[Federal Register Volume 72, Number 112 (Tuesday, June 12, 2007)]
[Notices]
[Pages 32395-32407]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-11247]


=======================================================================
-----------------------------------------------------------------------

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 INFORMATION CONTACT: 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 the Agent 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 issued its 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 notice of 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 previously reviewed 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

[[Page 32405]]

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 vicinity of industrial 
sites or municipal solid waste incinerators and a control group with no 
known exposures to dioxins or PCBs. There was no difference in the mean 
TEQ (toxicity equivalent) concentrations between the 10 cases and 132 
controls. The study's usefulness is compromised because of reliance on 
self-reports and because of the small number of cases. (Fierens et al., 
2003).
    The third study conducted a pilot case-control study of women of 
reproductive age in Italy and Belgium to determine whether there is a 
correlation between blood concentrations of dioxin-like compounds and 
endometriosis. Controls were patients suspected of having a benign 
adnexal mass; cases were suspected of having endometriosis. The data 
did not indicate that the concentration of 2,3,7,8-TCDD was elevated in 
women with endometriosis. Overall, the study did not show that women 
with endometriosis had higher 2,3,7,8-TCDD or total TEQ than did 
controls. The study was limited in its ability to detect differences, 
however, by the small number of subjects. The selection criteria, which 
allowed all women with suspected gynecological abnormality, also 
introduced bias. (De Felip et al., 2004).
    No relevant occupational or Vietnam-veteran studies have been 
published since Update 2002.
    None of the three studies demonstrated an increased risk for 
endometriosis with exposure to dioxin or dioxin-like compounds. NAS 
concluded that there is inadequate or insufficient evidence to 
determine whether an association exists between exposure to herbicides 
and endometriosis.
    Taking account of the available evidence and NAS' analysis, the 
Secretary has found that the credible evidence against an association 
between herbicide exposure and endometriosis outweighs the credible 
evidence for such an association, and he has determined that a positive 
association does not exist.

Effects on Thyroid Homeostasis

    The thyroid gland secretes hormones (T4 and T3) that stimulate 
metabolism. Secretion of T4 and T3 is under the control of thyroid-
stimulating hormone (TSH), which is secreted by the anterior pituitary 
gland. The thyroid also secretes calcitonin, a hormone that controls 
calcium concentration in the blood and storage of calcium in bones. 
Chemical-induced alterations in thyroid homeostasis can adversely 
affect the development of many organ systems, including the nervous and 
reproductive

[[Page 32406]]

systems. Most adverse effects are caused by lack of thyroid hormone 
alone rather than by increases in TSH. TCDD affects the concentrations 
of thyroid hormones; the effects appear to be species-dependent and may 
reflect both the dose and the duration of exposure. TCDD influences the 
metabolism of thyroid hormones and TSH. Studies of environmental 
exposure have emphasized thyroid alterations in prenatal and early 
childhood development rather than in adults.
    NAS reviewed the thyrotoxic potential of herbicides for the first 
time in Update 2002 and concluded that there was inadequate or 
insufficient information to determine an association between exposure 
to herbicides and adverse effects on thyroid homeostasis.
    An occupational study measured serum hormone and TCDD concentration 
in 37 men who had sprayed 2, 4,5-T. In correlation analysis, TCDD 
concentrations were inversely related to T3 and TSH. The association 
was strongest when historical, but not current, serum TCDD 
concentrations were considered. (Johnson et al., 2001).
    No relevant environmental studies were published since Update 2002.
    A Vietnam-veterans study examined thyroid hormone status in the 
AFHS cohort. At each examination there was a trend toward an increasing 
concentration of TSH, which was not accompanied by changes in 
circulating T4 or in the percentage uptake of T3. Ranch Hand veterans 
had TSH significantly higher than did the comparison population. No 
changes in microsomal or antithyroid antibodies were observed, nor was 
there any evidence of changes in clinical thyroid disease. (Pavuk et 
al., 2003).
    NAS determined the lack of data on the association between exposure 
to the chemicals of interest and adverse effects on thyroid 
homeostasis, coupled with the lack of exposure information on Vietnam 
veterans precludes quantification of any possible increase in their 
risk.
    NAS concluded that there is inadequate or insufficient evidence to 
determine whether an association exists between exposure to herbicides 
and adverse effects on thyroid homeostasis.
    Taking account of the available evidence and NAS' analysis, the 
Secretary has found that the credible evidence against an association 
between herbicide exposure and adverse effects on thyroid homeostasis 
outweighs the credible evidence for such an association, and he has 
determined that a positive association does not exist.

Gastrointestinal Tumors (Esophagus, Stomach, Pancreas, Colon, Rectum)

    Gastrointestinal Tract tumors are among the most common of cancers. 
NAS reviewed data on esophageal cancer, stomach cancer, pancreatic 
cancer, colon cancer, and rectal cancer. Colon cancer makes up about 
40% of gastrointestinal tract cancer diagnoses and deaths.
    The incidence of stomach, colon, rectal, and pancreatic cancers 
increase with age in people 50-64 years old. In general, the incidence 
is higher in men than women, and is higher in blacks than in whites. 
Other risk factors for those cancers vary but always include family 
history of the same form of cancer, some diseases of the affected 
organ, and dietary factors.
    NAS noted in VAO and subsequent reports that there was limited or 
suggestive evidence of no association between exposure to herbicides 
and gastrointestinal (GI) tract tumors.
    NAS examined two occupational studies. One study showed that male 
chemical production workers previously exposed to substantial amounts 
of dioxin experienced no increased risk from death from gastric cancer. 
(Bodner et al., 2003).
    In another study of licensed herbicide appliers in the Netherlands, 
a lower than expected number of deaths due to esophagus and stomach 
cancer was reported. (Swaen et al., 2004).
    An environmental study of 590 municipalities in Japan examined the 
relationships between indexes of dioxin emissions from incineration 
plants and cause-specific mortality among nearby residents. When the 
analysis was restricted to municipalities with incineration plants, 
there was a positive and statistically significant correlation in men 
for stomach cancer for one dioxin index and a statistically significant 
negative correlation for three dioxin indexes. (Fukuda et al., 2003).
    The Vietnam-veteran study reported on cancer incidence and 
mortality in Air Force veterans of the Vietnam War. Index cases were 
Operation Ranch Hand veterans who sprayed dioxin-contaminated 
herbicides in Vietnam. Comparison subjects served in Southeast Asia 
during the same period but did not spray herbicides. The group reported 
that the incidence of cancer of the digestive system was significantly 
lower than expected, compared with national incidence rates, in white 
Ranch Hand veterans. There were insufficient numbers of non-white Ranch 
Hand veterans to make estimates. (Akhtar et al., 2004).
    NAS concluded that there was no new evidence to change the previous 
determination that there is limited or suggestive evidence of no 
association between exposure to herbicides and gastrointestinal tract 
cancer.
    The evidence that suggests that there is no association between 
exposure to herbicides and gastrointestinal tumors also implies that 
Vietnam-veterans are not at increased risk of gastrointestinal tumors 
resulting from herbicide exposure.
    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 tract tumors outweighs 
the credible evidence for such an association, and he has determined 
that a positive association does not exist.

Brain Tumors

    The only well-established environmental risk factor for brain 
tumors is exposure to high doses of ionizing radiation. (American 
Cancer Society, 2004a; Wrensch et al., 2002). Several other potential 
risk factors have been examined, but most brain cancers are not 
associated with any known risk factors. Brain cancer occurs fairly 
infrequently.
    NAS noted in VAO and subsequent reports that there was limited or 
suggestive evidence of no association between exposure to herbicides 
and brain tumors.
    An occupational study conducted in 2003 updated cancer mortality 
among Dow Chemical Company workers who were likely to have been exposed 
to high concentrations of dioxins. Cancers of the brain and nervous 
system were not elevated. (Bodner et al., 2003).
    A 2004 study of the mortality of a cohort of 1,341 licensed 
herbicide appliers in the Netherlands showed an insignificant increase 
in brain cancer, but the study was limited by the small number of cases 
and by potential confounders that could not be evaluated. (Swaen et 
al., 2004).
    No relevant environmental studies were published since Update 2002.
    A Vietnam-veteran study describes cancer incidence and mortality in 
a prospective cohort study of Air Force Operation Ranch Hand veterans 
who sprayed Agent Orange while serving in Southeast Asia. The Ranch 
Hand cohort was compared to a group of veterans who did not serve in 
Southeast Asia as well as U.S. national cancer rates. There was a non-
significant increase in the incidence of cancer of the brain and 
nervous system compared with national rates, and a non-significant 
increase in Ranch Hand veterans who served during the heaviest use of 
Agent Orange. There

[[Page 32407]]

was no increase in mortality attributable to cancer of the brain and 
nervous system. This study was limited by the small number of cases. 
(Akhtar et al., 2004).
    NAS concluded that there was no new evidence to change the previous 
determination that there is limited or suggestive evidence of no 
association between exposure to herbicides and brain tumors.
    Taking account of the available evidence and NAS' analysis, the 
Secretary has found that the credible evidence against an association 
between herbicide exposure and brain tumors outweighs the credible 
evidence for such an association, and he has determined that a positive 
association does not exist.

Conclusion

    NAS reviewed scientific and medical articles published since the 
publication of its first report as an integral part of the process that 
resulted in ``Veterans and Agent Orange: Update 2004.'' The 
comprehensive review and evaluation of the available literature that 
NAS conducted in conjunction with its report has permitted VA to 
identify all conditions for which the current body of knowledge 
supports a finding of an association with herbicide exposure. 
Accordingly, the Secretary has determined that there is no positive 
association between exposure to herbicides and any other condition for 
which he has not specifically determined that a presumption of service 
connection is warranted.
    After careful review of the NAS findings in Update 2004 and other 
pertinent information, the Secretary has determined that no new 
presumptions of service connection are warranted for any illnesses 
based on exposure to herbicides used during the Vietnam War or to 
dioxin.

    Approved: June 5, 2007.
Gordon H. Mansfield,
Deputy Secretary of Veterans Affairs.
[FR Doc. E7-11247 Filed 6-11-07; 8:45 am]
BILLING CODE 8320-01-P