National Academies Press: OpenBook
« Previous: 3. Cellular and Molecular Considerations
Suggested Citation:"4. Animal Studies." National Research Council. 1998. Health Effects of Exposure to Low Levels of Ionizing Radiations: Time for Reassessment?. Washington, DC: The National Academies Press. doi: 10.17226/6230.
×

CONCLUSIONS

Considerable progress is being made toward understanding the mechanisms that lead to the formation of chromosomal aberrations and the induction of mutations. It appears that DNA DSBs and complex damage are the critical lesions, but there is no consensus. Both end points can readily be associated with carcinogenesis, so it is relevant that dose-effect relationships for both end points are curvilinear with a strong indication of linearity at low doses. Both end points also show similar behavior with respect to decreasing dose rate and radiation quality. It is also relevant that measurements of dicentric yields at doses less than 20 mGy do not, and probably will not, provide experimental data that will define the shape of the dose-effect relationship at low doses. The shape of the dose-effect curve will need to be inferred from a deeper understanding of the mechanisms involved in the formation of aberrations and the induction of mutations.

4
ANIMAL STUDIES

Experimental studies of radiation carcinogenesis in animals have been used to develop biologic principles applicable to human risk estimates and to the development and testing of mechanistic models. Long-term animal studies conducted from the 1950s through the 1980s provided a substantial amount of quantitative information on dose-response relationships for a number of radiation-induced tumors alter gamma irradiation and on the influence of dose rate and fractionation on these relationships (NCRP 1980; UNSCEAR 1988, 1993). Studies have also focused on the carcinogenic effects of fission-spectrum neutrons (NCRP 1980, 1989; UNSCEAR 1988). These studies were essentially complete before 1990 and were, for the most part, available to the previous BEIR committee.

The major conclusions derived from the studies were as follows:

  • The dose-response relationship for cancer induction after gamma irradiation could generally be described by a linear-quadratic function.

  • Lowering the dose rate resulted in a diminution of the carcinogenic effects at high total doses as a result of a reduction in the quadratic component; the dose-response relationship was linear over a wide range of total doses.

  • The linear slope of the response at low doses was similar to that for the linear portion of the linear-quadratic function after high-dose-rate exposures.

Suggested Citation:"4. Animal Studies." National Research Council. 1998. Health Effects of Exposure to Low Levels of Ionizing Radiations: Time for Reassessment?. Washington, DC: The National Academies Press. doi: 10.17226/6230.
×

Based on studies of the irradiation of animals with neutrons a linear dose-response relationship was observed for the induction of most tumors at doses of 0.0 to 0.2 Gy; it was followed by a plateau or bending over of the curve at higher doses. Reducing the dose rate either had no effect on the dose-response relationship in the low-dose range or, in some instances, it increased the response per unit of dose. The differences in shape of the dose-response curve for cancer induction by gamma rays and neutrons resulted in the assignment of rather high relative-biologic-effectiveness (RBE) values for cancer induction at low doses. All the above data are consistent with biophysical models of radiation effects applicable to a variety of other end points, including radiation-induced cell-killing, induction of chromosomal aberrations, and radiation-induced mutation. These models predicted linear-quadratic dose-response relationships and reduced effectiveness per unit dose of low-LET radiation at low doses and low dose rates (Kellerer and Rossi 1972; Ullrich and Storer 1979).

Because of their consistency with projections from biophysical models of radiation effects, the combination of dose response and dose-rate data for tumor induction obtained from animal studies and data on various end points in animal and human cells provide substantial support for the application of a dose and dose-rate effectiveness factor (DDREF) in the estimation of cancer risks in human populations at low doses and low dose rates (UNSCEAR 1988; NRC 1990; ICRP 1991).

The high RBEs for neutrons at low doses (also predicted on the basis of biophysical models) observed in animal studies was important in the modification of quality factors used in risk estimates for neutrons (ICRP 1963). The neutron data are also likely to be important in the future analysis of data on atomic-bomb survivors, inasmuch as a portion of the dose that they received was from neutrons, but the contribution is still being evaluated.

After analysis of the results of long-term studies, it was recognized that understanding of radiation risks at low doses would not be improved by attempting to measure the effect at low doses on animals, but rather would require a better understanding of the underlying mechanisms. As a result, experimental studies of carcinogenesis since the last BEIR report have focused on mechanisms and on the cellular and molecular events involved in neoplasia. Over this time, the understanding of molecular events involved in the carcinogenesis process, in general, has increased dramatically. It is now clear that cancer development entails alterations in multiple genes that are involved in the regulation of progression through the cell cycle, cell growth and differentiation, and cell death, and in genes that are involved in the maintenance of genomic fidelity. A number of investigators have now demonstrated that alterations in genes that control genomic fidelity can play a major role in the early events leading to cancer by conferring a mutator phenotype on the affected cells (Loeb 1991, 1997). Cells with alterations in other critical genes later arise as a result of clonal selection.

Suggested Citation:"4. Animal Studies." National Research Council. 1998. Health Effects of Exposure to Low Levels of Ionizing Radiations: Time for Reassessment?. Washington, DC: The National Academies Press. doi: 10.17226/6230.
×

The long latent periods and the complexity of the neoplastic process have been formidable obstacles in identifying specific radiation effects that initiate the sequence of events in cancer development at the cellular and molecular level. However, some generalizations can be made. Both in vitro and in vivo studies have amply demonstrated that radiation acts principally at the level of initiation of the carcinogenic process and is considerably less effective in promoting already-initiated cells or in influencing the progression of neoplasia (Han and Elkind 1982; Hill and others 1987, 1989; Bowden and others 1990). Mechanisms by which radiation initiates carcinogenesis are still poorly understood. It is generally accepted that the carcinogenic effects of radiation are related to its clastogenic and mutagenic effects, but no causal relationship between changes in specific genes and the development of radiation-induced cancer has been established. In fact, initiation frequencies derived from recent studies that used in vivo/in vitro models for radiation-induced cancer (with initiation frequencies around 10-2 initiated cells per Gy) are not compatible with a target whose size is limited to a specific gene or even a family of several genes (Kennedy 1985; Gould and others 1987; Selvanayagam and others 1995).

Rather, those frequencies indicate that the cellular target for the initiation of carcinogenesis after irradiation constitutes a substantial fraction of the entire genome. Such results have led to new approaches in the exploration of possible mechanisms of radiation carcinogenesis. A major focus of current research is on the role of radiation-induced genetic instability in carcinogenesis.

CONCLUSIONS

Over the next few years, two closely linked approaches using animal models of carcinogenesis are likely to contribute to the understanding of the mechanisms of radiation-induced cancer. Researchers conducting this new generation of animal studies are taking advantage of the current rapid development of molecular genetics. A number of laboratories have begun to use genetically engineered mice with alterations in specific genes to determine the influence of these genes (such as ATM, BRCA1, and BRCA2) on susceptibility to radiation-induced cancer. At the same time, other laboratories are focusing on the inherent differences in susceptibility to radiation-reduced cancer among different mouse strains and beginning to dissect genes involved in controlling susceptibility. Both approaches should yield useful information on susceptible subpopulations and might into the underlying lesions and the processing of these lesions, which initiate carcinogenesis after exposure to ionizing radiation. Progress on both fronts should be substantial over the next 4-5 years and results of relevance to risk estimates are expected to be available for an important BEIR VII phase-2 study.

Suggested Citation:"4. Animal Studies." National Research Council. 1998. Health Effects of Exposure to Low Levels of Ionizing Radiations: Time for Reassessment?. Washington, DC: The National Academies Press. doi: 10.17226/6230.
×
Page 30
Suggested Citation:"4. Animal Studies." National Research Council. 1998. Health Effects of Exposure to Low Levels of Ionizing Radiations: Time for Reassessment?. Washington, DC: The National Academies Press. doi: 10.17226/6230.
×
Page 31
Suggested Citation:"4. Animal Studies." National Research Council. 1998. Health Effects of Exposure to Low Levels of Ionizing Radiations: Time for Reassessment?. Washington, DC: The National Academies Press. doi: 10.17226/6230.
×
Page 32
Next: 5. Radiobiological Principles and Risk Modeling »
Health Effects of Exposure to Low Levels of Ionizing Radiations: Time for Reassessment? Get This Book
×
Buy Paperback | $47.00 Buy Ebook | $37.99
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

The US Environmental Protection Agency Office of Radiation and Indoor Air asked the National Research Council to evaluate whether sufficient new data exist to warrant a reassessment of health risks reported in Health Effects of Exposure to Low Levels of Ionizing Radiations (BEIR V) in 1990. To respond to this request, the National Research Council assembled the Committee on Health Risks of Exposure to Low Levels of Ionizing Radiations. The work of the committee was conducted in what was called the BEIR VII phase-1 study. To assist the committee during its deliberations, various scientists were consulted for advice, and a workshop on the impact of biology on risk assessment was held in collaboration with the Department of Energy Office of Health and Environmental Research. The intent of the workshop was to address the implications of new understanding of the biologic basis of radiation injury and carcinogenesis for risk assessment.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    Switch between the Original Pages, where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

    « Back Next »
  6. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  7. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  8. ×

    View our suggested citation for this chapter.

    « Back Next »
  9. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!