Radiation Biology and the Radiation Research Program

The Department of Energy (DOE) and its predecessor organizations, Energy Research and Development Agency (ERDA) and Atomic Energy Commission (AEC), always have been concerned about the health effects of ionizing radiation. Extensive research has been conducted under their sponsorship at all levels of biological organization from molecules to man. Over the past 60 years, studies using every type of radiation source have included exposure to both external radiation sources and to internally deposited radioactive materials. These exposures used different dose patterns and distributions delivered over a wide range of experimental times. This extensive research provided the basis for the new Low Dose Radiation Research Program, linking the program directly to both the study of radiation's health effects and recent developments in life sciences and technology.

This brief history will begin with the development of atomic energy and proceed to a review of research programs designed to understand the health effects of radiation in animals and man. Finally, the impact of past research into radiation's effects at the cellular and molecular level will be considered as a prelude to the Low Dose Radiation Research Program.

Atomic Energy

Parallel development of the atomic bomb and the use of nuclear energy for electricity production resulted in a difficult dilemma for the public. Nuclear energy can be a source of massive death and destruction but also has immense potential for useful applications. Because of negative associations and connotations regarding the A-bomb, concern about adverse health effects plays a major role in the public's acceptance or rejection of nuclear power.

The history of atomic energy has been reviewed extensively by the U.S. DOE (see http://www.em.doe.gov/timeline/index.html). Similar histories are available on the health effects of ionizing radiation, including a very good one on research associated with health effects induced by internally deposited radioactive materials (J. N. Stannard, "Toxicology of Radionuclides," Ann. Rev. Pharmacol. 13: 325–57, 1973) and the use of this information to help establish appropriate standards. DOE used these and other historic resources to help develop the research setting that initiated the new Low Dose Radiation Research Program. These historical summaries will not be reviewed in detail here but will be covered briefly to provide some background material.

The written history of radiation began with three nearly simultaneous events around the end of the 19th century. The nuclear era opened with Roentgen's discovery of X rays in 1895, Antoine-Henri Becquerel's observation in 1896 that uranium salts emit an invisible penetrating radiation, and the Curies' isolation of radium in 1898. Soon after the discovery of radiation, scientists became aware that it could cause biological damage and therefore the amount of exposure needed to be quantified, evaluated, and controlled. Evidence of such damage was established when Becquerel developed skin lesions from radium carried in his pocket. Injury to the reproductive organs was observed in 1903, followed closely by impairments in tissues that produce blood cells. In 1927 an early geneticist, H. J. Muller, found that X rays induced mutations in fruit flies. Bone cancer was observed in 1929 in workers who painted radium dials on clocks. These health problems triggered many animal studies to understand the dramatic biological effects induced by high doses of radiation and stimulated a rapid increase in radiation research. Over the next several decades, many advances occurred in understanding radiation's potential for inducing genetic effects and cancer.

Stimulated by World War II, research in physics also increased rapidly, culminating in 1945 with the explosion of the first atomic bomb in Alamogordo, New Mexico. The devastating use of atomic bombs in Japan to end World War II and the tragic acute effects of intense radiation exposure resulted in unprecedented public interest and concern over such adverse health consequences.

In 1946 Congress created the AEC, an independent civilian agency that took over the research programs associated with radiation exposure. A large research and educational effort begun at that time has continued under ERDA and DOE. The national laboratories, which were established to develop the atomic bomb, played a major role in defining the biological effects of ionizing radiation. Related research also has been conducted in major universities throughout the world.

More than 100,000 people were killed in 1945 by the A-bombs and the resulting radiation in Hiroshima and Nagasaki. Many years later, survivors continue to provide the major source of data used to estimate the risk for radiation-induced health effects following a single high-level exposure. Initiated within 5 years after the bombs were dropped, follow-up studies of the health status of survivors have continued to the present. During the first decade after exposure, the survivor population experienced a higher incidence of leukemia, followed by a significant increase in the frequency of solid tumors. In this population, there were over 450 cancer cases or about 5% more than would have developed without the radiation exposure.

Animal and Human Studies

Experimental animals have been used to estimate both the genetic and cancer risks associated with radiation exposure. Begun in 1947 by Liane and William Russell, the "megamouse" study at the Clinton Laboratories (later Oak Ridge National Laboratory) exposed hundreds of thousands of mice to radiation and measured the induction of mutations in their offspring. A cornerstone of mammalian radiation genetics, this work has helped place the risk of genetic disease in proper perspective. Radiation-induced genetic risk was found to be small relative to the cancer risk.

Life-span studies in rodents and dogs determined the risk from both external radiation exposure and the deposition of radioactive material into the body. Internally deposited radioactive materials became a major health concern because of fear about fallout from nuclear testing. This fear also was associated with the potential release of radioactive materials from nuclear reactors used to generate electricity.

In the 1950s, the beagle was selected for study in a large coordinated research effort among national and specialty laboratories and university scientists. Research was conducted at the University of California at Davis to estimate the health risk of ingested radioactive materials such as 224Ra and 90Sr. Strontium-90 is a radioisotope of great concern for nuclear power and fallout. To estimate the risk to humans exposed to these materials, the studies combined bone-cancer data from radium-dial painters with cancer data from dogs. University of Utah scientists, seeking to establish comparative toxicity ratios, injected dogs and rodents with nuclear fuel cycle isotopes such as 239Pu, 241Am, and 224,226Ra. Information from these human and animal studies provided a basis for predicting risk for humans exposed to 239Pu and 241Am.

During the late 1950s and 1960s, researchers at Argonne National Laboratory conducted studies on dogs and rodents to define the influence of 90Sr and chronic gamma-ray exposure on cancer induction, especially leukemia. Using a range of exposure protocols and dose levels, scientists at Pacific Northwest Laboratory and Lovelace Inhalation Toxicology Research Institute studied the health effects of inhaled radioactive materials. These extensive large-animal studies addressed such important problems as the "hot-particle" hypothesis. This hypothesis, which suggested that a single radioactive particle of 239Pu or 241Am had a very high probability of causing cancer, was disproved. These long-term studies, conducted over a span of more than 30 years, provided valuable input into the setting of radiation standards for internally deposited radioactive materials. They were especially instructive for isotopes, for which there were limited or no human data.

The study of radon in homes also was conducted under DOE funding. Radon, a high-LET alpha emitter, represents the major environmental radiation exposure. The mechanistic understanding of the radiation dose delivered by radon, the importance of radon in the induction of lung cancer, and the risk for lung cancer following exposure to low levels of radon were studied and characterized. These data were linked to those on the induction of lung cancer in uranium miners, who had elevated occurrences of lung cancer relative to the general population. As long-term animal studies reached their goals and established the risk for radiation-induced cancer from internally deposited radioactive material, they were phased out. Funding for these large-animal studies, as well as many other areas in radiation biology, decreased dramatically between 1970 and 1999.

Cellular and Molecular Studies

Following the development of new methods for growing cells in tissue culture, animal and human studies emphasized the effects of radiation on cellular systems. During the period when radiation research was at a low ebb, many of the studies that were conducted focused on events at the cellular level to define the toxic effects of radiation and the genetic and cytogenetic basis for radiation-induced disease. This research greatly enhanced the understanding of radiation's interaction with cells and tissues to produce changes involved in late-occurring diseases such as cancer.

Rather than using whole animals to determine the number of cancers produced, more mechanistic research was applied to learning how cancer develops. Such studies laid the scientific foundation for interest in the genetic basis of human disease, and tools developed in this research helped justify DOE's launching and funding in 1986 of the Human Genome Initiative, later called the Human Genome Program (HGP). Research conducted in the HGP was essential for the development of the Low Dose Radiation Research Program. [A brief history of DOE's role in developing the HGP is on the DOE Web site at http://www.er.doe.gov/production/ober/hug_top.html]

Low Dose Program

The studies outlined above show that radiation biology has a rich history of research. In recent years, major scientific advances have been made in both cellular and molecular biology, particularly in the genome programs. Recognizing the importance of applying these new tools and techniques to address the health effects of low levels of ionizing radiation, in 1998 Congress requested that DOE initiate a research program to establish risk-assessment standards and guidelines. These standards would be based on a strong scientific and mechanistic foundation rather than on the extrapolation of responses seen at high doses. Funding for the Low Dose Radiation Research Program was included in the Energy and Water Development Appropriations Act in 1998.

On June 1–2, 1998, a subcommittee drafted a research plan that was presented to the Biological and Environmental Research Advisory Committee (BERAC) and rewritten by a smaller committee to incorporate BERAC's suggestions. This plan was used by the DOE Office of Biological and Environmental Research (OBER) to draft a call for proposals that was issued in the Federal Register with an application deadline of April 13, 1999. From this call over 100 projects were peer reviewed, and 43 were selected for funding at national and international laboratories and universities.

The program's first contractors' meeting was held November 10–12, 1999, to evaluate the current program, plan its future directions, and focus the research toward standard setting. The meeting, which was structured to optimize interaction and input from all attendees, included members of the scientific community, regulatory agencies, national and international review committees, general public, and special interest groups. At the end of the contractors' meeting, a program advisory group convened for the first time. Members of this group were selected from a wide range of backgrounds, including the public sector and different fields of science, to provide guidance and direction to DOE OBER. The first committee chairman is Dr. Sharon Friedman, Iacocca Professor and Director of Science and Environmental Writing Program at Lehigh University.

The Low Dose Radiation Research Program had its second and third contractors meetings in 2001 and 2002 and continue to fund research. The research areas of the dynamic program have changed from single cell studies to those of more complex tissue and systems. These studies can better evaluate the role of signally pathways, cell/cell communication and cell/matrix interactions on the risk of cancer following low-doses of radiation.

Efforts are being made to study the shape of the dose-response relationship and to evaluate the usefulness of the mechanistic studies on risk assessment.

Selected Dates

1895 Roentgen discovers X-rays

1901 X-rays shown to be lethal

1902 X-rays shown to be harmful to the mammalian fetus

1913 Geiger unveils radiation detector

1938 Hahn first to split uranium atom

1942 Manhattan project formed to build atomic bomb

1943 Southam and Erlich introduce the term "Hormesis"

1945 Atomic bombs dropped on Japanese cities

1951 First atomic test in Nevada; fallout reaches New England in two days

1952 First breeder reactor built

Great Britain explodes first atomic bomb

1954 Public Law 83-703 authorizes AEC to conduct research on the biological effects of ionizing radiation

1956 National Academy of Sciences issues report asserting no safe threshold for radiation exposure

1969 Bloom paper concludes all exposure to high-energy ionizing radiation produces damage

1972 BEIR I report recommends linear model for estimating radiation risks

UNSCEAR VI report questions validity of linear model for estimating radiation risks

1979 Nuclear power plant at Three Mile Island, PA experiences meltdown

1981 Luckey revives issue of hormesis as it relates to radiation

1986 Nuclear power plant at Chernobyl, Ukraine experiences meltdown

1996 President's Advisory Committee publishes report "The Human Radiation Experiments"

1998 Congress directs DOE to initiate Low Dose Radiation Research Program (LDRRP)