Trends in U.S. Pleural Mesothelioma Incidence Rates Following Simian Virus 40 Contamination of Early Poliovirus Vaccines
Journal of the National Cancer Institute
Trends in U.S. Pleural Mesothelioma Incidence Rates Following Simian Virus 40 Contamination of Early Poliovirus Vaccines
Howard D. Strickler 0 1 2
James J. Goedert 0 1 2
Susan S. Devesa 0 1 2
John Lahey 0 1 2
Joseph F. Fraumeni 0 1 2
Philip S. Rosenberg 0 1 2
0 Affiliations of authors: H. D. Strickler, Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine , Bronx, NY; J. J. Goedert, S. S. Devesa, J. F. Fraumeni, Jr., P. S. Rosenberg , Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Bethesda, MD; J. Lahey , Information Management Services, Silver Spring, MD. miology and Social Medicine, Albert Einstein College of Medicine , 1300 Morris Park Ave., Belfer 1308, Bronx, NY 10461 , USA
1 Oxford University Press
2 Supported by the Cancer Center of Albert Einstein College of Medicine, National Cancer Institute (NCI) grant CA13330, and the Division of Cancer Epidemiology and Genetics, NCI, National Institutes of Health, Department of Health and Human Services. 24, 2002
Background: Poliovirus vaccines that were used during the late 1950s and early 1960s were contaminated with simian virus 40 (SV40), a monkey virus that is tumorigenic in rodents. SV40 DNA sequences have been detected in some human cancers, especially pleural mesotheliomas, although results are conflicting. We examined the relationship between SV40-contaminated poliovirus vaccine exposure and subsequent rates of pleural mesothelioma in the United States. Methods: We used data from the Surveillance, Epidemiology, and End Results Program to estimate age- and sex-specific pleural mesothelioma incidence rates per 105 person-years (py) from 1975 through 1997 and the Poisson distribution to determine 95% confidence intervals (CIs) for each rate. The prevalence, by birth cohort, of poliovirus vaccine exposure during the period of widespread SV40 contamination was determined from published survey data. Trends in mesothelioma incidence rates were assessed by examining age- and sex-specific rates over calendar periods and with the use of the age-period-cohort model. Trends in mesothelioma incidence were then compared with trends in prevalence of exposure. All statistical tests were two-sided. Results: The age-standardized pleural mesothelioma incidence rate for 1975 through 1997 was 1.29/105 py (95% CI = 1.24/105 to 1.34/105 py) in males and 0.21/105 py (95% CI = 0.20/105 to 0.23/105 py) in females. The rate in males increased from 0.79/105 py (95% CI = 0.62/105 to 1.0/105 py) in 1975 to a peak of 1.69/105 py (95% CI = 1.46/105 to 1.95/105 py) in 1992. Incidence rates increased the most among males who were 75 years of age or older, the age group least likely to have been immunized against poliovirus. Incidence rates among males in the age groups most heavily exposed to SV40-contaminated poliovirus vaccine remained stable or decreased from 1975 through 1997. Similar age-specific trends were observed among females. The age-periodcohort models for men and women also indicated that the trends in pleural mesothelioma incidence were not related to trends in exposure to SV40-contaminated poliovirus vaccine. Conclusions: Age-specific trends in U.S. pleural mesothelioma incidence rates are not consistent with an effect of exposure to SV40-contaminated poliovirus vaccine. Nonetheless, given reports of the detection of SV40 genomic DNA sequences in human mesotheliomas, monitoring of vaccineexposed cohorts should continue. [J Natl Cancer Inst 2003; 95:38-45]
That same year, the U.S. government required that all newly
manufactured poliovirus vaccine be free of SV40. However,
previously produced vaccine was not removed from the mass
immunization program and, considering its possible storage for
up to 1 year and its 6-month shelf life, SV40-contaminated
poliovirus vaccine was likely in widespread use in the United
States from the start of the mass immunization program in 1955
through 1963 (
The mass immunization program was initially targeted to
first- and second-graders (who were approximately 6?8 years of
age), then more broadly to children 5?9 years of age, persons
younger than 20 years, and pregnant women (
). As vaccine
availability improved, other groups were also immunized but not
as extensively as those initial groups. The U.S. population was
repeatedly surveyed during the mass immunization program to
assess the coverage of the program (
). Data from those surveys
now provide reliable information regarding the prevalence
(probability) of poliovirus vaccine exposure, by year of birth,
during the period of widespread SV40 contamination of the
vaccine. In 1961, contemporaneous surveys indicated that
approximately 90% of U.S. citizens younger than 20 years of age
(i.e., those born from 1941 through 1961) had received at least
one immunization with poliovirus vaccine. As shown in Fig. 1,
the rate of exposure to potentially SV40-contaminated vaccine
decreased with increasing age. Individuals who were 50 years of
age or older in 1961 (e.g., those born prior to 1912) had a less
than 10% prevalence of poliovirus immunization, and persons
born prior to 1902 were unlikely to have ever been vaccinated.
Further characterization of exposure to SV40-contaminated
poliovirus vaccine on an individual basis is impossible, because
necessary information about the titer of live SV40 in individual
vaccine lots is unavailable, and vaccinees typically received
multiple immunizations (a standard course of vaccination was a
series of three injections and a booster) (
). A frequently cited
review of the available data indicates that titers of live SV40
in specific vaccine lots varied from undetectable to high.
However, because each vaccinee received multiple immunizations,
the reported data suggest that most U.S. citizens who were
vaccinated between 1955 and 1963 had at least one exposure to live
Most epidemiologic studies of population groups that were
immunized with potentially SV40-contaminated poliovirus
vaccines during early childhood, the most vulnerable period for
exposure according to animal models, have failed to detect any
association of immunization with increased risks of cancer, even
more than 30 years following exposure (
). However, an
increasing number of DNA hybridization studies that have used
polymerase chain reaction amplification have reported the
detection of SV40 DNA sequences in certain human cancers (
Most such reports have involved brain tumors in children
); osteosarcomas, which mainly affect teenagers and
young adults (
); and pleural mesotheliomas, which
generally occur in adults older than 50 years (
Pleural mesothelioma has been the tumor most often reported
to contain SV40 DNA (
), although there are also a
small but growing number of studies (
) that have not
detected the virus in pleural mesothelioma specimens.
Mesothelioma is strongly linked to asbestos exposure, with approximately
60%?80% of cases having evidence of past exposure to asbestos
(29). Mesothelioma incidence rates are higher among
individuals who have had occupations that involved extensive use of
asbestos, such as shipbuilding, as well as in the communities
where these industries have been centered (
Previous epidemiologic investigations that examined the risks
of cancer associated with exposure to SV40-contaminated
poliovirus vaccine focused on birth cohorts that were of
appropriate ages for the analysis of childhood brain cancer and
osteosarcoma but that were young relative to the age groups that
account for most cases of pleural mesothelioma. In addition,
reports of SV40 DNA detection in pleural mesothelioma
specimens have typically involved patients who were adults during
the late 1950s and early 1960s, but little attention has been paid
to the potential cancer risks associated with adult exposure to
SV40-contaminated poliovirus vaccine. Therefore, we examined
pleural mesothelioma incidence trends among adults in various
age groups in relation to the probability of their exposure to
potentially SV40-contaminated poliovirus vaccine between
1955 and 1961.
Participation in the nationwide Salk poliomyelitis inoculation
program was monitored by national household sample surveys
that were conducted annually by the Bureau of the Census (
Available data from the 1961 survey provide nationally
representative estimates of the number of persons in the United States
who had received at least one dose of poliovirus vaccine during
the period of its widespread contamination with SV40 for the
following age groups: less than 1 year, 1 year, 2 years, 3 years,
4 years, 5?9 years, 10?14 years, 15?19 years, 20?29 years, 30?
39 years, 40?49 years, and 50?59 years. Because the
participation rate among persons younger than 1 year of age reflected a
midyear value (i.e., many infants born in 1961 were born after
the survey was conducted or had not yet received their first
vaccination), we assumed that the participation rate among
persons younger than 1 year of age was equal to the value reported
for persons who were 1 year of age at the time of the survey.
Because data were not reported for those individuals who were
60?70 years of age, we assumed that participation rates
continued to decline with age and used 5%, the midpoint value
between 0% and 10% (the rate for those aged 50?59 years), as the
rate of participation for the 60- to 70-year-old age group. Trends
in exposure by single-year birth cohorts were derived from these
data as follows. A step function was plotted to describe the
prevalence of inoculation by age group. The step function was
smoothed by using a cubic smoothing spline constrained to
match the area under each step. The resulting smoothed curve
provided estimates of prevalence by single year of age. The
smoothed curve was obtained by the use of a sequential
quadratic programming algorithm (the QUADPROG function in the
Optimization Toolbox for Matlab: The Language of Technical
Computing Version 6.0, 2002; The MathWorks Inc., Natick,
MA) and has the following properties: Within each age group,
the sum of the smoothed age-specific prevalences matched the
values that were observed in the survey exactly; this curve is the
smoothest function that does so.
Rates and Trends
We used the International Classification of Diseases for
Oncology (ICD-O) site code 384 and histology codes 9050, 9051,
9052, 9053, 9054, and 9055 (
) to obtain pleural mesothelioma
incidence data from the Surveillance, Epidemiology, and End
Results (SEER)1 Program of the National Cancer Institute (
Since 1973, SEER has collected detailed information on new
cancer cases that are reported to qualified population-based
tumor registries, and since 1975, SEER has comprised a
representative sample of approximately 10% or more of the U.S.
population. The SEER Program uses extensive quality-control
procedures, which include the rigorous training of abstractors
and coders, sample re-abstracting, and the review of case
findings. The Manual of Tumor Nomenclature and Coding (
which was used by SEER in the early years to code tumors,
made a distinction between pleural mesothelioma cases reported
to be malignant and those not specified as malignant, and both
sets of cases were recorded in the SEER database. However, this
distinction was eliminated with adoption of the International
Classification of Diseases for Oncology (
) in 1976. Inspection
of the annual number of cases did not reveal a surge around
1977, suggesting that the change in coding practices did not
affect case reporting.
The current analyses were limited to cases of pleural
mesothelioma, because almost all reports of the detection of SV40
DNA in mesotheliomas have specifically involved pleural
tumors. Annualized age- and sex-specific cancer incidence rates
from 1975 through 1997 were calculated with the use of data
from all SEER sites that were active since 1975 (i.e., those in the
San Francisco Bay area, the Puget Sound area of Seattle,
Connecticut, Detroit, Hawaii, Iowa, New Mexico, Utah, and Atlanta)
and of population demographic data from the U.S. Bureau of the
Census. Age-standardized incidence rates were determined
using the U.S. population distribution in 1970 as the standard, and
95% confidence intervals (CIs) for all incidence rates were
calculated on the basis of the Poisson distribution. The estimated
annual percent change in age-standardized rates was determined
with the use of a simple regression model in which the outcome
was the log (age-standardized incidence rate), the independent
variable was time, and weight was the number of cases.
We used the age?period?cohort model (
) to estimate the
expected incidence rate of pleural mesothelioma as a function of
age, calendar year, and birth cohort. The model simultaneously
accounts for birth-cohort effects, effects associated with aging,
and temporal trends that may have impacted all age groups in the
population at once. These latter ?period effects? most often
reflect changes in screening or diagnostic practice. Formally, the
model expresses the logarithm of the incidence rate as a sum of
an age-group effect, a calendar-period effect, and a birth-cohort
effect. However, because the linear trends in calendar period and
birth cohort are necessarily confounded, we based our inferences
on two sets of estimable functions (i.e., contrasts) of the
birthcohort effects. These contrasts were designed to measure
changes in the trend of the birth-cohort effects, which are also
called ?slope contrasts? or ?curvature effects.? The first set of
functions of the birth-cohort effects estimated changes in the
linear slope of the birth cohort effects that spanned
approximately 10 years and that covered periods during which the
cohort-specific vaccine prevalence curve was approximately
linear, specifically 1894 through 1899, 1900 through 1907, 1908
through 1917, 1918 through 1927, 1928 through 1935, 1936
through 1947, and 1948 through 1957. The second set of
functions of the birth cohort effects contrasted consecutive
differences of 2-year birth cohorts: 1900 through 1901, 1902 through
1903, and so on up to 1960 through 1961; these differences are
unique up to an arbitrary constant.
Slope contrasts measured whether the birth-cohort effects
were accelerating or moderating over birth year. In general,
acceleration indicated either that a rate was increasing or that a
decreasing rate was decreasing less quickly. Moderation
indicated either that a rate was decreasing or that an increasing rate
was increasing less quickly. We examined the first (i.e., 10-year)
set of contrasts specifically for evidence of acceleration in birth
cohorts that were exposed to potentially SV40-contaminated
poliovirus vaccine as adults. We examined the second (i.e., 2-year)
set of contrasts for evidence that respective differences in cohort
effects were related to corresponding differences in the
prevalence of exposure. In this latter analysis, we calculated the slope
of the regression line between changes in cohort effects and
changes in prevalence of exposure. Because the variances of
individual cohort effects were different, we weighted each
contrast by the inverse of its estimated variance. All statistical tests
throughout the analyses were two-sided.
Between 1955 and 1961, more than 90% of school-age
children had been inoculated with at least one dose of poliovirus
vaccine (Fig. 1). More than 60% of persons in their 20s and more
than 50% of persons in their 30s had also been vaccinated.
On the basis of 525 million person-years (py) of follow-up
data in SEER, we found that pleural mesothelioma was
uncommon from 1975 through 1997 (Fig. 2, A). The overall
ageadjusted incidence rate was 0.67/105 py (95% CI 0.65/105 to
0.69/105 py), and the rate in males (1.29/105 py, 95% CI
1.24/105 to 1.34/105 py) was sixfold higher than the rate in
females (0.21/105 py, 95% CI 0.20/105 to 0.23/105 py).
Among males, there was a statistically significant upward
trend in the age-adjusted rates of pleural mesothelioma over
time; those rates increased from 0.79/105 py (95% CI 0.62/105
to 1.0/105 py) and 0.84/105 py (95% CI 0.66/105 to 1.05/105
py) in 1975 and 1976, respectively, to a peak of 1.69/105 py
(95% CI 1.46/105 to 1.95/105 py) in 1992. After 1992, pleural
mesothelioma incidence rates in males appeared to plateau or
even to decrease, with rates in 1996 and 1997 of 1.45/105 py
(95% CI 1.24/105 to 1.68/105 py) and 1.26/105 py (95% CI
1.07/105 to 1.48/105 py), respectively. The overall average rate
of increase for males for the period from 1975 through 1997 was
3.25% per year (95% CI 2.41% to 4.09% per year). Similarly,
pleural mesothelioma incidence rates among females increased
approximately 2.99% per year (95% CI 1.92% to 4.08% per
year) during the period of observation, from 0.13/105 py (95%
CI 0.07/105 to 0.22/105 py) and 0.21/105 py (95% CI
0.13/105 to 0.32/105 py) in 1975 and 1976, respectively, to
0.26/105 py (95% CI 0.18/105 to 0.36/105 py) and 0.23/105 py
(95% CI 0.16/105 to 0.32/105 py) in 1996 and 1997,
respectively. The absolute number of cases in females remained low,
however. From 1991 through 1997, for example, there was an
average of only 38 cases in females each year among the
approximately 13 million females in SEER, compared with an
average of 177 cases in males diagnosed each year among the
approximately 12 million males in the SEER database.
The greatest increases in pleural mesothelioma incidence
occurred among men and women in the two oldest age groups
(i.e., ages 75?84 years and 85 years), who were the least likely
to have been exposed to SV40-contaminated poliovirus vaccine
(Fig. 2, B). For example, a man who was 85 years old in 1979
or 1980, when the initial large increases in mesothelioma
incidence occurred, would have been 66 years old in 1961, and his
probability of exposure to SV40-contaminated vaccine was less
than 5%. A man who was 85 years old in 1991 or 1992, when
mesothelioma rates peaked, would have been 54 years old in
1961, and the probability of his exposure to SV40-contaminated
vaccine was approximately 10%. By contrast, rates of
mesothelioma among the much more heavily exposed birth cohorts
(i.e., those in the 25- to 44-year and 44- to 54-year age groups)
remained stable or decreased between 1975 and 1997.
To further examine these relationships, we applied age?
period?cohort regression models to the pleural mesothelioma
incidence data for males and females, which were tabulated by
single year of age (for ages 30?84 years) and by period (for
Fig. 2. Pleural mesothelioma
incidence rates in the United
States based on data from the
and End Results Program. A)
mesothelioma incidence rates in
males, females, and both
combined for 3-year periods
1975?1977 through 1993?
1995, and 1996 through 1997.
B) Age-specific pleural
mesothelioma incidence rates in
males and females for 4-year
periods 1975?1978 through
1991?1994, and 1995?1997.
Longer time units were used
with the age-specific rates
because of the small number of
observations in any individual
calendar years 1975 through 1997). Among men, there were
130.1 million py of observation and 2928 incident cases of
pleural mesothelioma. The observed and expected incidence rates
were similar (the chi-square statistic for deviance was 1215.6
and was approximately equal to the degrees of freedom, which
numbered 1190). One set of the estimated birth-cohort effects in
men is shown in Fig. 3, A. These estimates were obtained by
fitting step functions for age, period, and birth cohort with 2-year
steps (the 1890 through 1891 and 1892 through 1893
birthcohort effects were set equal to each other because of the very
low rate of exposure and low incidence in early birth cohorts).
Slope contrasts are superimposed on this particular model; the
differences between the slope contrasts are estimable, because
they are invariant to the choice of the identifiability constraints
that were used to fit the model. The slope contrasts show that
there was a marked and statistically significant decrease in risk
of pleural mesothelioma for males born from 1928 through 1935
compared with the risk for those born from 1918 through 1927
Fig. 3. Birth-cohort effects in men. A) Birth-cohort
effects and slope contrasts, as estimated by the age?
period?cohort model. Vertical bars represent 95%
confidence intervals (CIs) for each birth-cohort
effect (indicated by circles), based on 2-year sets of
contrasts: 1894?1895, 1896?1897, and so on up to
1960?1961 are shown. Solid dark lines represent
slope contrasts, which measure whether the
birthcohort effects are accelerating (upward slope) or
moderating (downward slope). In general,
acceleration indicates either that a rate is increasing or that a
decreasing rate is decreasing less quickly.
Moderation indicates either that a rate is decreasing or that
an increasing rate is increasing less quickly. B)
Differences between adjacent 2-year birth-cohort
effects in relation to the differences in prevalence of
exposure to potentially SV40-contaminated
poliovirus vaccine. Individual data points are plotted as
solid circles. Ordinates equal the differences
between adjacent 2-year birth-cohort effects (i.e.,
1902?1903 versus 1900?1901, 1903?1904 versus
1902?1903, and so on), and abscissas equal the
corresponding differences in the prevalence of exposure
to potentially SV40-contaminated vaccine. The
dark horizontal line is the weighted regression line
between the changes in cohort effects and changes in
prevalence of exposure, and the upper and lower
curved lines indicate the 95% CIs for the regression
line. A positive association between SV40 exposure
and incidence of mesothelioma would be indicated
by increasing positive differences in adjacent
birthcohort effects with increasing differences in the
prevalence of exposure to SV40-contaminated
vaccine (i.e., a line with a positive slope).
(Table 1). The difference between the slopes for the 1928?1935
and the 1918?1927 birth cohorts was ?.068 (95% CI ?.122 to
?.015) (P value for Wald test .013). No other slope contrasts
for males were statistically significant. These results suggest that
the moderation in risk that started with the 1928?1935 birth
cohorts continued in the subsequent birth cohorts, despite the
much greater exposure of the subsequent birth cohorts to
We also examined short-term (i.e., 2-year) changes in
birthcohort effects and assessed the association between those
changes and trends in the prevalence of exposure to
SV40contaminated vaccine. The findings for males are summarized in
Fig. 3, B. As shown, the ordinates equal the difference between
adjacent (i.e., 2-year) birth-cohort effects (for example, 1902?
1903 versus 1900?1901 and 1903?1904 versus 1902?1903), and
the abscissas equal the corresponding differences in the
prevalence of exposure to potentially SV40-contaminated vaccine.
The slope of the weighted regression line did not differ
statistically significantly from zero (slope 0.0076, standard error
0.011, P .49). Thus, short-term changes in birth-cohort effects
were not related to short-term changes in rates of vaccine
exposure. The results among females were similar, except that a
statistically significant moderation in risk was observed earlier
among females, beginning with the 1918?1927 birth cohort, than
it was among males (Table 1). As in males, there was no
association in females between the short-term changes in
birthcohort effects and changes in the probability of exposure to
SV40-contaminated poliovirus vaccine; i.e., the slope of the
weighted regression line for the 2-year contrasts was not
statistically significantly different from zero (slope ?0.0096,
standard error 0.0253, P .70).
SV40 contaminated the poliovirus vaccines used during the
late 1950s and early 1960s, causing the largest single-source
exposure of humans to this tumorigenic monkey virus (
1961, most U.S. citizens under the age of 40 years had been
injected with poliovirus vaccine that potentially contained live
SV40. In the past few years, an increasing number of polymerase
chain reaction-based studies have reported the detection of SV40
genomic DNA sequences in pleural mesothelioma tumor
), raising concerns that exposure to contaminated
vaccine might have caused human infection with SV40, which in
turn might have led to the development of these tumors (12). To
assess the relationship between SV40-contaminated poliovirus
vaccine exposure and subsequent rates of pleural mesothelioma,
we studied cancer incidence data from SEER, which comprises
a representative sample of approximately 10% of the U.S.
population, and nationwide prevalence rates of poliovirus vaccine
immunization between 1955 and 1961.
The data show that pleural mesothelioma has remained an
uncommon tumor, with an incidence of less than one case per
100 000 py and a sixfold predominance in males versus females.
The persistent rarity of pleural mesothelioma among women,
whose average incidence of the disease is 0.21/105 py, is
noteworthy because both sexes were exposed to SV40-contaminated
poliovirus vaccine in similar numbers. The small number of
cases that did arise in women mainly involved those in the oldest
age groups, which were the least likely of all the age groups to
have ever received the poliovirus vaccine.
The paucity of pleural mesothelioma cases in females, and
the lack of an association between cases of the disease and
immunization (in either sex), argues against an independent
association between pleural mesothelioma and exposure to
SV40contaminated vaccine. Some investigators have suggested that
exposure to SV40-contaminated vaccine might have specifically
increased the risk of pleural mesothelioma in individuals who
were not exposed to asbestos (
). However, our findings
suggest that the number of such cases, if any, that might be
attributable to SV40-contaminated vaccine exposure would be a
fraction of the low number of cases in women plus a similar small
number of cases in men. Although it has been speculated that
alternative routes of exposure to SV40, such as person-to-person
transmission or unrecognized contamination of oral poliovirus
vaccines after 1963, might have caused an increased risk of
), recent studies have challenged the occurrence
of such exposures (
). Moreover, the persistent rarity of
pleural mesothelioma in females suggests that, even if
alternative exposures to SV40 exist, they did not have a substantial
independent effect on the risks of pleural mesothelioma.
Could SV40 represent an etiologic cofactor that interacts with
asbestos to cause pleural mesothelioma? An interaction of this
type would readily explain the predominance of cases in males,
given that men have had much greater occupational exposures to
asbestos than women (we are unaware of animal models or other
data to suggest any other basis for the sex-related differences in
the effects of SV40 exposure on risk of mesothelioma).
However, the age-specific incidence trends for pleural mesothelioma
in men during recent decades do not suggest an association with
SV40-contaminated poliovirus vaccine exposure. In men, as in
women, increasing rates occurred most among those in the
oldest age groups, which were the least likely to have been exposed
to poliovirus vaccine during the period of widespread SV40
contamination, whereas rates in the heavily exposed 25- to
44year and 45- to 54-year age groups remained stable or decreased
over time. In addition, most studies (
) that have reported
the detection of SV40 DNA in human pleural mesothelioma
have failed to detect differences in SV40 prevalence according
to asbestos exposure, which would be expected if the putative
association of SV40 with pleural mesothelioma was limited to
those who were also exposed to asbestos.
Our age?period?cohort model provided a comprehensive
statistical assessment of trends in pleural mesothelioma incidence.
Among men, birth-cohort effects showed a pattern of
moderation in incidence rates, beginning with the 1928?1935 birth
cohort, that was consistent with reported trends in occupational
exposure to asbestos (
). However, there was no evidence of an
acceleration in incidence in subsequent birth cohorts that had
higher exposures to SV40-contaminated poliovirus vaccine. The
similarity of the observed incidence rates to the expected
incidence rates derived by our model suggests that the data were
adequately described in the analysis. Similarly, in women, the
age?period?cohort model provided no evidence of an
acceleration in incidence among birth cohorts that was attributable to
exposure to SV40-contaminated poliovirus vaccine.
Our study has three important limitations. First, the absolute
number of pleural mesothelioma cases in the United States from
1975 through 1997 was both small and, in recent years,
decreasing. Second, we lacked individualized exposure data, including
the amount of live virus (most of which was probably low) in
each vaccination. Third, trends in incidence that are derived
from surveillance data reflect the net impact of all risk factors
that affect the population rather than any single effect that might
be associated with a calendar period or birth cohort. For all these
reasons, cancer incidence trends could fail to detect some
effects introduced by exposure to SV40-contaminated poliovirus
On the other hand, if an association between vaccine-related
SV40 exposure and incidence of pleural mesothelioma was
missed because of the limitations of the current analyses, it
would appear that the effect was too small to be detected using
the best available data in the United States, which consisted of
more than 500 million py of observation. Furthermore, our
findings are consistent with negative results obtained in previous
epidemiologic studies carried out both in the United States and
in Europe (
), as well as with the results of a recent
international multilaboratory study (25). In that study, none of nine
independent laboratories reproducibly detected SV40 DNA in
any of 25 frozen mesothelioma tumor specimens (
Our findings are also compatible with a recent survey of U.S.
mesothelioma incidence trends, which concluded that the
observed variations in mesothelioma rates could be adequately
explained by the changing patterns of asbestos exposure (
Notably, in Sweden, where adults did not receive
SV40contaminated poliovirus vaccine, there has been an upward trend
in mesothelioma incidence similar to that observed in the United
). A published model (
) of mesothelioma rates for
U.S. men predicts that those rates will continue their current
decline and eventually reach the very low levels observed in
Thus, after almost 40 years of follow-up, U.S. cancer
incidence data have not shown an increased incidence of pleural
mesothelioma among the birth cohorts that were exposed to
SV40-contaminated poliovirus vaccine. Although the findings
have been reassuring to date, continued surveillance of all
vaccine-exposed cohorts is needed, in view of conflicting reports on
the detection of SV40 genomic DNA sequences in
mesothelioma tumor samples.
1Editor?s note: SEER is a set of geographically defined, population-based
central cancer registries in the United States, operated by local nonprofit
organizations under contract to the National Cancer Institute (NCI). Registry data are
submitted electronically without personal identifiers to the NCI on a biannual
basis, and the NCI makes the data available to the public for scientific research.
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