## Potential Health Consequences from Exposure of the United States Population to Radioactive Fallout

Contents: This chapter provides a brief summary of what is currently
known about the health consequences of low-level radiation exposures.
The feasibility of analyzing the risk of cancer and non-cancer health
outcomes resulting from fallout is discussed. Methods for estimating the
number of cancers expected to occur in the United States population as a
result of fallout exposure are illustrated for total cancer and leukemia
using dose estimates provided in Chapter 3. Issues relating to the
uncertainty in these estimates are described.

### Introduction

Health effects of radiation exposure have been extensively studied and
documented. These effects are diverse and vary with radiation doses.
From the estimated doses presented in Chapter 3, it is clear that the
health effects of interest with regard to fallout radiation are those
that can be attributed to relatively low radiation exposure; the
estimated thyroid dose averaged over the population of the entire
country is about 10 mGy while the average bone-marrow dose is about 2
mGy. For most individuals, the doses are expected to have been less than
1,000 mGy for the thyroid gland and less than 100 mGy for bone marrow.
At these dose levels the most important health effect is likely to be
cancer, which typically occurs many years after the exposure. On an
individual basis, the risk of developing excess cancers as a consequence
of exposure to low-dose radiation is considered small. However, on a
population basis, widespread exposure of large numbers of people to
fallout may potentially lead to a large number of excess cancers and
hence a public health problem. One goal of this chapter is to
familiarize the reader with the weight of evidence linking cancer with
low radiation dose and to evaluate the magnitude of the impact of
fallout radiation on the cancer burden of the United States population.

In addition to cancer, some non-cancer diseases have been reported to
occur as late effects of radiation. Some of these are of neoplastic in
nature, though benign in their behavior (benign tumors). Recent data
from the Japanese atomic bomb survivor studies suggest that the risk of
certain diseases of non-neoplastic nature such as heart diseases may
also be increased after exposure to radiation; however, the magnitude of
the risk is considerably uncertain, especially at low dose levels, and
plausible biological mechanisms involved are unclear (Shimizu et al.
1999; Kodama et al. 1996).

Quantifying the risk of cancer and non-cancer health effects depends on
the availability of information about the disease-exposure relationship
from high quality observational studies (e.g., epidemiologic studies).
Using this information, several standards-setting organizations and
scientific committees have already developed mathematical models for
estimating cancer risks to populations exposed to specified doses of
radiation (NAS 1990; ICRP 1991; NRC. 1993; EPA 1994; UNSCEAR 1994,
2000). However, much less has been done to quantify non-cancer disease
risk. Thus, while there is little question that estimates of the
fallout-related lifetime risk of cancer for the United States population
can be obtained if dose estimates are available, only a qualitative
assessment of risk can be provided for non-cancer health effects. Cancer
risk estimates are appropriately represented by a range of numbers in
order to account for the large uncertainty in these estimates.
Therefore, the question remains as to whether or not these uncertain
estimates of risk will be useful for developing public health policy.

This chapter provides an overview of what is currently known about the
relationship between radiation exposure and cancer and other
late-occurring health effects. Two issues fundamental for understanding
this relationship between radiation and health effects, dose response
and time response patterns of the risk, are examined. Additionally, this
chapter provides approximate estimates of cancer risk resulting from
exposures from atmospheric nuclear weapons testing and indicates the
degree of uncertainty in these estimates. While the main emphasis of
this chapter is on cancer as a health effect of radiation exposure,
non-cancer health effects are also discussed.

### Health Effects of Ionizing Radiation

The most relevant sources of scientific information on the health
effects of ionizing radiation are the large number of epidemiological
studies that have been conducted to date. One of the most important
investigations of radiation health effects is the epidemiological study
of a large cohort of Japanese atomic bomb survivors. The continuing
follow-up of this cohort provides information on long-term health risks
associated with radiation exposure and is the major contributor to
quantitative risk estimates. Others include studies of occupational
groups such as uranium miners and nuclear production workers,
populations exposed to radiation as a result of living in areas
contaminated with fallout from nuclear weapons tests, and adults and
children exposed for medical (diagnosis or treatment of diseases) and
other reasons. Data on medically exposed populations have contributed
substantially to estimating risks of cancers of specific sites,
particularly breast and thyroid, and data on underground miners are the
main basis for estimating risks of lung cancer from exposure to radon.
However, the atomic bomb data are by far the most important source of
information for developing quantitative estimates of risks from
radiation exposure.. Laboratory studies of animals, microorganisms, and
cells grown *in vitro* also provide information helpful in understanding
the mechanisms of radiation-induced diseases. The data accrued from new
or continuing epidemiological and laboratory studies are regularly
reviewed and updated by international and national organizations such as
the United Nations Scientific Committee on the Effects of Atomic
Radiation (UNSCEAR), the International Commission on Radiological
Protection (ICRP), the National Academy of Sciences (NAS) and the
National Council on Radiation Protection and Measurements (NCRP).
Reports from these organizations provide comprehensive information on
health effects of radiation. The overview presented in this chapter is
largely drawn from conclusions and summaries derived by these national
and international expert groups and are supplemented by additional
literature considered relevant for this report.

#### Cancer (Malignant Tumors)

Before discussing radiation-induced cancer risk, a brief overview of the
possible biological basis of cancer formation is relevant. It is
currently thought that cancer (and possibly some other late effects)
reflects DNA damage (mutations). The exact mechanisms by which radiation
(or any other cancer-causing agent) leads to cancer are not completely
understood. However, it is generally believed that the development of
cancer requires a series of mutations accumulated over many years. Some
of these mutations occur spontaneously. Others result from exposure to
any of a wide range of mutagens, including radiation. Since many years
may have to pass for an irradiated cell or its progeny to acquire
sufficient mutations to present itself as clinical cancer, it may take
years before excess cancers accountable to radiation exposure are
recognized. The process of incurring DNA mutations from radiation is
thought to be random in nature. Thus, the probability of cancer
resulting from radiation exposure is a function of the number of
affected cells and is dependent on radiation dose. The excess cancers
that arise as a result of radiation exposure, with or without
contributions from other agents, are not distinguishable from those
occurring due to other reasons. At present there are no established
biological markers that can characterize radiation-induced cancers.

As noted previously, conclusions and inferences about the cancer (and
other health) effects of radiation are drawn from statistical
associations obtained from epidemiological data. Results from laboratory
experiments are also considered to judge the biological basis or
plausibility of the epidemiological data. The principal feature of the
cancer risk associated with radiation is that the probability that a
person will develop cancer due to radiation exposure depends on such
factors as the dose received, age at exposure, attained age (or time
since exposure) and gender. The relationship of cancer risk to radiation
doses (dose response) is essential in estimating the risk at low doses,
and the time pattern of the risk associated with age is important in
projecting the resulting cancer increase in exposed populations.

The way excess cancer risk increases with an increasing radiation dose
is mathematically described by a dose response curve (dose response
function or model), and the shape of this curve is important in
estimating the risk at low dose levels. There are basic limitations in
estimating the cancer risk at low doses using epidemiological data. At
low doses, the cancer risk becomes so small relative to the background
risk that it may not be possible to find and study a large enough
exposed population to detect the small risk. Furthermore, the background
cancer rates often vary by amounts that are comparable to or even
greater than the low-dose radiation risk that the study intends to
detect. So even if a sufficiently large population were available, it
would not be possible to rule out the potentiality that biases may
actually explain the observed difference. Despite these limitations,
much progress has been made recently in estimating the cancer risk at
low doses.

Although the Japanese atomic bomb study is generally regarded as a high
dose study, about 80% of the survivors in this cohort received doses
that were less than 100 mSv (Pierce et al. 1996). Thus, substantial
information can be obtained on low-dose risk from this study. Moreover,
the atomic bomb survivor study has several important advantages over
other studies including size of the cohort (about 87,000 exposed persons
of both genders and all ages, who were exposed to a wide range of doses
distributed throughout the body), and a follow-up period of more than 5
decades. The dose response for solid cancers (cancers excluding leukemia
and other cancers of the blood and blood forming organs) obtained from
this cohort data is remarkably linear. In other words, the increase in
risk is directly proportional to the increase in dose. The data do not
suggest the existence of a threshold below which there is no excess risk
(Pierce et al. 2000). Unlike solid cancers, the relationship between
radiation dose and leukemia risk is non-linear (either linear-quadratic
or quadratic) indicating an increase in risk per unit dose at low dose
levels that is about half that at high dose levels.

Studies of nuclear workers have a potential of providing more direct
data on the cancer risk associated with protracted exposures to low
doses of radiation. However, because of very low doses, most of the
individual studies do not have adequate statistical power to detect
small effects. To overcome this problem, the International Agency for
Research on Cancer (IARC) carried out an international pooled analysis
of data from studies of nuclear workers in the United States, Canada and
the United Kingdom (Cardis et al. 1995). The combined cohort in this
analysis includes 95,000 people with a mean dose of 40 mSv and
represents over 2 million person-years of follow-up. A statistically
significant dose response was found for leukemia but not for other
cancers. The confidence intervals for both risks of leukemia and of
cancers other than leukemia are still considerably broad but indicate
consistency with risk estimates obtained from the atomic bomb survivors
exposed to single doses of radiation.

In general, two distinctly different time-response patterns - one for
leukemia and the other for solid cancers - are recognized. Acute
exposure to radiation is followed by the excess risk of leukemia,
beginning shortly after exposure, increasing with time, reaching its
peak 5-10 years after initial exposure, and then declining gradually
thereafter. The time-response pattern is strongly dependent on age at
exposure, and generally the younger the age at exposure, the steeper the
initial rise and faster the subsequent decline (Preston et al. 1994,
Pierce et al. 1996). Similar time response patterns are seen in
populations with protracted exposure. In contrast to leukemia, the
excess risk of solid cancer, starting 5-10 years after exposure,
increases gradually and continues to rise as the background cancer rates
increase with age. The latest data from the atomic bomb survivor cohort
suggest that the excess solid cancer risk may be persistent for many
decades after exposure and remain throughout life (Pierce et al. 1996).
The excess risk of solid cancer is also dependent on age at exposure for
most types of cancer; those exposed at younger ages have relatively high
risk compared to those exposed at older ages. How the cancer risk
behaves over time in relation to age at exposure, time after exposure,
and attained age is still not completely understood. More definitive
answers to this issue are expected from continued follow-up of the
atomic bomb survivors. Further discussion of the relationship between
radiation and some specific cancers follows. Radiation-related excess
risks have been observed for cancers of many parts of the body. Since
exposures to radiation from fallout result in higher doses for the
thyroid glands and bone marrow, thyroid cancer and leukemia (which
originates in bone marrow cells) are first discussed, followed by other
cancers.

##### Thyroid Cancer

Thyroid cancer is one of the less fatal forms of cancer (Ries et al.
2000). The excess risk of thyroid cancer associated with exposure to
external radiation (x-rays and gamma rays) has been widely studied and
is well established (Ron et al. 1995). Age at exposure is the most
important factor that modifies the radiation-induced risk: risk
decreases dramatically with increasing age at exposure. In the atomic
bomb studies, the excess thyroid cancer cases are primarily seen in
those who were exposed at ages less than 20 years (Thompson et al.
1994). The carcinogenic effect of radiation is prolonged and persists at
least 40 years after exposure during childhood. Although thyroid cancer
occurs 2-3 times more frequently in women than in men, men and women are
equally affected by radiation in terms of relative excess risks. In
absolute terms, however, this means that more women are afflicted with
thyroid cancer than men for a given amount of radiation.

In the case of fallout, internal exposure to ^131^I is a major concern,
but the internal exposure effect has been less extensively studied.
Studies of people who received ^131^I treatment for medical reasons
(non-cancer thyroid diseases) have not shown a demonstrable excess
thyroid cancer risk. However, this should not be interpreted to suggest
the lack of the carcinogenic potential of ^131^I because the large
majority of the study subjects were adults at the time of ^131^I
administration, not allowing inferences on childhood exposure. The
thyroid is more radiosensitive in children than in adults, possibly
because the young thyroid cells are rapidly growing (Williams 2002), or
because of differences in metabolism or concentration of radionuclides
(Mettler and Upton 1995). It is noteworthy that following the Chernobyl
accident, dramatic increases in childhood thyroid cancer cases were
reported in areas heavily contaminated with radioactive fallout
including ^131^I. This has suggested a strong carcinogenic potential of
^131^I on the thyroid in infants and children, but the presence of other
radioactive contaminants and uncertain dose estimates are among the
major obstacles in developing more precise risk estimates. Thus, the
relative biological effectiveness of ^131^I to induce thyroid neoplasia
(malignant or benign) remains the subject of considerable uncertainty.
Also, relevant for thyroid cancer risk from fallout exposure are the
results from a recently completed study of people who were exposed
during childhood to ^131^I released between 1944 and 1957 from the
Hanford Nuclear Site in the State of Washington ("Hanford Thyroid
Disease Study") (www.cdc.gov/nceh/radiation). Compared to the Chernobyl
situation, exposure in the Hanford region lasted from months to years
and was lower and almost entirely from ^131^I. No demonstrable excess in
thyroid cancer risk was found, and this suggested that, if there was an
increase in risk at the range of exposure (from 0 to 400 mGy) to ^131^I
in Hanford, it was too small to detect in more than 3,000 people
examined in the study.

##### Leukemia

Leukemia is among the rarer forms of cancer, but there is a considerable
amount of epidemiological information on the risk of leukemia from
radiation exposure. This may in part be due to the higher relative risk
compared to other cancers and the relatively short period of time for
the leukemogenic effect to be manifested. There are various sub-types of
leukemia, the frequencies of which are age-dependent. Most leukemias
found in childhood are acute lymphocytic types whereas chronic myeloid
and chronic lymphocytic types make up a large proportion of adult
leukemias. Radiation has not been found to increase the risk of chronic
lymphocytic leukemia, which represents about half of adult leukemia
cases in the United States and other western populations.

There are some differences in the shape of the dose response for various
non-chronic lymphocytic leukemias reported from the atomic bomb
survivors and other studies, but they are likely to reflect the
uncertainty due to small numbers of cases or different dose
distributions. As noted previously, there is clear evidence of
non-linearity in the dose response that indicates the risk (per unit
dose) is lower if given in a smaller dose. However, this dose response
pattern is based on analyses of the total dose received. The issue
regarding fallout is whether a chronic cumulative dose (from fallout) is
equivalent in risk to a fractionated or acute dose. Therefore, it is of
special interest to see whether chronic or fractionated exposure to
radiation leads to a lower risk than expected from acute exposure (dose
rate effect). As discussed earlier, a large international study of
radiation workers (chronic exposure) suggests that the range for the
elevated leukemia risk among workers receiving chronic low dose
exposures is consistent with the risk estimates obtained from the atomic
bomb survivor studies (acute exposure). A number of studies are underway
to further address this issue, including updating and expanding the
worker study and follow-up of exposed populations in the former Soviet
Union and other countries.

##### Other Cancers

Excess cancers due to radiation exposure occur in a wide variety of body
sites although different organs and tissues have different sensitivities
to this cancer-causing agent. In addition to leukemia and thyroid
cancer, cancer types for which excess risks have been reported include
cancer of the salivary glands, esophagus, stomach, colon, liver, lung,
bone, urinary bladder, ovary, female breast, skin, thyroid, and brain
and central nervous system. Evidence is currently inconclusive for
non-Hodgkin's lymphoma and multiple myeloma and is weak for establishing
a radiation effect for a number of other cancer types such as Hodgkin's
Disease, cancers of the pancreas, prostate, testis, uterine cervix,
uterine corpus, small intestine, pharynx, larynx, and nasal cavity and
certain childhood cancers such as retinoblastoma and Wilm's tumor (Boice
et al. 1996; NAS 1990; UNSCEAR 1994; UNSCEAR 2000). As previously noted,
the excess risk for these cancers is generally dependent on age, time,
and gender, although there is considerably variability among different
cancers. For example, the dependence on age at exposure is stronger for
cancers of the breast and thyroid than for other cancers. How the risk
of various types of cancer is modified by gender, age, and
characteristics of the exposure such as the type of radiation and the
rate at which dose was received, as well as exposures to other risk
factors (e.g., smoking) and susceptibility factors is the continuing
subject of ongoing epidemiological research.

#### Benign Tumors

The induction of benign tumors appears to be similar to cancer
induction, but benign tumors are almost always non-fatal, with the
exception of brain tumors. Benign tumors are difficult to identify
adequately and their diagnoses are also difficult to validate for
epidemiological studies. Because the medical significance of benign
tumors can be minor compared with malignant tumors, benign tumors are
not routinely reported to cancer registries, do not usually require
hospitalization, and are rarely the underlying cause of death listed on
death certificates. Autopsy studies and screening programs are
potentially useful sources of information, but the differing levels of
effort in tumor diagnosis complicate these investigations and can lead
to biased ascertainment of cases. These reasons make is difficult to
conduct epidemiological studies of benign tumors. However, limited data
available to date suggest radiation exposure is capable of causing
excess benign tumors, especially of the thyroid. Information is
currently insufficient for characterizing the shape of the dose-response
and the magnitude of risk for most benign tumors. The risk of benign
tumors following radiation exposure appears to persist for many years,
but currently only limited information is available on the modifying
effects of gender and age and time patterns.

Radiation-associated benign tumors tend to occur in the same organs and
tissues as malignant tumors, such as the thyroid glands (Schneider et
al. 1993) salivary glands (Schneider et al. 1998; Land et al. 1996;
Modan et al. 1998), parathyroid glands (Fujiwara et al. 1992; Schneider
et al. 1995), gastrointestinal tract (Ron et al. 1995), female breast
(Tokunaga et al. 1994), and central nervous system (Ron et al. 1988;
Schneider et al. 1985). For fallout exposure, tumors of the thyroid are
the major concern because of the potential for relatively high exposure
to radioactive iodine. Thyroid adenomas are the major benign tumor of
the thyroid and present themselves as nodules. Childhood exposure to
external radiation, such as from the atomic bombs or given for medical
reason, has been linked to excess risk of thyroid adenomas (Ron et al.
1989; Shore et al. 1993; Yoshimoto et al. 1995). Therefore, one could
expect that internal irradiation to radionuclides resulting from fallout
exposure is capable of increasing the risk of benign thyroid tumors.
Although the limited data currently available from Utah (based on small
numbers) support this (Kerber et al. 1993), there are no fallout data
that provide adequate information for quantifying risks. Studies are
currently ongoing on benign thyroid tumors in other irradiated
populations, such as in Chernobyl, Ozyorsk in Russia, and Kazakhstan.

#### Other Diseases (Non-Neoplastic Diseases)

Exposure to ionizing radiation can directly affect health by damaging
the structure and function of various tissues and organs in the human
body. Clinical manifestation of an effect is thought to occur after a
sufficient proportion of cells are affected by radiation exposure
(Mettler and Upton 1995). This would imply that there may be a dose
level under which no health risk is observed. Most radiation-induced
non-neoplastic diseases are believed to occur through this process, and
the ICRP has estimated threshold dose levels for certain deterministic
effects for the reproductive organs, eyes, and bone marrow (ICRP 1991).
Non-neoplastic diseases do not represent a major concern for fallout
exposures that usually are below threshold values. However,
non-neoplastic diseases are discussed here because of new data coming
out of the atomic bomb survivor study as well as studies of various
exposed populations around Chernobyl. Concern has been expressed by
members of the public regarding non-neoplastic diseases and radiation,
particularly, non-neoplastic thyroid disease.

##### Thyroid Disease

Clinical experience has demonstrated that exposure to high-dose
radiotherapy to the head and neck or radioiodine therapy for
thyrotoxicosis causes subsequent non-neoplastic thyroid disease (IOM
1999; Maxon and Saenger 1996; Barsano 1996; UNSCEAR 1993). The response
at lower levels of exposure is not well understood. Results from studies
of environmental exposures have been inconsistent. The occurrence of
non-neoplastic thyroid disease in relation to environmental radiation
exposure has probably been best studied in the various populations near
the Chernobyl nuclear power plant and in the Hanford region. As a result
of the Chernobyl accident, these populations were exposed to a mix of
radioiodines, which included ^131^I, other shorter lived radioiodines,
and ^137^Cs among others. Besides thyroid cancer, non-neoplastic thyroid
conditions have been investigated in children who were exposed to
fallout from the accident. The largest study reviewed, which addresses
both neoplastic and non-neoplastic thyroid abnormalities, comes out of
the screening program conducted by the Chernobyl Sasakawa Health and
Medical Cooperation Project (Sasakawa Memorial Health Foundation 1994;
Sasakawa Memorial Health Foundation 1995). In this large examination
program, carried out in about 160,000 children less than 4 years of age
at the time of the accident, no increased risk of hypothyroidism,
hyperthyroidism or goiter related to radiation exposure was found.
Reviewing these and other Chernobyl data, UNSCEAR has recently concluded
that there has been no increased risk of thyroid abnormalities, with the
exception of thyroid cancer in those exposed at young ages, in affected
populations following the Chernobyl accident (UNSCEAR, 2000). The
Hanford Thyroid Disease Study found no increase in risk of benign
thyroid nodules, hypothyroidism, or hyperparathyroidism associated with
exposure to ^131^I (www.cdc.gov/nceh/radiation).

##### Other Non-Neoplastic Diseases

An increased risk of heart disease following high doses of radiation
therapy has been reported previously (Mettler and Upton 1995; Hancock et
al. 1993). More recently, the atomic bomb survivor data have shown a
small excess risk for non-neoplastic diseases, mostly heart disease and
stroke (Shimizu et al 1999). The excess non-neoplastic disease in the
atomic bomb survivors is seen at a level below that given for medical
purposes. However, the shape of the dose response is not clear,
especially at low dose levels, from the current data. A linear dose
response cannot be ruled out, but the data are also consistent with the
possibility of essentially zero risk below 0.5 Sv. No animal experiments
have shown cardiovascular changes following this level of low-dose
exposure, so the biological mechanisms for non-neoplastic disease
related to low-dose exposure are currently speculative. Given the lack
of a clear dose-response curve and the uncertainty of the risk at a low
dose, no quantitative assertions on non-neoplastic risks relevant for
fallout exposure can be made.

There has not been any demonstrable inherited adverse health effect,
including untoward pregnancy outcome, birth defects, or cancer, in a
cohort of over 70,000 children whose parents were exposed to radiation
from atomic bombs in Hiroshima and Nagasaki (Neel and Schull 1991). This
suggests that the excess health risks inherited from radiation-exposed
parents are very small and much less than those found for people who
were directly exposed to radiation.

### Risk Analysis

The large amount of epidemiological and experimental data on the health
effects of exposure to radiation, and specifically the quantitative data
that relates cancer to radiation dose, makes it possible to estimate the
risk as well as the likely number of people developing cancer as a
result of fallout radiation exposure. As noted earlier, several national
and international scientific committees periodically review the
literature relevant to radiation risk assessment, and recommend models
for estimating risks of several types of cancer. These models can then
be used to estimate risks -- or number of cases to be expected -- which
result from exposures of specific populations, such as those among the
United States population alive during the years of fallout and exposed
to its radiation. In contrast, little has been done to attempt to
develop similar models to quantify non-cancer disease risk. As observed
in previous sections of this chapter, a great deal is still unknown
about the relationship between radiation and non-cancer health effects,
particularly with regard to whether there is any risk at low doses.

Because models for estimating risks of cancer have been developed by
several groups of investigators, there is little question that estimates
for risk of cancer for the United States population resulting from
fallout exposures could be obtained if dose estimates are computed. It
must be noted, however, that the populations and exposures for which
risk projections are needed nearly always differ from those for which
epidemiological data are available. This means that resulting risk
projections must be based on assumptions about which there is
considerable uncertainty. This raises the question of whether or not
uncertain estimates of risk can be useful for developing public health
policy. To address this question, example estimates of cancer risks are
provided later in this chapter. Additionally, the degree of uncertainty
in these example estimates is evaluated. First, however, various
measures of risk are defined, a description of how cancer risk models
have been developed and applied is provided, and the major sources of
uncertainty in the risk estimates obtained from these models are
discussed. This section on risk analysis focuses primarily on cancer as
a health effect of radiation exposure; however, non-cancer health
effects are also discussed. Although the discussion of risk measures,
model development, and uncertainty are framed in terms of cancer risk,
the concepts reviewed are applicable to non-cancer risk as well.

#### Measures of Risk

An important measure of risk that has been emphasized in most recent
risk assessments is the "lifetime risk" or probability that a given
radiation exposure will lead to death from cancer in the remaining
lifespan of the individual. Although radiation risks have commonly been
measured in terms of mortality, projections of lifetime risks of cancer
incidence can also be made. Mortality and incidence are both of
interest, the former because it can be considered the most serious
adverse effect of exposure and the latter because it more fully reflects
the public health impact. The measures of lifetime risk that are
emphasized here are the risk of radiation-induced death or
radiation-induced cancer incidence.

As previously noted, epidemiological data generally support the use of
linear dose-response relationships for most cancers, that is, a
relationship in which risk is proportional to dose. Even when the
dose-response relationship is better described by a linear-quadratic
function (as is the case for leukemia), at low doses the linear term
dominates and the quadratic term can be ignored. For this reason,
lifetime risk, at least at lower doses, is usually specified by a
numerical coefficient expressing the risk per unit of radiation dose.
This means that the lifetime risk resulting from a specific dose can be
obtained by multiplying the 'lifetime risk coefficient' by the radiation
dose.

"Lifetime risk coefficients" depend on gender and age at exposure,
because both sensitivity to radiation exposure and the years of life
remaining for cancer to develop depend on these factors. Lifetime risks
for an entire population can be estimated by first carrying out the
calculations for each age at exposure and gender and then averaging the
risks according to characteristics of the population of interest.
Overall risk coefficients presented in reports such as those of the
National Academy of Science's BEIR V Committee (NAS 1990), the
International Commission on Radiological Protection (ICRP 1991), or the
U.S. Environmental Protection Agency (EPA 1994, 1999) have usually been
obtained as averages reflecting the age-gender composition of a
specified population. For example, the most recent EPA estimates (EPA
1999) reflect the 1990 population of the United States. Although it is
recognized that there is considerable variation in risk from a given
dose of radiation among individuals within any population, 'lifetime
risk coefficients' are summary measures that provide information on the
average risk for a group that shares common characteristics. Available
epidemiological data make it possible to obtain estimates that are
specific for categories defined by age at exposure and gender, but are
inadequate to take account of all factors that affect risks. Hence,
these average risks are useful for estimating overall public health
impact, but are much poorer for estimating the likelihood of an
individual developing cancer.

In evaluating risks from fallout exposure, there is interest not only in
risks for the overall United States population, but also for groups of
people living in certain geographic locations or for groups born near to
the same time. Within those groups, there may be considerable variation
in the doses that individuals have received. However, multiplying the
'lifetime risk coefficient' by the average dose for the group will yield
an estimate of the average risk. Multiplying this average risk by the
size of the population will then yield the estimated number of
radiation-induced cancers in the population that may occur in addition
to those expected without any nuclear fallout exposure.

#### Risk Model Development

The first step in developing risk estimates is to develop a model for
describing the relevant epidemiological data. This means expressing
age-specific cancer mortality or incidence rates as a function of
baseline cancer rates and parameters that characterize the relationship
between risk and radiation dose. The risk from radiation is often
expressed as a function of dose, age at the time of exposure, time since
exposure, gender, and sometimes other factors. A model that describes
the epidemiological data can then be used to calculate the lifetime risk
for a group of people with specific ages at exposure and gender. To do
this, one essentially follows the group forward in time and calculates
the risk of developing a radiation-induced cancer at each age subsequent
to the age at exposure. This requires probabilities of survival to each
subsequent age, obtained from life tables, and may also require
background rates, usually obtained from cancer mortality vital
statistics for the population of interest (or incidence rates if cancer
incidence is to be estimated). For more detail on risk model
development, the reader is referred to Bunger et al. (1981), Thomas et
al. (1992), or any of several reports from international committees and
agencies that provide risk models (NAS 1990; UNSCEAR 1994; ICRP 1991;
UNSCEAR, 2000).

##### Uncertainties in quantifying risk due to radiation

As noted above, risk models cannot precisely predict risk to an
individual or the number of health effects in a population; hence, all
risk projections are inherently uncertain. The more important
assumptions and associated uncertainties involved in estimating risks in
persons exposed to doses from fallout in the United States are discussed
below.

**[Uncertainties in the epidemiological data]{.underline}**. Estimates
obtained from epidemiological data are subject to random or chance
fluctuation, which is referred to as "statistical uncertainty". This
source of uncertainty can be quantified, and is often expressed by
presenting 90 or 95% confidence intervals that reflect a range of values
that are reasonably compatible with the data. Statistical uncertainty in
estimated risk coefficients expressing the risk per unit dose tends to
be larger when risks are small than when they are large, and this is the
primary reason that risk estimates have been based mainly on
epidemiological data from populations exposed at high doses.

Uncertainties also come about because of imperfect disease detection and
diagnosis and errors in the dose estimates that are used. In particular,
mortality studies often rely on death certificate information, which is
often inaccurate, especially for providing information on specific types
of cancer. In addition, because epidemiological studies are not
controlled experiments, estimates of risk may be biased (that is, may be
too high or too low) by unknown factors that differ by level of dose.
For example, if subjects with higher doses tended to smoke more than
subjects with lower doses, estimates of lung cancer risks resulting from
radiation exposure could be biased. This type of bias is known as
confounding, and is especially problematic in studying populations where
radiation risks are small. Furthermore, a selection bias may occur when
exposed subjects are healthier, as often observed in studies of healthy
occupational populations ("healthy worker effect"), or less healthy, as
with medically irradiated populations, than the general population. In
such cases, comparison of the cohort disease occurrence with that of the
general population may conceal or overstate the true radiation-related
risk. A surveillance bias may occur when heightened scrutiny (such as
screening) is undertaken to detect diseases of interest in exposed
populations. This has been an important source of concern in assessing
cancer risk, especially of thyroid cancer, in studies of Chernobyl
populations given medical attention.

**[Extrapolating to low doses and dose rates]{.underline}**. Probably
the most important source of uncertainty in risk estimates for persons
exposed to fallout radiation is the extrapolation from high to low doses
and high to low dose rates. Rudimentary dose estimates presented in
Chapter 3 indicate that most doses from weapons testing fallout are much
smaller than those that have been used to estimate risks, and in
addition, they are received at low dose rates.

Estimates obtained directly from epidemiological data on populations
exposed to low doses and low dose rates, such as nuclear workers, are
very imprecise (Cardis et al. 1995). The few studies of persons exposed
to fallout are also inadequate for estimating risks with any precision.
With small doses, the increased cancer risk from radiation is very small
relative to the baseline cancer risk, so that random fluctuation and the
possibility of confounding make it difficult if not impossible to detect
risk or to estimate it with any precision.

For this reason, it is necessary to extrapolate from risks estimated for
persons exposed to much higher doses and dose rates than those received
from fallout. Specifically, data on atomic bomb survivors have played an
important role in developing models for risk estimation. Although the
atomic bomb survivors include individuals who were exposed at low doses,
risk estimates derived from these data tend to be driven by those doses
exceeding 1 Gy (1000 mGy). To a lesser extent, medically exposed
populations have also been used in developing risk estimates, and these
also primarily involve relatively large doses. Usually, linear
dose-response functions in which cancer risk is proportional to
radiation dose have been used to extrapolate from high to low doses.
Although most epidemiological data are compatible with such a
relationship, other models such as a linear-quadratic relationship
cannot be excluded. Because experimental data have suggested that risk
per unit of dose is lower when radiation is received at low rates than
when it is received at high rates, linear estimates of risk at low doses
and dose rates are often reduced by a factor known as the dose and dose
rate effectiveness factor (DDREF). A factor of 2 for the DDREF has been
used in several risk assessments, but the magnitude of the factor, or
whether it is needed at all, is uncertain. Some think that there may be
a threshold, that is a dose below which there is no risk, though as
noted previously (Section 4.2.1), for most cancer sites, this hypothesis
is not supported by currently available data.

Because of the large uncertainty in the risks associated with exposures
at low doses, the National Academy of Science's BEIR V committee (NAS
1990) did not publish estimates of risk for single doses below 0.1 Gy
(100 mGy), and also noted the possibility of no risk at very low doses.
It should be noted that with the exception of dose to the thyroid, most
doses from fallout that were estimated for this feasibility report are
much smaller than 0.1 Gy, and estimates of average doses tend to be in
the range of 0.001 to 0.003 Gy (1-3 mGy). The relative uncertainties in
estimating risks at these low doses are especially large.

**[Transfer from Japanese atomic bomb survivors to the United States
population]{.underline}**. Another important source of uncertainty
results from applying risks estimated from studying a particular exposed
population to another population that may have different genetic and
lifestyle characteristics and different baseline cancer risks.
Specifically, the application of risk estimates based on Japanese atomic
bomb survivors to a United States population is a concern, particularly
for estimating risks of specific cancers for which baseline rates differ
greatly between the two populations. For example, colon cancer rates in
Japan are less than half those in the United States, whereas liver
cancer rates in Japan are several times as great as those in the United
States; colon and liver are two of the cancer sites where fallout doses
may be of concern. To address this general problem, the NAS BEIR V
committee calculations were based on the assumption that relative risks
resulting from radiation exposure were proportional to baseline risks,
whereas the earlier NAS BEIR III committee based their estimates on the
assumption that risks (on an absolute scale) did not depend on baseline
risks, and thus would be similar for Japanese and United States
populations. Some recent efforts have used intermediate approaches with
allowance for considerable uncertainty (EPA 1999; NIH 2000).

**[Differences in relative biological effectiveness
(RBE)]{.underline}.** Some doses from fallout involve internal exposure
from ^131^I, which primarily exposes the thyroid gland, and from other
radionuclides that expose a variety of organs including colon, liver,
kidney, red bone marrow, and bone surfaces. By contrast, Japanese atomic
bomb survivors were primarily exposed to external gamma rays, with some
exposure to neutrons. This means that both dose rate and the uniformity
of the dose within the organ may be different for fallout exposures
compared with doses to atomic bomb survivors. The manner in which this
might affect risk is not known with certainty. The ratio of the disease
risks resulting from equal doses of different types of radiation is
known as the relative biological effectiveness or RBE.

**[Projection of risks over time]{.underline}.** Many of the atomic bomb
survivors who were young at the time of the bombings (1945) are still
alive, and thus their risks at older ages -- when baseline cancer risks
are largest -- have not yet been studied. This is also true for other
exposed groups who are being studied. Thus, estimating lifetime risks
for those exposed at very early ages and who have lived for decades
afterwards requires assumptions about the time-response patterns of
disease. Most recently developed risk models for cancers other than
leukemia and bone cancer are based on the assumption that, after a
minimal latent period, the risk (measured on a scale relative to the
baseline cancer risk) remains constant over the entire lifespan. This
could overestimate risk if the relative risk decreases over time as is
suggested by some epidemiological data (Pierce et al. 1996; Thompson et
al. 1994; Little et al. 1998.), especially for those who were young at
exposure. For leukemia, the risk to those exposed early in life seems to
have decreased to near zero by 20-30 years following exposure (Preston
et al. 1994); however, there is some uncertainty in risks for the period
2-5 years following exposure, since data on atomic bomb survivors are
not available before 1950.

**[Quantifying uncertainties]{.underline}**. Recently, there has been
increased attention to quantifying the degree of uncertainty in risk
estimates \[NCRP 1997; EPA 1999; and NIH 2000\]. The approach that is
taken is first to quantify the uncertainty from each of several sources
by specifying distributions, or the probabilities associated with a
range of plausible values. For most uncertainty sources, this requires
informed judgments based on the weight of available scientific evidence
by those conducting the analysis. Because these judgments are
necessarily somewhat subjective, intervals reflecting uncertainty are
often referred to as "credibility intervals" instead of confidence
intervals (which are usually determined by more rigorous statistical
procedures). In order to allow flexibility in the distributions used to
indicate the uncertainties in the separate sources, computerized
simulations, called Monte Carlo calculations, are often needed.

In evaluating the uncertainty in the risk estimated for a group of
individuals exposed to a particular level of dose, it is necessary to
include the uncertainty in the dose estimate. Dose estimates are subject
to several sources of uncertainty, including those involved in the
determination of: (1) the deposition densities of the various
radionuclides as a function of time and space; (2) the transfer of those
radionuclides in the environment; and (3) the lifestyle and dietary
habits of the group of individuals that is considered. To a large
extent, these uncertainties have not been quantified in this feasibility
study. In principle, the uncertainty in dose can be included in risk
calculations.

#### Illustrations and Discussion of Problems in Estimating Cancer Risks from Fallout Doses

In this section, the problems involved in estimating risks of several
types of cancer are illustrated. With the exception of the thyroid
cancer, the examples were developed using approaches that could be
applied quickly, and are given for illustration only. The results
presented here need careful re-evaluation if a more detailed dose and
risk assessment for radioactive fallout is undertaken.

##### Thyroid Cancer Risks from Internal Exposure to ^131^I

A detailed evaluation of dose to the thyroid gland from ^131^I from
tests in Nevada has already been conducted (NCI 1997). Doses to the
thyroid are predicted to be much larger than those to other organs.
Results of this feasibility study indicate most of the dose to the
thyroid is from NTS rather than global fallout. Land (IOM 1999) has
already evaluated risks of thyroid cancer from exposure to ^131^I from
the NTS, and estimated that between 11,300 and 212,000 thyroid cancers
would be expected to occur among persons who were under age 20 in the
period 1951-1957 with a median estimate of 49,000. The risk coefficients
used in this evaluation were based on a pooled analysis of data from
seven epidemiological studies of persons exposed externally (Ron et al.
1995). Because both thyroid doses and 'lifetime risk coefficients'
depend strongly on age at exposure, the calculation of Land gave
separate consideration to different ages at exposure with the largest
risks for the youngest age groups and with no risk for those exposed at
ages 20 and older. Consideration of global fallout likely would increase
the thyroid cancer estimates for the United States by about 15% (Table
3.22), although thyroid cancers resulting from global fallout would tend
to occur in later birth cohorts than those resulting from NTS fallout.

The range of predicted thyroid cancer cases from NTS fallout allowed for
two of the most important uncertainty sources -- statistical uncertainty
and uncertainty in the estimated average dose -- but did not include
uncertainty in the relative biological effectiveness (RBE) of ^131^I
exposure compared with external exposure, or for the possibility of
reduction of thyroid cancer risk over time. Both Shore and Xue (1999)
and Little et al. (1998) find evidence of such a reduction; and Shore
and Xue indicate the reduction of the lifetime risk estimates of thyroid
cancer after childhood exposure might be about 40-60%.

Estimates of lifetime risks for groups of individuals sharing certain
characteristics could have also been made, such as groups defined by age
at exposure and geography. For example, based on tables describing the
Land calculations (Appendix B of the Institute of Medicine's review of
NCI's fallout report), the average lifetime risk for the entire United
States for persons exposed under age 5 can be estimated to be about
0.002 (or about 1 in 500), while no risk is estimated for persons
exposed at ages 20 and older (IOM 1999). The uncertainty estimates for
specific groups are likely to be larger than that for the population as
a whole. This example for thyroid cancer illustrates the feasibility of
estimating risks. In addition, the wide range in the number of thyroid
cancer cases predicted (11,300-212,000) illustrates the large
uncertainty that such estimates carry.

##### Total Cancer Risks from External Exposure to NTS and Global Fallout

For tissues other than thyroid, the crude dose estimates in Chapter 3
suggest that the contribution from external dose is larger than that
from internal dose. Specifically, the per capita external dose over the
period 1951-2000 from both NTS and global fallout is estimated to be
about 1.2 mGy (Table 3.14), whereas, with the possible exception of bone
surfaces, internal dose even to the more heavily exposed tissues is
likely to be less than this. External dose can be expected to expose all
tissues of the body in a reasonably uniform manner so that estimating
the risk of all cancers is important. An ideal assessment would evaluate
risks for each year of birth, taking account of the age at exposure in
each subsequent year. An assessment for groups exposed in separate
geographic areas could also be made to the extent that doses can be
estimated for such groups. However, because a substantial portion of the
external dose is from exposure to global fallout, geographical
variability may be much less than for internal dose.

Several scientific committees and groups have provided models for
estimating the risks of all fatal cancers combined. Here, we make use of
the ICRP (1991) coefficient of 5% per Sv for total cancer mortality. We
first evaluate risks for the 3.8 million people born in the United
States in 1951 (Bogue 1985), a group that would, on average, have
received larger doses at earlier ages than those born earlier or later.
The average dose for this population is estimated to be about 1.2 mSv,
resulting in a population dose of about 4600 person-Sv. If the ICRP
coefficient of 5% per Sv is applied, about 230 cancers would be
predicted to result from this exposure (a lifetime risk of about 1 in
16,500). However, because much of the dose would be received in
childhood for this group, risks might be larger; for example,
calculations shown in UNSCEAR (1994) indicate that risks for those
exposed under age 20 might be 2 or 3 times risks for those exposed in
adulthood. It seems unlikely, however, that consideration of age at
exposure would result in an estimate of more than 1000 excess cancers in
this group (about 1 in 3800). Since more than 20% of all deaths are due
to cancer (Greenlee et al. 2000), this can be contrasted with about
760,000 cancer deaths that might be predicted in this group in the
absence of radiation exposure from fallout. It is also noted that the
average annual dose from natural background for the US population is
about 1 mSv, with a total dose of 70 mSv over a 70-year lifespan. For
persons born in 1951, the population dose from natural background is
thus about 266,000 person-Sv. Applying the ICRP coefficient thus results
in an estimated 13,300 cancer deaths from natural background, more than
13 times the estimated number from fallout.

Cancer incidence estimates (including non-fatal cases) would be about
double those for cancer mortality (Ries et al. 1996), resulting in a
prediction of less than 2,000 fallout-induced incident cases among
persons born in 1951; about 1,520,000 incidence cancer cases would be
expected to occur in this group in the absence of exposure. In this
simple evaluation, we have not attempted to provide detail on the
distribution of the excess deaths and cases by gender, or by age and
calendar year of occurrence.

Risks for other birth cohorts could also be evaluated and would have
smaller risks than those for the 1951 cohort. For example, the 1931
birth cohort would receive about the same external dose, but it would
all be received in adulthood. The number of excess fatal cancers
predicted in the 2.5 million persons born in 1931 (Bogue 1985) would be
about 150, compared to about 500,000 fatal cancers that would be
predicted in the absence of fallout exposure. This can be further
contrasted to risks estimated for persons born in 1971. The average dose
for this birth cohort is only about 0.23 mSv (dose received by the year
2000), with most of this dose received in childhood. The predicted
number of excess fatal cancer among this cohort of 3.6 million persons
is likely to be less than 100, compared with about 720,000 cancer deaths
that would be predicted in the absence of fallout. Estimates for the
1931, 1951, and 1971 birth cohorts are summarized in Table 4.1.
Estimates for cancer incidence (including non-fatal cases) would be
about double those shown in Table 4.1.

Table 4.1. Estimates of the total number of excess cancer deaths
resulting from external exposures from NTS and global fallout for
persons born in 1931, 1951 or 1971.

+-------------+-------------+-------------+-------------+-------------+
| Birth       | Cancer      | Estimated   | Risk of     | Estimated   |
| cohort      | deaths      | excess      | cancer      | excess risk |
|             | expected in | cancer      | death in    | of cancer   |
| (Population | the absence | deaths.\*   | the absence | death       |
| size)       | of fallout  |             | of fallout  |             |
+-------------+-------------+-------------+-------------+-------------+
| 1931        | About       | About 150   | About 20%   | About       |
|             |             |             |             | 0.006%      |
| (2.5        | 500,000     |             | (1 in 5)    |             |
| million)    |             |             |             | (1 in       |
|             |             |             |             | 17,000)     |
+-------------+-------------+-------------+-------------+-------------+
| 1951        | About       | Less than   | About 20%   | Less than   |
|             |             | 1000        |             | 0.03%       |
| (3.8        | 760,000     |             | (1 in 5)    |             |
| million)    |             |             |             | (1 in 3800) |
+-------------+-------------+-------------+-------------+-------------+
| 1971        | About       | Less than   | About 20%   | Less than   |
|             |             | 100         |             | 0.003%      |
| (3.6        | 720,000     |             | (1 in 5)    |             |
| million)    |             |             |             | (1 in       |
|             |             |             |             | 36,000)     |
+-------------+-------------+-------------+-------------+-------------+

\*Includes deaths from leukemia.

It would be possible to repeat this exercise for every birth year that
contributed persons alive in the period 1950-2000; that is, persons born
in the years 1880 through 2000. As noted above, persons born in 1951
would experience the largest risks. Persons born before 1931 would have
risks that were lower than those indicated for those born in 1931, and
persons born after 1971 would have risks that were lower than those
indicated for 1971. Although it is not sensible to estimate an average
individual risk that applies to all contributing birth years, it is
possible to estimate the total number of excess cancers that might have
occurred among all exposed birth-year cohorts. This can be done by
considering the size of the exposed population in each of the years of
fallout. The population doses given in Table 3.14 are based on the
assumption that the population was 163 million (1954 population)
throughout the period 1951-2000, which does not allow for increases in
the United States population over time. For the purpose of this
illustration, we have made a crude correction by using a population of
250 million (1990 population) for the exposure received in the years
1973-2000, resulting in a total population dose of 217,000 person-Sv.
Applying the ICRP coefficient of 5%, it can be estimated that about
11,000 extra cancer deaths would be predicted to occur among the United
States population alive during the years of fallout. Cancer incidence
estimates (including non-fatal cases) would be about double those for
cancer mortality, resulting in a prediction of about 22,000
radiation-induced incident cases. The cancer deaths (and incident cases)
would be spread out over the period extending from the 1950s through
much of the 21^st^ century, and would be in addition to the far larger
number of cancer deaths that occur every year in the United States; for
example, about 500,000 cancer deaths occurred in 1990 (Bureau of the
Census 1997). About 40 million cancer deaths and 80 million incident
cases might be predicted to occur over a 75-year period. Another
perspective is provided by noting that if the same methodology were
applied to estimate risks from natural background exposure received
during the period 1951-1972, when 80% of the fallout dose was received
(Table 3.14), about 180,000 cancer deaths and 360,000 incident cases
would be predicted, about 16 times the number from fallout.

The National Council on Radiation Protection and Measurements evaluated
sources of uncertainty in the ICRP risk coefficient of 5% per Sv that
was used to obtain the above estimates (NCRP 1997). The uncertainty
sources evaluated were: statistical uncertainty, errors in reporting of
cancer deaths in atomic bomb survivors, errors in dose estimates for
atomic bomb survivors, extrapolation from acute exposure at high doses
and dose rates to low doses and dose rates, transfer of risk estimates
from Japanese atomic bomb survivors to a US population, and projection
of risks over time. Uncertainty from each source was quantified, and
computer simulations were conducted to evaluate the overall uncertainty
from all sources. Using that approach, the 90% credibility interval for
the lifetime risk coefficients for fatal cancer covered a range from
1.2% per Sv to 8.8% per Sv. Applying that range to the total population
dose from external fallout, the number of excess cancer deaths among the
United States population is predicted to be from 2,600 to 19,100 The
range for the number of incident cases would be about double these
values.

The range for the 'lifetime risk coefficient' does not account for
uncertainties in the estimated external doses from fallout. Inclusion of
all sources of uncertainty could be accomplished by conducting computer
simulations that used both the uncertainty distributions given by the
NCRP and a distribution reflecting uncertainties in the dose estimates.
Because the uncertainties in dose estimates are not provided in this
feasibility study, this computer simulation has not been performed. For
illustration only, it is assumed that the 90% credibility interval for
dose extends from a factor of three below the estimate to a factor of
three above the estimate. Under this assumption, simplified calculation
incorporating all of the above uncertainties result in risk projections
that range from 1,700 to 32,500 excess cancer deaths.

Although the estimates above should be regarded as illustrative only,
they indicate that the total number of incident cancers from external
fallout exposure (about 22,000 cancers) would be about half the
estimated number of thyroid cancers from ^131^I exposure (49,000). It is
likely that the number of deaths (roughly 11,000) might exceed deaths
from thyroid cancer, which generally has a low fatality rate. Doses from
external exposure, especially those from global exposure, vary less than
doses to the thyroid from ^131^I by geographic location, birth cohort,
and dietary habits (such as milk consumption). Risks for cancers other
than thyroid cancer are also less strongly dependent on age at exposure.
For these reasons, risks for all cancers from external exposure are
likely to vary less by geographic location, age at exposure and other
factors than risks of thyroid cancer from NTS ^131^I exposure, which
makes it much less likely that there will be groups with particularly
large risks.

It should also be noted that total cancer risk from external exposure
can be estimated with greater certainty than can risks of most
individual types of cancers or risks from internal exposure. This is
because of the relative wealth of epidemiological data on external
exposure (including the atomic bomb survivors studies), and because both
statistical uncertainties and uncertainties in extrapolating risks from
atomic bomb survivors to a United States population are smaller.
Nevertheless, the above discussion demonstrates that even estimates of
total cancer risk from external exposure are accompanied by large
uncertainties.

##### Leukemia Risks from External and Internal Exposure

Leukemia is perhaps of special interest because it has been strongly
linked with radiation in several epidemiological studies, because it
occurs in young people, and because of the strontium-90 component of
fallout exposure. Also, increased rates of leukemia have been reported
in participants in the Smoky nuclear weapons test conducted at the NTS
in 1957 (Robinette et al. 1985) and an association of leukemia and
fallout dose has been suggested among persons living downwind of the NTS
(Stevens et al. 1990). In addition, during numerous CDC public meetings
on other radiation-related issues, members of the public have
consistently identified leukemia as one of their main cancer concerns.

For leukemia, the ICRP (1991) lifetime risk coefficient is 0.5% per Sv.
Since this estimate was based on atomic bomb survivor data at a time
when nearly all leukemias were fatal, it can appropriately be considered
as an estimate of lifetime leukemia incidence as well as mortality.
Actually, modern leukemia survival rates would reduce mortality, but
this is seldom taken into account in estimating leukemia risks. As with
other cancers, the ICRP risk coefficient includes reduction by a DDREF
of 2. This is roughly equivalent to using the linear term of the
linear-quadratic function that has been used to describe the
dose-response relation in atomic bomb survivors.

It is noted first that the estimates for total cancer mortality from
external dose given in Table 4.1 include deaths from leukemia and that
roughly 10% of these deaths would be predicted to be from leukemia.
(About 3% of background cancer deaths are from leukemia.) Similarly,
about 1,100 of the 11,000 cancer deaths for all birth-year cohorts from
external exposure might be from leukemia. As shown in Table 3.22,
internal exposures would result in additional dose to the red bone
marrow, mostly from global fallout. For a person born 1 January 1951,
the average dose from internal sources is estimated to be 0.9 mSv,
resulting in a population dose of 3420 person-Sv. If it is assumed that
risk coefficients are similar for internal and external exposure, one
might predict about 17 (0.5% x 3420) leukemia deaths from internal
exposure, a lifetime risk of about 1 in 220,000. Lifetime risks for
leukemia do not depend strongly on age at exposure (UNSCEAR 1994).
Average bone marrow doses from internal exposure are not given in this
report for other specific birth-year cohorts, and thus we have not
attempted to estimate risks for these cohorts. However, Table 3.22 also
indicates that the average dose for an adult from internal sources is
estimated to be 0.7 mSv. A rough estimate of the total number of
leukemia deaths from internal exposure for all birth-year cohorts can be
obtained by noting that the adult internal exposure is about half of
that due to external exposure. If it is again assumed that risk
coefficients are similar for internal and external exposure, about 550
leukemias from internal exposure might be added to the 1,100 leukemias
estimated to result from external exposure.

##### Risks from Internal Exposure (Other Than Thyroid and Leukemia)

Dose from internal exposure varies considerably by organ, making it
important to separately consider risks of cancers in specific organs.
Presently available data on NTS and global exposures indicate that the
tissues or organs that can be expected to receive the largest internal
doses are thyroid, colon, kidney, liver, red bone marrow, and bone
surfaces. Risks of thyroid cancer and leukemia from internal exposure
were discussed earlier in this section.

Several groups of scientists have made estimates of risk coefficients
for at least some of these cancers. For illustrative purposes, those
lifetime risk coefficients developed by the EPA (1999) for cancer
mortality are provided in Table 4.2. These risk estimates are reasonably
recent and include estimates for all the tissues noted above. Estimates
of cancer incidence are also available.

Table 4.2. Environmental Protection Agency's age-averaged site-specific
lifetime cancer mortality risk estimates from low-dose, low-LET uniform
irradiation of the body.

  ----------------------------- -----------------------------------------
  Site                          Percent per Sv

  Colon                         1.04

  Liver                         0.15

  Bone                          0.01

  Kidney                        0.05

  Leukemia                      0.56

  All cancer                    5.75
  ----------------------------- -----------------------------------------

Except for leukemia and all cancer, the EPA has not carried out a
detailed analysis of the level of uncertainty in the risk coefficients
listed in Table 4.2, but sources of uncertainty are discussed and
approaches for evaluating them are suggested (EPA 1999). Uncertainty for
specific cancers is likely to be larger than that for all cancers
combined, both because statistical variation is greater, and, for
estimates based on atomic bomb survivor data, differences in United
States and Japanese baseline risks are greater.

Risk estimates for exposures involved in fallout could be obtained by
multiplying those coefficients by the dose to the tissue or organ that
was exposed. This feasibility report does not go through this exercise.
However, the following observations are made. First, the rudimentary
dose assessment performed indicates that most tissues received little
dose from internal sources (Tables 3.10, 3.19 and 3.22). Secondly, with
the exception of the thyroid, there are no organs that are likely to
receive doses that are substantially larger than those from external
exposure. For these reasons, the total risk of cancer (other than
thyroid cancer) from internal exposure is likely to be less than that
from external exposure.

#### Future Possibilities for Analyzing Cancer Risk

The examples above were intended only for illustration, hence, the
methods were based on readily available "lifetime risk coefficients". If
a more detailed assessment of doses from fallout is undertaken, several
improvements can likely be considered. In the illustrations provided, no
attempt was made to give detailed attention to developing risk estimates
for specific years of birth that took account of both specific ages at
exposure and specific population sizes for different exposure years.
Such estimates would help to provide information on which persons were
at greatest risk, and would also provide a slightly more accurate
estimate of the overall risk. In addition, risk estimates for specific
geographic locations could be developed, again providing information on
those at greatest risk. This latter refinement is probably of greater
interest for doses from NTS fallout since these show greater geographic
variation than doses from global fallout. Better information on the
predicted age and calendar period of appearance of predicted cancer
deaths and incident cases could also be developed.

Evaluation of uncertainty in risk estimates should include both the
uncertainty in the lifetime risk coefficient and uncertainty in the
estimated dose. To allow full flexibility in the distributions used to
describe uncertainties, computer simulations would be needed. Although
we have not used this approach in our illustrations, the feasibility of
conducting such simulations has been demonstrated by the NCRP (1997),
EPA (1999), and most recently by the NIH (NIH 2003) as discussed below.

The National Institutes of Health (NIH 2003) has recently updated the
Radioepidemiological Tables that were published in 1985 (NIH 1985). This
revision required developing risk models for more than 20 specific
cancers, including those organs and tissues that are of interest
following exposures to radioactive fallout. Although the tables are
being developed to estimate the "probability of causation" (that is, the
probability that a cancer that has been diagnosed in an individual is
the result of some previous exposure to radiation), the models could be
used to estimate the lifetime risk of developing cancer. The evaluation
of uncertainty in the revised tables is probably the most comprehensive
that has been undertaken in the field of radiation risk assessment. The
overall uncertainty distributions include statistical uncertainty of
parameters, as well as subjective evaluation of uncertainties in the
errors related to extrapolating to low doses and dose rates, the
differences between Japanese and United States populations, and
uncertainties in the dosimetry of atomic bomb survivors. Software has
been developed that allows a person interested in a specific
"probability of causation" to specify the type of cancer and when it
occurred, the age at exposure and gender, the radiation dose and when it
was received, and, if desired, the uncertainties in the dose estimate. A
computer calculation (simulation) is then performed, and the person is
provided with a range of estimates of the probability the cancer was a
result of radiation exposure (see
http://www.niosh-irep.com/irep_niosh/).

Although the software is now limited to evaluating "probability of
causation", it could be expanded to estimate lifetime risks -- a more
useful quantity for those exposed to fallout and who as yet have no
observable health effects. In addition to providing a comprehensive
evaluation of uncertainty, the NCI approach has the advantage that it is
based primarily on atomic bomb survivor cancer incidence data from the
Hiroshima and Nagasaki tumor registries. This means that diagnostic
information on specific cancer types is likely to be more reliable than
for the mortality data used in most other risk assessments.

In addition, the National Academy of Science's BEIR VII Committee is
expected to recommend models for risk estimates of the health effects of
exposure to low levels of ionizing radiation. The models to emerge from
that study are likely to make use of the latest mortality and incidence
data from the atomic bomb survivors as well as from other
epidemiological studies that provide relevant information. Analyses of
mortality data covering 1950-1997 have recently been published (Preston
et al. 2003), and analyses of updated atomic bomb survivor cancer
incidence data are currently underway and will extend the period covered
by eleven years (covering 1958-1998 instead of 1958-1987 as previously).

Finally, a thyroid dose and cancer risk calculator was developed by NCI
to allow any individual to obtain an estimate of the risk of thyroid
cancer resulting from the estimated thyroid dose from ^131^I arising
from nuclear tests conducted at the NTS. The NCI ^131^I thyroid
dose/cancer risk calculator for NTS fallout, together with educational
material, can be found on the internet at
[http://i131.nci.nih.gov](http://i131.nci.nih.gov/). Details are
provided in Chapter 5 of this report.

Although the approaches and resources noted above are expected to
provide a stronger basis for estimating risks and particularly for
quantifying their uncertainties, they cannot greatly reduce some
important sources of uncertainty in estimating the risks from exposures
received from fallout. These include uncertainties in extrapolating from
high to low doses and dose rates, uncertainties in using estimates from
Japanese atomic bomb survivors for a United States population, and
uncertainties in the relative biological effectiveness of some of the
exposures involved in nuclear fallout.

#### Analyzing the Risk of Non-Cancer Health Effects

Data presented earlier in this chapter described the relationship
between radiation and non-cancer health effects, including benign tumors
of the thyroid, the salivary glands, and other sites and non-neoplastic
diseases such as hypothyroidism and heart disease. While a number of
epidemiologic studies have demonstrated an association between radiation
and non-cancer health effects, more fundamental research is needed
clarify the biological mechanisms by which low-dose, and low-dose-rate
radiation exposure causes disease. Also, dose response and time response
patterns of the disease-exposure relationship require further assessment
before risk analyses can be performed reliably.

In considering the dose data available in this feasibility assessment,
the most likely non-cancer health outcomes that may affect the American
people are those involving the thyroid gland. Present estimates of dose
from fallout radiation indicate that the internal organ-specific dose to
the thyroid is much higher than the dose to other organs/tissue
evaluated (Tables 3.10 and 3.22). Internal and external exposures
(delivering a uniform dose to the whole body) to fallout radiation are
unlikely to result in an increase in other non-neoplastic disease at the
currently estimated dose levels. However, it is conceivable that select
individuals may have much greater sensitivity to radiation than has been
found on average. For example, individuals with pre-existing disease
could be more radiosensitive.

##### Benign Tumors of the Thyroid

While considerable effort has gone into quantifying the lifetime risk of
cancers, much less has been done to quantify non-malignant disease in a
similar manner. Among those benign tumors that have been related to
radiation exposure in various studies, lifetime projections of risk are
available only for benign thyroid nodules. This lifetime risk
coefficient was developed for the Nuclear Regulatory Commission (NRC
1989, 1993) for predicting health effects from nuclear power plant
accidents and has been reviewed by the NCRP (1993). The risk estimate is
based on data from studies of external x-ray irradiation of children and
is based on the assumptions that women are more sensitive to exposure
than men are and children are more sensitive than adults are. Internal
exposure to ^131^I is assumed to be substantially less effective than
external irradiation in inducing benign neoplasms in the general
population (NRC 1993).

At this point in time, however, quantifying the lifetime risk of benign
thyroid nodules resulting from fallout exposure is not advisable.
Although risk estimates can be developed using available risk
coefficients, these estimates do not take into consideration recent
studies of the relationship between radiation and thyroid disease,
specifically those studies conducted in populations exposed to ^131^I
from the Chernobyl accident. More importantly, existing risk
coefficients do not adequately account for uncertainty. Given the
important issues surrounding the detection and diagnosis of these benign
nodules, the uncertainty associated with this health endpoint will
likely be much greater than that seen for thyroid cancer. Additionally,
issues related to the effectiveness of internal exposure to ^131^I in
inducing benign nodules, extrapolation of risk estimates from one
population to another, and projection of risk over a lifetime need to be
considered.

Separate from actually developing risk estimates, but, equally important
in determining whether it is advisable to estimate the lifetime risk of
benign thyroid nodules, is the clinical significance of these tumors.
Currently, the significance of small ultrasound detected lesions remains
unknown. Most thyroid nodules are benign (IOM 1999) and there is no
evidence to date to suggest that radiation exposure induces adenomas
that are more likely to progress to malignant disease than adenomas
occurring in unexposed individuals (Wang and Crapo 1997; Mettler and
Upton 1995).

##### Non-Neoplastic Thyroid Disease

Clinical and epidemiological data clearly indicate an association
between high-dose radiotherapy and hypothyroidism; however, the
association with low-dose exposures and, in particular with low doses of
^131^I, is less clear. Hyperthyroidism after radiotherapy has also been
reported (IOM 1999). The IOM, in reviewing the NCI ^131^I report, did
not consider the impact of thyroid dose from NTS fallout on other
nonmalignant thyroid diseases because the review committee felt the data
describing these health effects were inconclusive for the range of doses
estimated for average Americans (NAS 1999). And, a recent review of the
Chernobyl studies by UNSCEAR was unable to conclude that non-malignant
diseases were increased as a result of low dose radiation exposure
(UNSCEAR 2000). Given the current state of knowledge, a quantitative
risk analysis of non-neoplastic thyroid disease from fallout is not
feasible. Additional studies of exposed populations, especially those
exposed from the Chernobyl accident, that have longer follow-up periods,
sufficient sample size, and individual dosimetry, may be necessary to
provide adequate data on which to base a risk assessment. It is likely,
however, that the uncertainty associated with any future quantitative
risk estimates will be quite large.

The IOM reported that the risk of non-malignant thyroid disease
resulting from exposure to ionizing radiation could extend into the
range of doses of less than 1 Gy (1000 mGy). Maxon and Saenger (1996)
reported that hypothyroidism from radioiodine exposure is unlikely to
occur at doses less than 0.1 to 0.2 Gy (100 to 200 mGy). These lower
values can be used as a "threshold" to qualitatively assess the
potential risk of hypothyroidism from fallout exposures. Using these
values will more likely result in an overestimate than an underestimate
of a health effect. Based on the data presented in Chapter 3, the
average American was exposed to a significantly lower dose than the dose
range described by Maxon and Saenger (1996). However, it is clear from
Figure 3.17 that there may be subgroups of the population who, based on
their age during the testing period and place of residence, have
received doses approaching 0.2 Gy. Higher doses for some individuals
would be expected if non-commercial milk sources (backyard cow or goat)
and above-average milk consumption patterns were considered. Thus, this
health effect is the most likely non-cancer health consequence of
fallout exposure.

### Conclusions

It is feasible to estimate fallout-related risks of developing cancer
among population groups or for representative exposure scenarios, and to
quantify the range of uncertainty in these risks. This range is likely
to be large because of uncertainties in dose estimates and in the risk
models that are used. In spite of the large uncertainties, it is likely
that there is an increased risk of cancer from fallout, but it is also
highly likely that this increase is very small relative to the usual
risk of cancer in the absence of fallout exposure. For example, the 3.8
million people born in the United States in 1951 might experience a few
hundred extra fatal cancers as a result of fallout exposures compared
with more than a half a million fatal cancers that would be predicted in
the absence of fallout. Persons born in 1951, on average, have received
larger doses than those born earlier or later. Because doses from global
fallout vary less by geographic location and birth cohort than do
thyroid doses from NTS ^131^I exposure, it is much less likely that
there would be groups with unusually large risks. At this time, not
enough information is available to perform a quantitative radiation risk
analysis for non-cancer health outcomes. A crude evaluation of the doses
estimated for this feasibility report and the available epidemiological
literature indicate, however, the most likely non-cancer health outcomes
are those affecting the thyroid gland.

With regard to the exposures of the American people from Nevada Test
Site fallout, the Institute of Medicine has indicated that further
epidemiologic studies could help to clarify the extent to which the
Nevada tests increased the incidence of thyroid cancer. The University
of Utah is currently extending the follow-up for a previous
epidemiological study of children who lived in the vicinity of the
Nevada Test Site in the 1950s; results are expected to be available in a
few years. Outcomes evaluated will include neoplastic and non-neoplastic
thyroid disease.

A number of non-United States populations have been exposed to
substantially higher levels of radioiodine and other radionuclides than
the United States population. These populations include the residents of
the Republic of Marshall Islands; the people living near the nuclear
weapons test site in Semipalatinsk, Kazakstan; those exposed in the
former Soviet Union to accidental releases from the Chernobyl nuclear
power station in Ukraine; and persons living near the Mayak nuclear fuel
reprocessing plant in Russia. Ongoing dosimetric and epidemiological
studies of these populations are expected to provide additional data
regarding the health consequences of fallout exposure. In particular, it
is fairly clear from the results from the Chernobyl studies that
exposure to ^131^I in childhood can increase thyroid cancer risks,
although these risks cannot yet be quantified accurately and only time
will tell how long they will persist. Also, on-going studies of
populations living near the Mayak nuclear fuel reprocessing plant in
Russia may improve the risk estimate for leukemia at low dose rates.
Expansion or enhancement of these investigations may be useful to better
characterize risks. The results from these epidemiological studies
should be available before further health research is considered.

References

Amemiya, T., Takano, J., and Shoshi, K. Did atomic bomb radiation
influence the incidence of retinoblastoma in Nagasaki and Hiroshima?
Ophthalmic Paediatr. Genet. 14(2):75-79, 1993.

Barsano, C.P. Other Forms of Primary Hypothyroidism. In: Werner and
Ingbar's The Thyroid. 7^th^ edition. Braverman, L.E., Utiger, R.D.
(Editors). Lippincott-Raven Publishers, Philadelphia, PA, 1996.

Bogue, D.J. The Population of the United States: Historical Trends and
Future Projections. The Free Press (A Division of Macmillan Inc.). New
York, 1985.

Boice, J.D. Jr., Land, C.E., and Preston, D.L. Ionizing Radiation. In:
Cancer Epidemiology and Prevention. Schottenfeld, D., Fraumeni, J.F. Jr.
(Editors). Oxford University Press, New York, NY, 1996.

Bunger, B.M., Cook, J.R. and Barrick, M.K. Life table methodology for
evaluating radiation risk: an application based on occupational
exposures. Health Phys., 40:439-455, 1981.

Bureau of the Census, Statistical Abstract of the United States: 1997
(117^th^ edition), Washington DC, 1997.

Cardis, E., Gilbert, E.S., Carpenter, L., Howe, G., Kato, I., Armstrong,
B.K., Beral, V., Cowper, G., Douglas, A., Fix, J., et al. Effects of low
doses and low dose rates of external ionizing radiation: cancer
mortality among nuclear industry workers in three countries. Radiat.
Res. 142:117-132, 1995.

EPA. U.S. Environmental Protection Agency. Estimating radiogenic cancer
risks. EPA 402-R-93-076. Washington, DC, June 1994.

EPA. U.S. Environmental Protection Agency. Estimating radiogenic cancer
risks. Addendum: uncertainty analysis. EPA 402-R-99-003. Washington, DC,
May 1999.

Fujiwara, S., Sposto, R., Ezaki, H., Akiba, S., Neriishi, K., Kodama,
K., Hosoda, Y., and Shimaoka, K. Hyperparathyroidism among atomic bomb
survivors in Hiroshima. Radiat. Res. 130:372-378, 1992.

Greenlee, R.T., Murray, T., Bolden, S., Wingo, P.A. Cancer Statistics,
2000. CA Cancer J Clin 50:7-33, 2000.

Hancock S.L., Tucker M.A., and Hoppe R.T. Factors affecting late
mortality from heart disease after treatment of Hodgkin's disease. JAMA
270:1949-55, 1993.

Kerber R.A., Till J.E., Simon S.L., Lyon J.L., Thomas D.C.,
Preston-Martin S., Rallison M.L., Lloyd R.D., and Stevens W. A cohort
study of thyroid disease in relation to fallout from nuclear weapons
testing. JAMA 270: 2076-82, 1993.

Kodama K., Fujiwara S., Yamada M., Kasagi Y., Shimizu Y., and Shigematsu
I. Profiles of non-cancer diseases in atomic bomb survivors. World
Health Stat Q 49:7-16, 1996.

IOM. Institute of Medicine. NRC. National Research Council. Exposure of
the American people to Iodine-131 from Nevada nuclear-bomb tests. Review
of the National Cancer Institute report and public health implications.
National Academy Press, Washington, DC, 1999.

ICRP. International Commission on Radiological Protection. 1990
Recommendations of the International Commission on Radiological
Protection. ICRP Publication 60. Ann ICRP 21(1-3). Pergamon Press,
Oxford, UK, 1991.

Land, C.E., Saku, T., Hayashi, Y., Takahara, O., Matsuuma, H., Tokuoka,
S., Tokunaga, M., and Mabuchi, K. Incidence of salivary gland tumors
among atomic bomb survivors, 1950-1987. Evaluation of radiation-related
risk. Radiat. Res. 146:28-36, 1996.

Little, M.P., De Vathaire, F., Charles, M.W., Hawkins, M.M. and
Muirhead, C.R. Variations with time and age in the risks of solid cancer
incidence after radiation exposure in childhood. Statist. Med.
17:1341-1355, 1998.

Maxon, H.R. and Saenger, E.L. Biologic effects of radioiodines on the
human thyroid gland. In: Werner and Ingbar's The Thyroid. 7^th^ edition.
Braverman, L.E., Utiger, R.D. (Editors). Lippincott-Raven Publishers,
Philadelphia, PA, 1996.

Mettler, F.A. Jr. and Upton, A.C. Medical Effects of Ionizing Radiation.
2^nd^ edition. W.B. Saunders Company, Philadelphia, PA, 1995.

Modan B., Chetrit A., Alfandary E., et al. Increased risk of salivary
gland tumors after low-dose irradiation. Laryngoscope 108:1095-7, 1998.

NAS. National Academy of Sciences. NRC. National Research Council.
Committee on the Biological Effects of Ionizing Radiation. Health
effects exposure to low levels of ionizing radiation (BEIR V Report).
National Academy Press, Washington, DC, 1990.

NCI. National Cancer Institute. Cancer Incidence and Mortality in the
United States, 1973-1977, NCI Monograph No. 57. Surveillance,
Epidemiology and End Results (SEER) Program, National Institutes of
Health, Bethesda, MD, 1981.

NCI. National Cancer Institute. Estimated exposures and thyroid doses
received by the American people from Iodine-131 in fallout following
Nevada atmospheric nuclear bomb tests. Bethesda, MD, 1997.

NCRP. National Council on Radiation Protection and Measurements. NCRP
Report No. 80. Induction of thyroid cancer by ionizing radiation.
Bethesda, MD, 1985.

NCRP. National Council on Radiation Protection and Measurements. NCRP
Report No. 115. Risk estimates for radiation protection. Bethesda, MD,
1993.

NCRP. National Council on Radiation Protection and Measurements. NCRP
Report No. 126. Uncertainties in fatal cancer risk estimates used in
radiation protection. Bethesda, MD, 1997.

Neel J.V. and Schull W.J. (eds). The Children of Atomic Survivors. A
Genetic Study. National Academy Press, Washington, DC,1991.

NIH. National Institutes of Health. NIH Publication No. 85-2748. Report
of the National Institutes of Health Ad Hoc Working Group to develop
radioepidemiological tables. Bethesda, MD, 1985.

NIH, Land C.E., Gilbert E., Smith J., Hoffman F.O., Apostoiae I., Thomas
B., Kocher D.M. Report of the NCI-CDC Working Group to revise the 1985
NIH Radioepidemiological Tables. U.S. Dept. of Health and Human
Services, National Institutes of Health, National Cancer Institute,
Bethesda, Maryland. NIH Publication No. 03-5387, 118 pp, 2003.

NRC. Nuclear Regulatory Commission. Health Effects Models for Nuclear
Power Plant Accident Consequence Analysis. Low- LET Radiation, Part II:
Scientific Bases for Health Effects Models. NUREG/CR-4214, Rev. 1, Part
2, U.S. Government Printing Office, Washington, DC, 1989.

NRC. Nuclear Regulatory Commission. Health Effects Models for Nuclear
Power Plant Accident Consequence Analysis. Part I: Introduction,
Integration, and Summary. NUREG/CR-4214, Rev. 2, Part 1, ITRI-141. U.S.
Government Printing Office, Washington, DC, October 1993.

Pierce, D.A., Shimizu,Y., Preston, D.L., Vaeth, M., and Mabuchi, K.
Studies of mortality of atomic bomb survivors. Report 12, Part I.
Cancer: 1950-1990. Radiat Res 146:1-27, 1996.

Pierce D.A. and Preston D.L. Radiation-related cancer risks at low doses
among atomic bomb survivors. Radiat Res 154:178-186, 2000.

Preston, D.L., Kusumi, S., Tomonaga, M., et al. Cancer incidence in
atomic bomb survivors. Part III: Leukemia, lymphoma and multiple
myeloma, 1950-1987. Radiat Res 137:S68-S97, 1994.

Preston, D.L., Shimizu, Y., Pierce, D.A., Suyama, A. and Mabuchi, K..
Studies of mortality of atomic bomb survivors Report 13: Solid cancer
and noncancer disease mortality: 1950-1997. Radiat. Res., in press,
2003.

Ries, L.A., Hankey, F., Harras, A., and Devesa, S.S. Cancer incidence,
mortality and patient survival in the United States. In: Schottenfeld
D., Fraumeni, J.F. Jr., editors. Cancer Epidemiology and Prevention.
Oxford University Press, New York, NY, 1996: 168-191.

Ries L.A.G., Eisner M.P., Kosary C.L., Hankey B.F., Miller B.A., and
Edwards B.K. (eds). SEER Cancer Statistics Review, 1973-1997. National
Cancer Institute, Bethesda, MD, 2000.

Robinette, C.D., Jablon, S., and Preston, D.L. Mortality studies in
nuclear weapons tests participants. P.1-47 in: Medical Follow-up Agency,
National Research Council. National Academy Press, Washington, 1985.

Ron E., Modan B., Boice J.D., et al. Tumors of the brain and nervous
system after radiotherapy in childhood. New Engl J Med 319:1033-39,
1988.

Ron E., Modan B., Preston D., Alfandary E., Stovall M., and Boice J.
Thyroid neoplasia following low-dose radiation in childhood. Radiat Res
120:516-531, 1989.

Ron, E., Lubin, J.H., Shore, R.E., Mabuchi, K., Modan, B., Pottern, L.,
Schneider, A.B., Tucker, M.A., and Boice, Jr. J.D. Thyroid cancer after
exposure to external radiation: a pooled analysis of seven studies.
Radiat Res 141:259-277, 1995.

Ron, E., Wong, F,L., Mabuchi, K., et al. Incidence of benign
gastrointestinal tumors among atomic bomb survivors. Am J Epidemiol
142:68-75, 1995.

Sasakawa Memorial Health Foundation. A report on the 1994 Chernobyl
Sasakawa Project Workshop Moscow, 16-17, May 1994.

Sasakawa Memorial health Foundation, Tokyo, 1994, Sasakawa Memorial
Health Foundation. A report on the 1995 Chernobyl Sasakawa Project
Workshop, St Petersburg. 7-8July 1995. Sasakawa Memorial health
Foundation, Tokyo, 1995.

Schneider A., Shore-Freedman E., Ryo U., et al. Radiation-induced tumors
of the head and neck following childhood irradiation. Medicine 64:1-15,
1985.

Schneider A.B., Ron E., Lubin J., Stovall M., and Gierlowski T.C..
Dose-response relationship for radiation-induced thyroid cancer and
thyroid nodules: evidence for the prolonged effects of radiation on the
thyroid. J Clin Endocrinol Metab 77:362-369, 1993.

Schneider A.B., Gierlowski T.C., Shore-Freedman E., et al. Dose-response
relationship for radiation-induced hyper-parathyroidism. J Clin
Endocrinol Metab 80:254-7, 1995.

Schneider A.B., Lubin J., Ron E., et al: Salivary gland tumors after
childhood radiation treatment for benign conditions of the head and
neck: dose response relationship. Radiat Res 149:625-30, 1998.

Shimizu, Y., Pierce, D.A., Preston, D.L., and Mabuchi, K. Studies of the
mortality of atomic bomb survivors. Report 12, Part II. Noncancer
mortality: 1950-1990. Radiat Res 152:374-89, 1999.

Shore, R.E., Hildreth N., Dvoretsky P., and Anderson E. Benign thyroid
adenomas among persons x-irradiated in infancy for enlarged thymus
gland. Radiat Res 134:217-223, 1993.

Stevens, W., Thomas, D.C., Lyon, J.L. et al. Leukemia in Utah and
radioactive fallout from the Nevada test site. JAMA 264: 585-591, 1990.

Thomas, D., Darby, S., Fagnani, F., Hubert, P., Vaeth, M., and Weiss, K.
Definition and estimation of lifetime detriment from radiation
exposures: Principles and methods. Health Phys., 63:259-272, 1992.

Thompson, D.E., Mabuchi, K., Ron, E., et al. Cancer incidence in atomic
bomb survivors. Part II: solid tumors, 1958-1987. Radiat. Res.
137:S17-S67, 1994.

Tokunaga M., Land C.E., Tokuoka S., Nishimori I., Soda M., and Akiba S.
Incidence of female breast cancer among atomic bomb survivors,1950-1985.
Radiat Res 138:209-23, 1994.

UNSCEAR. United Nations Scientific Committee on the Effects of Atomic
Radiation. Sources, effects and risks of ionizing radiation. 1993 Report
to the General Assembly, with annexes. United Nations, New York, NY,
1993.

UNSCEAR. United Nations Scientific Committee on the Effects of Atomic
Radiation. Sources, effects and risks of ionizing radiation. 1994 Report
to the General Assembly, with annexes. United Nations, New York, NY,
1994.

UNSCEAR. United Nations Scientific Committee on the Effects of Atomic
Radiation. Sources, effects and risks of ionizing radiation. 2000 Report
to the General Assembly, with annexes. United Nations, New York, NY,
2000.

Wang, C. and Crapo, L.M. The epidemiology of thyroid disease and
implications for screening. Endocrinology and metabolism clinics of
North America. 26(1):189-218, 1997.

Williams, D. Cancer after nuclear fallout: Lessons from the Chernobyl
accident. Nature Rev. Cancer 2:543-549, 2000.

Wong, F.L., Yamada, M., Sasaki, H., Kodama, K., Akida, S., Khimaoka, K.,
and Hosoda, Y. Noncancer disease incidence in the atomic bomb survivors:
1958-1986. Radiat. Res. 135:418-430, 1993.

Yoshimoto Y., Ezaki H., Etoh R., Hiraoka T., and Akiba S. Prevalence of
thyroid diseases among autopsy cases of the atomic bomb survivors in
Hiroshima, 1951-1985. Radiat Res 141:278-286, 1995.