Amifostine

Introduction

The overall theme of Session 2 of the International Conference on Low-Level Radiation Injury and Medical Countermeasures held in 1999 was prevention and treatment of injuries sustained under low-level radiation (LLR) exposure conditions with LLR being defined in terms of the North Atlantic Treaty Organization (NATO) Allied Command Europe (ACE) directive in which five levels of radiation exposure and the associated health risks are listed (NATO ACE Directive Number 80-63, 1996).1 The session covered topics that ranged from the nature of pharmacological targets to descriptions of protective agents, systems, and devices. Also covered were pharmacological methods of protecting personnel not only against early responses to radiation but also against late-arising pathologies that will predominate under LLR exposure conditions.

These topics encompassed the session's four major goals, namely (1) to examine the nature of LLR-induced lesions; (2) to evaluate these lesions as potential targets for pharmacological intervention so as to block initial stages of evolving pathology; (3) to explore the use of select types of drugs, nutritional factors, and biologics in providing radioprotection; and (4) to identify the gaps in our understanding of LLR health consequences and to start to define critical research needs.

Nature of LLR-Induced Lesions and the Potential for Pharmacological Intervention

The first three speakers (Woloschak, Morgan, and Fliedner) and a later speaker (McBride) spoke about characterizing LLR-- induced responses according to increasingly complex levels of biological organization, from targeted genes to chromosomes to subcellular organelles to tissue and organ systems. This represented the first of the session's four stated goals. For example, Gayle Woloschak (Argonne National Laboratory) described a series of elegant studies that indicated that the molecular mechanism of an inheritable proliferating cell nuclear antigen gene mutation results in marked LLR-sensitivity of vital immune cells (T-cells) within the body. This mutation involves a three nucleotide base-pair deletion within the promoter region of the proliferating cell nuclear antigen gene; the mutation serves to control gene expression and, in turn, apoptosis.

The nature of chromosome damage as it relates to LLR dose and dose rate was discussed by Bill Morgan (University of Maryland), who spoke about two important issues-genomic instability and bystander effects-that no doubt influence onset and progression of radiation-induced late-arising pathology (e.g., cancer) but that are largely total-dose and dose-rate independent. On the basis of his observations (which were made principally by chromosome painting assays) and the observations of others, Morgan drew the conclusions that LLR responses of interest (those used in risk assessment) probably cannot be extrapolated from responses to high doses and that reactive oxygen species probably play a very significant role in LLR-- induced responses.

Tissue and organ system responses under chronic, daily doses of LLR were explored by Ted Fliedner (University of Ulm). Based on hematopoietic capacity, a projected maximum tolerance to radiation was set at 10 mSv per day. At dose rates lower than the threshold, the hematopoietic system accommodated, enabling long-term survival, whereas at higher daily dose rates, marrow cell loss exceeded the self-renewing and production limits of the hematopoietic tissues. If chronic exposure persists, the hematopoietic system will fail and death will ensue unless treatment (e.g., cytokine therapy, marrow cell transplant) is undergone.

Exploring the Use of Select Types of Drugs, Nutritional Factors, and Biologics in Providing Radioprotection

The subject of radioprotective agents for both acute and late-- arising effects was addressed. Most of the studies presented used relatively high doses and acute effects of radiation to illustrate the efficacy of various types of radioprotective agents and to illustrate the possible use of such agents for LLR-related injuries. This assumes, however, that radioprotective effects for injuries sustained following high-level, acute radiation exposures are translatable to low-level or chronic radiation exposures. This assumption remains in question, however. The types of protective agents described included the nitroxides, aminothiols, androstene steroids, and nutritional adjuvants.

Nitroxides

Jim Mitchell (National Institutes of Health) reported on the effectiveness of a rather new class of radioprotectant, the stable nitroxides, which exert their radioprotective effect without undue toxicity, largely by free radical quenching. Nitroxide prophylaxis can protect not only against cell killing, organ dysfunction, and lethality in mice, but also against DNA damage, chromosome aberrations, and mutation induction in mice receiving potentially lethal levels of whole-body irradiation. The use of the nitroxides in protecting against late-arising pathologies under LLR exposure conditions remains in question.

Aminothiols

Aminothiols have been extensively studied and reported on over the last several decades (e.g., Capizzi and Schein, 1994).2 The archetype drug within this chemical class of radioprotectants is amifostine (WR 2721, Ethyol). Amifostine is the only radioprotective agent that is currently approved by the U.S. Food and Drug Administration (FDA) for use in protecting normal tissues in cancer patients undergoing radiotherapy of the head and neck. Despite amifostine's potent cytoprotective attributes, its toxicity severely restricts its use to a clinical setting and prohibits its use in military operations. In the presentation made by Dave Grdina (University of Chicago), these issues were again raised, but with a new treatment option offered. In a series of more recent studies (both from Grdina's lab and others), amifostine has been shown to be highly effective in blocking long-term pathological effects (e.g., mutagenesis and cancer) of prior radiation exposure, even at a much reduced, minimally toxic level of drug. Grdina suggested that amifostine should not be used as a cytoprotectant due to the drug's toxicity and the necessity of using high doses for this purpose; rather, it should be used at lower doses as an antimutagenic and anticarcinogenic agent.

Although the effectiveness of amifostine and its analogs in protecting against mutagenesis and cancer induction is clear and unambiguous, the dose of amifostine required to exert late-- effects protection, relative to the extent of performance decrement, needs to be determined before military use is seriously considered.

Nutritional Adjuvants

Although Grdina argued for the possible use of a low-dose regimen of amifostine as a preventive treatment for the major radiation-induced late effects, he also suggested that attempts to use amifostine as a cytoprotectant for acute effects would be nonproductive. Countering the latter suggestion, Sree Kumar (Armed Forces Radiobiology Research Institute) described experiments in mice that demonstrated that select nutritional agents with marginal radioprotective attributes, such as selenium and vitamin E, when combined with low, nontoxic, but also nonprotective doses of amifostine, could elicit significant levels of radioprotection that greatly exceeded the level of radioprotection exerted by these agents alone. In contrast to Grdina's bleak assessment of amifostine's potential as a militarily relevant cytoprotectant, Kumar's results suggested the opposite, namely that nutritional adjuvants could possibily be used to limit the toxicity of amifostine without sacrificing its radioprotective features.

Modifiers of Gene Expression

Cancer chemoprevention is an extremely active area of basic research and applied clinical studies. Although the chemoprevention of radiation-induced cancers is certainly part of this effort, it is unfortunately a very minor component, with limited information to leverage for military medical purposes. Alexandra Miller (Armed Forces Radiobiology Research Institute) spoke about this issue and discussed her work on identifying and assessing the effectiveness of a small number of chemopreventive agents for radiation-induced cancers. One example she gave was regarding the effect of administration of buthionine sulfoximine, an agent normally thought of as a potent radiosensitizer. This agent effectively down-regulated the proto-oncogene H-ras, controlling its overexpression and associated proliferative signaling following protracted exposure to ionizing radiation. Miller's results clearly indicated the potential of selected drugs to target and control overexpression of specific genes (proto-oncogenes) that are intimately tied to aberrant proliferative signal transduction and, in turn, to radiogenic precancerous states.

Search for Nontoxic Radioprotectants

The key issue identified by the session chair (Dr. Seed) in his opening remarks was the necessity of research into identifying and developing for military purposes effective, nontoxic, nonperformance-decrementing radioprotectants for countering and managing radiological threats. In this regard, three participants (Kumar, Schwartz, and Whitnall) presented work suggesting that such protective agents might well already exist but simply need to be identified, further researched, and field tested. Sree Kumar presented work on the potential of using injectable vitamin E for this purpose. Art Schwartz (Temple University) and Mark Whitnall (Armed Forces Radiobiology Research Institute) presented information on a novel class of radioprotectors (the androstene steroids and related analogs) with broad-spectrum, radioprotective, and chemoprotective attributes. Schwartz presented studies indicating that a fluorinated analog of the adrenal steroid dehydroepiandrostenone (DHEA) lacks substantial androgenic activity (a principal source of drug toxicity) while retaining a rather impressive array of protective attributes, including anticancer effects against both induced and spontaneous neoplasms as well as anti-inflammatory, immune-modulating, and antidiabetic responses. The apparent molecular target for this fluorinated DHEA analog (Schwartz calls it fluasterone) is one of the rate-limiting enzymes of the pentose phosphate pathway, glucose-6-dehydrogenase.

Following Schwartz's introduction to this interesting class of chemopreventive agents, Whitnall presented results of recent work done at the Armed Forces Radiobiology Research Institute on the radioprotective properties of 5-androstenediol (5-AED), a naturally occurring metabolite of DHEA. Whitnall made a strong argument for the potential use of 5-AED and related analogs in military operations. Results presented suggested that 5-AED has many of the attributes of the "ideal radioprotector." For example, 5-AED is relatively stable with a long shelf life and is easily administered by subcutaneous injection, yet it could possibly be used orally as well. The agent is effective against acute, life-threatening radiation injuries and is essentially nontoxic and nonperformance-decrementing. 5-AED has immune-bolstering and anti-infective properties, along with a very useful extended time window of effectiveness (24 hours as a pretreatment and several hours as a postexposure treatment).

Use of Cytokines in the Treatment of Radiation Injury

A select number of hematopoietic growth factors (HGFs) can be very effective in the medical management of acutely irradiated individuals, whether or not the irradiation is intentional (clinical use) or accidental in nature (Moore and Vadhan-Raj 1994).3 In this regard, three HGFs currently have FDA approval for use in treating acute myelosuppression regardless of etiology: These include recombinant human granulocyte colony-- stimulating factor (rhG-CSF) (Neupogen; Amgen, Inc., Thousand Oaks, CA), recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) (Leukine; Immunex Corp., Seattle, WA), and recombinant human interleukin 11 (rhIL- 11) (Neumega; Genetics Institute). A fourth recombinant, erythropoietin (Epogen; Amgen, Inc.), is currently available, but it is generally considered not particularly useful as a primary therapeutic for patients suffering from acute myelosuppression due to its highly specific erythropoietic tissue targeting (rather than myelopoietic targeting). In addition to these recombinants, a new generation of chimeric growth factors is being developed. Tom MacVittie and his colleagues (University of Maryland at Baltimore) reported impressive preclinical results using a subhuman primate model of three such recombinants, namely, myelopoietin, promegapoietin, and progenipoietin. All of these agents are laboratory constructs that do not exist in nature; they are engineered as hybrid molecules formed by the combination of two hematopoietic receptor agonist arms linked by a common bridging scaffold. In the case of myelopoietin, for example, interleukin 3 (IL-3) and G-CSF ligands are linked and serve to stimulate those hematopoietic progenitors bearing IL-3 and G-CSF surface receptors. In the case of promegapoietin, IL-3 and MPL ligands are linked, whereas progenipoietin combines flt-3 and G-CSF ligands. All three chimeric molecules exhibit an enhanced capacity (relative to the individual agents given singly) to minimize the duration and severity of the initial myelosuppression that follows acute, potentially lethal, highdose exposure to radiation. The long-term consequences of using these recombinants in establishing a fully reconstituted and stable hematopoietic system, however, are not known.

After some prompting by the organizers, MacVittie also discussed in some detail the current deficits in our understanding of the usefulness of these HGFs in treating LLR-exposed individuals who might be at risk to late-arising pathologies.

MacVittie's article and the preceding article by Bill McBride (UCLA) titled "NF-kappaB, Cytokines, Proteasomes, and Low-Level Radiation Exposure" made it obvious that the use of cytokines in treating LLR-exposed individuals depends on the nature of the LLR injuries and their radiological dependencies. In this regard, McBride pointed out in his presentation that for ionizing radiation exposures in the LLR range (

Utility of Stem Cell and Gene Transfer Technologies in Managing Radiation Injuries

Although not yet seriously considered as potential preventive treatments for LLR-associated injuries, the conference organizers asked whether stem cell or gene replacement technologies might have a future role in the management of health risks associated with LLR exposure. The question was intended to be provocative and to motivate the attendees to consider what these newer forms of cellular and molecular treatments might offer in controlling LLR-associated late effects. Although none of the speakers who addressed this topic (Epperly, Chute, and Mandalam) specifically discussed the LLR issue per se, all spoke about the potential use of these treatments in management of radiation injuries in general. For example, Mike Epperly (University of Pittsburgh) presented results of a novel series of gene transfer experiments in which the human gene manganese superoxide dismutase was transfected into normal pulmonary and esophageal epithelia; manganese superoxide dismutase was shown to be overexpressed and to provide significant protection against acute, high-dose (2,000 cGy), local thoracic irradiation and associated induced tissue pathology (pneumonitis). Interestingly, Epperly and colleagues showed that only normal tissue was radioprotected by the manganese superoxide dismutase transgene; developing tumors were not. The mechanism by which this differential transfection takes place was not explained, however. Despite the promising nature of Epperly's work, it will take a lot more work and time before gene transfer technologies can be used in clinics or the workplace for the purpose of radioprotecting high-risk individuals.

Stem cell replacement was the second technology discussed as having potential in the treatment of radiation injuries. Similar to the work of many other presenters, the work presented by John Chute (Uniformed Services University of the Health Sciences) and Ramkumar Mandalam (Aastrom Biosciences, Inc.) focused on acute, high-dose exposures and on using hematopoietic stem cell replacement to treat critically injured individuals with ablated lymphohematopoietic capacity. Both presentations concentrated on new technologies designed to amplify in vitro vital primitive progenitors with marrow-repopulating capacity. In the rodent model used by Chute and colleagues, the phenotype of the primitive progenitors targeted for in vitro expansion was a +Sca-Thy-low-bearing cell type, whereas the human hematopoietic progenitors that Mandalam reported had a +CD34-lin- phenotype. In both studies, these progenitors were initially obtained from the acutely irradiated, severely myelosuppressed individual, amplified manyfold through selective in vitro culture, and subsequently infused back into the gravely ill individual in the hope that the infused cells would engraft and repopulate the depleted marrow. Although the in vitro amplifying systems used by Chute and Mandalam are distinct (Chute's system is based on a static "feeder layer" system, while Mandalam's is a dynamic, continuous flow, cytokine-cocktail-supplemented cell-generator system that has been commercially developed as the AastromReplicell Cell Production System), both reports indicate that in vitro amplification of stem cells is not only possible but also practical in preclinical and clinical settings for the effective treatment of acute radiation syndrome. However, the use of these stem cell amplification and transplantation technologies to treat sublethal radiation injuries and to manage long-term pathological risks remains to be addressed experimentally. In this regard, it is hoped that the potential of these systems for the management of patients with LLR-associated injuries will be recognized and actively researched.

Effects of Natural Adaptive and Accommodative Systems

The final speaker of the session was Tom Seed, who spoke about natural adaptive and accommodative systems evoked by LLR and how these natural systems influence both near-term and long-term hematopoietic functions. Depending on the dose rate at which the LLR exposure occurs, these adaptive responses appear to affect long-term health in dramatically different ways. At very low dose rates, they appear to dampen the development of life-threatening myeloproliferative disorders (MPDs) such as myeloid leukemia, but under high dose rates delivered continuously, the magnitude and duration of these adaptive responses are linked both temporally and causally to protracted, radiation-induced MPD. It is noteworthy that periodic administration of a low dose of bacterial lipopolysaccharide during chronic irradiation seemingly enhanced adaptive and accommodative responses in select subgroups of animals and, in turn, extended survival and lowered risk of MPD development. Whether other biomodulating agents, such as the rHGFs mentioned earlier, can similarly reduce LLR-associated hematopathologies remains to be determined.

Major Goals, Issues, Comments, and Consensus

Questions Posed to the Expert Panel: Their Comments, Thoughts, and Discussion

Regarding Issue 1 and Question 1

Dr. Shirley Fry: Advances in protection against and treatment (or mitigation) of radiation-induced injury were presented with respect to the nature and detection of such injury and with respect to protective devices and chemopreventive and genopreventive strategies. It was agreed, on the basis of clinical and epidemiological studies of exposed individuals and populations, respectively, that an increased risk of malignant disease and exposure-related psychoses is the major health effect that may be expected after exposure to low levels of radiation as defined by NATO ACE Directive 80-63 (1996).' Thus, the focus of research in this area must be on prevention and treatment of radiation-induced cellular and molecular injury, particularly in relation to mutagenic and carcinogenic effects, and of psychoses.

Dr. Ruth Neta: There is indisputable evidence that doses in the low range (below 0.7 Gy) do not lead to life-threatening deterministic effects. Since the Do for hematopoietic precursors and unprimed T-helper and -suppressor cells is in the range of 0.8 Gy to 1.0 Gy (acute exposure), the hematopoietic and lymphoid tissues show transient depression.

The dominant late effect of radiation exposure within the dose range of interest (

Recent work has identified the molecular and genetic changes that occur after exposure to radiation in the dose range below 0.7 Gy. These include the following: - induction of stress-responsive genes, many of which, however, overlap with genes induced by stressors other than radiation. Such genes include up-regulation of the hsp 70 family,4 NF-kappaB5 McBride's presentation 6,7; PKC and p38 MAPK8; p21, GADD45, Mdm2, ATF3, and Bax,9 and downregulation of Myc.9,10

cellular apoptosis; the cells that undergo apoptosis after exposure below 0.7 Gy include hematopoietic progenitors and unprimed T-helper and T-suppressor cells.

genomic instability, which is characterized by diverse genomic alterations that are not immediately evident but that occur many generations after radiation exposure. Such alterations include karyotypic abnormalities, gene mutations and amplifications, cellular transformation, clonal heterogeneity, and delayed reproductive cell death.11

alterations of cytokine expression, hormones, and neuropeptides, for which to date there is only anecdotal evidence for a dose range below 0.7 Gy.

Regarding Question 2, Issue 3, and Questions 3 through 7

Dr. Shirley Fry: Several modalities and strategies were reported to be effective in experimental and some clinical situations involving high acute or high cumulative radiation doses. Further research is needed to evaluate the following:

- the efficacy of these treatments in the management of radiogenic injury associated with doses in the range of interest (

- the risk of their induction of adverse effects in the long term compared with their short-term benefit; and

- the risk, if any, of serious adverse effects in the long term after the use of these treatments as countermeasures compared with the excess risk of fatal malignancy due to LLR exposure (4%/Sv for adults 18-65 years old).

Countermeasures that need to be looked at in this regard include:

- nutritional protectors, such as trace elements (e.g., Se, Cu, Zn) administered pre- or postexposure and acting alone or in combination (e.g., with amifostine) and exogenous vitamins (e.g., vitamin E);

- currently available pharmacological agents such as certain antioxidants (e.g., nitroxides) and steroids (e.g., fluasterone, a DHEA analog); and

- conventional pharmaceuticals that have proven effective in the management of injuries resulting from high-dose exposures and in some conditions unrelated to biological effects of radiation exposure that have been shown to have other actions of potential benefit in the management of LLR-induced exposures, such as specific but yet-to-bedetermined cytokines, cytoprotectors (e.g., amifostine), Captopril, and Zoloft (for exposure-related psychoses).

Dr. Joe Weiss: When discussing the feasibility of human use of protective or therapeutic agents, it is necessary to distinguish the application needed, for example, protection against accidental external or internal exposures and against acute high-dose or low-dose or low dose-rate exposures. The specific question at this conference was what agents could be used to protect against or treat external radiation doses of up to 0.7 Sv in military personnel. With respect to hematopoietic damage, the consensus of the participants was that it was not necessary to use measures shown to be effective after higher radiation doses, namely, the administration of colony-stimulating factors, platelets, fluids, or antibiotics.

There is very little information from experimental animal studies about protection against LLR exposure. Most experimental studies of radioprotectors (agents administered before radiation exposure) aimed to show protection against hematopoietic damage after relatively high doses of radiation using 30-day lethality or other endpoints. The large number of pharmacological and nutritional agents that have this capability cannot be recommended at this time to protect against hematopoietic injury due to LLR exposure because spontaneous recovery is likely.

Although there may be additional low-dose effects that could be moderated by protective or therapeutic agents, the main issue appears to be whether any agent would be useful in preventing low-dose radiation-induced mutagenesis or carcinogenesis. It is clear that many of the same agents that can protect experimental animals from hematopoietic damage and death also have antimutagenic properties. The most prominent are WR-2721 (Ethyol, amifostine) and related phosphorothioates. The superiority of phosphorothioates in protecting against and repairing DNA damage appears to be related to similarities in the structures of naturally occurring polyamines and phosphorothioate metabolites, and these properties may be associated with the antimutagenic and anticarcinogenic effects of WR-compounds in experimental studies. However, antimutagenic and anticarcinogenic effects of WR-2721 have not yet been reported in humans. The arguments against the current use of WR-2721 (some of these arguments would apply to other agents) in military personnel include the following: no FDA approval for use as a protector against carcinogenesis, administration problems, side effects that would hamper full use of capabilities under conditions in which physical and psychological stressors are present and in which wearing protective gear is necessary, and ethical and moral considerations such as informed and voluntary consent. Other synthetic agents such as mercaptopropionylglycine have demonstrated antimutagenic effects after radiation exposure, but in all cases quantitative data obtained from clinical studies are required to perform a proper risk-benefit analysis with respect to the use of these agents in military scenarios. In the future, recommendations might be made on the basis of changes in intermediate biomarkers rather than cancer incidence.

A large number of nutritional and natural agents have also shown antimutagenic effects when administered before or after radiation exposure in experimental systems. These agents include cysteine, superoxide dismutase, vitamins A, E, and C, selenium, polyamines, ginkgo biloba, allicin, lycopene, and others. It is unlikely that adequate information on the antimutagenic and anticarcinogenic effects of these agents can be obtained in controlled clinical trials involving radiation exposures. In the future, however, useful information may be obtained from chemoprevention trials in which these agents show cancer prevention (or changes in intermediate markers) in individuals exposed to carcinogens other than radiation. The antimutagenic potential of various antioxidants was suggested by their suppression of clastogenic factors in the plasma of Chernobyl emergency workers long after their exposure to radiation, but it is unclear how this relates to cancer incidence in this population. If ongoing chemoprevention trials in normal individuals show that antioxidants, specifically vitamin E and selenium compounds, have a general protective effect against cancer development, it might be reasonable to assume that they would be effective against radiation-induced cancer in humans. If there are FDA-approved general recommendations on cancer prevention through the use of vitamins and food supplements, these recommendations should be conveyed to the military in the context of an overall health promotion program.

Regarding Issue 4 and question 8

Dr. Ruth Neta: In animal and cellular models of LLR exposure, there is a need to identify the biomarkers, if any, that are characteristic of radiation-induced cancers or of susceptibility to radiation-induced cancers (several of which-p53, ATM, NBS-- have been identified), including their potential synergistic or antagonistic interaction in promoting tumor progression. For example, genes upstream or downstream of a critical gene may function to modify the effect of a mutated tumor suppressor or oncogene function. At present, however, we lack knowledge about biomarkers for radiation-induced cancers, but we do know about biomarkers that predispose individuals (i.e., biomarkers for susceptibility to cancer) to cancer, including those that may be specifically induced by radiation.

We also need to develop a better understanding of organ/ tissue/matrix influences in promoting tumor growth or suppression to further expand on accumulating evidence that such tissue determines the potential for growth and expansion of malignant cells. The work of Dr. Bissel (University of California at Berkeley) in this area represents a prime example of the direction that needs to be taken.

Furthermore, we need to be mindful of the possibility that pathways and agents used in attempting to reverse tumor initiation or progression may have harmful side effects and pose health risks far greater than those posed by the LLR exposure.

Dr. Joe Weiss: Future development of improved protective agents appears promising. Information from the genome project, for example, and other research will lead to the development of targeted radioprotectors through improved understanding of DNA structure, function, and repair; radiation-induced cancer; and identification of radiation-sensitive individuals. Any future recommendations must be compatible with agents already approved for military use for protection against radiation-induced emesis, nerve agents, and biological warfare agents.

Dr. Ruth Neta: In this regard, the major technological advances achieved recently should help in assessing potential health risks of LLR exposure and associated drug interventions. Improved technology (e.g., cDNA or protein microarrays) should enable these studies to be conducted in a context of examining multiple genetic changes after radiation exposure.

Dr. Shirley Fly: Newer biotechnologies, including gene transfer and cell replacement (or supplementation), show promise in the management of individuals exposed to radiation at levels that are beyond the range of interest here but which are of continuing importance. The improved potential for recovery from the hematopoietic syndrome after formerly lethal radiation doses and subsequent survival of sufficient duration allows clinical expression of the respiratory syndrome, a syndrome that has not been amenable to conventional or currently available treatments. Therefore, studies of the application of newer techniques in the management of acute high-dose injury should continue to be supported. These experimental approaches are also worthy of continued research into their use for the management of the long-term effects of LLR exposure.

The following additional comments relate to several of the issues and questions under consideration and were contributed by Drs. E. Parshkov, A. Tsyb, and V. Sokolov (Medical Radiological Research Center, Obninsk, Russia) and Jim Barnes (Foundation for Advancement of Science and Education, Los Angeles):

At the present time, risk estimates for somatic and stochastic effects in the human are based largely on two sets of epidemiological data: data from the Japanese A-bomb survivors and data from the population affected by the Chernobyl accident. In Japan, the radiation was delivered in a brief external exposure at a high dose rate, so risk estimates for radiation-induced disorders under low-level and prolonged modes of radiation may be obtained only from the Chernobyl experience. Data from the World Health Organization show that the total radioactivity of the materials released as a result of the Chernobyl accident is estimated to have been 200 times the radiation resulting from the atom bombs dropped on Hiroshima and Nagasaki.

The 200,000 people who participated in the 1986-1987 recovery operations in Chernobyl received doses of 100 mSv on average. Approximately 10% (20,000 people) received doses of 250 mSv or more. In the contaminated areas, the average absorbed dose to the thyroid in children was approximately 30 to 40 cGy, but a very large range of doses was seen within the affected population (from 0 to 1,000 cGy.

Extensive studies of the oncological and nononcological diseases found in the affected Chernobyl population have been performed by the Medical Radiological Research Center in Obninsk, Russia. It has been convincingly demonstrated that the pathobiological response of the thyroid under chronic irradiation (via incorporation of radioiodine) is highly dependent on the functional status of the thyroid during the time of exposure (increased function is found in newborns, pubescent girls, and pregnant and lactating women). Furthermore, it has been found that in pooling the data for different cohorts within the exposed population, one could lose critically important information on the effects of gender, age, iodine deficiency, and so on. For example, in women under 30 years old, thyroid cancer morbidity exceeded the morbidity in men 10-fold, Examination of a cohort of youths who were 15 to 16 years old at the time of the Chernobyl accident indicated that the number of thyroid cancers (registered cases) was approximately an order of magnitude higher in girls than it was in boys. Similar radiobiological and pathological relationships might be expected for other types of radiation-induced endocrine disorders as well.

Our data on the incidence of thyroid pathology further suggest that indiscriminate use of iodine prophylaxis in cases of radiation exposure may be ill advised. Although the timely administration of stable iodine will block uptake of radioactive iodine from the nuclear accident, prolonged administration can result in a modification of the cellular division rates in the thyroid and in derangement of thyroid hormone control. In the design of preventive programs, the functional activity of thyroid should be taken into account; otherwise, iodine prophylaxis will be inefficient or even harmful in some of the population.

A method to detoxify chronically irradiated patients has been developed and tested at the Medical Radiological Research Center in Obninsk, Russia. This method has demonstrated effectiveness in the alleviation of symptoms displayed by Chernobyl victims and appears to have wide applicability for similar situations.

References

1. NATO ACE Directive 80-63: ACE policy for defense measures against low level radiological hazards during military operations, 1996.

2. Capizzi RL, Schein PS: Chemo and radiation protection with amifostine. In Advances in the Treatment of Radiation Injuries, Advances in the Biosciences, Vol 94, pp 91-101. Edited by MacVittie TJ, Weiss JF, Browne D. Oxford, UK, Pergamon/Elsevier Science Ltd., 1994.

3. Moore DF Jr, Vadhan-Raj S: Hematopoietic growth factors in bone marrow failure states. In Advances in the Treatment of Radiation Injuries, Advances in the

Biosciences, Vol 94, pp 63-74. Edited by MacVittie TJ, Weiss JF, Browne D. Oxford, UK. Pergamon/Elsevier Science Ltd., 1994.

4. Sadekova J, Lehnert S, Chow TY: Induction of PBP74/mortalin/Grp75 a member of HSP70 family of low radioresistance. Int J Radiat Biol 1997: 721: 653-60.

5. Prasad AV, Mohan N, Chandrasekan B, Meltz ML: Activation of nuclear factor kappa in human lymphoblastoid cells by low-dose ionizing radiation. Radial Res 1994; 138: 367-72.

6. McBride WH, Pajonk F, Chiang C-S, Sun J-Pc NF-KB, cytokines, proteasomes, and low-level radiation exposure. Milit Med 2002; 167: 66-7.

7. Pajonk F, Pajonk K, McBride WH: Inhibition of NF-KB, clonogenicity and radiosensitivity of human cancer cells. J Natl Cancer Inst 1999; 91: 1956-60.

8. Shimizu T, Kato T Jr, Tachibana A, Sasaki MS: Coordinated regulation of radioadaptive response by protein kinase C and p38 mitogen-activated protein kinase. Exp Cell Res 1999; 251: 424-32.

9. Amundson SA, Do KT, Fornace AJ Jr: Induction of stress genes by low doses of gamma rays. Radial Res 1999: 152: 225-31.

10. Liu SC, Murley JS, Woloschak G, Grdina DJ: Repression of c-myc gene expression by the thiol and disulfide forms of the cytoprotector amifostine. Carcinogenesis 1997; 18: 2457-9.

11. Morgan WF, Day JP, Kaplan MI, McGhee EM, Limoli CL: Genomic instability induced by ionizing radiation. Radial Res 1996; 146:247-58.

Guarantor: Thomas M. Seed PhD

Contributors: Shirley A. Fry, MD*; Ruth Neta, PhD^; Joseph F. Weiss, PhD^; David G. Jarrett, MD^^; David Thomassen, PhD(Sec) Thomas M. Seed, PhD^^

*Life Sciences Division, Oak Ridge National Laboratory, 209 Briarcliff Avenue, Oak Ridge, TN 37830.

^International Health Programs, EH-63, 270CC, U.S. Department of Energy, 19901 Germantown Road, Germantown, MD 20874-1290.

^^Armed Forces Radiobiology Research Institute, 8901 Wisconsin Avenue, Bethesda, MD 20889-5603.

(Sec)Office of Health Science, Intramural Research Office, ER-72, U.S. Department of Energy, 19901 Germantown Road, Germantown, MD 20874-1290.

This manuscript was received for review February 2001. The revised manuscript was accepted for publication in November 2001.

Reprint & Copyright by Association of Military Surgeons of U.S., 2002.

Copyright Association of Military Surgeons of the United States Feb 2002
Provided by ProQuest Information and Learning Company. All rights Reserved