|
Items in cart [0] |
Questions? Call 888-624-8373 |
|
||||||||||||||||
|
||||||||||||||||
|
||||||||||||||||
| ||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||
| Copyright © 2009. National Academy of Sciences. All rights reserved. Terms of Use and Privacy Statement |
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 15
Research Highlights
BIRTH DEFECTS
Introduction
This section taken from Chapter 9 of the full report summarizes published
scientific literature on exposure to herbicides and birth defects. A complete
discussion of the evidence is presented for these adverse reproductive/develop-
mental outcomes because the committee has changed its assessment of this litera-
ture since the release of VAO. In VAO, the committee concluded that the evi-
dence at that time was inadequate or insufficient to determine whether an
association existed between exposure to herbicides and birth defects.
Background
The March of Dimes defines a birth defect as "an abnormality of structure,
function or metabolism, whether genetically determined or as the result of an
environmental influence during embryonic or fetal life" (Bloom, 1981~. Other
terms often used interchangeably with birth defects are "congenital anomalies"
and "congenital malformations." Major birth defects are usually defined as those
abnormalities that are present at birth and severe enough to interfere with viabil-
ity or physical well-being. Major birth defects are seen in approximately 2 to 3
percent of live births (Kalter and Warkany, 1983~. An additional 5 percent of
birth defects can be detected with follow-up through the first year of life. Given
the general frequency of major birth defects of 2 to 3 percent and the number of
15
OCR for page 16
6
VETERANS AND AGENT ORANGE: UPDATE 1996
men who served in Vietnam (2.6 million), and assuming that they had at least
one child, it has been estimated that 52,000 to 78,000 babies with birth defects
have been fathered by Vietnam veterans, even in the absence of an increase due
to exposure to herbicides or other toxic substances (Erickson et al., 1984a).
Epidemiologic Studies of Birth Defects
Because the publication of new data from the Ranch Hand study has caused
the committee to change its conclusion about the strength of the evidence regard-
ing the association between exposure to herbicides used in Vietnam and birth
defects, the following material was included from VAO to present a complete
picture about the evidence for the committee's conclusions. The section entitled
"Ranch Hand Study," however, is based on the new information. Chapter 6 of
the full report discusses in greater detail the characteristics of each study.
Occupational Studies
Four occupational epidemiology studies have examined the potential asso-
ciation between herbicide exposure of male workers and birth defects. The
Townsend study (Townsend et al., 1982) of workers with potential dioxin expo-
sure at a Dow Chemical plant did not find an increased risk of birth defects
among dioxin-exposed workers (30 births with anomalies; 47/1,000 births) com-
pared to unexposed workers (87 births with anomalies; 49/1,000 births; OR = 0.9,
CI 0.5-1.4~. A major limitation of this study is its limited statistical power to
detect an elevated odds ratio for specific defects. The authors noted that the study
had 26 percent power to detect a doubling of risk due to exposure for a group of
indicator malformations (anomalies thought to be easily recognized and reported
by the mother, such as an oral cleft, spine bifida, and Down's syndrome). An
additional problem is that despite the use of these "indicator malformations,"
without medical records, validation of the accuracy of maternal self-report of
birth defects is questionable for many conditions.
Two studies of workers from a 2,4,5-T plant in Nitro, West Virginia, did not
report an association with birth defects among offspring (Moses et al., 1984;
Suskind and Hertzberg, 1984~. The relative risk estimates for any birth defect
were 1.3 (CI 0.5-3.4) for Moses et al. and 1.1 (CI 0.5-2.2) from the Suskind and
Hertzberg study. Both studies had limited statistical power, given the small
number of subjects (204 exposed workers in the Suskind and Hertzberg study;
117 exposed workers in the Moses study). This is especially problematic for the
evaluation of most specific birth defects. Both studies also relied on self-reports
for the ascertainment of birth defects.
A study of 2,4,5-T sprayers found only a slightly elevated odds ratio for
congenital anomalies (OR = 1.2, CI 0.5-3.0) associated with the spraying group
(Smith et al., 1982~. The study used self-administered questionnaires to deter
OCR for page 17
RESEARCH HIGHLIGHTS
17
mine outcomes. Like the other studies, it had limited power for the analysis of
individual birth defects.
Environmental Studies
A variety of environmental studies have examined the relationship between
herbicide exposure and prevalence of birth defects (Nelson et al., 1979; Gordon
and Shy, 1981; Hanify et al., 1981; Mastroiacovo et al., 1988; Stockbauer et al.,
1988; White et al.,1988; Fitzgerald et al., 1989; Jansson and Voog,1989~. Some
studies reported a statistical association with specific birth defects (clubfoot,
Fitzgerald et al., 1989; cleft lip with or without cleft palate, Gordon and Shy,
1981; heart, hypospadias, clubfoot, Hanify et al., 1981; oral clefts, Nelson et al.,
1979), although others have not reported an association (Stockbauer et al., 1988;
Fitzgerald et al., 1989; Jansson and Voog, 1989), including the Seveso study
(Mastroiacovo et al., 1988~. Interpretation of the results of these environmental
studies is difficult, because most of the studies were inconsistent, were based on
ecologic correlations, had inadequate statistical power, did not validate birth
defects recorded from vital statistics or self-reports, and included both male and
female exposures.
A recently published study from Vietnam evaluated the risk of birth defects
among the offspring of mothers who resided in a village in the southern part of
the country that had been sprayed during the conflict (Phuong et al., 1989~; 81
cases of birth defects (diagnosis not specified) were identified. No differences
were reported between cases and controls for the potentially confounding factors
investigated. Strong associations were found for birth defects (calculated from
data presented; OR = 3.8, CI 1.1-13.1~. The paper is difficult to evaluate given
the sparse details presented. Study design factors such as how birth defects were
diagnosed and what types were detected, the size of the original case and control
groups from which the final groups were sampled, the pattern of patient accrual
for this hospital, the method of data collection, and how the potential herbicide
spraying histories were determined were not specified. Finally, to put the study
in the context of this review, the potential exposure 17 to 22 years earlier pertains
to both the mother and the father.
Results from a number of other studies from Vietnam, both of sprayed vil-
lages in the southern part of the country and of veterans returning to the unsprayed
northern regions, have been reported, mostly in a review by Constable and Hatch
(1985~. These studies indicate an increased risk of birth defects, including anen-
cephaly, oral clefts, and a variety of other anomalies. Nonetheless, these studies
generally suffer from poor reporting and a variety of methodologic problems
such as limited control of confounding factors, use of a referral hospital, lack of
comparison groups, uncertainty of exposure classification, and no validation of
reported birth defects. Although the findings are suggestive of an association
OCR for page 18
8
VETERANS AND AGENT ORANGE: UPDATE 1996
between herbicide spraying and birth defects, the available studies are insuffi-
cient to draw firm conclusions.
Vietnam Veterans Studies
As part of the CDC Vietnam Experience Study (1989), the reproductive
outcomes and the health of children of male veterans were examined. The VES
assessment included a telephone interview, a review of hospital birth defect
records for a subsample of veterans who underwent a medical examination, and a
review of the medical records of selected birth defects for all study subjects.
The interview data revealed that Vietnam veterans reported more birth de-
fects (64.6 per 1,000 total births) among offspring than did non-Vietnam veterans
(49.5 per 1,000 total births). The adjusted odds ratio estimate for congenital
anomalies as a group was 1.3 (CI 1.2-1.4~. When examined by specific defect
category, elevated adjusted odds ratios were found for defects of the nervous
system (OR = 2.3, CI 1.2-4.5~; ear, face, neck (OR = 1.6, CI 0.9-2.8~; and
integument (OR = 2.2, CI 1.2-4.0~. A small but statistically significant odds ratio
of 1.2 (CI 1.1-1.5) was found for musculoskeletal defects. An analysis of specific
defects considered by the investigators to be relatively common and reliably
diagnosed was also conducted. Elevated (crude) odds ratios were reported for
hydrocephalus (OR = 5.1, CI 1.1-23.1), spine bifida (OR = 1.7, CI 0.6-5.0), and
hypospadias (OR = 3.1, CI 0.9-11.3~. Vietnam veterans also reported having
more children with multiple defects (OR = 1.6, CI 1.1-2.5) than non-Vietnam
veterans. An analysis of Vietnam veterans' self-reported herbicide exposure
found a dose-response gradient, with an adjusted odds ratio for birth defects of
1.7 (CI 1.2-2.4) at the highest level of exposure.
The VES also examined serious health problems in the veterans' children;
that is, the veterans were asked to report physician-diagnosed major health prob-
lems or impairments during the first five years of their children's lives. About
half of the health conditions reported were respiratory disease (mostly asthma
and pneumonia) and otitis media. For most of the conditions, the veterans re-
ported more health conditions than non-Vietnam veterans (all conditions, OR =
1.3, CI 1.2-1.4~. After excluding children with a serious health condition or
either a birth defect or cancer, the overall crude OR was 1.2 (CI 1.1-1.3~. E1-
evated crude odds ratios were found for anemias (OR = 2.0, CI 1.2-3.3), diseases
of the skin (OR = 1.5, CI 1.1-1.9), rash (OR = 2.3, CI 1.1-4.9), and allergies (OR
= 1.6, CI 1.2-2.1~. Without medical records that validate for many of these types
of common conditions and health problems, recall bias may be an explanation for
many of these findings.
The CDC (1989) did conduct two substudies using hospital records to iden-
tify birth defects among the veterans' offspring. The first, the General Birth
Defects Study (GBDS), compared the occurrence of birth defects recorded on
hospital records for the children of Vietnam and of non-Vietnam veterans (130
OCR for page 19
RESEARCH HIGHLIGHTS
19
cases and 112 cases, respectively) who participated in the medical examination
component of the VES. For a variety of characteristics, there were no apparent
differences between the group of men who participated in the exam and the total
interview group. There was no difference in the prevalence of birth defects be-
tween the two groups of children (crude OR = 1.0, CI 0.8-1.3~. There was a slight
but nonsignificant excess for major birth defects (OR = 1.2, CI 0.8-1.9~. When
analyzed by organ system, only digestive system defects appeared to be elevated
(OR = 2.0, CI 0.9-4.6), although the small number of defects precluded the
analysis of several broad categories. The number of defects was also too small
for the analysis of specific individual defects. An analysis by race did indicate an
elevated odds ratio (3.4, CI 1.5-7.6) for black Vietnam veterans. An examination
of the specific defects listed on hospital records for children of black veterans did
not reveal any particular pattern. A comparison of interview and hospital records
was also conducted to evaluate the extent of potential misclassification of veteran
responses. In general, interview responses were not predictive of the presence of
a defect for either veteran group. The agreement between interview and hospital
records was slightly poorer for Vietnam veterans. For example, the positive
predictive value of the interview response for the presence of a defect in the
hospital record was 24.8 percent among Vietnam veterans and 32.9 percent among
non-Vietnam veterans. Sensitivity was 27.1 percent among Vietnam veterans
and 30.3 percent among non-Vietnam veterans. The kappa measure of agreement
was also lower (20.9 percent versus 27.6 percent) among Vietnam veterans.
The second substudy, the Cerebrospinal Malformation (CSM) Study, in-
volved the analysis of medical records for all cases of cerebrospinal malforma-
tions (spine bifida, anencephalus, hydrocephalus) and stillbirths reported by vet-
erans in the interview study. The substudy found 26 cerebrospinal malformations
(live and stillbirths) among children of Vietnam veterans and 12 among children
of non-Vietnam veterans. No formal analysis of the difference in malformations
between the veteran groups was conducted, because negative responses (i.e.,
children without a reported malformation) were not verified and the participation
rates differed between groups (7.8 percent of Vietnam veterans and 22.1 percent
of non-Vietnam veterans refused to participate).
The VES did find suggestive associations for birth defects. It is interesting to
note that some potential associations were found for birth defects considered by
the investigators to be "relatively common, easily diagnosed, and observable at
birth" (CDC, 1989~. These include hydrocephalus (OR = 5.1, CI 1.1-23.1) and
hypospadias (OR = 3.1, CI 0.9-11.3~. The GBDS did not replicate these findings,
but this sample had limited power for the analysis of specific defects. Although
associations were not found for all conditions, there was clearly a general pattern
of a greater prevalence of birth defects in the offspring of Vietnam veterans,
according to self-reports. The authors properly note the potential for recall bias
as an explanation for the pattern of excess risk. As an attempt to evaluate recall
bias, two record validation studies of birth defects were conducted. Overall, the
OCR for page 20
20
VETERANS AND AGENT ORANGE: UPDATE 1996
GBDS did not find any association with an increased risk of birth defects among
offspring of Vietnam veterans. However, this validation study had limited power
to detect an increased risk for specific birth defects. The second validation
substudy, the CSM review, was flawed by the differentially poor response rate
among the non-Vietnam veteran group. This result and the fact that negative
responses were not pursued discouraged the investigators from estimating the
relative risk for cerebrospinal malformations.
Another important study of Vietnam veterans was the CDC Birth Defects
Study (Erickson et al., 1984a,b). In this study, children with birth defects among
428 fathers who were reported to have been Vietnam veterans were compared to
children with birth defects among 268 control fathers who were non-Vietnam
veterans. The odds ratio for Vietnam veteran status in relation to any major birth
defect among offspring was 1.0 (CI 0.8-1.1~. Analysis of the Agent Orange
exposure opportunity index (EOI; see VAO Chapter 6 for details) based on both
military records and self-reports did not indicate a statistically significant trend of
increasing risk of all types of birth defects (combined) with increasing levels of
Agent Orange exposure. No association was noted between Vietnam veteran
status or self-reported Agent Orange exposure and risk of fathering a child with
multiple birth defects (OR = 1.1, CI 0.7-1.7~. The odds ratios for Vietnam
veteran status, self-reported Agent Orange exposure, and logistic regression coef-
ficients for EOI based on self-report and military records for most of the 95 birth
defect groups were not significantly elevated. Although the odds ratio for spine
bifida was not elevated with Vietnam veteran status (OR = 1.1), the EOI indices
showed a pattern of increasing risk. For example, the odds ratios for the EOI
based on information obtained during the interview for low to high levels of
exposure (levels 1 to 5) were 1.2 (CI 1.0-1.4), 1.5 (CI 1.1-2.1), 1.8 (CI 1.1-3.0),
2.2 (CI 1.2-4.3), 2.7 (CI 1.2-6.2~. A similar pattern was found for cleft lip with/
without cleft palate namely, EOI-1 (OR = 1.2, CI 1.0-1.4), EOI-2 (OR = 1.4, CI
1.0-1.9), EOI-3 (OR = 1.6, CI 1.0-2.6), EOI-4 (OR = 1.9, CI 1.0-3.6), and EOI-5
(OR = 2.2, CI 1.0-4.9~. The category "specified anomalies of nails" had an
increased odds ratio for Vietnam veteran status and elevated coefficients (not
statistically significant) for the two exposure indices. The category "other neo-
plasms" was related to the EOI based on the father's self-reported Agent Orange
exposure. This group included a variety of congenital neoplasms such as cysts,
teratomas, and benign tumors. In an attempt to search for a Vietnam veteran birth
defect "syndrome," pairs and triplets of defects were examined for combinations
that yielded significant differences in the distribution among Vietnam veterans
and controls. According to the authors, these analyses did not produce any
important associations or patterns among defect combinations.
The results of this study were generally negative; that is, there was not a
general pattern of increased risk for birth defects among the offspring of Vietnam
veterans. However, the analysis of the Agent Orange EOIs based on military
records found a significant trend for increased risk for spine bifida with increased
OCR for page 21
RESEARCH HIGHLIGHTS
21
exposure. As the authors note, this finding must be viewed with caution, because
a related defect, anencephalus, was not found to be associated with a significant
EOI trend. Another positive association was noted for cleft lip without cleft
palate, where a significant regression coefficient was found for the EOI index
based on the father's interview. No association was found for the EOI from
military records.
The CDC Birth Defects Study has many strengths, including the use of a
population-based registry system with careful classification of birth defects for
analysis. The statistical power of the study was excellent for many major birth
defects. Use of the Agent Orange EOIs is an attempt to refine exposure assess-
ment procedures compared to measures used in most other studies. The study did
have several important limitations. First, the response rates among cases and
controls were problematic, with approximately 56 percent of eligible case and
control fathers interviewed. Examination of the nonparticipation group revealed
lower participation among persons classified as "nonwhite." The analyses by
race did not find important differences, but the potential for bias should not be
overlooked. Another problem relates to the fact that case births occurred from
1968 through 1980, but interviews took place during 1982 and 1983, up to 14
years after the birth. To minimize the potential recall bias induced by this long
lag period, controls were matched on year of birth.
Aschengrau and Monson (1990) studied late adverse pregnancy outcomes
among 14,130 obstetric patients who delivered at Boston Hospital for Women
from August 1977 to March 1980. History of the fathers' military service in
Vietnam was determined from Massachusetts and national military records by
using the husbands' names and Social Security numbers. The likelihood of
combat experience, based on branch of service and military occupation, was used
to estimate potential herbicide exposure. The analyses compared the risk of
malformations among children of 107 Vietnam veterans to that for children of
1,432 men without known military service; the risk in 313 non-Vietnam veterans
compared to the men without military service; and the risk in the Vietnam veter-
ans compared with the non-Vietnam veterans. There was a slight, nonsignificant
increase in the odds ratio for all congenital anomalies for Vietnam veterans
compared to men without known military service (OR = 1.3, CI 0.9-1.9) and for
Vietnam veterans compared with non-Vietnam veterans (OR = 1.2, CI 0.8-1.9~.
For major malformations, the odds ratio was elevated for Vietnam veterans com-
pared with men without military service (OR = 1.8, CI 1.0-3.1), but the ratio
decreased for Vietnam veterans compared with non-Vietnam veterans (OR = 1.3,
CI 0.7-2.4~. Only slight increases were found for the analysis of minor malfor-
mations and "only normal variants." Although based on small numbers, the
analyses of 12 malformation groups found that children of Vietnam veterans,
compared to children of men with no known military service, had an increased
risk of malformations of the nervous system, cardiovascular system, genital or-
gans, urinary tract, and musculoskeletal system. Confidence intervals were not
OCR for page 22
22
VETERANS AND AGENT ORANGE: UPDATE 1996
presented with the odds ratio estimates, but it was noted that they included 1.0, so
elevated risks were not significantly increased. Further examination of specific
anomaly diagnoses for the 18 infants of Vietnam veterans with major malforma-
tions did not reveal any pattern of association with potential herbicide exposure.
Although the study did find a positive association between paternal military
service in Vietnam and the risk of major malformations in offspring, the authors
suggest cautious interpretation of their findings, given the small number of sub-
jects in many of the comparisons involving specific groups of birth defects.
Additionally, it was noted that some of the malformations observed can also be
due to maternal and delivery factors (endocrine condition and fetal presentation).
An important problem relates to misclassification of herbicide exposure due to
equating exposure to service in Vietnam.
Two state health surveys of veterans (Iowa and Hawaii) did not indicate an
increased prevalence of birth defects (Rellahan, 1985; Wendt, 1985), but a survey
in Maine did report an increased risk of birth defects among veterans (Deprez et
al., 1991~. The limitations of these general survey studies affect their usefulness
in this evaluation.
As part of the National Vietnam Veterans Birth Defects/Learning Disabili-
ties Registry and database, a joint project of the Association of Birth Defect
Children and the New Jersey Agent Orange Commission, a self-administered
questionnaire was sent to Vietnam veterans to inquire about birth defects and a
variety of conditions and disabilities in the children of Vietnam veterans and non-
Vietnam veterans (Lewis and Mekdeci, 1993~. A preliminary analysis indicated
no differences in birth defects between the two groups; however, for a variety of
conditions, including allergies, frequent infections, benign tumors, cysts, and
chronic skin disorders, the veterans showed a higher frequency. The possibility
of recall bias and the self-selected nature of the registry are of concern. Nonethe-
less, a carefully designed and comprehensive epidemiologic study with review of
medical records could address the possibility of an association with some of these
childhood health conditions.
A study of birth defects among offspring of Australian Vietnam veterans was
conducted using a total of 8,517 matched case-control pairs, with 127 infant cases
and 123 infant controls having a father who served in Vietnam (Donovan et al.,
1984~. There were 202 cases and 205 controls whose fathers were in the Army
but did not serve in Vietnam. The adjusted odds ratio for birth defects among
children of Vietnam veterans versus all other men was 1.02 (CI 0.8-1.3~. Analy-
sis of subgroups based on the type of Army veteran (Australian Regular Army
enlisters, National Service draftees) did not detect any increased odds ratios for
these comparisons. There was a slight, statistically nonsignificant increase in the
odds ratio for National Service Vietnam veterans versus those who did not serve
in Vietnam (OR = 1.3, CI 0.9-2.0~. The risk was independent of the length of
Vietnam service and the time between service and conception. Analyses by
diagnostic group (central nervous system, cardiovascular, oral clefts, hypospadias,
OCR for page 23
RESEARCH HIGHLIGHTS
23
musculoskeletal, dislocation of hip, chromosomal anomalies) did not show an
excess risk for Vietnam veterans. However, two defects had odds ratios above
1.5 (statistically nonsignificant) ventricular septal defects (OR = 1.8) and
Down's syndrome (OR = 1.7~.
Overall, this study was negative; that is, there was no evidence of an in-
creased risk of fathering a child with a congenital anomaly for Australian Army
veterans who served in Vietnam. As indicated by the upper confidence limit
(1.3), this study had adequate power to rule out an odds ratio greater than 1.3 for
congenital anomalies. Assessment of potential Agent Orange exposure in this
study is limited, because "history of service" in Vietnam was used as the primary
"exposure" variable. This uncertainty is further compounded by potential differ-
ences in the location and nature of service of Australian veterans in Vietnam and
their resultant herbicide exposure.
The Australian study of veterans living in Tasmania reported more congeni-
tal anomalies among the 357 Vietnam veterans than among the comparison fami-
lies (Field and Kerr, 1988~. The authors suggested that the results indicated a
pattern of association with congenital heart disease and anomalies of the central
nervous system. As described earlier in the section on spontaneous abortion,
there are several notable problems with this study, including inadequate presenta-
tion of results, potential selection bias, self-reported health outcomes, and using
service in Vietnam as a surrogate for herbicide exposure.
Ranch Hand Study The latest report from the Air Force Health Study (AFHS)
of Operation Ranch Hand veterans ("Ranch Hands") and their children was pub-
lished in 1995 (Wolfe et al., 1995~. The Air Force released a first report on the
analysis of reproductive effects in 1982, and this report was reviewed in VAO
(AFHS, 1992~. The original study cohort comprised 1,098 Ranch Hands who
regularly handled and sprayed herbicides in Southeast Asia from 1962 to 1971
("exposed cohort") and a comparison group of 1,549 Air Force veterans who
were in Southeast Asia at the same time but presumably were not exposed to
herbicides. In 1987, 995 Ranch Hands (91 percent of original study group) and
1,299 comparison veterans (84 percent of original group) participated in a physi-
cal exam and agreed to provide serum samples for the dioxin assay. A total of
872 Ranch Hands (79 percent of original cohort, 88 percent of 1987 cohort) and
1,036 comparison subjects (67 percent of original group, 80 percent of 1987
cohort) were available for analysis, after exclusion of samples that were unreli-
able because of laboratory error or that had dioxin levels below the level of
detection or above an upper threshold for background (10 parts per trillion [ppti)
for comparison subjects. Of the 872 Ranch Hands, 454 had 1,006 self-reported
conceptions and 419 fathered 792 liveborn infants during their service in Viet-
nam or until January 1990. Of the 1,036 comparison veterans, 570 had 1,235
conceptions and 531 fathered 981 liveborn infants during this period.
The initial dioxin level was estimated from the current level using a first
OCR for page 24
24
VETERANS AND AGENT ORANGE: UPDATE 1996
order decay rate model with a fixed 7.1-year half-life estimate. The referent
group for the Ranch Hands included the conceptions and offspring of comparison
men with "background" levels (<10 ppt, N= 570, mean = 3.9 ppt). Ranch Hands
with levels at background were analyzed as a separate stratum (N= 179), since
the authors felt this group included a mixture of exposed and unexposed veterans,
given their mean level of 6.1 ppt and uncertainties in dioxin elimination. The
other strata used in the analysis included Ranch Hand "low" (current <10 ppt and
initial < 1 10 ppt, N = 1 19) and Ranch Hand "high" ~ current <10 ppt and initial
>110 ppt, N= 156~. The 110 ppt level was chosen because it is the median
estimated initial dioxin level at the time of conception of the Ranch Hands with
levels greater than 10 ppt. As the authors point out, this cutoff is arbitrary, with
no assumed biologic meaning. Reproductive outcomes of comparison veterans
with a current dioxin levels of greater than 10 ppt were not analyzed, because the
investigators suspected that these may reflect dioxin exposure after service in
Vietnam.
The reproductive and developmental outcomes included in the analyses in-
cluded spontaneous abortion (miscarriage, fetal death less than 20 weeks gesta-
tion), stillbirth (fetal death 20 weeks or greater gestation), and birth defects. All
conceptions reported by the men, their wives, or their partners were verified
through medical records and vital statistics review. The proportion of adverse
outcomes verified by specific sources was not stated. This may be important,
given the known limitations of vital statistics records for the identification and
classification of certain pregnancy outcomes.
Stratified analyses were performed, adjusting for six covariates, including
father's race, mother's smoking and drinking during pregnancy, mother's and
father's age at birth or conception, and father's military occupation (officer,
enlisted flyer, enlisted nonflyer). In addition, adjustment was made for history of
spontaneous abortion prior to service in Southeast Asia. The authors noted that
the adjustment of father's military occupation was performed because it may
serve as a proxy for education and occupation is associated with dioxin level.
Adjustment for occupation may, in fact, lead to some degree of "overadjustment"
owing to the high correlation between occupation and exposure potential. Com-
parison of the adjusted estimates with the unadjusted risk ratio estimates derived
from the data provided in the paper showed little difference, indicating that the
adjustment for military occupation did not materially affect the results.
The validation of self-reported birth defects in this study was systematic and
of high quality. Although the etiology of most birth defects remains unknown,
the study accounted for an array of factors controlled for in most previous studies
of birth defects. Considering all birth defects combined, there was a slightly
higher proportion of defects among Ranch Hand children than among compari-
son children (22.3 percent versus 20.8 percent). No general pattern of increasing
risk with increasing dioxin levels was found. A small increased RR of 1.3 (CI
1.0-1.6) was found for the low-dioxin category. There was a slightly higher
OCR for page 25
RESEARCH HIGHLIGHTS
25
prevalence or major birth defects among Ranch Hand children compared to com-
parison children (7.4 percent versus 5.7 percent). There was an elevated risk ratio
for the low-level category (RR = 1.7; CI 1.1-2.7), although a dose-response
gradient was not evident, with an RR of 1.1 for background (0.6-1.8) and 1.2 (CI
0.8-2.1) for the high-level category. The analysis of birth defect groups yielded a
total of 11 increased and five decreased risk ratios for the low- and high-level
comparisons with the referent category. For example, the analysis of circulatory
system and heart defects found risk ratios of 2.3 for low and 0.9 for high levels.
Genital defects had risk ratios of 1.8 for low and 1.2 for high; urinary system
defects had risk ratios of 2.0 for low and 2.1 for high. Examination of specific
defects included in this larger defect grouping did not show any specific associa-
tions or patterns. Interestingly, neural tube defects (spine bifida, anencephaly)
were in excess among offspring of Ranch Hands, with four total (rate of five per
1,000), in contrast to none among the comparison infants (exact p = .04~. The
four cases were distributed as two spine bifida in the high-level category, one
anencephaly and one spine bifida in the low-dioxin category. There was no clear
pattern of association with developmental disabilities in terms of specific delays
in development or hyperkinetic syndrome, although the low-level stratum for
specific delays in development had a risk ratio of 1.5 (CI 1.0-2.3~.
Summary
The recently published results of the analysis of birth defects among the
offspring of Ranch Hands suggest the possibility of an association between di-
oxin exposure and risk of neural tube defects. These findings require a consider-
ation of the current evidence for an association between herbicides and neural
tube defects and an increased risk among Vietnam veterans exposed to herbi-
cides. Table 2.1 includes a summary of the studies that have reported results
specifically for neural tube defects (typically anencephaly and/or spine bifida),
including studies in VAO and more recent publications. Unfortunately, some
studies (e.g., Seveso), particularly the occupational and environmental studies,
do not have results specific for individual birth defects, usually because of the
small number of cases. A number of studies of veterans appear to show an
elevated relative risk for either service in Vietnam or estimated exposure to
herbicides or dioxin and neural tube defects (anencephaly and/or spine bifida) in
their offspring. Many of the estimates are imprecise, and chance cannot be ruled
out. Nonetheless, the pattern of association warrants further evaluation. The
CDC Birth Defects Study (Centers for Disease Control, 1988), the CDC Vietnam
Experience Study (Centers for Disease Control, 1989), and the Ranch Hand
Study (Wolfe et al., 1992) are of the highest overall quality. The CDC VES
cohort study found that more Vietnam veterans reported that their children had a
central nervous system anomaly (OR = 2.3; 95 percent CI 1.2-4.5) than did non-
Vietnam veterans (Centers for Disease Control, 1989~. The odds ratio for spine
OCR for page 26
26
VETERANS AND AGENT ORANGE: UPDATE 1996
bifida was 1.7 (CI 0.6-5.0~. A substudy was conducted in an attempt to validate
the reported cerebrospinal defects (spine bifida, anencephaly, hydrocephalus) by
examination of hospital records. A difference was detected, but its interpretation
was limited by differential participation between the veteran groups and failure to
validate negative reported that is, the veterans not reporting their children hav-
ing a birth defect. Thus, the issue of a recall bias remains a major concern with
this study.
The CDC Birth Defects Study utilized the population-based birth defects
registry system in the metropolitan Atlanta area (Centers for Disease Control,
1988~. There was no association between overall Vietnam veteran status and the
risk of spine bifida (OR = 1.1, CI 0.6-1.7) or anencephaly (OR = 0.9, CI 0.5-1.7~.
However, the exposure opportunity index based on interview data was associated
with an increased risk of spine bifida; for the highest estimated level of exposure
(EOI-5), the OR was 2.7 (CI 1.2-6.2~. There was no similar pattern of association
for anencephaly. This study has a number of strengths, including the use of a
population-based birth defects registry system and adjustment for a number of
potentially confounding factors. Two study limitations include the relatively low
response proportions among the case and control subjects (approximately 56
percent) and the lag between birth and interview for some cases and controls.
Thus, all three epidemiologic studies (Ranch Hand, VES, CDC Birth Defects
Study) suggest an association between herbicide exposure and an increased risk
of spine bifida in offspring. Although the studies were judged to be of relatively
high quality, they suffer from methodologic limitations, including possible recall
bias, nonresponse bias, small sample size, and misclassification of exposure. In
addition, the failure to find a similar association with anencephaly, an embryo-
logically related defect, is of concern.
Conclusions
Strength of Evidence in Epidemiologic Studies
There is limited/suggestive evidence of an association between exposure to
the herbicides considered in this report and spine bifida. There is inadequate or
insufficient evidence to determine whether an association exists between expo-
sure to the herbicides and all other birth defects. The evidence regarding associa-
tion is drawn from occupation and other studies in which subjects were exposed
to a variety of herbicides and herbicide components.
Biologic Plausibility
Laboratory studies of the potential developmental toxicity, specifically birth
defects, of TCDD and herbicides as a result of exposure to adult male animals are
too limited to permit conclusions. Chapter 3 of the full report examines these
OCR for page 27
RESEARCH HIGHLIGHTS
TABLE 2-1 Epidemiologic Studies Neural Tube Defects
27
OR/RR
Reference Description N (95% CI)
Occupational
No specific results for neural tube defects
Environmental
Hanify et al., 1981 Anencephaly
Spina bifida
Stockbauer et al., 1988 TCDD soil contamination in Missouri
Central nervous system defects
Vietnam veterans
Erickson, 1984a,b
CDC, 1989
10 1.4 (0.6-3.3)
13 1.1 (0.6-2.3)
3 3.0 (0.3-35.9)
Birth Defects Study
Vietnam veteran: spine bifida
Vietnam veteran: anencephaly
EOI-5: spine bifida
EOI-5: anencephaly
Vietnam Experience Study
Interview study
Spina bifida
Anencephaly
19 1.1 (0.6-1.7)
12 0.9 (0.5-1.7)
ga 2.7 (1.2-6.2)
7a 0.7 (0.2-2.8)
9 1.7 (0.6-5.0)
among Vietnam
veterans
5 among non
Vietnam veterans
3 among Vietnam
veterans
among non
Vietnam veterans
Australian veterans Birth defects and father's Vietnam service
(Australia)
Health Studies, 1983 Neural tube defects 16 0.9
AFHS, 1995 Follow-up of Air Force Ranch Hands
Neural tube defects 4 among Ranch Handb
0 among comparison
NOTE: N= number of exposed cases; OR/RR = Odds Ratio/Relative Risk; CI = Confidence
Interval; SIR = Standardized Incidence Ratio.
aNumber of Vietnam veterans fathering a child with a neural tube defect given any exposure
opportunity index score.
bFour neural tube defects among Ranch Hand offspring include 2 spine bifida (high dioxin
level), 1 spine bifida (low dioxin), and 1 anencephaly (low dioxin). Denominator for Ranch
Hand group is 792 liveborn infants.
OCR for page 28
28
VETERANS AND AGENT ORANGE: UPDATE 1996
experimental studies at greater length, as well as others focusing on developmen-
tal toxicity.
Risk in Vietnam Veterans
Since the strongest associations are from studies of Vietnam veterans and
there are some data suggesting that the highest risks were for those veterans
estimated to have had exposure to Agent Orange (e.g., Ranch Hands), it therefore
follows that there is limited/suggestive evidence for an increased risk in Vietnam
veterans of spine bifida in offspring.
PERIPHERAL NEUROPATHY
Introduction
This section taken from Chapter 10 of the full report summarizes published
scientific literature on exposure to herbicides and acute and subacute transient
peripheral neuropathy. At the specific request of the Department of Veterans
Affairs (DVA), earlier data in VAO relating to chronic persistent and transient
acute or subacute peripheral neuropathy were reclassified and reexamined in the
Update 1996 report.
Although some of the case reports reviewed in VAO suggested that an acute
or subacute peripheral neuropathy can develop with exposure to TCDD and
related products, other reports with comparison groups did not offer clear evi-
dence that TCDD exposure is associated with chronic peripheral neuropathy.
The most rigorously conducted studies argued against a relationship between
TCDD or herbicides and chronic persistent neuropathy.
The current report places chronic persistent peripheral neuropathies and acute
or subacute peripheral neuropathies into distinct disease categories. The commit-
tee found there is inadequate or insufficient evidence of an association between
exposure to the herbicides considered in this report and chronic persistent periph-
eral neuropathy.
The methodology used to establish associations between putative causal
agents and persistent chronic neurological deficits relies heavily on epidemio-
logical studies with adequate control or comparison populations. Such methodol-
ogy can rarely be set in motion with sufficient speed to assess relationships
between unexpected chemical exposure and the development of acute or subacute
transient neurological disturbance. Because of the very transient nature of the
conditions, documenting signs and symptoms in association with documented
exposures can be difficult to accomplish in a systematic manner. In such in-
stances, greater reliance must be placed on isolated case histories and less well
controlled studies. This section reviews the data from such sources regarding
occupational, environmental, and Vietnam herbicide exposure. Because this
OCR for page 29
RESEARCH HIGHLIGHTS
29
disorder is of special interest to the DVA, this discussion integrates the studies
reviewed in VAO with those published more recently.
The following text reviews the data from such sources regarding occupa-
tional, environmental, and Vietnam herbicide exposure and acute and subacute
transient peripheral neuropathy. Because this disorder is of special interest to the
DVA, this discussion integrates the studies reviewed in VAO with those pub-
lished more recently. Chapter 6 of the full report expounds on many of these
studies.
Review of the Scientific Literature on Acute and
Subacute Transient Peripheral Neuropathy
Occupational Studies A number of reports have suggested that acute or sub-
acute peripheral neuropathies can be associated with occupational exposure to
herbicides (Ashe and Suskind, 1950; Baader and Bauer, 1951; Goldstein et al.,
1959; Todd, 1962; Berkley and Magee, 1963; Poland et al., 1971; Jirasek et al.,
1974~. However, only a very limited number of studies on the PNS provide any
control or comparison group data. Since peripheral neuropathies can be induced
by such common medical and environmental conditions as diabetes and poor
nutrition, especially in alcoholics, the presence of neuropathy in an herbicide-
exposed population cannot be attributed necessarily to the herbicide without
consideration of these other factors. Rigorously defined and examined compari-
son groups, although especially important in the analysis of peripheral neuro-
pathies, are not available for the topic of acute and subacute neuropathies. The
studies cited below provide suggestive but limited evidence of the concept that
acute or subacute peripheral neuropathy can develop after exposure to dioxin or
related compounds.
Todd (1962) reported a sprayer of 2,4-D weedkiller who developed a gas-
trointestinal disturbance and, within days, a severe sensory/motor polyneuropathy
after contact with the chemical. Recovery occurred gradually over the ensuing
months. Berkley and Magee (1963) reported another patient who developed a
polyneuropathy four days after exposure to a liquid solution of 2,4-D, which was
being sprayed in a cornfield. The neuropathy was purely sensory in type. His
symptoms gradually resolved over months. Goldstein et al. (1959) described
three patients who had sensory/motor polyneuropathies that developed over sev-
eral days and progressed over several weeks after exposure to 2,4-D. All had
incomplete recovery after several years. Although these patients were not exam-
ined neurologically before their exposure, the temporal relationship between the
development of their clinical problem and the herbicide exposure was clearly
documented. Nonetheless, the possibility that their occurrence was unrelated to
the herbicide exposure and represented examples of other disorders, such as
idiopathic Guillain-Barre syndrome, cannot be entirely excluded.
OCR for page 30
30
VETERANS AND AGENT ORANGE: UPDATE 1996
Environmental Studies After the Seveso, Italy, chemical explosion, inhabitants
from the high-exposure zone were evaluated for signs and symptoms of periph-
eral nerve disease and compared with inhabitants of a lower-exposure zone. No
information is available on acute transient neuropathic effects, since the first
reports documented findings in patients evaluated more than six months after the
disaster. Boeri et al. (1978) conducted clinical and neurophysiological examina-
tion of the peripheral nerves 7 to 11 months after the explosion and reported
descriptive differences between 470 volunteer subjects in Zone A (high-exposure
group) and 152 volunteer residents of Zone R (low-exposure group). Peripheral
nerve problems were frequent in both groups, suggesting to the authors that
undefined neuropathic factors predating the explosion may well have been re-
sponsible for their findings. Although cranial and peripheral nerve problems
were generally more prevalent among the highly exposed group, no statistical
analyses were performed on the prevalence data. The electrophysiological studies
failed to show any significant abnormalities in either group.
As a complement to the above screening in the first year after exposure,
Pocchiari et al. (1979) echoed the observation that neuropathic symptoms were
more prevalent in the high-exposure group. No new data were provided. Report-
ing on symptoms and signs in patients examined eight or more months after the
accident, Filippini et al. (1981) compared 308 Seveso residents with 305 non-
exposed residents from nearby towns. They examined patients clinically and
electrophysiologically, using strict physiological criteria for defining peripheral
neuropathy. The authors found no increased risk of "acute" peripheral neuropathy
among the exposed residents. However, within the subgroup of exposed subjects
who showed clinical signs of significant exposure (chloracne or elevated hepatic
enzymes), the risk ratio was 2.8 (CI = 1.2-6.5~. Similarly, for Seveso residents
with other risk factors for peripheral neuropathy (alcoholism, diabetes, and in-
flammatory diseases), an elevated risk ratio was also observed (2.6, CI = 1.2-5.6~.
The authors argued that heavy exposure to dioxin was associated with mild
peripheral neuropathy in this two-year follow-up report. Subsequent follow-up
studies suggested that there was no increased prevalence of peripheral neuropathy
several years after the accident among the high-risk Seveso group (Barbieri et al.,
1988; Assennato et al., 1989~.
Vietnam Veterans Studies The committee has identified no data on acute or
subacute neuropathies related to herbicide exposure in Vietnam. All published
data concern chronic effects.
Summary of Acute and Subacute
Transient Peripheral Neuropathy
There is some evidence to suggest that neuropathy of acute or subacute onset
may be associated with herbicide exposure. This is based primarily on case
OCR for page 31
RESEARCH HIGHLIGHTS
31
histories from occupational exposure and the descriptive reports following the
Seveso accident. The trend to recovery in the individual cases reported and the
negative findings of many long-term follow-up studies of peripheral neuropathy
(see section on Chronic Persistent Peripheral Neuropathy in the full report) sug-
gest that if a neuropathy indeed develops, it resolves with time.
Conclusions
Strength of Evidence in Epidemiologic Studies
There is limited/suggestive evidence of an association between exposure to
the herbicides considered in this report and acute and subacute transient periph-
eral neuropathy. The evidence regarding association is drawn from occupational
and other studies in which subjects were exposed to a variety of herbicides and
herbicide components.
New data from animals (Grehl et al., 1993; Grahmann et al., 1993) suggest
biological plausibility for an association between TCDD and peripheral
neuropathy. Chapter 3 of the full report discusses the toxicologic studies in
greater detail.
Increased Risk of Disease among Vietnam Veterans
If TCDD is associated with the development of transient acute and subacute
peripheral neuropathy, the disorder would become evident shortly after exposure;
therefore, there is no evidence that new cases that develop long after service in
Vietnam are associated with herbicide exposure that occurred there.
OCR for page 32
Representative terms from entire chapter:
vietnam veterans
