese 2013), the tone of the claim of no threshold dose indicating
extreme certainty does indeed appear to be out of line, and may reflect poorly
on his judgment.
The
claim of BEIR VII report that there is no threshold dose for carcinogenic
effect of radiation in humans without actual evidence showing increased cancers
from a human absorbing a single ray of radiation reflects poorly on its
judgment also, since such claims have resulted in the fear of even the smallest
amount of radiation. Whereas the use of
no threshold dose concept has been claimed to be a conservative approach to
radiation safety, claiming something is dangerous when it is not, can itself be
dangerous due to the evasive actions that would be taken to avoid the perceived
danger, which can lead to real danger.
This has been demonstrated vividly in Chernobyl where the prolonged
evacuation due to LNT model based concerns has caused considerable casualties (Balonov 2007). The advisory bodies have failed to stop relying
on the LNT model even after observing such harm caused to others by following
their advice based on the LNT model. Tragically, such casualties have occurred
again in Fukushima, where considerable number of stress-related illnesses and
deaths have been reported due to the prolonged evacuation because of the
perceived dangers from the low dose radiation (LDR) (Ishikawa 2013; Saji 2013). The resettlement of the evacuated residents (after
education about the invalidity of the LNT model to allay their fears of LDR)
would have led to a reduction in the stress-related casualties while not
increasing the risk of cancer measurably, since any predicted increase in
cancer, even using the LNT model, would not be detectable for radiation doses
of less than ~5 cSv per year (AAPM 2011; HPS 2010).
Whereas concerns regarding increased DNA damage due to
LDR were expressed by Muller, it is now well known that increased DNA damage is
a common occurrence from normal
activities in our lives such as exercise (Fogarty et al. 2011) and thinking (Suberbielle et al. 2013). It is also well known that regular physical and cognitive exercises
result in improved physical health (Leitzmann et al. 2007) and mental health (Cheng et al. 2013; Wang et al. 2012). Hence, the concerns that have been expressed regarding DNA damage from
exercise and thinking in the above referenced articles, as well as in a related
article entitled “Breaking News: Thinking may be bad for DNA” (Herrup et al. 2013) appear to be misguided, because they have ignored the
beneficial effects of the adaptive response which would result in reduced DNA
damage and improved physical and mental health in the long term (Doss 2013c). The evidence
for such adaptive response was not known at the time of Muller’s Nobel Prize
speech, and so the projected DNA damage from LDR may have genuinely caused deep
concerns, resulting in his claim of no threshold dose as a conservative measure. Recently, considerable data have been
published on the effect of LDR on drosophila (Koana and Tsujimura 2010; Ogura et al. 2009) and in animal models (Osipov et al. 2013; Phan et al. 2012) which have demonstrated the presence of LDR adaptive response and reduced
DNA damage following LDR. Recent publications have also shown evidence for the
cancer preventive effect of LDR in humans (Doss 2012a; Hwang et al. 2006; Tubiana et al. 2011). In view of such new published evidence
contradicting the main conclusion of the BEIR VII report of support for the LNT
model, I was indeed surprised to note that President Cicerone quoted the
outdated BEIR VII report in his Letter, implying that the current state of
knowledge continues to support the LNT model, without explaining why all the
new evidence against the LNT model should be discarded.
One
of the key reasons quoted by BEIR VII report for dismissing the LDR adaptive
response and the absence of a threshold dose was the atomic bomb survivor
cancer data, as stated in the report: “The arguments for thresholds or
beneficial health effects are not supported by these data” (NRC 2006) (p. 10). The latest update to the atomic bomb
survivor cancer mortality data with improved statistics, published about two
years ago, has displayed a significant curvature in the dose-response curve (Ozasa et al. 2012) (Table 7, p. 237), due to the lower than expected
cancer mortality rate in the 0.3 Gy to 0.7 Gy range (Ozasa et al. 2012) (p. 238). The LNT model cannot explain the reduction
in cancers with increasing dose in this region whereas the radiation hormesis
model can provide a possible explanation (Doss 2012a; Doss 2013b). Also, the
functional form used in the dose-threshold analysis (Ozasa et al. 2012) (p. 231) did not encompass the full range of the
observed data (i.e. it did not include negative values of excess relative risk),
invalidating the analysis and the conclusion of no threshold dose, since analysis
with a more general functional form would have resulted in the conclusion that
a dose threshold cannot be excluded (Doss 2013b; Doss et al. 2012).
Another
dataset quoted in support of the carcinogenicity of LDR in the BEIR VII report
(p. 336) was the 15-country study of radiation workers (Cardis et al. 2005). Deficiencies have been
identified in the Canadian data which played a key role in the conclusion of
the 15-country study, and the data were withdrawn from use over two years ago (CNSC 2011). With the Canadian
data withdrawn, the 15-country study would no longer result in the conclusion
of increased cancer risk from LDR (Cardis et al. 2005) (p. 4).
BEIR
VII report has also dismissed the evidence for immune system stimulation from LDR
and for radiation hormesis in animal studies with the following statement:
“Although evidence for stimulatory effects from low doses has been presented,
little if any evidence is offered concerning the ultimate deleterious effects
that may occur” (NRC 2006) (p. 333). In
making such a statement, the report ignored publications that showed reduced
tumor growth, reduced metastasis, and improved survival following LDR, not only
in animal models (Liu 2003) but also in human clinical trials (Sakamoto 1997; Sakamoto 2004). These
publications demonstrated the ultimate effects were not deleterious but
beneficial.
Though
the arguments provided in BEIR VII Report for the validity of the LNT model
have crumbled in the past several years as described above, and increasing
evidence has accumulated against the LNT model and for the reduction of cancers
and other diseases from LDR (Doss 2012b; Doss 2013c), the president of the National Academy of Sciences is
continuing to invoke the outdated BEIR VII report implying its arguments supporting
the LNT model are still valid. Such continuing reliance on outdated publications
(whose conclusions have been discredited in later publications) is a major
systemic deficiency in our scientific infrastructure, as identified in a recent
analysis (Doss 2013a), and it is disconcerting to note that the deficiency
pervades the highest levels of the scientific infrastructure.
The use of the LNT model
since the 1950s has resulted in a tremendous waste of resources with little
gain in terms of improved health or reduced sickness, because even according to
the LNT model proponents, the effects of the small decrease in the radiation
doses resulting from the LNT model based policies would not be measureable in
terms of health outcomes. The use of the
LNT model has also resulted in disastrous economic and health consequences in
Fukushima and Chernobyl due to the prolonged evacuations. In addition, the LNT model based fear of LDR
has prevented study of LDR applications in humans for aging-related diseases
for which presently there are no effective methods of treatment, even though
animal models have shown promise for the reduction of such diseases using LDR (Doss 2013c). Another major
consequence of the adoption of the LNT model hypothesis is that the resulting
fear of LDR prevented the study of radiation hormesis hypothesis for cancer
prevention in humans when it was proposed in 1980 (Luckey 1980), derailing the scientific method, since scientific
method requires the study of competing hypotheses to determine their validity (Doss 2013a). Considering the increasing amount of evidence that
has been reported for the validity of radiation hormesis in the recent past, not
studying it in the 1980s and not utilizing it since the 1990s have likely
resulted in nearly 15 million preventable cancer deaths worldwide in the past
two decades (Doss 2013b).
In view of such a large
toll (which is still continuing) from the use of the LNT model, it is indeed
appropriate to attempt to identify the root causes and reasons behind the
adoption of the LNT model, to help avoid similar tolls in the future, even
though it requires analysis of actions of scientists who are no longer present
to justify their actions, conclusions, or statements. Hence, the attempts by Prof. Calabrese to
identify the reasons behind the adoption of the LNT model are fully
justified. Though Muller has been
honored for his pioneering work on DNA damage from X‑rays with Nobel Prize and
other awards, they do not make him immune from criticism if he made
scientifically unjustifiable statements or conclusions, as he did in proclaiming
extreme confidence in the concept of no threshold dose in spite of there being no
evidence supporting it, and in spite of being aware of unpublished data supporting
a threshold dose. Similarly, since the
present advisory bodies and their predecessors have deviated from the
scientific method in supporting the use of the LNT model without evidence and
preventing the study of radiation hormesis resulting in major harm to public
health, it is important to analyze the reasons for such support, so that corrective
actions can be taken.
I
hope you will publish this letter so that your readers would become aware of
the tremendous harm caused by the deviations of our society’s scientific
leaders from scientific methods and principles so that steps can be taken to
avoid their recurrence.
Sincerely,
Mohan
Doss
Note:
The above letter represents the personal, professional opinion of the author,
and does not necessarily represent the views or positions of his employer.
References
AAPM
(2011) AAPM Position Statement on Radiation Risks from Medical Imaging
Procedures. http://www.aapm.org/org/policies/details.asp?id=318&type=PP. Accessed
Dec 21, 2013
CNSC (2011) INFO-0811. Verifying Canadian Nuclear Energy
Worker Radiation Risk: A Reanalysis of Cancer Mortality in Canadian Nuclear
Energy Workers (1957-1994) Summary Report, Canadian Nuclear Safety Commission. http://nuclearsafety.gc.ca/pubs_catalogue/uploads/INFO-0811-Verifying-Canadian-Nuclear-Energy-Worker-Radiation-Risk-A-Reanalysis-of-Cancer-Mortality-in-Canadian-Nuclear-Energy-Workers-1957-1994_e.pdf. Published
June 2011. Accessed Sep 1, 2013
HPS (2010) Radiation Risk in Perspective - Position Statement
of the Health Physics Society Health Physics Society. http://hps.org/documents/risk_ps010-2.pdf. Accessed
June 21, 2011
Koana T, Tsujimura H (2010) A U-shaped dose-response
relationship between x radiation and sex-linked recessive lethal mutation in
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al. (2007) Physical activity
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Muller HJ (1946) Hermann J. Muller - Nobel Lecture: The
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Dec 20, 2013
Osipov AN, Buleeva G, Arkhangelskaya E, Klokov D (2013) In
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Breaks Below the Spontaneous Level in Mouse Blood and Spleen Cells. Mutat Res
doi:10.1016/j.mrgentox.2013.04.016
Ozasa K, Shimizu Y, Suyama A, et
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Suberbielle E, Sanchez PE, Kravitz AV, et al. (2013)
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Tubiana M, Diallo I, Chavaudra J,
et al. (2011) A new method of
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Commentary published in Archives of Toxicology in Feb 2014.
The final publication is available at:
http://rd.springer.com/article/10.1007/s00204-014-1208-8/fulltext.html
