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Suggested Citation:"2. Epidemiologic Investigations." 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.
×

2
EPIDEMIOLOGIC INVESTIGATIONS

This chapter considers epidemiologic evidence that has accumulated since the BEIR V report (NRC 1990). The first section identifies epidemiologic studies of low-LET ionizing radiation that have appeared since the BEIR V report and summarizes their results. The second section discusses recent developments in methodology, and the third the relevance of new data to the possible utility and function of a BEIR VII phase-2 committee. The final section discusses the radioepidemiologic tables.

NEW EPIDEMIOLOGIC RESULTS

Table 1 summarizes some of the more important epidemiologic data that have been published since 1990, when the BEIR V report appeared, or that were not available to the BEIR V committee. The table includes studies that the current committee expects to produce new and useful epidemiologic data during the term of a BEIR VII phase-2 committee. Table 1 is intended not to be exhaustive, but rather to be a guide to the new epidemiologic data that have become available since 1990, and are expected to become available in the next few years.

Suggested Citation:"2. Epidemiologic Investigations." 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.
×

Table 1. Summary of epidemiologic studies of low LET ionizing radiation and cancer since 19901

STUDY

REFERENCE

TYPE OF STUDY

SERIES

SEX

NO. IN STUDY

FOLLOW-UP

PERIOD

CANCER SITES REPORTED

Ankylosing spondylitis patients

Weiss and others, 1994

Weiss and others, 1995

Cohort

Cohort

Mortality

Mortality

Male and Female

Male and Female

15,577

14,767

1935-1992

1935-1992

All cancer and multiple cancer sites

Leukemia

Atomic-bomb survivors

Preston and others, 1994

Thompson and others, 1994

Ron and others, 1995a

Cohort

Cohort

Cohort

Incidence

Incidence

Incidence

Male and Female

Male and Female

Male and Female

93,696

79,972

80,311

1950-1987

1958-1987

1958-1989

Leukemia, lymphoma, multiple myeloma

Multiple cancer sites (solid tumors)

Benign tumors of stomach, colon, and rectum

Atomic-bomb survivors

Pierce and others, 1996

Cohort

Mortality

Male and Female

86,572

1950-1990

Non leukemias, leukemia, and multiple cancer sites

Atomic-bomb survivors

Land and others, 1994a

Land and others, 1994b

Case control

 

Female

Cases: 196 Controls: 566

1955-1981

Breast cancer

Atomic-bomb survivors (in utero cohorts)

Canadian fluoroscopy

Delongchamp and others, 1997

Howe, 1995

Howe and McLaughlin, 1996

Cohort

Cohort

Cohort

Mortality

Mortality

Mortality

Male and Female

Male and Female

Female

17,601

64,172

31,917

1950-1992

1950-1987

1950-1987

Non leukemias, leukemia, and multiple cancer sites

Lung cancer

Breast cancer

Cervical cancer patients

Kleinerman and others, 1995

Cohort

Incidence

Female

86,193

1935-1990

Multiple cancer sites

Contralateral breast (Denmark)

Storm and others, 1992

Case control in cohort

 

Female

Cohort: 56,540 Cases: 691 Controls: 691

1943-1986

Breast cancer

Suggested Citation:"2. Epidemiologic Investigations." 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.
×

STUDY

REFERENCE

TYPE OF STUDY

SERIES

SEX

NO. IN STUDY

FOLLOW -UP

PERIOD

CANCER SITES REPORTED

Contralateral breast (US)

Boice and others, 1992

Case control in cohort

 

Female

Cohort: 4,109 Cases: 655 Controls: 1,189

1935-1987

Breast cancer

Fallout from Nevada Test Site

Kerber and others, 1993

Simon and others, 1995

Cohort

Case control

Incidence

Male and Female

Male and Female

2,473

Cases: 1,177 Controls: 5,330

1965-1986

1952-1981

Thyroid cancer and other thyroid disease

Leukemia

Massachusetts fluoroscopy

Davis and others, 1989

Boice and others, 1991

Cohort

Cohort

Mortality

Incidence

Male and Female

Female

13,385

4,940

1929-1986

1925-1986

Multiple cancer sites

Breast cancer

Multiple diagnostic xrays of scoliosis patients

Hoffman and others, 1989

Cohort

Incidence

Female

1,030

1935-1986

Breast cancer

Nuclear industry workers (combined analysis)

Cardis and others 1994

Cardis and others, 1995

Cohort

Cohort

Mortality

Mortality

Male and Female

Male and Female

95,673

95,673

1943-1988

1943-1988

Multiple cancer sites

Solid tumors and leukemia

Nuclear workers at Mayak Production Association

Koshurnikova and Shilnikova, 1996

Cohort

Mortality

Male and Female

18,879

1948-1993

Lung cancer and leukemia

Pelvic radiotherapy for benign gynecologic disease

Inskip and others, 1993

Cohort

Mortality

Female

12,955

1929-1985

Multiple hematopoietic cancers

Pooled analysis of external radiation and thyroid cancer

Ron and others, 1995b

Cohort Case control

Incidence

Male and Female

120,000

1926-1990

Thyroid cancer

Radiation treatment for benign head and neck conditions (benign thyroid tumors)

Wong and others, 1996

Cohort

Incidence

Male and Female

544

1939-1991

Benign thyroid nodules

Radiation treatment for

Schneider and others, 1993

Cohort

Incidence

Male and

4,296

1939-1990

Thyroid cancer and

Suggested Citation:"2. Epidemiologic Investigations." 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.
×

STUDY

REFERENCE

TYPE OF STUDY

SERIES

SEX

NO. IN STUDY

FOLLOW-UP PERIOD

CANCER SITES REPORTED

benign head and neck conditions (thyroid cancer and thyroid nodules)

 

 

 

Female

 

 

nodules

Radiation treatment for breast cancer

Curtis and others, 1992

Case control in cohort

 

Female

Cohort: 82,700 Cases: 90 Controls: 264

1973-1985

Leukemia

Radiation treatment for peptic ulcer

Griem and others, 1994

Cohort

Mortality

Male and Female

3,609

1937-1985

Multiple cancer sites

Radiotherapy for Hodgkin disease (breast cancer)

Hancock and others, 1993

Cohort

Incidence and Mortality

Female

885

1961-1990

Breast cancer

Radiotherapy for Hodgkin Disease (gastrointestinal cancer)

Birdwell and others, 1997

Cohort

Incidence and Mortality

Male and Female

2,441

1961-1993

Multiple cancer sites (gastrointestinal only)

Radiotherapy for metropathia hemorrhagic anemia

Darby and others, 1994

Cohort

Mortality

Female

2,067

1940-1991

Multiple cancer sites

Radiotherapy for pituitary adenoma

Brada and others, 1992

Cohort

Incidence

Male and Female

334

1962-1986

Multiple cancer sites (solid tumors only)

Radiotherapy for skin, hemangioma in childhood

Furst and others, 1990

Case control in cohort

 

Male and Female

Cohort: 14,647 Cases: 94 Controls: 359

1920-1986

Multiple cancer sites (solid tumors)

Radiotherapy for thymus enlargement

Shore, 1990

Cohort

Incidence

Male and Female

7,450

1953-1989

Skin cancer

Radiotherapy for uterine bleeding

Inskip and others, 1990

Cohort

Mortality

Female

4,153

1925-1984

Multiple cancer sites

Tinea capitis (Israel)

Ron and others, 1989

Ron and others, 1991

Cohort

Cohort

Incidence

Incidence

Male and Female

Male and Female

10,834

27,060

1950-1986

1950-1980

Thyroid cancer and other thyroid disease

Melanoma, other skin cancer and benign skin tumors

Suggested Citation:"2. Epidemiologic Investigations." 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.
×

STUDY

REFERENCE

TYPE OF STUDY

SERIES

SEX

NO. IN STUDY

FOLLOW-UP PERIOD

CANCER SITES REPORTED

Women treated for infertility

Ron and others, 1994

Cohort

Mortality

Female

816

1925-1991

Multiple cancer sites

STUDY

REFERENCE

DESCRIPTION

In utero exposure

Doll and Wakeford 1997

A review of case-control and cohort studies of childhood cancers.

1Table 1 is a summary of the more important epidemiologic data that have been published since the 1990 publication of the BEIR V report or that are expected to provide new and useful data during the 3-year term of the proposed BEIR VII phase-2 study. Although not exhaustive, the list should serve as a guide to some of the pertinent new and upcoming epidemiologic data on the subject.

The following list presents categories where additional data have become available since the BEIR V report.

  1. Nonleukemia cancer mortality. In a recent mortality update from the Japanese atomic-bomb survivor Life Span Study cohort, Pierce and others (1996) modeled mortality to the end of 1990. This extension of the existing data added 10,500 persons to the cohort with DS86 doses and 1,227 nonleukemia cancers to the mortality data. The increase in the number of cancer deaths for analysis was particularly noticeable among the members of the cohort who were under the age of 20 years at the time of the atomic bombings; in this category the number of deaths increased from 545 to 889 in the most recent 5-yr period of follow-up. The primary focus of this analysis was on modeling the risk of the nonleukemia cancers as a single entity, in that the authors concluded that the apparent variation in site-specific cancer risks could often not be distinguished from random variation. With that approach, the preferred risk model was a linear excess-relative-risk model; the excess relative risk (ERR) per sievert was lower for men (0.375) than for women (0.774) and was reduced with age at exposure by the same exponential factor for men and women.

  2. Mortality in the British series of patients treated with x-rays for ankylosing spondylitis. This data has been updated (Weiss and others 1994, 1995).

  3. Mortality among radiation workers. A combined analysis of risk estimates can be compared with those obtained at higher doses from other series (Cardis and others 1994, 1995).

Suggested Citation:"2. Epidemiologic Investigations." 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.
×
  1. Site-specific analyses:

    • Leukemia: includes a downwind study (Preston and others 1994; Weiss and others 1994; Simon and others 1995).

    • Breast cancer: possibility that sensitive groups might show up in form of high excess relative risk for early-onset cancer, new evidence on risk of exposure to radiation for various reproductive histories, and new data on transfer of risk between populations with different baseline risks (Land and others 1994a,b; Tokunaga and others 1994; UNSCEAR 1994; Land 1995a).

    • Lung: Cancer evidence relating to dose and dose rate effectiveness factor (DDREF) (Howe 1995).

    • Gastrointestinal cancers: longer follow-up periods by studies such as Birdwell and others (1997).

    • Lymphatic and hematopoietic cancers other than leukemia (Thompson and others 1994).

    • Lung, salivary gland, skin, and central nervous system cancers: evidence of specificity of radiation-related risk in terms of histologic subtype (Land and others 1993, 1996; Land 1995b; and data from the Radiation Effects Research Foundation).

    • Thyroid cancer (including that caused by Iodine-131): combined analysis of childhood exposure to x rays and gamma rays (Kerber and others 1993; Ron and others 1995b); given the recent National Cancer Institute report (National Cancer Institute 1997) estimating thyroid doses to the US population from Iodine-131 in fallout from the Nevada Test Site, BEIR VII phase-2 will be expected to address the issue of thyroid cancers induced by Iodine-131.

    • Other cancers (including atomic-bomb incidence series not addressed above).

    • Noncancer outcomes.

  1. New data on radiation-related risk in patients known to be genetically susceptible to cancer:

    • Retinoblastoma patients (Tucker and others 1987; Eng and others 1993; Hawkins and others 1996; Wong and others 1997): evidence that ERR for bone sarcoma (Tucker and others 1987) and bone sarcoma and soft-tissue sarcoma (Wong and others 1997) increases with increasing therapeutic radiation dose to the tumor site with dose-specific relative risks comparable with those in survivors of other childhood cancers treated with radiation. Given evidence that baseline rates of bone and soft-tissue sarcoma are orders of magnitude higher among survivors of heritable retinoblastoma, this suggests that the excess rate (or absolute risk) of radiation-related cancer is also orders of magnitude higher among heritable retinoblastoma patients, and that, therefore, these patients constitute a genetic subpopulation highly susceptible to radiation-related bone and soft-tissue sarcoma.

Suggested Citation:"2. Epidemiologic Investigations." 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.
×
  • Swift and others (1991) hypothesis regarding the protein mutated in ataxia telangiectasia (ATM) and breast cancer and increased susceptibility to radiation-related breast cancer.

  • International Commission on Radiological Protection study group on genetic susceptibility to radiation-related cancer (Cox and others in press).

ADVANCES IN METHODOLOGY

In addition to new data, there have been advancements reported for analytical methods including:

  • Adjustment for bias due to random errors in dosimetry (Pierce and others 1990; Gilbert 1998).

  • Systematic presentation of sources of uncertainty in various components of risk estimates and their combined influence (NCRP 1997).

CONSIDERATIONS FOR A BEIR VII PHASE-2 COMMITTEE

From the epidemiologic point of view, the prime motivation for a BEIR VII phase-2 study is the substantial increase in the mount of epidemiologic data that have been published since the BEIR V report. That applies particularly to some subjects on which data have previously been sparse, for example, cancer mortality in those exposed as children to whole-body irradiation. The new data permit the development of richer risk models and alternatives to models presented in the BEIR V report. Furthermore, there have been methodologic developments, such as the incorporation of dose measurement errors in fitting risk models.

The primary purpose of a BEIR VII phase-2 study would be to present a balanced overview of the new epidemiologic evidence and in particular to synthesize results from all the relevant studies, giving appropriate weight to the value of each study.

The committee could develop a generalized strategy for risk modeling and illustrate it with specific examples. Ideally, the strategy would be applied to all relevant exposure circumstances and outcomes; if this task were too onerous, the committee could at least develop a generalized approach that could be applied by others to other relevant situations.

In a general strategy for modeling, models should provide a good fit to the empirical epidemiologic data, be biologically plausible, be readily understood by the scientific community in general (which argues in favor of simple, rather than complex, models), and take into account all the relevant epidemiologic and biologic data.

Suggested Citation:"2. Epidemiologic Investigations." 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.
×

Obviously some specific issues would have to be considered in such models, including the dose and dose rate effectiveness factor (DDREF) and the shape of the dose-response curve, the temporal distribution of risk after exposure, and the interaction of radiation with other risk factors and with other possible modifying factors, such as sex, age at exposure, attained age, and population differences.

Approaches to the modeling process could include:

  • Fitting of purely empirical models to original data from studies or combined studies.

  • Fitting of purely empirical models with meta-analysis; this is relatively underdeveloped and might be particularly useful when there are a number of studies of a particular outcome such as esophageal cancer.

  • Fitting semiempirical biologically based models to epidemiologic data to improve understanding of the biologic basis of some of the empirical effects observed.

  • Fitting (and testing) of simple models now being used in radiation protection, such as linear nonthreshold models in which the estimated relative risk at 1 sievert might depend upon age at exposure but remains invarient over time after exposure (with a minimal latent period) or an otherwise similar quadratic (linear-quadratic) model with an appropriate DDREF and particular attention given to the principal contending alternatives. Such alternatives include hormesis, threshold models, the Kellerer-Barclay model, and supralinear models.

Committee members will be selected who will be able to access original data from completed or ongoing studies, or who will be able to directly contact the original investigators.

RADIOEPIDEMIOLOGIC TABLES

The NIH radioepidemiologic tables, mandated by Congress, were developed to meet a perceived need for an objective way to present and evaluate compensation claims for adverse health outcomes, such as cancer, that might be related to radiation exposure. The concept is simple: given a documented history of exposure to radiation d1, . . ., dk at ages a1, . . ., ak and a cancer diagnosis at age A, compute the ERR of a cancer at that age. The ''probability of causation" (NIH 1985), or "assigned share" (NRC 1984), computed as ERR/(1 + ERR), is an informed quantitative estimate of the proportion of similar cancers at that age, in a large population of similar people with similar exposure histories that, would not have occurred in the absence of exposure, that is, the proportion of such cancers attributable to radiation. The ERR might depend on exposure history and age at diagnosis, but also on sex, time from each exposure until diagnosis, history of exposure to other carcinogens (such as tobacco), and other risk modifiers (such as reproductive history). Thus, all relevant factors known to influence radiation-related risk can be incorporated, as can various sources of uncertainty.

Suggested Citation:"2. Epidemiologic Investigations." 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 6
Suggested Citation:"2. Epidemiologic Investigations." 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 7
Suggested Citation:"2. Epidemiologic Investigations." 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 8
Suggested Citation:"2. Epidemiologic Investigations." 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 9
Suggested Citation:"2. Epidemiologic Investigations." 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 10
Suggested Citation:"2. Epidemiologic Investigations." 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 11
Suggested Citation:"2. Epidemiologic Investigations." 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 12
Suggested Citation:"2. Epidemiologic Investigations." 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 13
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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.

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