Thursday, February 6, 2014

Adoption of linear no‑threshold model violated basic scientific principles and was harmful

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

Leitzmann MF, Park Y, Blair A, et al. (2007) Physical activity recommendations and decreased risk of mortality. Arch Intern Med 167(22):2453-60 doi:10.1001/archinte.167.22.2453
Ozasa K, Shimizu Y, Suyama A, et al. (2012) Studies of the mortality of atomic bomb survivors, report 14, 1950-2003: an overview of cancer and noncancer diseases. Radiat Res 177(3):229-43 doi:10.1667/RR2629.1
Tubiana M, Diallo I, Chavaudra J, et al. (2011) A new method of assessing the dose-carcinogenic effect relationship in patients exposed to ionizing radiation. A concise presentation of preliminary data. Health Phys 100(3):296-9


 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