JOHN D. ZIMBRICK

As RERF enters its second half-century of research on the human health effects of acute radiation exposure, it stands poised to provide answers to a number of important questions related to the delayed incidence of cancers and other diseases in the atomic bomb survivors and their offspring. One of the most important of these is whether humans irradiated in utero, as infants, or as juveniles are more sensitive to the delayed effects of radiation than humans irradiated as adults. Since over 90% of the atomic bomb survivors who were irradiated at or below nine years of age are still alive in 1995, it will take more years of follow-up and study before sufficient incidence and mortality data are available to answer this question. Some other important questions center on whether acute radiation exposure will lead eventually to delayed health effects other than cancers, such as cardiovascular disease. New genetic and molecular biologic methodologies will allow questions about variations in radiation sensitivity among individual survivors and genetic changes in first-generation offspring to be addressed. Tissue samples from living survivors as well as stored autopsy materials from deceased survivors will be used to develop and test new ''biomarkers" of exposure and disease. RERF scientists are uniquely qualified to help conduct similar follow-up studies on other radiation-exposed populations, such as those found in the countries of the former Soviet Union. RERF will be able to accomplish this extraordinary and unique set of tasks only if it continues to enjoy adequate funding and a positive management climate which fosters collaborations with extramural scientists, encourages some non-Japanese staff scientists and directors to spend extended periods at RERF in order

to develop and care for long-term research projects, and emphasizes maintenance of high-quality laboratories and state-of-the-art data management systems.

Descartes aptly stated what I believe many of us feel about the RERF program. It is at once the longest-running human radiobiology research program in history as well as the source of the greatest amount of data on the health consequences of acute external radiation in humans. Nevertheless, in the context of contemporary knowledge of molecular etiology of diseases such as cancer, it can be argued that the RERF program has yielded only the first glimpses of the enormously complicated processes involved in the induction of disease by ionizing radiation. This chapter will present and discuss some of the major questions that RERF is uniquely positioned to address in order to shed more light on these processes. But first we must finish the discussion of events leading to the present difficult situation in which RERF finds itself, because the resolution of this situation may have a significant influence on RERF's future research program.

At this syposium, Frank Putnam provided a vivid and accurate history of ABCC, RERF, and the constant involvement of the National Academy of Sciences (NAS) in the development and management of both institutions. The history is rich with periods of uncertainty and events, some of which brought ABCC and RERF to a crossroads very near brink of disaster. We now find ourselves at another crossroads, brought to this point by a combination of management issues at the Department of Energy (DoE) and the NAS, and by a crisis in funding due to the sharp weakening of the dollar against the Japanese yen and the limitations in funding provided for RERF by DoE.

Dr. Putnam summarized the events leading up to the historical NAS business meeting of April 1995, during which a resolution expressing concern over a DoE plan to abruptly terminate calling for continued NAS involvement with RERF was introduced and discussed. The resolution was signed immediately after the meeting by 191 NAS members and transmitted with a supporting letter by NAS President Bruce Alberts to Secretary of Energy Hazel O'Leary. Two months later, Secretary O'Leary responded to President Alberts, stating in her letter that she continued to support the termination of the NAS management of RERF. The letter contained a series of additional statements, one of which could be interpreted as alleging that the NAS conducted secret research in the early days of ABCC to support the

nuclear weapons program. The Secretary copied her letter to numerous parties so that it quickly was circulated throughout the scientific community, Capitol Hill, and the press. Since no written evidence was presented that ABCC ever conducted secret research, and since the pioneers of ABCC/RERF, notably Jim Neel who was intimately involved from the very beginning, provided verbal assurance that ABCC conducted its programs openly and published its results regularly, the O'Leary letter prompted a major outcry from numerous quarters.

Meanwhile during this period, RERF held its annual Scientific Council meeting in April and its Board of Directors meeting in June 1995. The Science Councillors, worried about the many negative management and budgetary issues which had been raised over the past many months, recommended that a blue ribbon panel of international experts be established by the US and Japanese governments to provide an independent review of the RERF scientific programs. The Scientific Council also recommended that DoE defer any decision to remove the NAS from its management of RERF until after the blue ribbon panel had submitted its final report to both governments. These recommendations were presented to the RERF Board of Directors at its June 1995 meeting. After considerable discussion, the Board voted to accept them.

Within hours after the RERF Board's decision to accept the Scientific Council's recommendations, NAS President Bruce Alberts received a call from DoE's Assistant Secretary for Environment, Health and Safety, Tara O'Toole, informing him that DoE had decided to accept the recommendations made by the RERF Scientific Council and approved by the RERF Board. NAS would receive a two-year extension of its RERF management activities (October 1, 1995, through September 30, 1997) and DoE would defer its decision on whether to replace the NAS to a later time. DoE would support the formation of the blue ribbon panel, an action that the NAS President had recommended to the Secretary during a meeting in November, 1994.

After the decision by DoE discussed above, the Japanese government also endorsed the RERF Scientific Council recommendations. The two governments have now formed an independent blue ribbon panel composed of nine members with Dr. Roger Clarke as Chair. Dr. Clarke is President of the International Commission on Radiological Protection and Chairman of the National Radiation Protection Board of the UK.

The NAS negotiated the scope of its management activities for the two-year extension period with DoE. While it appears that many of the activities that the NAS has always conducted (e.g., recruiting of non-Japanese staff and directors, dissemination of RERF reports, and arranging for audits of financial matters at RERF) will be continued, there is one important activity which will not be. The US funding provided to RERF under the 50:50 sharing agreement with Japan passed through the NAS as it always was until April 1995; after that, it was sent by DoE through the US Embassy in Tokyo to RERF. This pass-through arrangement was always considered to be a major facet of the "buffer" between the US government

and RERF, and it provided the consideration for a subcontract between RERF and the NAS. Without the financial consideration, there is no longer a basis for a formal subcontract. Nevertheless, a "memorandum of understanding" was negotiated in good faith between the two parties that formalized all of the NAS activities related to RERF except the pass-through of funds from the US government.

As it always has in the past, RERF will move away from its present position at a crossroads. During this new journey, RERF's strengths and its overall ability to address and answer the questions outlined below will depend on a number of issues whose outcomes are not clear at present. Most important of these are: (1) the financial crisis, which must be resolved so that RERF will have sufficient staff in critical positions to continue its major scientific programs at a high enough level of quality that the data and analyses it produces are accepted by the international radiation science community; (2) the results and recommendations of the blue ribbon panel review and how these are accepted and implemented by the Japanese and US governments; (3) the stabilizing of the US management and oversight of RERF such that: (a) the independence and objectivity of the RERF data and analyses are ensured; and (b) a positive environment is maintained which encourages outside collaborations, extended terms for a core of non-Japanese scientists who can develop and maintain long-term research projects, and the maintenance of high-quality laboratories and state-of-the-art equipment and data processing facilities.

A crucial question yet unanswered by the RERF studies is whether humans exposed to ionizing radiation in utero, as infants, or as young children or teenagers, are more sensitive to the induction of delayed health effects than are humans exposed as adults. The answer to this question is important because of its possible implications for the setting of radiation exposure standards for the public and for the use of radiation to treat diseases in juveniles.

The Life Span Study (LSS) at RERF has shown that excess cancer mortality risks from exposure to acute external ionizing radiation depend upon certain modifying factors such as sex, attained age, and age at exposure. Further, it appears that for solid cancers the excess risk persists after radiation exposure and mortality rates increase throughout life, whereas for leukemias the risks persist throughout life for those exposed as adults but decrease for those exposed as children.

Although the LSS data are complete for those survivors who were exposed at or above the age of 50, they are far from complete for cohorts exposed at ages below 50. In fact, about 51% of all of the survivors (who have assigned radiation

doses) were alive in 1995. Table 20.1 shows cohort sizes for the youngest survivors projected over time until the year 2020.

It can be seen in Table 20.1 that over 90% of the survivors exposed between the ages of 0 to 9 years were still alive in 1995. The cancer mortality in this cohort will increase rapidly in the coming years, and must be studied in order to gain more understanding about the age variations in risks for radiation-induced solid cancers and leukemias in survivors exposed as juveniles versus survivors exposed as adults.

With regard to survivors who were in utero at the time of the bombings, this relatively small cohort thus far exhibits a cancer mortality rate similar to that of the survivors exposed as children. More follow-up will be necessary to gain more quantitative understanding of the cancer mortality rates in this group.

Another important question which will be addressed in future studies at RERF relates to whether acute radiation exposure induces excess mortality risks from diseases other than cancer.

Recent studies on the data obtained from the LSS have revealed a statistically significant increase in noncancer mortality with increasing radiation dose. Such an increase could be due to confounding factors or bias, rather than to radiation, and further studies are necessary to produce more definitive results. Thus far, only misclassification (classifying a cancer death as a noncancer death) has been ruled out as the cause of the radiation-induced increase in noncancer mortality.

The Adult Health Study (AHS) is likely to contribute key information to help understand the possible induction of noncancer diseases by radiation. This study, one of the longest-running and largest clinical studies in history, initially suggested that acute radiation induces a variety of cardiovascular diseases, such as

coronary heart disease. However, when confounding risk factors such as smoking, age, and sex, were factored into the statistical analysis, the radiation effect on cardiovascular diseases was reduced to non-significance, except for atherosclerosis. Hyperparathyroidism has also been demonstrated to be a radiation-induced disease, and its effects may be related to the observed atherosclerosis incidence. Further, chronic liver disease and myoma uteri (benign tumors) have been shown to be induced by radiation, and it is possible that radiation exposure induces earlier onset of female menopause, senile dementia, and late onset of cataracts. As the AHS continues, its careful clinical studies on the young survivors (those shown in the table above) are expected to provide valuable new data to help increase our understanding of the possible relationships between radiation dose and these noncancer diseases, including the involvement of confounding variables such as alcohol consumption, smoking, and infections.

Are heritable excess cancer or noncancer health risks found in the first-generation offspring (F₁) of A-bomb survivors? Answers to this question have been sought since the very early days of ABCC. To date, no excess risks of any kind have been found in a very large cohort of over 80,000 F₁. However, their average age is 39 years, so follow-up must be continued for a number of decades in order to determine whether any delayed effects, thus far undetected, will occur. Thus far, follow-up has been done like that in the LSS, that is, through death certificate data from family registries. No clinical examinations like those of the AHS have been done on the F₁ since their first year after birth. An important goal will be to conduct a well-designed clinical study of a subset of F₁ to search for possible inherited health effects. This is because inherited diseases, which might be caused by radiation-induced genetic defects in survivor-parents, are frequently not manifest until after the first 10 years of life, and sometimes not until well into adulthood.

Another major question to be addressed in the F₁ studies is whether germ-line mutations can be detected by state-of-the-art molecular biologic techniques (e.g., deletions or insertions of DNA fragments) in the cells of irradiated parent-child families (called trios). RERF has a cell bank which already contains immortalized B lymphocyte cells from 800 families (composed of 1,600 parents and 1,200 children), and their goal is to obtain cells from 1,000 families, half of them from families with radiation-exposed parents.

The RERF survivor-volunteers and bank of stored biologic materials provide an invaluable and unique resource which can be used to address some very important mechanistic questions, such as:

• What is the lowest assigned radiation dose for which subcellular changes, such as chromosome aberrations and DNA changes, can be reliably detected

• in the biologic samples from the survivors? What is the shape of the dose-response relationship for these changes?
• Can state-of-the-art molecular biologic techniques be used to identify and quantify systematic, radiation-induced changes in genes identified as being involved in the process of carcinogenesis?
• Will biomarkers developed in model cellular and animal systems prove useful in humans as determined by testing them on the AHS cohort and/or the stored biologic samples at RERF?
• Will it be possible to determine the susceptibility of an RERF survivor to radiation-induced injury by, for example, the use of biomarkers to measure his/her capacity to repair radiation damage in DNA? Does the measured susceptibility relate to the observed health status of the survivor?
• What are the shapes of the dose-response curves for various radiation injury endpoints such as site-specific solid cancers, and how can they contribute to the development of new predictive models as well as to the increased understanding of mechanisms underlying the observations of radiation-induced injury?

The AHS cohort will be extremely valuable for use in obtaining answers to the above questions. So will the bank of stored biologic specimens, which contains 110,000 serum samples, 11,000 plasma samples, and 13,000 lymphocyte specimens from the AHS, along with 7,500 autopsy specimens, 13,000 surgical specimens from the LSS, and transformed lymphocytes from 800 family trios in the F₁ studies.

The collective expertise gained by ABCC/RERF scientists during the nearly 50 years of study on the A-bomb survivors at Hiroshima and Nagasaki has given them unique qualifications to advise and help conduct similar studies on other exposed populations, such as those found in the countries of the former Soviet Union. Thus it seems inevitable, and in fact desirable, that RERF will evolve into a unique international center for human radiobiology research. RERF directors and staff were among the very first foreign scientists invited to Russia to survey and advise Russian scientists after the Chernobyl accident in 1986. Since then, RERF scientists have worked with other internationally based groups, such as the World Health Organization and the International Atomic Energy Agency, to provide assistance to Russian scientists in studies on exposed workers and members of the general population living in the southern Ural mountains of the Russian Federation.

Epidemiologic studies on the exposed populations in the Russian Federation will be especially valuable in furthering our understanding of radiation effects on

humans when the radiation doses are delivered over an extended period of time, and from sources of radiation both external to the body, as well as from internally deposited radioactive materials. Comparisons of the dose-response data obtained from the Russian victims with the analogous data obtained from the RERF studies on the acutely irradiated A-bomb survivors should provide crucial information on possible variations in health effect risks due to changes in rate of delivery of radiation dose.

The views expressed herein are those of the author and are not necessarily those of the NRC or any of its constituent units. The author is grateful for helpful discussions with Jim Neel, Frank Putnam, Jack Schull, Gil Beebe, Seymour Jablon, Stu Finch, Charlie Edington, Mort Mendelsohn, Seymour Abrahamson, Don Harkness, Cathie Berkley, and the staff at RERF.