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OCR for page 74
9
Alternative Approaches
Data on the occurrence of adverse reproductive outcomes following expo-
sure to ionizing radiation could be derived from a variety of cohorts, in addition
to the atomic bomb survivors, such as the children of (1) people residing in areas
where the background of naturally occurring radiation is substantially higher
than usual, (2) individuals, other than Atomic Veterans, exposed to fallout from
atmospheric weapons testing, (3) people living near nuclear installations, (4)
individuals exposed occupationally, (5) patients undergoing medical diagnostic
procedures, and (6) patients undergoing medical therapy for benign or malignant
disease. Each of these cohorts has strengths and limitations. Usually, these are
related to sample size, population composition, certainty of dose, presence of
concurrent disease, and other confounding factors.
The study of the atomic bomb survivors is the largest, longest, and most
comprehensive epidemiologic study of radiation-induced carcinogenesis and
mutagenesis that has been undertaken. Its strengths are that it includes a large
population of all ages and both sexes who were not selected because of occupa-
tion or disease. Other strengths are that it includes a wide range of doses, has
included follow-up for more than 45 years, has comprehensive individual do-
simetrv, and can use internal comparisons. Weaknesses include the following:
although the clinical examinations of the children of the survivors began in the
spring of 1948 and the surveillance of mortality among these children covers the
time since May 1946, the cohort on which the studies of cancer among the survi
74
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ALTERNA TI BE APPROA CHES
75
vors themselves rests was defined on the basis of the 1950 national census and
thus does not include the years 1945 through 1949. Moreover, of importance in
the present context is the fact that the exposure was at a high rather than a low
dose rate, and the possible contribution of neutrons is somewhat uncertain. The
fact that the population is Japanese raises some question about the transfer of
risk factors derived from this population to other populations that may have dif-
ferent baseline rates of health outcomes.
There have been a number of studies of populations (other than Atomic Vet-
erans) exposed to radioactive fallout from weapons testing, weapons use, and
nuclear plant accidents. These studies may involve relatively few people (as in
the Marshall Islands), but most involve thousands or hundreds of thousands of
people. The advantages of such studies is that they involve populations of both
sexes and all ages. In addition, they may yield information on the effects of
chronic exposure. The difficulties in risk assessment arise from the fact that the
doses are usually quite low and are rarely available on an individual, specific
basis. Typically, dose estimates are derived from computer modeling of the
source, meteorology, environmental pathways, and assumptions about ingestion
patterns and amounts. Often, the dose estimates can be made only collectively.
Although fallout patterns can be modeled by computer, experience from the
Chernobyl nuclear power plant accident in 1986 has shown that individual doses
may vary by a factor of 10 or more from the estimated average.
Studies of fallout within the United States as a result of weapons testing at
the Nevada Test Site have been performed as part of a significant scientific effort
to reconstruct doses. The advantages of that study were comprehensive expo-
~sure evaluation and protracted exposures at a low rate. In spite of the dosimetry
estimates, there still remains considerable uncertainty about individual doses. In
addition, the estimated cumulative doses are much lower than those experienced
from natural background radiation.
Studies have been performed on localized fallout from the 1954 BRAVO
weapons tests in the Marshall Islands. Fewer than 8,000 people on these islands
were affected. The advantages of that study are that the population was unse-
lected, there has been an attempt at determining individual dosimetry, and there
has been long-term comprehensive medical follow-up. The small sample size
remains a problem for conducting studies in this population, as does the uncer-
tainty about the dose due to short-lived radioiodines.
There have also been studies on the populations exposed to fallout as a re-
sult of the Chernobyl accident in 1986. The advantages of this group are that it
is large, the population is unselected, and dosimetry has been done for highly
contaminated villages. The limitations are that the length of follow-up is limited
and the iodine dosimetry remains somewhat uncertain.
Data on the environmental contamination of the Techa River in the eastern
part of Russia and Semipalatinsk, the weapons testing site of the former Soviet
Union, have also recently become available. Difficulties in both instances in
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76
ADVERSE REPRODUCTIVE OUTCOMES
elude accurate estimation of the absorbed doses or inadequate ascertainment of
exposed individuals. Strengths include a wide range of doses, long follow-up, an
unselected population, and a large population.
Studies of populations living around nuclear power plants have the advan-
tage that they can be well defined assuming that there has been little population
mobility. Unfortunately, in the United States mobility is common and so an ef-
fort must be made to guarantee that the patients with disease, in fact, lived near
the plant at the appropriate time before the latent period for cancer induction.
The very low doses from emissions of most normally functioning nuclear power
plants makes the required sample sizes for statistical significance almost impos-
sible to achieve in circumstances where the exposure (dose) is less than that at
Chernobyl.
Occupational studies are a major source of epidemiologic information. They
have the advantage that work records and times of employment are known.
Knowledge of the dosimetry in these studies ranges from good for workers in
nuclear facilities to very poor for groups such as the early uranium miners. An-
other advantage is that there is usually a large number of people who can be
studied. One problem with occupational studies is that the workforce is pre-
dominantlv voting or middle-aaed healthy males, and the applicability of these
risk factors to other populations requires some assumptions. The so-called
healthy worker effect needs to be considered. This effect tends to give standard-
ized mortality rates (SMR) or standardized incidence rates (SIR) that are less
than unity. Confounding factors, such as exposures to chemicals and other sub-
stances in the workplace, also need to be considered. Smoking is another com-
mon confounding factor that needs to be considered. Moreover, in these studies,
and indeed in all studies in which the dose is low, other sources of exposure to
ionizing radiation, such as diagnostic or therapeutic irradiation, loom large as
possible sources of confounding.
Exposures to ionizing radiation as a result of medical diagnostic procedures
are another potential source for information about the effects of ionizing radia-
tion. The advantages of these studies are that the doses are reasonably well
known, as is the field irradiated. The doses may not be as precise on a percent-
age basis as those from radiation therapy since the doses are known to be low
and the technical factors are not usually recorded.
~ ~ ~ ~ ~ A ~ ~ ~ ~ ~ J ~ ---I, ~ - ~ A
~ 1 1
The exposed populations
consist of people of both sexes as well as most age ran Yes. The generally low
~1 , _t
doses used In medical diagnostic procedures require extremely large sample
sizes for statistical significance to be achieved. The purpose of the diagnostic
study may also be a confounding factor,
available for long-term follow-up.
although generally the patients are
Studies of patients who have received radiation therapy for benign diseases
have the advantage of a known exposure field, a known type of radiation, and
usually, good dosimetry. However, the dosimetry can be a problem in some
cases in which children were irradiated and the organ of interest was near the
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ALTERNA TINE APPROACHES
77
primary radiation field. In those cases, patient motion could cause substantial
uncertainty in the actual doses to the organ of interest. The high doses of radio-
therapy allow risk estimates to be derived with relatively small population
groups, but the high doses also introduce the confounding factor of potential cell
killing. The disadvantages typically are patient selection bias or confounding by
disease, confounding by other therapies or economic status, and potential loss to
follow-up if the disease did not require further treatment.
Studies of the treatment of malignant diseases with ionizing radiation have
the advantages of a well-defined dose and a known type of radiation in a local-
ized field, confounders can be documented, and good follow-up is possible be-
cause patients who receive these treatments are often followed closely for life.
The disadvantages are the possibility of concurrent or other therapies that may
confound the analysis, selection bias due to the disease, the possibility of cell
killing rather than cancer or mutation induction, and a shortened lifespan for
follow-up as a result of the malignant disease. A group including individuals
who have been treated for malignant disease with ionizing radiation are survivors
of childhood cancer. Current data do not indicate an increased risk for adverse
reproductive and developmental effects in the offspring of male cancer survivors
(Hawkins, 1991~. A study of more than 20,000 survivors and their offspring
currently being conducted in the United States and Canada should provide im-
portant new data on this particular population.
Other exposed populations, however, have not been studied or have been
studied inadequately. These include the children of (1) medical personnel who
are occupationally exposed, (2) workers in nuclear facilities, and (3) members of
The armed forces whose service functions involve exposure to ionizing radiation
such as nuclear submariners and the crews of aircraft of the U.S. Strategic Air
Command (SAC).
Some of these groups offer opportunities pertinent to the concerns that have
previously been discussed in this report. For example, studies of the reproduc-
tive outcomes of SAC crews might be informative. These crewmen, officers,
and enlisted personnel have the same age distributions as the Atomic Veterans at
the time of their exposure to ionizing radiation, a similar dose distribution, and
access to uniform health care. Also, hospital records are available for most, if
not all, births to the wives of these SAC crews. Several tens of thousands of
individuals are involved. l?resumably, much of the relevant information could be
obtained by computer. Some of the potentially informative data are already
available in a machine-retrievable format at the Armstrong Laboratory of Brooks
Air Force Base in San Antonio, Texas. Moreover, a computer program, known
as CARI, for estimating exposure to aircraft crews was developed at the request
of the Federal Aviation Administration for commercial crews, but it should be
applicable to Air Force crews as well. It requires information on flight pattern,
duration, and altitude.
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78
AD VERSE REPRODUCTI HE OUTCOMES
Such a study would not be without its limitations. These include the possi-
ble exposure to other potential mutagens such as chemicals, as well as heavy ion
particles originating in space. Some of the information needed to estimate doses
may be classified, but if the doses are computed by individuals in the Air Force
with the appropriate security clearance, this might not be a major difficulty. It
warrants noting, perhaps, that this same problem arose in the estimation of the
doses received by the survivors of the atomic bombings of Hiroshima and Na-
gasaki and was overcome by using suitably cleared technical personnel.
Still other strategies, such as the applicability of recent developments in
molecular and cellular biology, could be explored. These developments have
given rise to a series of biological markers or biomarkers that can be used as
estimators of exposure or dose, of biologic effects, and susceptibility. They in-
clude such chromosomal techniques as fluorescent in situ hybridization (FISH),
and biochemical measures of damage to the genetic material (DNA) at specific
loci, for example, the X-linked hprt locus or the autosomal glycophorin A locus.
At present, these techniques have limited applicability as measures of exposure
or dose to doses of less than 0.10 Gy (10 red), and thus would seem to be of
marginal use in the case of the Atomic Veterans, but this may change through the
use of combined biomarker assays. The limitations of biomarkers as estimators
of dose at doses of less than 0.10 Gy (10 red) reflect to a substantial degree the
relatively large, normally occurring interindividual response to a given dose.
However, even now these markers could be useful as measures of effect or sus-
ceptibility. The strengths and current limitations of these methods have been
addressed in recent workshops (NRC, 1995~. It must be noted, however, that
these techniques are often time-consuming, expensive, and difficult to implement
with large numbers of individuals and cannot be routinely applied to all people.
For example, the glycophorin A assay can be used only on individuals who are
of the MN blood type, and these individuals constitute only half of most popula-
tions.
Representative terms from entire chapter:
weapons testing
