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OCR for page 40
3
Epidemiologic Studies
T o assess the presumptive period for the association between exposure to
herbicides in Vietnam and their contaminants (2,4-dichlorophenoxyace-
tic acid [2,4-D], 2,4,5-trichlorophenoxyacetic acid [2,4,5-T] and its con-
taminant 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], cacodylic acid, and
picloram) and increased risk of respiratory cancer, the epidemiology literature
must be examined. Veterans and Agent Orange: Health Effects of Herbicides
Used in Vietnam (IOM, 1994) and its updates (IOM, 1996, 1999, 2001, 2003)
review the entire relevant literature on herbicide exposure, but this chapter dis-
cusses articles that the committee believes reflect, with reasonable accuracy, the
length of time between herbicide or TCDD exposure and occurrence of respira-
tory cancer with sufficient respiratory-cancer cases to support some judgment
about the patterns of relative risks reported. The committee searched the litera-
ture for epidemiologic studies on the presumptive period for exposure to TCDD
or the herbicides used in Vietnam and the risk of respiratory cancer. No such
studies were found. However, evidence regarding the latent period was found
and, because that evidence can provide some information related to the presump-
tive period, the results of those studies are reviewed in detail.
The chemicals of interest that were sprayed in Vietnam were 2,4-D, 2,4,5-T
and its contaminant TCDD, picloram, and cacodylic acid. No data are available
that are relevant to the latent or presumptive periods that might exist if there
were an association between 2,4,5-T or picloram and respiratory cancer. There
are also insufficient data on humans to assess the latent period for cacodylic acid
and respiratory cancer. Cacodylic acid is dimethylarsinic acid. In addition to
being produced for use as a herbicide, dimethylarsinic acid is formed as a me-
tabolite in humans after exposure to inorganic arsenic. Many epidemiologic stud-
40
OCR for page 41
EPIDEMIOLOGIC STUDIES 41
ies have been conducted on populations exposed occupationally to inorganic
arsenic. Although data indicate that dimethylarsinic acid might be the metabolite
that mediates the carcinogenicity of inorganic arsenic, the dose-response and
kinetics underlying the carcinogenicity of inorganic arsenic compared to expo-
sure to dimethylarsinic acid are not characterized well enough to directly ex-
trapolate epidemiologic data from inorganic arsenic exposure to dimethylarsinic
acid exposure. Therefore, studies of inorganic arsenic exposure are not reviewed
here. Of the chemicals, the most data are available on populations exposed to
TCDD or 2,4-D. The relevant epidemiologic studies of those chemicals are de-
scribed in this chapter. The pertinent discussion that appeared in Update 1998 is
included here for completeness.
Because respiratory cancer is fairly common, the committee has focused on
studies with at least seven cases.
REVIEW OF STUDIES
The National Institute for Occupational Safety and Health (NIOSH) study of
chemical-production workers gives the most detailed account of timing effects
and exposure to TCDD (Fingerhut et al., 1991). Standardized mortality ratios
(SMRs) for respiratory cancer (lung, bronchus, and trachea) were 0.8, 1.0, and
1.2 for 09, 1019, and 20+ years, respectively, since first exposure to TCDD,
on the basis of a total of 85 cases. SMRs for time since first exposure are further
stratified by duration of exposure, as reproduced in Table 3-1. An association
between TCDD exposure and respiratory cancer is not observed in years 09
after first exposure. Effects begin to be observed in the second decade after
exposure began among those with at least 5 years of exposure, and they have not
TABLE 3-1 NIOSH Study: Respiratory-Cancer Relative Mortality, by
Time Since First Exposure and Duration of Exposure to TCDDa
Duration of Exposure to TCDD (years)
Time Since <1 14 514 15+ Overall
First Exposure
(years) Obs SMR Obs SMR Obs SMR Obs SMR Obs SMR
09 3 0.8 3 1.0 1 0.8 0 0.0 7 0.8
1019 6 0.7 5 0.8 9 1.8 1 1.4 21 1.0
20+ 17 1.0 17 1.3 14 1.5 9 1.6 57 1.2
Total 26 0.9 25 1.1 24 1.5 10 1.5 85 1.1
aData from Fingerhut et al. (1991), Table 4. No confidence intervals were provided, but all p-
values were greater than 0.05.
ABBREVIATIONS: NIOSH, National Institute for Occupational Safety and Health; Obs, observed;
SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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42 VETERANS AND AGENT ORANGE
disappeared 20 or more years after first exposure. The latency may be longer for
those with shorter exposure.
A later assessment of this cohort (Steenland et al., 1999) was based on an
additional 6 years of follow-up and a job-exposure matrix that ranked 3,538
workers (69% of the cohort) on relative exposure to TCDD. An analysis using
Cox regression models and an assumption of 15-year latency after initial em-
ployment found a statistically significant trend between exposure and lung can-
cer mortality among the workers, with highest mortality in the top two septiles of
exposure (hazard ratios = 2.6 (1.35.0) and 1.6 (0.83.4) for septiles 6 and 7,
respectively). Analyses were repeated with different values for latency (5, 10,
and 20 years, in addition to 15 years). The authors reported that the model based
on 15-year latency provided the best fit with the data for the analysis of all
cancers combined. No information was provided on the alternative latency as-
sumptions for the analysis of lung cancer alone, and goodness of fit in a limited
set of models is not necessarily a reliable means of determining the appropriate
latent period, which will vary across individuals.
One of the largest industrial accidents involving environmental exposure to
TCDD occurred in Seveso, Italy, in July 1976 as a result of an uncontrolled
reaction during trichlorophenol production. On the basis of soil sampling, three
areas were defined about the release point: Zone A, the most heavily contami-
nated, from which all residents were evacuated within 20 days; Zone B, an area
of less contamination that children and pregnant women in their first trimester
were urged to avoid during the daytime; and Zone R, a region with some con-
tamination in which consumption of local crops was prohibited. Data from
Seveso in Bertazzi et al. (1989a,b) and summarized in Tables 3-2a and 3-2b
indicate that lung cancer mortality was not increased among those in the exposed
areas during the period from 0 to 5 years after the accident but was increased in
years 610 for Zones A and B. In the 15-year follow-up of the Seveso cohort, no
additional data are presented on latency for lung cancer (Bertazzi et al., 1997),
but given the results from several publications, the committee has calculated the
relative risk for years 1115 as 1.0 in all three zones.
A report on the 20-year follow-up of the Seveso cohort (Bertazzi et al.,
2001) is summarized in Table 3-2c. Data are shown for lung cancer (ICD-9 code
162) mortality in men of Zones A and B combined and for periods since expo-
sure that are slightly different from the categories displayed in Table 3-2a. A
modest increase in lung cancer mortality is observed for years 59 and 1520,
but there is no increase in the first period or in years 1014. No latency analyses
are presented for Zone R, and the number of lung-cancer deaths in women (four)
is too small for an informative analysis of latency.
In an 18-year follow-up of Finnish herbicide appliers, Asp et al. (1994) gave
the SMRs for respiratory cancer (lung, bronchus, and trachea) relative to the
Finnish male calendar-year- and age-specific rates in such a way that SMRs
could be calculated by time since first exposure for 09, 1015, and >15 years.
OCR for page 43
EPIDEMIOLOGIC STUDIES 43
TABLE 3-2a Seveso Study: Lung Cancer Mortality Risk Ratios in Men,
by Calendar Period
Relative Risk
Time Since
Exposure (years) Zone A Zone B Zone R
05 0.0 1.1 0.7
610 2.0 1.8 0.9
1115a 1.0 1.0 1.0
aRelative risks have been calculated by using data from the two published reports.
Data from Bertazzi et al., 1997, Table 3; Bertazzi et al., 1989b, Tables 4, 5, and 7.
TABLE 3-2b Seveso Study: Lung Cancer Mortality in Men for 15-year
Follow-up
Relative 95%
Observed Expected Risk Confidence Interval
Zone A 4 4.2 1.0 (0.42.6)
Zone B 34 27.6 1.2 (0.91.7)
Zone R 178 194.4 0.9 (0.81.1)
Data from Bertazzi et al., 1997, Table 3.
TABLE 3-2c Seveso Study: Lung Cancer Mortality in Men, by Years
Since First Exposure
Zones A and B
Time Since First Relative 95%
Exposure (years) Observed Expected Risk Confidence Interval
04 9 8.9 1.0 (0.52.0)
59 15 9.7 1.5 (0.92.6)
1014 14 12.7 1.1 (0.61.9)
1520 19 12.8 1.5 (0.92.4)
Data from Bertazzi et al., 2001, Table 7.
There is no clear pattern according to time since first exposure, but there also is
no overall association with respiratory cancer, probably because the exposures
averaged only 4 weeks.
Another study from Finland examined the incidence of cancer in a cohort of
152 male workers in a pulp and paper mill (Jappinen and Pukkala, 1991). The
cohort was limited to workers employed in 19451961 in jobs with the greatest
OCR for page 44
44 VETERANS AND AGENT ORANGE
respiratory or skin exposure to chlorinated organic compounds, including TCDD.
The expected incidence of cancer was calculated from age- and calendar-specific
rates for the mill district. During 34 years of follow-up (19531987), seven cases
of lung cancer occurred (standardized incidence ratio, 3.0; 95% confidence inter-
val (CI), 1.26.2). Six of the seven cases were diagnosed 15 years or more after
initial employment in the mill. The authors acknowledged that company health
records showed that six of the cases were in smokers.
In a report on four occupational cohorts involved in phenoxy herbicide and
chlorophenol manufacturing in Germany, Becher et al. (1996) showed the rela-
tive risk to be highest in the first decade (SMR, 1.80) and to decline but remain
elevated thereafter (SMR, 1.38 1020 years after exposure, 1.35 thereafter).
The chemicals produced included 2,4-D and 2,4,5-T, and exposure to TCDD
was also likely in most of the cohorts. Those results are based on 47 lung cancer
deaths, and the study had an overall SMR of 1.4. The data are presented in
Table 3-3.
A different pattern of results was observed in a study of 549 men in the
Netherlands employed during 19551985 in a factory whose main product was
2,4,5-T. Bueno de Mesquita et al. (1993) monitored cause-specific mortality for
the same 30-year period and identified nine deaths from respiratory cancer (SMR,
1.0; bronchus, lung and trachea). In analyses stratified by time since first expo-
sure, six of the respiratory cancer deaths occurred after 20 years of exposure
(SMR, 1.7). Hooiveld et al. (1998) extended the follow-up by 6 years (through
1991) and reported SMRs of 1.0 overall (based on 14 deaths) and 1.3 for workers
first exposed 20 years ago or earlier.
Coggon et al. (1991) examined cancer mortality in the male employees of
four British factories that manufactured a variety of phenoxy herbicides. The
cohort included 2,239 men who worked during 19631985, and follow-up for
mortality was complete through 1987. Nineteen deaths were attributed to respi-
ratory cancer (SMR, 1.3; lung, pleua, and mediastinum), but only six of the
cases occurred more than 10 years after initial exposure to phenoxy compounds
(SMR, 0.9).
TABLE 3-3 German Phenoxy Herbicide and Chlorophenol Manufacturing
Workers Study: Observed and Expected Lung Cancer Deaths and SMRs
for Men, by Time Since First Exposure
Time Since First
Exposure (years) Observed Expected SMR 95% CI
<10 8 4.4 1.8 (0.83.6)
10 to <20 14 10.1 1.4 (0.82.3)
20+ 25 18.4 1.4 (0.92.0)
Data from Becher et al., 1996, Table 4.
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EPIDEMIOLOGIC STUDIES 45
TABLE 3-4 IARC International Study of Workers Exposed to TCDD or
Higher Chlorinated Dioxins: Observed and Expected Lung Cancer Deaths
and SMRs for Men, by Time Since First Exposure
Time Since First
Exposure (years) Observed Expected SMR 95% CI
09 34 27.9 1.2 (0.91.7)
1019 64 61.5 1.0 (0.81.3)
20 127 110.4 1.2 (1.01.4)
Data from Kogevinas et al., 1997, Table 5.
The cohorts from Germany, the Netherlands, and England (and the afore-
mentioned NIOSH study cohorts) were included in the much larger International
Agency for Research on Cancer (IARC) multicohort occupational study
(Kogevinas et al., 1997). The IARC study found a weak overall association
between exposure to phenoxy herbicides or chlorophenols and lung cancer mor-
tality (SMR, 1.1 based on 225 deaths). The SMRs for 09, 1019, and 20+ years
in the IARC study were 1.2, 1.0, and 1.2, respectively, on the basis of 34, 64, and
127 lung cancer deaths. The IARC results are shown in Table 3-4.
The study of Ranch Hands (Michalek et al., 1998) examines latency for
several cancer sites but does not define whether it involves time since first ser-
vice, since last service, since start of service in Vietnam, or since last service in
Vietnam. This group of veterans experienced fewer respiratory cancer deaths
than expected in the first 20 years (3 observed and 5.6 expected) and a slight
excess after 20 years (9 observed and 7.2 expected).
A report on the Australian veterans who served in Vietnam provides addi-
tional information on the time since first year of service (Crane et al., 1997). The
first year of service may have been earlier than the first year in Vietnam or the
first year of exposure, so latency observed in these data would be longer than the
actual latency. The pattern of SMRs for lung cancer deaths during 19801994
(no lung cancers were observed before 1980) was as follows: 2.5, 0.9, 1.3, 1.3,
and 1.1 for the periods 25 years, respectively,
since the start of service. Note, however, that the SMR of 2.5 in the early period
is based on only three lung cancer deaths, whereas the remaining periods had 17,
60, 95, and 35 lung cancer deaths, respectively. The results can be found in
Table 3-5.
In addition, two recent studies have used toxicokinetic models to obtain a
measure of cumulative dose and have used this as an exposure metric in analy-
sis of increased cancer risk associated with TCDD exposure. Steenland et al.
(2001) estimated cumulative dose from both estimated external exposure and
known serum TCDD. The cumulative dose was calculated with a simple one-
compartment first-order model, assuming a half-life of 7.1 years. The study
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46 VETERANS AND AGENT ORANGE
TABLE 3-5 Australian Vietnam Veterans Study:
Observed and Expected Lung Cancer Deaths and
SMRs for Men, by Time Since Start of Military
Service
Time Since Start
of Service (years) Observed Expected SMR
<10 3 1.2 2.5
1115 17 19.7 0.9
1620 60 45.9 1.3
2125 95 73.0 1.3
>25 35 32.2 1.1
Data from Crane et al., 1997, Table E-19.
assumed a background intake of 0.5 pg/kg of body weight per day, leading to a
steady-state level of about 5 parts per trillion (ppt) in blood lipids. To estimate
risk, the authors assumed an intake of 10 pg/kg per day. The exposure-response
analysis used a cumulative TCDD dose and integrated time-specific serum con-
centrations over time to obtain a cumulative serum concentration for each per-
son in the study. A similar cumulative dose was obtained from exposure scores
at the end of exposure, and this did not differ much from the cumulative expo-
sure based on serum concentrations. There was an increasing cancer risk with
increasing cumulative TCDD dose in the serum, assuming a 15-year lag. The
authors acknowledged limitations in their approach, one being the use of a
constant estimated half-life; TCDD half-life may vary with body-mass index,
initial body burden, and other factors. However, the cumulative dose (derived
from serum concentrations) was judged to be a "reasonably good predictor" of
cancer risk. The study by Steenland et al. dealt with all cancers, and although the
analysis did not deal specifically with respiratory cancer, it does demonstrate a
use of cumulative dose measures.
Salvan et al. (2001) also used a cumulative dose as an exposure metric to
estimate cancer risk, for all cancers and for lung cancer specifically. They exam-
ined the NIOSH cohort data by using a minimal physiologic toxicokinetic model
that assumes TCDD concentrations to be in dynamic equilibrium among three
lipid compartments in the body--blood, liver, and adipose tissue--with assump-
tions about TCDD elimination and intake. The model used for analysis of the
NIOSH cohort was developed with data on Ranch Hands, for whom serum con-
centrations were available at multiple times. The study used three methods to
estimate elimination and input, including nonlinear least squares, a nonlinear
mixed-effects model, and a hierarchic model with Bayesian analysis. The cumu-
lative dose, expressed in ppt-years, was related to the all-cancer risk, assuming a
10-year lag from first exposure. The analysis showed an increase in risk ratio of
OCR for page 47
EPIDEMIOLOGIC STUDIES 47
2 for exposures at 100 times background. The authors acknowledged limitations,
including an inability to adjust for smoking. Despite the limitations, the value of
using a cumulative dose as an exposure metric appears to be upheld.
When reviewing those two studies (Salvan et al., 2001; Steenland et al.,
2001), however, it must be remembered that the relationships between cumula-
tive dose and respiratory-system dose and between dose and response in the
respiratory system are not clear. It is assumed that the continuing exposure esti-
mated from serum concentrations indicates the degree to which the respiratory
system is exposed. Whether the cumulative dose pertains to questions of latency
when serum concentration has fallen to the background value is not clear.
SUMMARY
In reviewing the epidemiologic evidence on the timing of exposure to the
chemicals of interest (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid,
and picloram) and respiratory cancer, the relevant studies had exposure to either
the herbicides and TCDD, or TCDD alone. There were no data available on the
latent or presumptive period for the individual herbicides.
Despite a few suggestions in the literature, based on small numbers of deaths,
that the highest risk is shortly after start of exposure, the preponderance of the
evidence suggests that risk remains elevated at least 15 and probably more than
20 years after exposure. There is no indication that risks return to background
levels during the entire length of follow-up, which in many studies is more than
25 years after exposure ends. Nevertheless, no data have been published at all
regarding the time between cessation of exposure to TCDD and risk of respira-
tory cancer.
The NIOSH study (Fingerhut et al., 1991) does not begin to show an effect
until 10 years after exposure, and risks were increased the most 20 years or more
after exposure began. Six years later, a follow-up study of this cohort found a
statistically significant trend between exposure and lung cancer mortality among
workers; a 15-year latency period was the best fit for the study data (Steenland et
al., 1999). The data on the Seveso cohort (Bertazzi et al., 1989a,b; 1997) show
an increased occurrence of death from lung cancer beginning 610 years after
initiation of an exposure. The 20-year follow-up of the Seveso cohort also showed
similar elevations in risk for the periods 59 and 1520 years since first exposure
(Bertazzi et al, 2001). A study of workers involved in the manufacturing of
phenoxy herbicide and chlorophenol showed the relative risk to be high in the
first three decades after exposure begins (Becher et al., 1996). A mortality study
of a different cohort of male factory workers employed by factories that manu-
factured phenoxy herbicides found nineteen deaths attributed to lung cancer
(SMR, 1.3); 6 of these cases occurred more than 10 years after exposure in the
factory (SMR, 0.9) (Coggon et al., 1991). The IARC cohort (Kogevinas et al.,
1997) demonstrates elevations in lung cancer in the first and third decade after
OCR for page 48
48 VETERANS AND AGENT ORANGE
exposure. Among Australian Vietnam veterans (Crane et al., 1997), risks were
elevated 2125 years, but not greater than 25 years, after exposure. The latest
report on Ranch Hands (Michalek et al., 1998) shows a reduced risk of lung
cancer death in the first 20 years after exposure and a slightly elevated risk after
20 years.
A study of Finnish pulp and paper mill workers found 7 cases of lung cancer
(3.0; 95% CI, 1.26.2); 6 of the 7 cases were diagnosed 15 years or more after
initial employment (Jappanin and Pukkala, 1991). Six out of 9 respiratory cancer
deaths in a cohort of factory workers involved in the production of 2,4,5-T
occurred after 20 years of exposure (Bueno de Mesquita et al., 1993). A follow-
up study of this cohort reported 14 respiratory cancer deaths and SMRs of 1.0
overall (based on 14 deaths); workers first exposed 20 years or more earlier had
an SMR of 1.3 (Hooiveld et al., 1998).
The committee finds evidence in the literature that the time between expo-
sure and the detection of respiratory cancer depends on the duration of exposure;
this evidence is in the Fingerhut et al. (1991) study, the only analysis that pre-
sented a cross-classification of time since first exposure with duration of expo-
sure. With latency depending on the duration of exposure, one would not neces-
sarily expect to see the same pattern for time since exposure in all studies. Nor
would one expect the pattern of risk over time since exposure to be the same in
Vietnam veterans as in those exposed in manufacturing plants or through acci-
dental environmental releases of the same chemicals.
In summary, numerous studies have examined latency by stratifying on time
since first exposure using the simplest approaches described in Chapter 2. Some
of the data suggest that an increased risk of respiratory cancer occurs within 10
years of first exposure. No analyses examined the presumptive period for TCDD,
that is, the time between termination of exposure and the end of an effect on the
incidence of respiratory cancer. Data on latency in epidemiology studies provide
a framework for the consideration of a presumptive period, but are not sufficient
for drawing quantitative conclusions regarding the length of that period. The
relationship between cumulative or peak dose in TCDD carcinogenesis is un-
known, and the relative importance of the first or any specific window of expo-
sures remains unclear because information from epidemiologic studies has not
been sufficient to disentangle them. Although risk factors for cancer can be
determined in a population, for any given individual who develops respiratory
cancer, the exact exposures that contributed to the pathogenesis of that cancer
cannot usually be determined with certainty. Therefore, there is no clear indica-
tion of the presumptive period; but in many of the studies, there also is no
indication that the risk returns to background values during the entire length of
follow-up, often more than 25 years. That is, some increased risk remains for at
least 20 or 25 years after exposure began. Most of the studies, however, have not
followed the cohort beyond 30 years, leaving no data with which to determine a
latent or presumptive period beyond that time frame.
OCR for page 49
EPIDEMIOLOGIC STUDIES 49
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Representative terms from entire chapter:
lung cancer
