PROTECTION AGAINST RADIATION
- THE SECOND LINE OF DEFENSE
Review Article and Position Paper
By Vincent E. Giuliano
Minor update: November 17, 2008 Copyright 2008 by Vincent E. Giuliano, all rights reserved
The increasing use of diagnostic radiology is unquestionably beneficial. However, per-capita exposure to medical radiation has grown some six fold in the last two decades and appears to be still increasing. The issue of medical radiation protection is therefore achieving central importance for the health of both patients and radiation professionals. It is well established that the effects of radiation are cumulative and lead to increased incidence of cancers, cell deaths, genetic damage and numerous forms of body tissue pathology.
The first line of defense against gamma and X radiation damage, long established in clinical practice, is simply radiation avoidance such as by use of shorter exposure and more sensitive film, carefully focused beams, lead aprons and other shielding. This paper is concerned with a second and complimentary line of defense one not yet established in clinical practice but potentially of great importance. That is, radiation damage minimization by interfering with the biological mechanism of radiation damage, that is, interfering with the propagation in tissues of free radicals created by X-rays. This kind of protection can be achieved through using commonly-available antioxidant supplements.
Despite the large body of research supporting the effectiveness of antioxidants to quench radiation-induced free radicals, this second line of defense against radiation damage is neither taught to radiology students in medical schools nor is embodied in general clinical radiology practice. The author discusses the research basis for widespread adoption of this “second line of defense” for radiation protection and provides some 60 research citations to support his points.
HEALTH IMPACTS OF RADIATION
The concern of this paper is long-term health of people exposed to significant radiation exposure, high doses as well as low doses received repeatedly over a long period of time. Ionizing x-radiation in any quantities is potentially deleterious to health. Radiation ionizes oxygen to produce Reactive Oxygen Species (ROS) like OH which steal electrons from lipids in cell membranes, a process called lipid peroxidation. A chain of damaging events can be let lose from a single high-energy electron event as unstable fatty acid radicals propagating in tissues produce other unstable radicals. The result can be damage to DNA or mitochondrial DNA, mangled chromosomes, protein cross-linking, cell apoptosis, genetic mutations, mutated germ cells and other forms of cell havoc. Radiation damage can show up in many ways including skin erythema, hair loss, vascular damage, internal bleeding, cataracts, cancers, weakened immune systems, sterility, mutations in offspring, premature ageing and death. Cell DNA repair mechanisms are effective in correcting some radiation-induced damage but may themselves be compromised by radiation.
Radiation’s impact is potentially cumulative and all possible precautions should be taken to minimize exposure. A linear no-threshold model of radiation damage has long been accepted,    (53 and 54 in Appendix A). According to this model there is no safe minimum threshold for received radiation and danger increases linearly with dose. The negative effects of low-level radiation can only be statistically (stochastically) established and may or may not be clinically observable until years after the exposure or seen in children yet to come. These dangers include cancer induction, DNA damage, and damage of germ cell DNA which can lead to mutations in offsprings. Cancer induction associated with radiation has a latency of 5 to 10 years for leukemia but is measured in decades for solid tumors.
The International Commission on Radiological Protection recommends an upper limit of 2 rem per year (20mSv/yr) of whole-body radiation for radiological workers. “In accordance with current knowledge of radiation health risks, the Health Physics Society recommends against quantitative estimation of health risks below an individual dose of 5 rem1 In one year or a lifetime dose of 10 rem above that received from natural sources.” According to the Society’s position paper health risks below those estimates are unknown and cannot be estimated. The position paper relates to estimation of health risk only.
The need for better protection against medical radiation has been growing along with the growth of exposure to such radiation. In a recently-published American College of Radiology White Paper on Radiation Dose in Medicine, it is pointed out that the use of CT exams in the US has increased by a factor of 20 from 1980 to 2005, from 3 million to over 60 million. And the use of nuclear medicine exams over the same period has increased by a factor of almost 3, from 7 million to over 20 million. The per-capita dose of ionizing radiation from clinical imaging exams is estimated to have grown six-fold over the last 20 years. A recent publication in the New England Journal of Medicine points to the same public health issue. The authors estimate that in the future up to 2% of all malignancies in the US could be due to radiation from CT scans alone.
Exposure associated with interventional procedures using radiation imaging has also grown by many orders of magnitude during the last decade. The health issue of excessive radiation exposure applies to radiation professionals as well as patients, especially those whose jobs require them to be next to the patient in the room with the radiation source: interventional radiologists, cardiologists, neuro-surgeons, fluoroscope operators, nurses and technicians. Despite standard protective measures, parts of these professional’s bodies are still exposed to the radiation and many do not use the leaded gloves, glasses or neck collars leaving their eye lenses and thyroids exposed. Wearable lead shields protect against only 80% - 90% of incident radiation; the rest penetrates. Cumulative exposure by those directly involved in fluoroscopy multiple times a week or even a day may reach dangerous levels.
Radiation avoidance can be paraphrased as “say no to radiation whenever possible.” Radiation avoidance is embodied in a well established set of clinical practices based on knowledge of radiation physics that is 60 years or more old. Thus the widely used term for radiation protection came to be known as “health physics.” Following well-established guidelines, patients are given lead aprons. Radiology professionals and technicians stay behind shielding when they can, or wear lead aprons, eyeglasses and sometimes leaded gloves and collars, stay away from the X-ray source as much as possible and wear dosimeter badges. X-ray beams are collimated when possible so the radiation mostly goes where it is wanted to go. Hospitals and radiation clinics have Health Physics departments and appoint safety officers to assure these guidelines are followed and monitor the staff’s dosimeter badges.
A number of professional councils and organizations are directly concerned with radiation safety such as The National and International Councils on Radiation Protection, the Health Physics Society, and of course their local branches and counterpart international groups. Again, these groups are focused on the health physics radiation avoidance paradigm of protection.
The author believes radiation avoidance should continue to be central in efforts to protect against radiation. While he suggests a second line of protective defense based on radiation damage minimization, this should not be a substitute for radiation avoidance.
RADIATION DAMAGE MINIMIZATON
There is a known “second line” of radiation protection that is yet to be embodied in mainline clinical radiology practice – protection against adverse biologic effects of radiation received. It is concerned with minimizing or eliminating the biological impact of unavoidable radiation. The impact of radiation on the body lies in additional domains beyond physics, namely cellular biology, biochemistry and genetics. And in these domains there is additional protection that can minimize the negative effects of the radiation that goes around or through shielding or is otherwise unavoidable. This protection is based on cell biology-related sciences rather than physics and on relatively recent knowledge – much of it only 5-10 years old. While there has been research on radio-protective substances for decades now, their use in clinical practice has been very limited. And most focus has been on using powerful synthetic agents with toxicities that limit their usage. The awareness that combinations of common and safe antioxidants could do the job safely and inexpensively has been dawning only slowly.
As mentioned earlier, radiation mainly damages cell and cell components by producing cascades of free radicals, particularly the ROS responsible for most negative impacts of X-radiation.
Antioxidants, in simple terms, quench the free radicals and their propagation, neutralizing ROS ions before they can do their damage. That raises the prospect that a person can protect herself or herself from the harm radiation does simply by taking antioxidant supplements. In principle at least the supplements would contribute to the quenching of free radicals produced by the radiation and thus provide some degree of protection. Research studies on radioprotectivity of antioxidants validates this view. Interestingly, much of this research appears to have been motivated by a desire to find ways to protect the health of astronauts exposed to high radiation in space. The author cites research abstracts relating to how antioxidants can limit radiation damage in animals and human tissues in Appendix A. This research suggests that several easily-available substances like vitamins C and E, selenium, co-enzyme Q-10, l-carnosine, alpha-lipoic acid, omega-3 oils, acetyl-l-carnitine, resveratrol and curcumin are quite effective in limiting radiation damage in animal and human models.
Of course the degree of protection depends on many complex factors such as dosage, when the antioxidant is taken, and the, bioavailability, retention and radical-quenching profiles of the particular antioxidant in the particular organ or cell involved. Factors of importance include water and fat solubility of the antioxidant, whether it can penetrate into cell mitochondria, cross the blood-brain barrier, etc. Fortunately, the important properties of many of the commonly used antioxidants are fairly well researched today and the author believes good protection can be achieved by using a combination of them. For example, alpha-lipoic acid and acetyl-l-carnitine can cross the blood-brain barrier and are known to have a capability to penetrate into cell mitochondria, l-carnosine is both fat and water soluble, and bioavailability profiles are available for many of these substances.
As mentioned, radioprotectivity by use of antioxidants is rarely applied in current clinical radiology practice. This appears to be an example of where there is a large gap between research knowledge on the one hand and professional practice on the other hand. Major medical school textbooks, concerned with radiation protection read by radiologists and others going into radiology do not even mention this cell biology approach, basically the use of antioxidants, and it is not part of the training of those going into radiology. The 2006 edition of Radiobiology for the Radiologist mentions a few little-used radioprotective drugs and briefly discusses Amifostine (Ethyol), a potentially toxic drug sometimes used as an adjunctive therapy in radiation oncology. This textbook makes no reference to the use of common antioxidants for free-radical scavenging or for radioprotectivity of either radiation professionals or patients.
Nutritionists and researchers like Prasad have called for using multiple antioxidants for protecting humans against low doses of ionizing radiation. My impression is that the practicing radiology community has paid little attention so far. Thirty years ago there was little-to-no hard research on the actions or effectiveness of antioxidants and most mainstream medical doctors viewed their use as peripheral to health as best, quackery at worst. Today there is much research validating both their effectiveness and their biological mechanisms of action - but penetration of this knowledge into medical curricula has been slow and the old attitudes still have much force.
ANTIOXIDANTS, GENETICS AND RADIOPROTECTIVITY
Our understanding of what happens within cells under conditions of oxidative stress involving pathways of gene expression and protein signaling, is rapidly growing. For example, recent research indicates there is a pathway involving the protein p66Shc that detects oxidative conditions in the cell and signals the mitochondria to induce cell apoptosis compromising longevity. Also, there is recent discovery of a "bystander affect." A cell directly hit and wounded by radiation can send distress signals to nonirriadiated neighboring cells or release substances on them that cause deleterious genetic or epigenetic changes in them.
Some of the actions of antioxidants in protecting against ROS damage is revealed by recent research relating antioxidants to telomere lengths. According to a significant school of thought, cellular aging and ensuing disease or organ damage is thought mainly to be the result of shortening of telomeres, simple repeated DNA subunits which ensure genomic stability at the end of chromosomes. Telomeres shorten with each cell replication and when they get too short the results are cell senescence and/or apoptosis or perhaps a genetic error in daughter cells. Senescent cells stop reproducing but are bad neighbors secreting growth factors, inflammatory cytokines and other substances that can provoke adjacent cells over the edge into premature aging or neoplasia. Worse yet, senescent cells encourage angiogenesis, providing plenty of oxygen for incipient tumors. In other words, if even a few cells become senescent due to telomere loss, they create ripe conditions for the onset of cancers. Under ROS attack and damage such as from radiation, cells replicate much more rapidly shortening the lifespan of their cell lines before senescence. Telomerase is a substance that pastes the telomere ends back onto chromosomes after cell replication, prolonging the number of normal subsequent replications when it is expressed. Telomerase is produced by activation of the hTERT gene which is expressed differently in different body cell lines. The gene is not active in normal adult somatic cells.
Put simply, lowering oxidative stress via ROS scavenging inhibits telomere shortening, sometimes remarkably so. It appears that ascorbic acid, for example, can significantly reduce age-dependent telomerase- shortening in cells thus allowing a cell line under ROS attack to achieve more replications and survive longer before reaching senescence. Further, it appears that high ROS levels can induce the export of the TERT component of hTERT out of cell nuclei thus accelerating cell senescence. However, antioxidants can slow or stop this exportation and counteract increased ROS production linked to aging of cells thus delaying replicative senescence, at least in endothelial cells.
Gene-activation properties of several antioxidants are being discovered. For example, selenium compounds induce apoptotic death of tumor cells. Curcumin acts upon the IL-1 and other complex genetic pathways to achieve its antioxidant, anti-cancer and anti-inflammatory effects. Recent research relates to how resveratrol activates the SIRT1 gene in mammals thus activating the FOXO4 gene - the same longevity genes activated by calorie-restricted diets. The result is protection against oxidative stress. It appears that SIRT1 is a key regulator of energy and metabolic homeostasis. Alpha-lipoic acid and l-carnitine are thought also possibly to have gene activation-related calorie-restriction mimetic capability.
According to another parallel school or research thought, cell mitochondria play a key role in signaling that can lead to cell apoptosis or cancer when subject to mitochondrial DNA mutation due to radiation or other causes. Oxidative damage due to radiation can damage mitochondrial DNA (mtDNA) by producing deletions and mutations, and also compromise the natural repair mechanisms for mtDNA. Damaged mtDNA is a marker for cancer, and mtDNA damage due to radiation appears to be dose-dependent.
NATURE OF THE RESEARCH DATA
There are hundreds, perhaps thousands, of literature research references related to how antioxidants work to quench free radicals in human cell lines, animals, and in some cases humans in-vivo. Almost none of this research existed back when current radiation-protection standards were established. For each of the antioxidants I mention here there is a substantial set of literature references related to how the substance works, how effective it is in scavenging free radicals and reducing their damage, and impacts on the organism as a whole.
In Appendix A, I cite only selected publication that specifically relate antioxidants to control of damage due to X-ray or gamma radiation. There are many supportive studies in closely allied areas: antioxidants reducing damage due to UV or electromagnetic radiation, the specific free radical scavenging and damage-control mechanisms of different antioxidants, their gene-activation pathways, etc. The antioxidants I suggest using have multiple other positive health effects, but discussing these effects or providing citations related to them is beyond the scope of what can be included in this paper.
Limitations of the data
The evidence for the author’s conclusions lies in a large number of scattered studies combined with basic knowledge of the biological impact of free radical ions and the ability of antioxidants to quench such radicals. Yet, much remains unknown related to radio-protectivity and much research is yet to be done. Existing studies do not provide definitive answers as to the most effective antioxidants and combinations of antioxidants for human use - either for general radioprotection, for protection in case of radiation-stress events such as CAT scans or radiation oncology treatment, or for protection of radiology professionals. And the same absence of definitive answers is also true for dosages.
The existing research studies on radio-protectivity via antioxidants tend to be highly specific. For example a study may focus on a particular organ from a specific strain of rats using a specific antioxidant after a specific exposure of radiation. Yet there is a very large number of studies all pointing in the same direction, both in terms of the theory of action and observed experimental results. Almost without exception the abstracts I have found conclude that a particular antioxidant or combination of them is effective in combating radiation injury in some specific animal or tissue. And there appears to be ample understanding of the mechanisms through which free radical scavenging work. Also there seems to be no controversy in extrapolating results related to ROS scavenging from vertebrate animal models to humans.
The author does not know of any systematic clinical trials that clearly quantify the value of taking antioxidants as a radio-protective measure in human beings. Hopefully we will see large-scale clinical trials testing various antioxidant combinations for radio-protectivity in the future. These would require government sponsorship. Because most of the antioxidants of concern are in the public domain, pharmaceutical companies have had no incentive to sponsor such trials.
Safety, Effectiveness and Dosage
However, there is knowledge that points strongly to what the basic conclusions of such clinical trials would be were they conducted. Clinical trials are basically concerned with three issues: 1. establishing safety of the substance of concern, 2. establishing effectiveness towards an identified objective, and 3. establishing dosage. There exists relevant knowledge with respect to each of these three issues and use of antioxidants for radio-protectivity.
With regard to safety, it is important to recall that clinical trials protocols were instituted mainly to test novel laboratory-created chemical compounds – substances with unknown bioactivity. The antioxidant supplements of concern here are naturally occurring substances available to everyone in vitamin shops, drug stores and supermarkets. Many have been used for decades, centuries and even millennia. They are taken daily by millions of people. They have few significant side effects except at massive doses,. These antioxidants represent a major chunk of dietary supplement sales (a market if $4.8 billion in 2003, US alone).
With regard to effectiveness, the literature research exemplified in Appendix A indicates ample and consistent experimental evidence that antioxidants can quench the damaging free radicals produced by radiation significantly reducing their impact on tissues and, when measured, on whole organisims. (Also references 1-33 in the Appendix A). Thus the conclusion: antioxidants can protect animals and humans against the negative impacts of radiation.
One segment of the medical radiation community already embraces this conclusion. Most radiation oncologists tell their cancer patients to stop taking antioxidants - because these oncologists are concerned that the antioxidants would reduce the effectiveness of their powerful x-ray beams for killing cancer cells. This conclusion is not supported by research the author has seen. In fact the opposite conclusion appears to be true. This point is dealt with later in this paper..
With regard to dosage, safe levels are known for all the antioxidants suggested here, consistent with normal and safe use of these substances as daily dietary supplements.
What is not known is the best combination of antioxidants and associated dosages to protect against repeated low-level radiation exposure or necessary high-level exposures such as in radiation cancer treatment.
The author concludes that the studies cited here and may similar ones together with our understanding of the processes of radiation damage and free-radical quenching collectively establish that common antioxidants, either taking singly or in combination, are effective in mitigating the negative impacts of radiation in animals and in humans.
1. Patients and radiation professionals exposed to intense or repeated low-level radiation can further protect their and themselves from the negative health effects of radiation by taking antioxidant supplements.
2. A second conclusion, not surprising, is that a wide variety of well-known antioxidants are effective in this regard, including the “usual suspects” commonly available at vitamin counters.
The author surmises that effectiveness of an antioxidant is generally proportional to its ROS scavenging capabilities and depends on specific characteristics of the antioxidant. These characteristics include bioavailability in different organs and as a function of time, fat and water solubility profile, rapidity of elimination by the body, whether the antioxidant penetrates the mitochondria, whether it crosses the blood-brian barrier, and many other biological properties unique to the molecules involved.
3. A third conclusion of the author is a corollary of the previous one. A combination of antioxidants is likely to be superior for radio-protectivity to focusing on only one.
Different antioxidants vary in their solubility properties, in their half-lives of effectiveness, in the organs in which they concentrate and in their mechanisms of operation. There is no single antioxidant that is optimal for every desired biologic action characteristic. And if there were, an effective dose for a high-level of ROS scavenging would possibly have to be so high as to create risk of toxicity. Perhaps for this reason, the body employ multiple antioxidants to protect itself from free radical damage. By combining antioxidants the dosage for any single one can be kept within the range established safe for dietary supplementation. The author encountered a number of studies involving the radio-protectivity of antioxidant combinations. A few of these are cited in Part C of Appendix A. For example, at least one study suggests that ascorbic acid and melatonin can be used to reduce toxic effects of repeated doses of the synthetic antioxidant amifostine.
4. A fourth conclusion is that X-ray radio-protectivity is best achieved by maintaining a high levels of body antioxidants both before, during, and after radiation exposure
It appears to be established in a number of studies that a result of significant x-ray irradiation is a precipitous drop in naturally occurring antioxidants in tissues. A likely explanation for this is that, confronted by large numbers of free radicals resulting from irradiation, the naturally-occurring antioxidants go to work neutralizing these free radicals and are soon exhausted. Some studies suggest that the naturally-occurring levels of antioxidants in tissues may not be restored until weeks after intensive radiotherapy.
5. A fifth and surprising conclusion of my literature review is that a number of antioxidants not only protect normal tissues from radiation damage but they also make cancer cells more sensitive to destruction by ionizing radiation and have cytotoxic effects on cancer cell lines even without radiation.
Studies, including ones cited in Part D of Appendix A, have established this effect for:
- Vitamin E
- Omega-3 oils
- Curcumin (tumeric)
- Amifostine, the classical radioprotective sometimes used in radiation oncology
These antioxidants are known to be re-activators of apoptotic genes like P53 and P21 in cancers, genes that get turned off in the process of caricinogenesis. Without such P53/P21 protection, the radiation could induce more genetic mutations in the already malignant cells instead of killing them and, possibly, induce even different cancers. Serious chromosome and telomere damage due to radiation will generally lead to cell apoptosis providing that P53 protection is functioning normally. By restoring P53 protection in cancer cells, these antioxidants enhance the killing power of the radiation.
If and as this fifth conclusion becomes generally accepted, it should reverse the current practice of asking patients about to undertake radiotherapy to discontinue their use of antioxidants. Instead, a cocktail of antioxidants that are pro-apoptotic in cancers would be recommended.
There is a lively debate on this topic in the current literature with many traditional cancer oncologists tending to hold the line (Discontinue antioxidants while undergoing cancer radiation therapy, the implication being that using them would be like putting a lead apron over the tumor to be irradiated.) and many nutritionists asserting the opposite - radiation patients should take a broad spectrum of antioxidants before, during and after their courses of radiation therapy, not only in the interest of their general health but also to make the radiation therapy more effective.
What is interesting is that parties on both sides of this debate agree as to the free radical mechanisms by which X-rays damage tissues. They also appear to agree that antioxidants are effective in nullifying the negative biological effects of ionizing radiation on normal tissues, the central pillar of my argument here. Regardless of this contention about cancer patients, the author suggests that patients, health professionals and technicians exposed to chronic or large doses of radiation should take antioxidants to protect themselves.
SUGGESTED ANTIOXIDANTS AND DOSES
As mentioned, the author conjectures, though the supporting evidence is limited, that radiation protection for patients and radiation practitioners can best be achieved through a regime of multiple antioxidants involving moderate amounts of each, that is doses associated with normal dietary supplementation.
No studies that that the author is aware of have been concerned with identifying an optimal regime of antioxidants for x-ray radio-protectively. Nor are there retrospective studies of radiation professionals who have taken or not taken antioxidant supplements.
Simply put, nobody knows what the best combination of antioxidants or doses of them are, either for radiation professionals or for patients, and either to protect against chronic low-dose exposure or against high-dose exposure. Clearly, this is an area in which further study is merited.
The author believes there is a common-sense approach to antioxidant supplementation which can be pursued now. That approach involves taking significant but not megadose amounts of several commonly available antioxidants - focusing specifically on ones shown by research to have radiation-protective effects.
The author does not think the safety of such an approach is a major concern. Drug interactions and side effects of these antioxidants at the dosage levels mentioned below appear to be minimal or nonexistent. Tens of millions of people take these antioxidants and have done so for years. Cost need not be a major concern either. Antioxidants are the basis of a multi-billion dollar industry and most are sold in a highly competitive marketplace. Being over-the-counter or over-the-Internet they are not considered as drugs and contents of antioxidant pill bottles are not monitored by the FDA. However, there are a several and large reputable suppliers that pride themselves on the quality of their products.
Here are my candidate substances that I suggest be taken: a) by interventional radiologists, nurses and technicians who are repeatedly exposed to whole or partial-body x-radiation, and b) by individuals who have recently been or are going to be subject to large x-ray doses such a via fluoroscopic procedures or whole-body CAT scans. . These doses suggested are “conventional wisdom” ones, such as are recommended for elderly patients by nutritionists.
· Ascorbic Acid (vitamin C) - 1g twice daily
· L-Carnosine - 500mg twice daily
· Actyl l-Carnitine (ACL) - 500mg twice daily
· Alpha-lipoic acid - 200mg twice daily
· Selenium – 100mcg twice daily
· Resveratrol – 200mg twice daily
· Omega 3 oils and Essential Fatty Aids – 1200mg capsule twice daily
· Co-enzyme Q-10 (ubiquinone) – 100mg twice daily
· Alpha Tocopherol. (most active ingredient in Vitamin E) - 400iu twice daily
· Curcumin (turmeric) - 500mg of standardized extract twice daily
· Pycnogenol – 75 mg twice daily
· Beta Carotene (converts to Vitamin A in the body) – 25,000 i.u. daily
· Quercetin – 500 mg twice daily
· Melatonin - 3mg at bedtime
The doses all, to the author’s knowledge, are well within generally-recognized safety limits. The citations in Appendix A are literature references relating to research on the radio-protective effects of each of these and other antioxidant substances. Also cited in Appendix A are references relating to how some of these antioxidants potentiate the destructive effects of X-rays on tumor cells.
This paper is intended to open serious consideration of the second half of radiation protection. Hopefully, at some point large clinical trials will be initiated to help determine the best combination of antioxidants and the best doses for radiation protection.
The Appendix to this document contains annotated references and is very large. It can be obtained on request by contacting the author at firstname.lastname@example.org.
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 Ph.D. Applied Physics, Harvard University
 Note the review articles on this topic #47 and #48 in the Appendix
 What are the risks from medical X-rays and other low dose radiation? B F Wall, BSc, G M Kendall, PhD, A A Edwards, MSc, S Bouffler, PhD, C R Muirhead, PhD and J R Meara, FFPH British Journal of Radiology (2006) 79, 285-294
 See for example the 2004 position paper of the Health Physis Society at http://hps.org/documents/radiationrisk.pdf
 Radiation Bioeffects and Management Text and Syllabus, Louis K Wagner et all, The American College of Radiology, 1991 pg 160
 2004 position paper of the Health Physics Society at http://hps.org/documents/radiationrisk.pdf
 White Paper on Radiation Dose in Medicine American College of Radiology, E. Stephen Amis, Jr, MDa, Priscilla F. Butler, MSb, Kimberly E. Applegate, MDc, Steven B. Birnbaum, MDd, Libby F. Brateman, PhDe, James M. Hevezi, PhDf, Fred A. Mettler, MDg, Richard L. Morin, PhDh, Michael J. Pentecost, MD
Geoffrey G. Smith, MDj, Keith J. Strauss, MSk, Robert K. Zeman, MD. J Am Coll Radiol 2007;4:272-284.
 Review article by David J. Brenner and Eric J. Hall, N Engl J Med 2007;357:2277-2284
 Radiation Bioeffects and Management Text and Syllabus, Louis K Wagner et all, The American College of Radiology, 1991 pg 164
 Review of Radiologic Physics, Walter Huda and Richard Stone, Second Edition Lippincott Williams & Wilkins, 2003
 Radiation Bioeffects and Management Text and Syllabus, Louis K Wagner et all, The American College of Radiology, 1991
 Radiobiology for the Radiologist, sixth edition, Eric J. Hall and Amato J. Garcia, Lippencott Willians & Wilkins, 2006
 Amifostine is an FDA-approved pharmaceutical developed at Walter Reed Hospital, on the market since the mid-90s. Although Amifostine is an antioxidant (free-radical scavenger) its radioprotective effects are most-frequently ascribed to its other properties. Amifostine must be administered intravenously or subcutaneously and is known to have toxic side effects.
 Rationale for using multiple antioxidants in protecting humans against low doses of ionizing radiation
K N Prasad, PhD, British Journal of Radiology (2005) 78, pgs 485-492. Prasad is with theCenter for Vitamins and Cancer Research, Department of Radiology, School of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA
 Protein Kinase C ß and Prolyl Isomerase 1 Regulate Mitochondrial Effects of the Life-Span Determinant p66Shc; Pinton P, Rimessi A, Marchi S, Orsini F, Migliaccio E, Gi Protein Kinase C ß and Prolyl Isomerase 1 Regulate Mitochondrial Effects of the Life-Span Determinant p66Shc M, Contursi C, Minucci S, Mantovani F, Mariusz R. Wieckowski, Del Sal G, Pelicci G, Rizzuto R; Science 2 February 2007:Vol. 315. no. 5812, pp. 659 - 663
 See Fossel M. CELLS, AGING, AND HUMAN DISEASE. Oxford University Press, New York, 2003. Pubmed searches will reveal hundreds ofcurrent references related to telomerase, diseases and antioxidants
 Shortened telomeres can activate a gene called Smurf2 that is sufficient to induce cell senescence. See Smurf2 up-regulation activates telomere-dependent senescence, Cohen, SN, GENES & DEVELOPMENT 18(24):3028-3040 2004 DEC 15
“ Here, we succeeded in artificial slowdown of age-dependent telomere shortening to 52-62% of the untreated control, in human vascular endothelial cells, by addition of the oxidation-resistant type of ascorbic acid (Asc), Asc-2-O-phosphate (Asc2P), which concurrently achieved both extension of cellular life-span and prevention of cell size enlargement indicative of cellular senescence.” From Pubmed abstract for following reference.
 Age-dependent telomere shortening is slowed down by enrichment of intracellular vitamin C via suppression of oxidative stress. Furumoto K, Inoue E, Nagao N, Hiyama E, Miwa N. Life Science 1998;63(11):935-48.
 Antioxidants Inhibit Nuclear Export of Telomerase Reverse Transcriptase and Delay Replicative Senescence of Endothelial Cells, Judith Haendeler, Jörg Hoffmann, J. Florian Diehl, Mariuca Vasa, Ioakim Spyridopoulos, Andreas M. Zeiher, Stefanie Dimmeler, Molecular Medicine 2/12/2004
 DNA Damage-mediated Apoptosis Induced by Selenium Compounds. Nai Zhou, Hai Xiao, Tsai-Kun Li, Alam Nur-E-Kamal and Leroy F. Liu, J. Biol. Chem., Vol. 278, Issue 32, 29532-29537, August 8, 2003 Hematopathol Mol Hematol. 1997-1998;11(1):49-62.
 The emerging therapeutic potential of sirtuin-interacting drugs: from cell death to lifespan extension, Marco Porcu and Alberto Chiarugi, TRENDS in Pharmacological Sciences Vol.26 No.2 February 2005.
 Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1a Marie Lagouge Carmen Argmann, Zachary Gerhart-Hines, Hamid Meziane, Carles Lerin, Frederic Daussin,4 Nadia Messadeq, Jill Milne, Philip Lambert, Peter Elliott5 Bernard Geny4 Markku Laakso, Pere Puigserver, and Johan Auwerx, Cell 127, 1–14, December 15, 2006 ª2006 Elsevier Inc.
 See the citations in the Appendix, all relating to the efficacy of particular antioxidants to protect against radiation-induced damage