Subject: Boots on the Ground Issue
Date: Thu, 28 Jun 2007 18:32:40 -0400
Cc: <Eve@nvlsp.org>
Hi John,
We are preparing to take action on cases the VA has stayed, despite evidence the veteran actually set foot in Vietnam. I was wondering if you could post the following on the Blue Water Navy site:
NVLSP is preparing to challenge the VA’s stay on cases in which the claimant has alleged that the veteran actually set foot on the landmass of Vietnam. As such, we are trying to identify veterans who meet the following criteria:
The claimant has a letter from the VA informing him or her that the claim may be affected by Haas v. Nicholson, and the VA is awaiting the outcome of the Haas appeal before taking further action on the claim;
At some point since filing the original claim, the claimant has submitted evidence (including his or her own testimony) to the VA demonstrating that the veteran actually set foot on the landmass of Vietnam;
The claimant hasrequested, in writing, that the VA adjudicate the claim as a “boots on the ground” claim (or similar language); and
The VA has informed the claimant, after it has received the request and preferably in writing, that it will not adjudicate the claim as a “boots on the ground” claim (or similar language).
We would like anyone who meets all of the criteria listed above to contact NVLSP law clerk Eve Hoffman by email at Eve_Hoffman@nvlsp.org. We ask that you put “Boots on the Ground” as the subject of the message, and provide your name, address, and telephone number in the text of the email, along with any other relevant information pertaining to the criteria listed above. Eve will then contact you with further information. Thanks!
Thanks John. Also, if you know of anyone who meets the above criteria, please point me in their direction.
Sincerely,
Rick
[Federal Register: June 12, 2007 (Volume 72, Number 112)]
[Notices]
[Page 32395-32407]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr12jn07-88]
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DEPARTMENT OF VETERANS AFFAIRS
Health Outcomes Not Associated With Exposure to Certain Herbicide
Agents
AGENCY: Department of Veterans Affairs.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: As required by law, the Department of Veterans Affairs (VA)
hereby gives notice that the Secretary of Veterans Affairs, under
authority of the Veterans Education and Benefits Expansion Act of 2001,
Public Law 107-103, Section 201(d), has determined that a presumption
of service connection is not warranted based on exposure to herbicides
used in the Republic of Vietnam during the Vietnam Era for the
following health outcomes: Hepatobiliary cancers; oral, nasal, and
pharyngeal cancer; bone and joint cancer; skin cancers (melanoma,
basal, and squamous cell); breast cancer; female reproductive cancer
(cervix, uterus, and ovary); testicular cancer; urinary bladder cancer;
renal cancer; leukemia (other than chronic lymphocytic leukemia (CLL));
abnormal sperm characteristics and infertility; spontaneous abortion;
neonatal or infant death and stillbirth in offspring of exposed
individuals; low birthweight in offspring of exposed individuals;
neurobehavioral disorders (cognitive and neuropsychiatric); movement
disorders including Parkinson's disease and amyotrophic lateral
sclerosis (ALS); chronic peripheral nervous system disorders;
respiratory disorders; gastrointestinal, metabolic, and digestive
disorders (changes in liver enzymes, lipid abnormalities, ulcers);
immune system disorders (immune suppression, autoimmunity); circulatory
disorders; amyloid light-chain (AL) amyloidosis; endometriosis; effects
on thyroid homeostasis; gastrointestinal tumors (esophagus, stomach,
pancreas, colon, rectum; brain tumors; and any other condition for
which the Secretary has not specifically determined a presumption of
service connection is warranted.
The Secretary's determinations regarding individual diseases are
based on all available evidence in a 2004 report of the National
Academy of Sciences (NAS) and prior NAS reports. This notice generally
states specific information only with respect to significant additional
studies that were first reviewed by NAS in its 2004 report. Information
regarding additional relevant studies is stated in VA's prior notices
following earlier NAS reports, and will not be repeated here.
FOR FURTHER INFORMATIONCONTACT: Rhonda F. Ford, Consultant,
Regulations Staff, Compensation and Pension Service, Veterans Benefits
Administration, Department of Veterans Affairs, 810 Vermont Avenue,
NW., Washington, DC 20420, (202) 273-7210.
SUPPLEMENTARY INFORMATION: Section 3 of the Agent Orange Act of 1991,
Public Law 102-4, 105 Stat. 11, directed the Secretary to seek to enter
into an agreement with the National Academy of Sciences (NAS) to review
and summarize the scientific evidence concerning the association
between exposure to herbicides used in support of military operations
in the Republic of Vietnam during the Vietnam Era and each disease
suspected to be associated with such exposure. Congress mandated that
NAS determine, to the extent possible: (1) Whether there is a
statistical association between the suspect diseases and herbicide
exposure, taking into account the strength of the scientific evidence
and the appropriateness of the methods used to detect the association;
(2) the increased risk of disease among individuals exposed to
herbicides during service in the Republic of Vietnam during the Vietnam
Era; and (3) whether there is a plausible biological mechanism or other
evidence of a causal relationship between herbicide exposure and the
health outcome. Section 3 of Public Law 102-4 also required that NAS
submit reports on its activities every two years (as measured from the
date of the first report) for a ten-year period.
Section 2 of Public Law 102-4, codified in pertinent part at 38
U.S.C. 1116(b) and (c), provides that whenever the Secretary
determines, based on sound medical and scientific evidence, that a
positive association (i.e. the credible evidence for the association is
equal to or outweighs the credible evidence against the association)
exists between exposure of humans to an herbicide agent (i.e. a
chemical in an herbicide used in support of the United States and
allied military operations in the Republic of Vietnam during the
Vietnam Era) and a disease, the Secretary will publish regulations
establishing presumptive service connection for that disease. If the
Secretary determines that a presumption of service connection is not
warranted, he is to publish a notice of that determination, including
an explanation of the scientific basis for that determination. The
Secretary's determination must be based on consideration of the NAS
reports and all other sound medical and scientific information and
analysis available to the Secretary.
Section 2 of theAgent Orange Act of 1991 provided that the
Secretary's authority and duties under that section would expire 10
years after the first day of the fiscal year in which NAS transmitted
its first report to VA. The first NAS report was transmitted to VA in
July 1993, during the fiscal year that began on October 1, 1992.
Accordingly, VA's authority under section 2 of the Agent Orange Act of
1991 expired on September 30, 2002. In December 2001, however, Congress
enacted the Veterans Education and Benefits Expansion Act of 2001,
Public Law 107-103. Section 201(d) of that Act extended VA's authority
under 38 U.S.C. 1116(b)-(d) through September 30, 2015.
Although 38 U.S.C. 1116 does not define ``credible,'' it does
instruct the Secretary to ``take into consideration whether the results
[of any study] are statistically significant, are capable of
replication, and withstand peer review.'' The Secretary reviews studies
that report a positive relative risk and studies that report a negative
relative risk of a particular health outcome. He then determines
whether the weight of evidence supports a finding that there is or is
not a positive association between herbicide exposure and the
subsequent health outcome.
The Secretary does this by taking into account the statistical
significance, capability of replication, and whether that study will
withstand peer review. Because of differences in statistical
significance, confidence levels, control for confounding factors, bias,
and other pertinent characteristics, some studies are more credible
than others. The Secretary gives weight to more credible studies in
evaluating the overall evidence concerning specific health outcomes.
Chronology
NAS issuedits initial report, entitled ``Veterans and Agent
Orange: Health Effects of Herbicides Used in Vietnam,'' (VAO) on July
27, 1993. The Secretary subsequently determined that a positive
association exists between exposure to herbicides used in the Republic
of Vietnam and the subsequent development of Hodgkin's disease,
porphyria cutanea tarda, multiple
[[Page 32396]]
myeloma, and certain respiratory cancers. The Secretary also determined
that there was no positive association between herbicide exposure and
any other health outcome, other than chloracne, non-Hodgkin's lymphoma,
and soft-tissue sarcomas, for which presumptions already existed. A
notice of the health outcomes that the Secretary determined were not
associated with exposure to herbicides was published on January 4,
1994. (See 59 FR 341 (1994)).
NAS issued its second report, entitled ``Veterans and Agent Orange:
Update 1996'' (Update 1996), on March 14, 1996. The Secretary
subsequently determined that a positive association exists between
exposure to herbicides used in the Republic of Vietnam and the
subsequent development of prostate cancer and acute and subacute
peripheral neuropathy in exposed persons. The Secretary further
determined that there was no positive association between herbicide
exposure and any other condition, other than those for which
presumptions already existed. A notice of the diseases that the
Secretary determined were not associated with exposure to herbicide
agents was published on August 8, 1996. (See 61 FR 41442 (1996)).
NAS issued a third report, entitled ``Veterans and Agent Orange:
Update 1998'' (Update 1998), on February 11, 1999. The focus of this
update was new scientific studies published since the release of Update
1996 and updates of scientific studies previously reviewed. After NAS
issued Update 1998, the Secretary determined that there was no positive
association between herbicide exposure and any other condition, other
than those for which presumptions already existed. A noticeof the
health outcomes that the Secretary determined were not associated with
exposure to herbicide agents was published on November 2, 1999. (See 64
FR 59232 (1999)).
At VA's request, NAS issued a special interim report, ``Veterans
and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes'' (VAO:
Diabetes) on October 11, 2000. NAS concluded that: ``there is limited/
suggestive evidence of an association between exposure to the
herbicides used in Vietnam or the contaminant dioxin and Type 2
diabetes.'' NAS based its conclusion on the conglomeration of
scientific evidence, not one particular study. (VAO: Diabetes.) After
considering all of the evidence, the Secretary determined that there is
a positive association between exposure to herbicides and Type 2
diabetes and, therefore, a presumption of service connection was
warranted. (See 66 FR 2376 (2001)).
NAS issued a fourth report, entitled ``Veterans and Agent Orange:
Update 2000'' (Update 2000), on April 19, 2001. The focus of this
update was the new scientific studies published since the release of
Update 1998 and updates of scientific studies previously reviewed.
After NAS issued Update 2000, the Secretary determined that there was
no positive association between herbicide exposure and any other
condition, other than those for which presumptions already existed. A
notice of the health outcomes that the Secretary determined were not
associated with exposure to herbicide agents was published in June 24,
2002 (See 67 FR 42600 (2002)).
NAS issued its fifth report, entitled ``Veterans and Agent Orange:
Update 2002'' (Update 2002) on January 23, 2003. The focus of this
update was the new scientific studies published since the release of
Update 2000 and review of the studies previouslyreviewed along with
the newest scientific evidence. The Secretary subsequently determined
that a positive association exists between exposure to herbicides used
in the Republic of Vietnam and the subsequent development of chronic
lymphocytic leukemia (CLL) in exposed persons. After NAS issued Update
2002, the Secretary determined that there was no positive association
between herbicide exposure and any other condition, other than those
for which presumptions already existed. A notice of the health outcomes
the Secretary determined were not associated with exposure to herbicide
agents was published on May 20, 2003 (See 68 FR 27630 (2003)).
Update 2004
NAS issued its sixth report entitled ``Veterans and Agent Orange:
Update 2004'' (Update 2004) on March 4, 2005. Consistent with its prior
reports, NAS in Update 2004 found that there was ``sufficient evidence
of an association'' between herbicide exposure and five categories of
diseases in veterans and ``limited/suggestive evidence'' of an
association between herbicide exposure and six other categories of
diseases in veterans. VA has previously established presumptions of
service connection for each of these diseases. NAS, in Update 2004,
categorized certain health outcomes to have ``inadequate/insufficient''
evidence to determine whether an association exists. This category is
defined to mean that the available studies are of insufficient quality,
consistency, or statistical power to permit a conclusion regarding the
presence or absence of an association with herbicide exposure. Health
outcomes that met the inadequate/insufficient category include:
Hepatobiliary cancers; oral, nasal, and pharyngeal cancer; bone and
joint cancer; skin cancers (melanoma, basal, and squamous cell); breast
cancer; female reproductive system cancer (cervix, uterus, ovary);
testicular cancer; urinary bladder cancer; renal cancer; leukemia
(other than chronic lymphocytic leukemia (CLL)); abnormal sperm
characteristics and infertility; spontaneous abortion; neonatal or
infant death and stillbirth in offspring of exposed individuals; low
birthweight in offspring of exposed individuals; birth defects (other
than spina bifida) in offspring of exposed individuals; childhood
cancer (including acute myelogenous leukemia) in offspring of exposed
individuals; neurobehavioral disorders (cognitive and
neuropsychiatric); movement disorders, including Parkinson's disease
and amyotrophic lateral sclerosis (ALS); chronic peripheral nervous
system disorders; respiratory disorders; gastrointestinal, metabolic,
and digestive disorders (changes in liver enzymes, lipid abnormalities,
ulcers); immune system disorders (immune suppression, autoimmunity);
circulatory disorders; AL amyloidosis; endometriosis; and effects of
thyroid homeostasis.
In this same report, NAS found two health outcomes that fell into
the ``limited or suggestive evidence of no association category. These
health outcomes were deemed consistent in not showing a positive
association between them and any magnitude of exposure to herbicides.
Those health outcomes that met the ``no association'' category were:
gastrointestinal tumors (esophagus, stomach, pancreas, colon, rectum),
and brain tumors.
The Secretary's determinations regarding individual diseases are
based on all available evidence in Update 2004 and prior NAS reports.
This notice generally states specific information only with respect to
significant additional studies that were first reviewed by NAS in
Update 2004. Information regarding additional relevant studies has been
stated in VA's prior notices following earlier NAS reports, and will
not be repeated here.
Hepatobiliary Cancers
Hepatobiliary cancers are cancers of the liver and intrahepatic
bile ducts. There are a variety of known risk factors, including
chronic infections with hepatitis B or C, exposure to aflatoxin, vinyl
chloride and polychlorinated biphenyl (PCB), and
[[Page 32397]]
smoking, which should be considered by a credible study.
NAS noted in VAO and subsequent reports that there were relatively
few occupational, environmental, or veteran studies of hepatobiliary
cancer. It also noted that most of the few existing studies addressing
hepatobiliary cancer contain methodological difficulties such as small
study size and inadequate control for life-style-related risk factors,
or do not support an association with herbicide exposure.
An occupational study by Swaen et al. (2004) examined cancer
mortality in herbicide appliers in the Netherlands, and no deaths from
liver or biliary cancer were observed in the cohort.
NAS found that there was no information contained in the research
reviewed for Update 2004 to change the conclusion that there is
inadequate or insufficient evidence to determine whether an association
exists between exposure to herbicides and hepatobiliary cancer.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and hepatobiliary cancer outweighs the
credible evidence for such an association, and he has determined that a
positive association does not exist.
Oral, Nasal, and Pharyngeal Cancer
Oral, nasal, and pharyngeal cancers are relatively rare in the
United States and thus difficult to study epidemiologically. Reported
risk factors for nasal cancer include occupational exposure to nickel
and chromium compounds, wood dust, and formaldehyde. Studies reported
associations with the consumption of salt-preserved foods, cigarette
smoking, and Epstein-Barr virus. NAS noted in VAO and subsequent
reports that there was inadequate or insufficient evidence to determine
whether an association exists between herbicide exposure and oral,
nasal, and pharyngeal cancer.
An occupational study by Swaen et al. (2004) examined cancer
mortality in herbicide appliers in the Netherlands. No deaths from
nasal, oral, or pharynx cancers were observed in that cohort.
In a Vietnam-veteran study, cancers of the cavity between the jaw
and cheek were examined in Operation Ranch Hand veterans who were
involved in the aerial spraying of herbicides. No significant
difference was reported between Ranch Hand veterans and a comparison
group of veterans who did not spray herbicides. (Akhtar et al., 2004).
NAS found there was no information contained in the research
reviewed for Update 2004 to change the conclusion that there is
inadequate or insufficient evidence to determine whether an association
exists between exposure to herbicides and oral, nasal, and pharyngeal
cancer.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and oral, nasal, and pharyngeal cancers
outweighs the credible evidence for such an association, and has
determined that a positive association does not exist.
Bone and Joint Cancer
Primary bone cancers are among the least common malignancies. The
bones are a frequent site of secondary tumors of other cancers that
have metastasized. NAS studied only primary bone cancer in Update 2004.
Bone cancer is most common among teenagers, and is very rare among
people in the age groups of most Vietnam veterans. Among the risk
factors for adults are exposure to ionizing radiation from treatment
for other cancers and a history of certain non-cancerous bone diseases.
NAS found in VAO and subsequent reports that there is inadequate or
insufficient information to determine whether an association exists
between exposure to herbicides and bone and joint cancer.
NAS reviewed one occupational study that examined cancer mortality
in 1,341 licensed herbicide appliers in the Netherlands. No deaths from
bone cancers were observed. (Swaen et al., 2004.) No other relevant
environmental or Vietnam-veteran studies were published since Update
2002.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and bone and joint cancer outweighs the
credible evidence for such an association, and has determined that a
positive association does not exist.
Skin Cancers--Melanoma, Basal, and Squamous Cell
NAS noted in VAO and subsequent reports that there was inadequate
or insufficient information to determine whether an association exists
between exposure to herbicides and skin cancer. NAS examined two
categories of skin cancer: melanoma and nonmelanoma (basal-cell and
squamous-cell).
Melanomas occur more frequently in fair-skinned people. Incidence
also increases with age, though more so in males than in females. Other
risk factors can include moles on the skin, suppressed immune system,
and excessive exposure to ultraviolet radiation, usually from the sun.
Family history of melanoma is also a risk factor, though it is unclear
whether that is the result of genetic factors or attributable to
similarities in skin type and sun exposure.
NAS reviewed an occupational study conducted on licensed herbicide
applicators in the Netherlands. No data was available on any risk
factor for skin cancer, other than age. Five deaths from skin cancer
were recorded for the cohort of 1,341 people. Only 1.4 deaths would be
expected. (Swaen et al., 2004). NAS noted that a significant limitation
of this study was its inability to discern whether, or to what extent,
the increased incidence of skin cancer was attributable to herbicide
exposure rather than to exposure to UV radiation, which is a
significant and well-known risk factor for skin cancer. NAS concluded
that herbicide applicators are likely to have had significant exposure
to UV radiation, but that limitations of the study design made it
impossible to separate the effect of the two occupational exposures.
No environmental studies of melanoma have been published since
Update 2002.
In 2004, a study on the incidence of cancer in Operation Ranch Hand
veterans compared with both a group of Air Force veterans not involved
in herbicide spraying and a sample of the general population, showed
that melanoma was more common among the Ranch Hand veterans and the Air
Force veterans than in the general population. NAS noted significant
limitations concerning the comparison with the general population,
including the lack of control for the confounding factor of sun
exposure and the possibility that rates of detection among the study
population may be higher than the general population due to the
heightened detection methods employed in the study. In the analyses
limited to Ranch Hand and comparison Air Force veterans, the
associations with melanoma were restricted to the stratum of veterans
with no more than 2 years of service in Southeast Asia and to a stratum
created by the subset of Ranch Hand veterans who served only in Vietnam
and comparison veterans who served elsewhere in Southeast Asia.
NAS found that no satisfactory rationale was given to support why
the analysis was limited to veterans with less than 2 years of service
or to a definition that confounds Ranch Hand status with service in
Vietnam. NAS
[[Page 32398]]
stated that, if the classifications employed in the study somehow
captured a confounding factor, the proper analysis would have been to
combine information from each stratum (more than 2 years of service and
2 years or less) to produce an adjusted relative risk. In view of these
limitations, NAS decided that the overall association between exposure
to herbicides and the incidence of melanoma in this study was not
definitive. (Akhtar et al., 2004).
NAS concluded that there is inadequate or insufficient evidence to
determine an association between exposure to herbicides and melanoma.
Although some recent studies reported findings suggestive of an
association, the weight of those findings is limited by the
methodological concerns discussed in the NAS report. Taking account of
the available evidence and NAS' analysis, the Secretary has found that
the credible evidence against an association between herbicide exposure
and melanoma outweighs the credible evidence for such an association,
and has determined that a positive association does not exist.
Excessive exposure to ultraviolet radiation is the most important
risk factor for non-melanocytic skin cancer, though some skin diseases
and exposure to chemicals such as inorganic arsenic have also been
identified as possible risk factors.
NAS noted in VAO and subsequent updates that there was inadequate
or insufficient information to determine an association between
exposure to herbicides and basal-cell or squamous-cell cancers.
There were no relevant environmental or Vietnam-veteran studies
published regarding basal-cell and squamous-cell (non melanoma) skin
cancers.
NAS concluded that there is no information contained in the
research reviewed for Update 2004 to change the conclusion that there
is inadequate or insufficient evidence to determine whether an
association exists between exposure to herbicides and basal-cell and
squamous-cell skin cancers.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and basal-cell and squamous-cell skin
cancers outweighs the credible evidence for such an association, and he
has determined that a positive association does not exist.
Breast Cancer
NAS noted that breast cancer is the second most common cancer among
women in the U.S. Breast cancer incidence generally increases with age.
Risk factors other than aging include a personal or family history of
breast cancer and certain reproductive characteristics; specifically,
early onset of menarche, late onset of menopause, and either no
pregnancies or first full-term pregnancy after age 30. NAS noted in VAO
and subsequent reports that there is inadequate or insufficient
information to determine whether an association exists between exposure
to herbicides and breast cancer.
No studies published since Update 2002 have investigated breast
cancer. Previously published studies support the conclusion that the
evidence is inadequate or insufficient to determine an association
between exposure to herbicides and breast cancer.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and breast cancer outweighs the credible
evidence for such an association, and he has determined that a positive
association does not exist.
Female Reproductive Cancer (cervix, uterus, ovary)
NAS noted that the cancers of the female reproductive system
include cancers of the cervix, endometrium (also referred to as the
corpus uteri), and ovaries. Cervical cancers occur more often in
African-American women than in white women, whereas white women are
more likely to develop endometrial and ovarian cancers. The incidence
of endometrial and ovarian cancer also depends on age, with older women
at greater risk. Human papillomavirus infection is the most important
risk factor for cervical cancer. Diet, a family history of the disease,
and breast cancer are among the risk factors for endometrial and
ovarian cancers.
NAS noted in VAO and subsequent reports that there is inadequate or
insufficient information to determine whether an association exists
between exposure to herbicides and cancers of the female reproductive
system.
No studies published since Update 2002 have investigated cancers of
the female reproductive system.
NAS concluded that there is inadequate or insufficient information
to determine an association between exposure to herbicides and female
reproductive cancers. Taking account of the available evidence and NAS'
analysis, the Secretary has found that the credible evidence against an
association between herbicide exposure and cancers of the female
reproductive system outweighs the credible evidence for such an
association, and he has determined that a positive association does not
exist.
Testicular Cancer
Testicular cancer is far more likely in men younger than 40 than in
men over the age of 40. Cryptorchidism, or undescended testes, is a
major risk factor for testicular cancer. Family history of the disease
also appears to be a risk factor for testicular cancer.
NAS noted in VAO and subsequent reports that there was inadequate
or insufficient information to determine whether an association exists
between exposure to herbicides and testicular cancer.
No relevant occupational, environmental, or Vietnam-veteran studies
have been published since Update 2002.
NAS concluded that there is inadequate or insufficient evidence to
determine an association between exposure to herbicides and testicular
cancer.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and testicular cancer outweighs the credible
evidence for such an association, and he has determined that a positive
association does not exist.
Urinary Bladder Cancer
Urinary bladder cancer is the most common of the urinary tract
cancers. Bladder cancer incidence increases greatly with age over 40
years. The most important known risk factor for bladder cancer is
smoking. Occupational exposures to aromatic amines (also called
arylamines), polycyclic aromatic hydrocarbons (PAHs), and certain other
organic chemicals used in the rubber, leather, textile, paint products,
and printing industries are also associated with higher incidence of
bladder cancer. High-fat diets have been implicated as risk factors,
along with exposure to the parasite Schistosoma haematobium. Exposure
to inorganic arsenic is also a risk factor for bladder cancer, and
cacodylic acid is a metabolite of inorganic arsenic. The data remain
insufficient to conclude that studies of inorganic arsenic exposure are
directly relevant to exposure to cacodylic acid. Therefore, NAS did not
consider the literature on inorganic arsenic.
A study of the incidence of urinary bladder cancer in Vietnam
veterans who participated in Operation Ranch Hand was published in
2004. The study found no significant difference between the expected
and observed incidence of
[[Page 32399]]
urinary bladder cancer. (Akhtar et al., 2004).
NAS noted in VAO and Update 1996 that there was limited or
suggestive evidence of no association between exposure to herbicides
used in Vietnam or the contaminant dioxin and urinary bladder cancer.
Update 1998 provided additional information that led NAS to change its
conclusion to inadequate or insufficient information regarding an
association with urinary bladder cancer.
No relevant occupational or environmental studies regarding urinary
bladder cancer have been published since Update 2002.
The new evidence presented by Akhtar et al., (2004) did not change
the committee's previous findings, which placed urinary bladder cancer
in the inadequate or insufficient category.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and urinary bladder cancer outweighs the
credible evidence for such an association, and has determined that a
positive association does not exist.
Renal Cancer
Renal cancer is twice as common in men as in women. With the
exception of Wilms' tumor, which is more likely to appear in children,
renal cancer is more common in individuals over age 50. Smoking is a
risk factor for renal cancer. Other potential risk factors include
diet, weight, and occupational exposure to asbestos, cadmium, and
organic solvents. Some people with rare syndromes such as von Hippel-
Lindau syndrome and tuberous sclerosis are at higher risk. Firefighters
who are exposed to pyrolysis products are also in a known higher-risk
group.
NAS noted in VAO and subsequent reports that there was inadequate
or insufficient information to determine whether an association exists
between exposure to herbicides and renal cancer.
In 2004, Swaen et al., published the results on a total of 21 years
of follow-up on the mortality experience of an established cohort of
1,341 licensed herbicide appliers in the Netherlands. (Swaen et al.,
2004). Four deaths from kidney cancer were reported, and only three
were expected. Due to the relatively small study size and lack of
exposure information, NAS did not find this study to be sufficiently
suggestive of an association.
No relevant environmental or Vietnam-veteran studies have been
published since Update 2002.
On the basis of its evaluation of the epidemiologic evidence
reviewed and in previous VAO reports, NAS concluded that there is
inadequate or insufficient evidence to determine an association between
exposure to herbicides and renal cancer.
Taking account of the available evidence and NAS' analysis, the
Secretary has found the credible evidence against an association
between herbicide exposure and renal cancer outweighs the credible
evidence for such an association, and he has determined that a positive
association does not exist.
Leukemia (Other Than Chronic Lymphocytic Leukemia (CLL))
There are four primary types of leukemia: the acute and chronic
forms of lymphocytic leukemia and the acute and chronic forms of
myeloid (or granulocytic) leukemia.
Acute lymphocytic leukemia (ALL) is a disease of the young and of
individuals older than 70, and plays a small role in the age groups
that characterize most Vietnam veterans. Exposure to high doses of
ionizing radiation is a known risk factor. Acute myeloid leukemia (AML)
is the most common leukemia among adults. Risk factors for AML include
high doses of ionizing radiation, occupational exposure to benzene, and
some medications used in cancer chemotherapy. Genetic disorders
including Fanconi's anemia and Down's syndrome are associated with an
increased risk for AML. Tobacco smoking has also been suggested as a
risk factor.
The incidence of chronic myeloid leukemia (CML) increases with age
for individuals over 30. For individuals in the age groups that
characterize most Vietnam veterans, CML accounts for about one in five
leukemias. CML is associated with an acquired chromosomal abnormality
known as the ``Philadelphia chromosome.'' Exposure to high doses of
ionizing radiation is a known risk factor for that abnormality.
NAS noted in VAO and subsequent reports that there is inadequate or
insufficient information to determine whether an association exists
between exposure to herbicides and leukemia.
In Update 2004, NAS reviewed two relevant occupational studies. A
study of 1,341 licensed herbicide appliers in the Netherlands showed
that three deaths from all leukemias were reported when 2.2 deaths were
expected. (Swaen et al., 2004).
An occupational population-based, case-control study conducted in
11 agricultural and industrial areas of Italy showed an increased risk
of leukemia based on exposure to phenoxy herbicides. (Miligi et al.
2003.) NAS noted that the small number of cases and other limitations
prevented adequate analysis of the increased risk based on the study
data.
No environmental studies have been published since those reviewed
in Update 2002.
A study of Operation Ranch Hand veterans and a cohort of other Air
Force veterans who were not involved in the spraying of herbicides was
published in 2004. In this study, all leukemias were combined with
multiple myeloma and the lymphomas to form the category of
lymphopoietic cancers. No excess of such cancers was reported in the
Operation Ranch Hand veterans. These results did not change when the
analyses were restricted to veterans whose tours of duty ended between
1966 and 1970, the years when Agent Orange was the predominant
herbicide in use in Vietnam. (Akhtar et al., 2004).
On the basis of its evaluation of the epidemiologic evidence
reviewed and in previous VAO reports, NAS concluded that there was
inadequate or insufficient evidence to determine an association between
exposure to herbicides and leukemias other than CLL.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and leukemia (other than CLL) outweighs the
credible evidence for such an association, and he has determined that a
positive association does not exist.
Abnormal Sperm Characteristics and Infertility
NAS noted in VAO and subsequent reports that there is inadequate or
insufficient information to determine whether an association exists
between exposure to herbicides and altered sperm parameters or
infertility.
A study examined factors possibly associated with infertility in a
group of women living in an agricultural region of Wisconsin. For the
study, a woman was considered infertile if she had 12 months of
unprotected intercourse without conceiving a pregnancy that ended in
live birth. Nine case subjects and 11 control subjects reported being
exposed to 2,4,5-T and four case subjects and four control subjects
reported being exposed to 2,4-D. This study was limited because the
sample sizes were small presenting an inability to examine the effects
of specific herbicides. Moreover, information on risk factors were
obtained from self-reports, which can be subject to recall bias.
(Greenlee et al., 2003).
[[Page 32400]]
A study examined whether previously poor semen quality in men from
rural and urban areas was attributable to use of pesticides including
herbicides, fungicides, and other substances. None of the subjects from
Minnesota had detectable 2,4-D metabolites in their urine. The subjects
from Missouri had 2,4-D metabolite levels that were only of borderline
statistical significance. The study showed that 2,4-D was not
associated with sperm mobility or concentration, but showed a weak
association with sperm morphology. (Swaen et al., 2003).
A study was conducted to determine whether there was an association
between TCDD exposures and the menstrual characteristics of women
exposed to it for the next 20 years. The study used women who lived
near the site of an industrial explosion in 1976 at Seveso, Italy. The
main conclusion from the study was that serum TCDD concentration was
associated with some menstrual cycle characteristics, with possible
effect modification by menarchial status. (Eskenazi et al., 2002).
No relevant Vietnam-veteran studies have been published since
Update 2002.
NAS concluded that there is inadequate or insufficient evidence to
determine an association between exposure to herbicides and
infertility, subfertility, sperm quality or count, or altered hormone
concentrations.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and infertility and sperm abnormalities in
veterans outweighs the credible evidence for such an association, and
he has determined that a positive association does not exist.
Spontaneous Abortion
Spontaneous abortion is the expulsion of a nonviable fetus, usually
before 20 weeks of gestation. The background risk of a spontaneous
abortion is generally 7-15%, but this does not include the many more
pregnancies that terminate before the woman becomes aware of the
pregnancy.
NAS concluded in VAO and subsequent updates that there was
inadequate or insufficient information to determine an association
between exposure to herbicides and spontaneous abortion.
No relevant occupational or Vietnam-veteran studies have been
published since Update 2002.
Eskenazi et al. (2003) evaluated data from the Seveso Women's
Health Study of women who lived near the site of an industrial
explosion in 1976 at Seveso, Italy for an association between
individual serum TCDD concentrations and birth outcomes in women who
resided near the accident. No association was revealed by the Eskenazi
study. Because the spontaneous abortions were self-reported, a truly
unexposed control population could not be used in the study. Therefore,
it could be hypothesized that the study does not rule out the
possibility of a TCDD effect during the earliest period of pregnancy.
NAS concluded that there is insufficient information available to
determine whether an association exists between the risk of spontaneous
abortion and maternal exposure to herbicides.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and spontaneous abortion outweighs the
credible evidence for such an association, and he has determined that a
positive association does not exist.
Neonatal or Infant Death and Stillbirth in Offspring of Exposed
Individuals
Stillbirth, or late fetal death, typically refers to the delivery
at or after 20 weeks of gestation of a fetus that shows no signs of
life. Neonatal death refers to the death of a liveborn infant within 28
days of birth. Typically, causes of stillbirth and neonatal death
overlap considerably and are commonly analyzed together in a category
called perinatal mortality. The most common causes of perinatal
mortality among low-birthweight liveborn and stillborn infants are
placental and delivery complications. Among infants weighing more than
2,500 grams at birth, the most common causes are complications of the
cord, placenta, and membranes and lethal congenital malformations.
(Kallen, 1988).
NAS concluded in VAO and subsequent updates that there was
inadequate or insufficient information to determine an association
between exposures to herbicides and stillbirth, neonatal death, or
infant death.
No relevant occupational, environmental, or Vietnam-veteran studies
have been published since Update 2002.
NAS concluded that there is inadequate or insufficient evidence to
determine an association between exposure to herbicides and stillbirth,
neonatal death, or infant death in offspring of exposed individuals.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and stillbirth, neonatal death, and infant
death in offspring of exposed individuals outweighs the credible
evidence for such an association, and he has determined that a positive
association does not exist.
Low Birthweight in Offspring of Exposed Individuals
The World Health Organization (WHO) recommends 2,500 grams as the
threshold determination for low birthweight. Low birthweight is among
the important predictors of neonatal mortality and morbidity, and
preterm delivery is a significant cause. Factors most strongly
associated with reduced birthweight are maternal tobacco use during
pregnancy, multiple births, and race or ethnicity. Other potential risk
factors are socioeconomic status, maternal weight, birth order,
maternal complications during pregnancy, and obstetric history.
Established risk factors for preterm delivery include race, marital
status, low socioeconomic status, tobacco use, and cervical, uterine,
or placental abnormalities. (Berkowitz and Papiernik, 1993).
A case-control study examined birthweight in the offspring of women
who were involved in farming for seven (7) or more days during their
pregnancies. In total, the study included 117 women who delivered low
birthweight infants (cases) and 377 women who delivered infants
weighing at least 2,500 grams (controls). No significant differences
were exhibited in the birthweights in the exposed and non-exposed
groups. Pregnancy duration was also the same time, with a mean of 38
weeks in cases and controls. NAS determined the study was limited by
its retrospective nature. (Dabrowski et al., 2003).
An environmental study examined the association between TCDD
exposure and reproductive outcomes among 510 women exposed to TCDD who
had complete pregnancies within 20 years of their exposure. The study
showed a small non-significant association between maternal dioxin
concentrations and decreased birthweight and prematurity. NAS
determined that there were flaws in the study, such as the fact that
information was obtained by self-report, and that there was no control
group or a measurement of background dioxin. (Eskenazi et al., 2003).
No relevant Vietnam-veteran studies were published since Update
2002.
NAS concluded that there is inadequate or insufficient evidence to
determine an association between
[[Page 32401]]
exposure to herbicides and low birthweight and preterm delivery in
offspring of exposed individuals.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and low birthweight and preterm delivery in
offspring of exposed individuals outweighs the credible evidence for
such an association, and he has determined that a positive association
does not exist.
Birth Defects (Other Than Spina Bifida) in Offspring of Exposed
Individuals
The March of Dimes defines a birth defect as ``an abnormality of
structure, function, or metabolism, whether genetically determined or
as a result of an environmental influence during embryonic or fetal
life.'' (Bloom, 1981). Major birth defects, which occur in 2-3% of live
births, are severe enough to interfere with viability or physical well-
being. Birth defects are detected in another 5% of babies through their
first year of life.
The causes of most birth defects are unknown. Known causes include
genetic factors, exposure to some medications, environmental
contaminants, occupational hazards, and lifestyle factors.
In 1994, NAS found in VAO that there was inadequate or insufficient
information to determine an association between exposure to herbicides
and birth defects among offspring. But in Update 1996 and subsequent
studies, NAS concluded that there was limited or suggestive evidence of
an association between at least one of the compounds of interest and
spina bifida in the children of exposed veterans. There was no change
in the conclusions about other birth defects.
An environmental study examined the impact of exposure to emissions
from municipal solid waste incinerators on birth defects in a region of
France over a ten-year period. Congenital anomalies were not
significantly associated with exposure overall, but some specific
anomalies (facial clefts, renal dysplasia, obstructive uropathies,
cardiac anomalies) showed significant dose-response relationships. The
exposure indicator in this study could not differentiate exposure to
dioxins from exposure to metals. (Cordier et al., 2004).
An ecologic study compared rates of adverse birth outcomes in U.S.
agricultural states. The use of herbicides on the fields during the
times when certain babies were conceived showed a possible increased
risk for some defects, such as musculoskeletal and integumental
anomalies. However, this study did not directly measure herbicide
exposure; instead, it measured by acreage. (Schreinemachers, 2003).
No relevant occupational studies have been published since Update
2002.
Data from the Centers for Disease Control and Prevention (CDC)
regarding birth defects in the past 25 years showed that there was no
greater risk among Vietnam veterans for fathering babies with serious
birth defects. (Correa-Villasenor et al., 2003).
Excluding spina bifida, NAS concludes that there is inadequate or
insufficient evidence to determine an association between exposure to
herbicides and all other birth defects in offspring of exposed
individuals.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and all other birth defects other than spina
bifida outweighs the credible evidence for such an association and he
has determined that a positive association does not exist.
Childhood Cancer (Including Acute Myelogenous Leukemia) in Offspring of
Exposed Individuals
Cancer remains the leading cause of death from disease in children
under the age of 15. Leukemia is the most common cancer in children.
The second most common group of cancers in children is that of the
central nervous system.
NAS concluded in VAO and subsequent studies that there was
inadequate or insufficient information to determine an association
between exposure to herbicides and childhood cancers.
An agricultural health study examined childhood cancer in the
offspring of male pesticide applicators in Iowa. Incidence was compared
with the Iowa Surveillance, Epidemiology and End Result data. Potential
associations between pesticide exposure and individual types of cancer
were not examined. There was a higher rate of childhood cancers for
paternal exposure to herbicides than for maternal exposure. (Flower et
al., 2004).
No relevant environmental or Vietnam-veteran studies have been
published since Update 2002.
The only new study reviewed for this update (Flower et al., 2004),
did not show any significant association between the relevant exposures
and childhood cancer in offspring of exposed individuals.
On the basis of its evaluation of the epidemiologic evidence
reviewed here and in previous VAO reports, NAS concluded that there is
inadequate or insufficient evidence to determine an association between
exposure to herbicides and childhood cancer in offspring of exposed
individuals.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and childhood cancer in offspring of exposed
individuals outweighs the credible evidence for such an association,
and he has determined that a positive association does not exist.
Neurobehavioral Disorders (Cognitive or Neuropsychiatric)
NAS noted in VAO and subsequent reports that there was inadequate
or insufficient information to determine whether an association exists
between exposure to herbicides and cognitive and neuropsychiatric
effects.
Since Update 2002, five reports have investigated associations
between neurobehavioral disorders and possible exposure to herbicides.
The five reports are: (1) An update of the Air Force Health Study
(AFHS) (Barrett et al., 2003), (2) a cross-sectional study of a cohort
of Korean veterans who served in Vietnam (Kim et al., 2003), (3) an
update of an occupational cohort from the Czech Republic (Pelclova et
al., 2002), (4) a cohort study from the Bordeaux region of France
(Baldi et al., 2003) and (5) a semi-ecological study from a community
adjacent to a wood treatment plant (Dahlgren et al., 2003).
Psychological functioning was compared in Ranch Hand veterans and
other Vietnam veterans (Barrett et al., 2003). The characteristics of
the study groups indicated that those with high exposure were more
likely to be younger enlisted personnel; those with background or low
exposure were older officers. Two standard psychological test
instruments were administered: The Minnesota Multiphasic Personality
Inventory (MMPI) and the Millon Clinical Multiaxial Inventory (MCMI).
MMPI results were inconsistent and showed no significant associations
with exposure. The conclusions from the studies were limited by the
possibility of misclassification of exposure, selection bias, and
uncontrolled confounding. The authors concluded that there were few
consistent differences in psychological functioning between groups
based on serum dioxin concentrations.
A study published results of a cross-sectional study of Korean
veterans who served in Vietnam. Health outcomes were assessed by a
group of four family
[[Page 32402]]
practitioners, blinded to subjects' exposure status, using a
``standardized comprehensive clinical investigation.'' There was a
significantly higher prevalence of post-traumatic stress disorder
(PTSD) and mood disorder in Vietnam veterans than in the non-Vietnam
comparison group; although the association was not significant after
controlling for multiple potential confounders, and it did not differ
by exposure in Vietnam veterans. The study was limited because of the
possibility of selection bias and a chance of residual confounding
because of the demographic difference between groups. (Kim et al.,
2003).
The Bordeaux study (Baldi et al., 2003) examined a cohort of 2,792
persons over age 65, enrolled in 1987 for the purposes of studying
normal and pathological cerebral aging and loss of independence in the
elderly. Exposures were categorized into quartiles by the likelihood of
occupational use of chemical pesticides on the basis of self-reports,
which introduced the possibility of recall bias. The high drop-out rate
raises concerns of selection bias. The authors of the study could not
identify exposure to specific compounds. The study offered no evidence
that would implicate the compounds of interest because the exposures
were not comparable to herbicide exposures in Vietnam.
Dahlgren et al. used a semi-ecological design to assess the
possibility that self-reported symptoms suggesting neurobehavioral
disorders in a group of people from eastern Mississippi were related to
residence near a creosote treatment plant. (Dahlgren et al., 2003). The
study suffered from design weaknesses, including selection and
ascertainment bias, lack of objective exposure data, and lack of
physician-confirmed diagnoses.
NAS concluded that there is no consistent evidence for any
association between neurobehavioral disorders and herbicide exposure.
On the basis of its evaluation of the epidemiological evidence
reviewed here and on previous VAO reports, NAS concludes that there is
still inadequate or insufficient evidence to determine whether an
association exists between exposure to herbicides and neurobehavioral
disorders (cognitive or neuropsychiatric).
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and neurobehavioral disorders (cognitive or
neuropsychiatric) outweighs the credible evidence for such an
association, and he has determined that a positive association does not
exist.
Movement Disorders, Including Parkinson's Disease (PD) and Amyotrophic
Lateral Sclerosis (ALS)
Parkinson's Disease
Parkinson's Disease (PD) is a progressive neurodegenerative
disorder that affects millions of people worldwide. Its primary
clinical manifestations are bradykinesia, resting tremor, cogwheel
rigidity, and gait instability. These signs were first described in
1817 as a single entity by James Parkinson, who believed that severe
fright from a traumatic experience was a probable cause.
Because of the increasing concern that a link exists between PD and
various chemicals used in herbicides, NAS, in VAO and subsequent
reports, suggested that as Vietnam veterans move into the age groups
when PD is more prevalent, attention be given to the frequency and
character of new cases of PD in exposed versus non-exposed individuals.
In the Bordeaux cohort study, new cases at the 8- and 10-year
follow-up were identified by self-report in response to the question,
``Do you have Parkinson's disease?'' The incidence for exposed and
unexposed subjects, respectively, was estimated at 8.9 and 4.1 cases
per 1,000 person-years. The results do suggest increased risk to men
with occupational exposure to pesticides, but the use of fungicides in
vineyards predominated, rather than any of the compounds of interest.
The case-control study from Bordeaux compared 84 subjects over age 70
with PD who had been recruited from hospital-based specialty clinic
practices with a control group of 252 subjects without PD, identified
from the previously described cohort. There is no evidence from that
study to implicate herbicides to Vietnam veterans. (Baldi et al.,
2003).
On the basis of its evaluation of the epidemiologic evidence
reviewed here and in previous VAO reports, NAS concluded that there is
inadequate or insufficient information to determine whether an
association exists between exposure to herbicides and PD.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and PD outweighs the credible evidence for
such an association, and he has determined that a positive association
does not exist.
Amyotrophic Lateral Sclerosis (ALS)
ALS is a progressive motor neuron disease with adult onset that
presents with muscle atrophy, weaknesses, and fasciculations. The
incidence of ALS peaks between the ages of 55 to 75 years. Known risk
factors for ALS are age and a family history of ALS. Interest in the
role of occupational or environmental exposure originated in cases of
motor neuron disease associated with exposure to heavy metals, chemical
plants, animal carcasses, heavy manual labor, work with electricity,
pneumatic tools, work in the plastic industry, and work as a truck
driver.
No relevant epidemiologic studies have been published since Update
2002.
On the basis of its evaluation of the epidemiologic evidence
reviewed here and in previous VAO reports, NAS concluded that there is
inadequate or insufficient evidence of an association between exposure
to herbicides and motor neuron disease or ALS.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and ALS outweighs the credible evidence for
such an association, and he has determined that a positive association
does not exist.
Chronic Peripheral Nervous System Disorders
Peripheral neuropathy consists of disorders of the peripheral
nervous system. Manifestations of this syndrome can include a
combination of sensory changes, motor weakness, or autonomic
instability.
NAS noted in VAO and subsequent reports that there was inadequate
or insufficient evidence of an association between exposure to
herbicides and peripheral neuropathy.
Peripheral neuropathy was one outcome considered in a study of
Korean Vietnam veterans (Kim et al., 2003). It was significantly more
common in Vietnam veterans than in non-Vietnam veterans, with a 2.4-
fold risk even after controlling for alcohol use and age, although
there were no differences based on estimated TCDD exposure within
subgroups of Vietnam veterans. Diabetes was also more common in Vietnam
veterans. The authors of the study concluded that there was an excess
frequency of peripheral neuropathy in Vietnam veterans. The report
distinguishes between ``peripheral neuropathy'' and ``neuropathy with
diabetes,'' which was not significantly different between the groups.
The possibility of selection bias was a concern in this study, only 28%
of eligible Vietnam veterans participated in the study and
participation may have been related to health status. Therefore,
[[Page 32403]]
the study provides some evidence of an association between service in
Vietnam and peripheral neuropathy. However, the study does not provide
evidence for an association between specific exposure to the compounds
of interest and chronic persistent neuropathy.
NAS concluded that there remains inadequate or insufficient
evidence of an association between exposure to herbicides and chronic
persistent peripheral neuropathy.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and chronic persistent peripheral neuropathy
outweighs the credible evidence for such an association, and he has
determined that a positive association does not exist.
Respiratory Disorders
Non-malignant respiratory disorders comprise acute and chronic lung
diseases other than Cancer. Acute respiratory disorders include
pneumonia and other respiratory infections. Those disorders can be
increased in frequency and severity when the normal defense mechanisms
of the lower respiratory tract are compromised.
The major risk factor for many non-malignant respiratory disorders
is cigarette smoking. Cigarette smoking is the major cause of many
airway disorders, and makes almost every respiratory disorder more
severe and symptomatic than would otherwise be the case. Vietnam
veterans are reported to smoke more heavily than are non-Vietnam
veterans (McKinney et al., 1997).
NAS noted in VAO and subsequent updates that there was inadequate
or insufficient information to determine an association between
exposure to herbicides and respiratory disorders.
A cross-sectional environmental study used questionnaires to gather
information on potential adverse health effects among residents near a
wood treatment plant. Exposed residents reported greater frequency of
chronic bronchitis by history and asthma by history. Selection bias and
recall bias limit the utility of the results. It is unclear whether the
authors adequately controlled for history of tobacco use. In addition,
multiple environmental exposures occurred in the neighborhood near the
plant, and the authors could not determine which exposures were
responsible for the reported adverse health effects. (Dahlgren et al.,
2003).
No relevant occupational or Vietnam-veteran studies have been
published since Update 2002. No new studies provide evidence of a
direct risk of non-malignant respiratory disorders in adults since
those reviewed in Update 2002.
On the basis of its evaluation of the epidemiologic evidence
reviewed in Update 2004 and in previous VAO reports, NAS concluded that
there is inadequate or insufficient evidence to determine an
association between exposure to herbicides and non-malignant acute or
chronic respiratory disorders.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and respiratory disorders outweighs the
credible evidence for such an association, and he has determined that a
positive association does not exist.
Gastrointestinal, Metabolic, and Digestive Disorders (Changes in Liver
Enzymes, Lipid Abnormalities, Ulcers)
Gastrointestinal and digestive disease includes diseases of the
esophagus, stomach, intestines, rectum, liver, and pancreas. The two
conditions most often discussed in the literature reviewed are peptic
ulcer disease and liver disease. The symptoms and signs of gastro
intestinal disease and liver toxicity are highly varied and often
vague.
The most convenient way to categorize diseases that affect the
gastrointestinal system is by the affected anatomic segment.
NAS in VAO and subsequent reports found there was inadequate or
insufficient information to determine whether an association exists
between exposure to herbicides and gastrointestinal and digestive
disease, including liver toxicity.
No relevant environmental or Vietnam-veteran studies have been
published since Update 2002.
NAS concluded that there was no information contained in the
research reviewed for Update 2004 to change the conclusion that there
is inadequate or insufficient evidence to determine whether an
association exists between exposure to herbicides and gastrointestinal
and digestive diseases.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and gastrointestinal and digestive disease
outweighs the credible evidence for such an association, and he has
determined that a positive association does not exist.
Plasma lipid (notably cholesterol) concentrations have been shown
to predict cardiovascular disease and are considered fundamental to the
underlying atherosclerotic process. The two major types of lipids,
cholesterol and triglycerides, are carried in the blood attached to
proteins to form lipoproteins. NAS in VAO and subsequent reports found
there was inadequate or insufficient information to determine whether
an association exists between exposure to herbicides and lipid and
lipoprotein disorders.
No relevant environmental or Vietnam-veteran studies of lipid and
lipoprotein disorders have been published since those reviewed in
Update 2002.
An occupational study conducted measured cholesterol and
triglyceride concentrations in 12 men who were exposed to extremely
high concentrations of TCDD in the late 1960s while they were employed
in herbicide production at a chemical factory in the former
Czechoslovakia. The correlation between TCDD in 1996 and highest
recorded measurement of triglyceride or cholesterol at any point
between 1968 and 2001 was 0.66 for triglyceride and 0.78 for
cholesterol. No information was given about follow up measures of
lipids collected in standard or periodic fashion for participants and
there is no discussion of how individual differences in treatment of
elevated cholesterol could influence the highest recorded value for
total cholesterol. (Pelclov[aacute] et al., 2002).
Hu et al. (2003) conducted a cross-sectional study of dioxin-furan
exposures and lipids in workers at municipal-waste incinerator plants
in Taipei City, Taiwan. A total of 133 workers were randomly sampled
from 3 plants; the workers had to have been employed for at least 6
months in the operation and control or maintenance departments.
Seventeen (17) cogeners were measured, including TCDD. Workers with
TCDD above the median had higher average cholesterol and were more
likely to have cholesterol above 220 mg/dL. The relationship between
TCDD and cholesterol was not statistically significant when TCDD was
measured by tertiles, quartiles, or as a continuous variable. TCDD was
not associated with triglyceride as a continuous or categorical
measure.
The study by Pelclov[aacute] et al. has some shortcomings,
including the small sample (12 men). The study by Hu et al.
successfully recruited a cross-section of workers and did show
significant variation in cholesterol by a dichotomous measure of TCDD.
The loss of statistical significance with more detailed categories or
along the full continuum of TCDD values suggests that
[[Page 32404]]
the findings from the initial analysis are not robust or consistent.
Several individual cogeners other than TCDD were identified as
statistically significant correlates of elevated cholesterol. The study
did not allow for isolation of the effect of any single exposure. The
relationship between herbicide exposure and lipid remains uncertain.
NAS concluded that there is inadequate or insufficient evidence to
determine whether an association exists between exposure to herbicides
and lipid and lipoprotein disorders.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and lipid and lipoprotein disorders
outweighs the credible evidence for such an association, and he has
determined that a positive association does not exist.
Immune System Disorders (Immune Suppression, Autoimmunity)
The immune system defends the body against infection by viruses,
bacteria, and other disease-producing microoganisms (pathogens). The
immune system's cells arise from stem cells in the bone marrow; they
are found throughout the body's lymphoid tissues, and they circulate in
the blood as white blood cells. The immune system also operates in
cancer surveillance, destroying cells that have transformed and might
otherwise develop into tumors.
Autoimmune disease is an example of the immune system's causing
rather than preventing disease. In this case, the immune system
mistakenly attacks the body's own cells and tissues as if they were
foreign.
In new studies from Seveso, Italy, plasma immunoglobulin (Ig) and
complement concentrations were measured in a random sample of the
population. This was conducted in highly exposed zones and in the
surrounding uncontaminated areas. The concentrations of one plasma
immunoglobulin (IgG), significantly decreased with increasing TCDD
concentration. The association was present after adjusting for age,
sex, tobacco use, and computation of domestic livestock and poultry.
(Baccarelli et al., 2002).
Two studies have evaluated the influence of exposure to TCDD-like
compounds on immune response in children. One study characterized the
immune status of adolescent boys and girls in Flanders, Belgium, in
relation to their blood concentrations of PCBs and dioxin like
compounds. The results found in the adolescents might suggest a dioxin-
induced suppression of the immune response, consistent with the
findings in the laboratory animals exposed to TCDD. (Van Den Heuvel et
al., 2002).
In a follow up study of 8 year-old Dutch children perinatally
exposed to dioxin, researchers found a decrease in allergy in relation
to increasing dioxin exposure. The study found an increased percentage
of naive versus activated T cells, which is consistent with a
generalized decrease in immune responsiveness associated with dioxin
exposure. (Tusscher et al. 2003).
One study examined Korean Vietnam War veterans for evidence of
immune system changes in relation to their operation in various areas
of Vietnam. A significant increase in plasma IgE was found in both
groups of veterans compared with control subjects. The patient group
also had significantly decreased plasma IgG1. Those changes correlated
with decreased production of interferon gamma in the patient group and
with increased production of interleukin 4 in both veterans' groups
when the T cells from the subjects were cultured in vitro. No changes
in the plasma concentrations of antibodies against double-stranded DNA
or extractable nuclear antigens, both markers of autoimmune disease,
were found in the veterans, nor were changes found in frequency
distribution of peripheral blood leukocyte subpopulations. (Kim H-A et
al., 2003).
TCDD is a well known immunosuppressive agent in laboratory animals;
it is among the most potent immunotoxicants in the environment.
Therefore, one would expect that exposure of humans to sufficiently
high doses of TCDD would result in immune suppression. However, several
studies of various parameters of human immune function have failed to
reveal consistent correlations with TCDD exposure, and no detectable
pattern of increased infectious diseases has developed in veterans
exposed to high concentrations of TCDD or other herbicides used in
Vietnam. Although suppression of the immune response by TCDD could
increase the risk of some cancers in Vietnam veterans, there is no
evidence to support that connection.
Studies that examined the influence of TCDD on IgE production have
generated additional conflicting data. Two studies revealed a
significant reduction in IgE production and associated allergic
responses correlated with increasing exposure to TCDD and related
compounds among children in Belgium and the Netherlands (Tusscher et
al., 2003; Van Den Heuvel et al., 2002). In contrast, Korean Vietnam
veterans had increased rather than decreased IgE concentrations in
plasma--independent of health status. (Kim H-A et al., 2003).
No relevant occupational studies were published since those
reviewed in Update 2002.
NAS noted in VAO and subsequent reports that there was inadequate
or insufficient information to determine whether an association exists
between exposure to herbicides and immune system disorders.
NAS concluded that there was no information reviewed for Update
2004 to change the conclusion that there is inadequate or insufficient
evidence to determine whether an association exists between exposure to
herbicides and immune system disorders.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between immune system disorders and herbicide exposure outweighs the
credible evidence for such an association, and he has determined that a
positive association does not exist.
Circulatory Disorders
The term circulatory disorder includes hypertension, heart failure,
arteriosclerotic heart disease, peripheral vascular disease, and
cerebrovascular disease. NAS noted in VAO and subsequent reports that
there was inadequate or insufficient information to determine whether
an association exists between exposure to herbicides and circulatory
disorders.
An occupational study presented results for a 21-year-old follow up
of mortality in a cohort of 1,341 licensed herbicide applicators
working for government agencies in the Netherlands. The workers had
relatively low cardiovascular mortality. (Swaen et al., 2004).
An ecological study reported no association between measure of
dioxin emissions and cardiovascular or cerebrovascular mortality after
adjustment for socioeconomic correlates of dioxin emissions. However,
the study design precludes inferences about the relationship between
exposure and disease among individuals. This study cannot be
interpreted as important evidence of no association. (Fukuda et al.,
2003).
A Vietnam-veteran study reported the results of a cross-sectional
study of exposure to Agent Orange and the prevalence of large number of
health outcomes in Korean veterans who had served in Vietnam. The study
shows an elevated prevalence of hypertension in
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Vietnam veterans compared with that for veterans who served elsewhere.
However, some of the weaknesses included in this study include no
information on the measurement of disease, and therefore no opportunity
to comment on the quality of measurement. There is also the possibility
of selection bias in the formation of the study population due to a law
in Korea to support medical care and compensation for herbicide
victims. (Kim J-S et al., 2003).
The new occupational and environmental studies of circulatory
conditions do not support an association for exposure to herbicides,
but they also do not represent compelling evidence for the lack of an
association.
On the basis of its evaluation of the epidemiologic evidence
reviewed here and in previous VAO reports, NAS concluded that there is
no information contained in Update 2004 to change the conclusion that
there is inadequate or insufficient evidence to determine whether an
association exists between exposure to herbicides and specific
circulatory disorders (coronary artery disease, myocardial infarction,
stroke, hypertension) or circulatory conditions in general.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and circulatory disorders outweighs the
credible evidence for such an association, and he has determined that a
positive association does not exist.
AL Amyloidosis
Amyloidosis refers to a group of related disorders that share the
common feature of the deposition of insoluable, fibrous amyloid
protein, mainly in the extracellular spaces of organs and tissues to a
point that causes organs to malfunction. NAS reviewed AL amyloidosis
(also sometimes referred to as primary amyloidosis), in which the light
chain of immunoglobulin molecules is the aberrant protein. AL
amyloidosis is the most common form of amyloidosis in the United
States.
VA identified AL amyloidosis as a concern in Update 1998. It was
examined specifically by the committees responsible for Updates 2000
and 2002. In Update 2002, NAS found there was inadequate or
insufficient information to determine whether an association exists
between exposure to herbicides and AL amyloidosis.
No relevant occupational, environmental, or Vietnam-veteran studies
have been published since Update 2002.
NAS concluded that there is no information to change the conclusion
that there is inadequate or insufficient evidence to determine whether
an association exists between exposure to herbicides and AL
amyloidosis.
Taking account of the available evidence and NAS' analysis, the
Secretary has found that the credible evidence against an association
between herbicide exposure and amyloidosis outweighs the credible
evidence for such an association, and he has determined that a positive
association does not exist.
Endometriosis
The endometrium is the tissue that lines the inside of the uterus.
In endometriosis, the endometrium is found outside the uterus, usually
in other parts of the reproductive system, the abdomen, or the tissues
near the reproductive organs. The tissue develops into growths or
lesions that respond to hormonal changes in the body, and break down
and bleed each month in concert with a woman's menstrual cycle. It
results in inflammation, internal bleeding, and degeneration of blood
and tissue, which can cause scarring, pain, infertility, adhesions, and
intestinal problems. The exact cause of endometriosis is unknown,
though genetics is a possible etiology.
NAS reviewed endometriosis for the first time in Update 2002. Since
Update 2002, three environmental studies have been conducted that
examined the relationship between exposures to some of the compounds of
interest and endometriosis. One such study investigated the development
of endometriosis among participants of the Seveso Women's Health Study.
The cohort consisted of women who had lived in proximity to the Seveso
accident site in 1976 and had TCDD serum measurements in blood
collected between 1976 and 1980. Women in the highest exposure group
showed a doubling in the risk of endometriosis compared with the lowest
exposure group, although the increase was not statically significant,
possibly because of the small number of confirmed cases. A major
limitation of the study was the inability to confirm with laparoscopy
the disease state of the largest group, those with an uncertain
diagnosis. No truly unexposed control group was included in the study.
(Eskenazi et al., 2002).
The second study completed a population-based cross-sectional study
of residents in several Belgian towns in the vici
