Health Effects Not Associated With Exposure to Certain Herbicide Agents, 32540-32553 [2010-13653]

Agencies

• DEPARTMENT OF VETERANS AFFAIRS

[Federal Register Volume 75, Number 109 (Tuesday, June 8, 2010)]
[Notices]
[Pages 32540-32553]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2010-13653]



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DEPARTMENT OF VETERANS AFFAIRS




Health Effects Not Associated With Exposure to Certain Herbicide 

Agents



AGENCY: Department of Veterans Affairs.



ACTION: Notice.



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SUMMARY: As required by law, the Department of Veterans Affairs (VA)



[[Page 32541]]



hereby gives notice of a May 2008 determination by the Secretary of 

Veterans Affairs that evidence available at that time did not warrant a 

presumption of service connection based on exposure to herbicides used 

in the Republic of Vietnam during the Vietnam era for the following 

health outcomes: Cancers of the oral cavity (including lips and 

tongue), pharynx (including tonsils), or nasal cavity (including ears 

and sinuses); cancers of the pleura, mediastinum, and other unspecified 

sites within the respiratory system and intrathoracic organs; 

esophageal cancer; stomach cancer; colorectal cancer (including small 

intestine and anus); hepatobiliary cancers (liver, gallbladder and bile 

ducts); pancreatic cancer; bone and joint cancer; melanoma; non-

melanoma skin cancer (basal cell and squamous cell); breast cancer; 

cancers of reproductive organs (cervix, uterus, ovary, testes, and 

penis; excluding prostate); urinary bladder cancer; renal cancer; 

cancers of brain and nervous system (including eye); endocrine cancers 

(thyroid, thymus, and other endocrine); leukemia (other than chronic 

lymphocytic leukemia (CLL)); cancers at other and unspecified sites; 

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, and ulcers); 

immune system disorders (immune suppression, allergy, and 

autoimmunity); ischemic heart disease; circulatory disorders (including 

hypertension); endometriosis; effects on thyroid homeostasis; certain 

reproductive effects, i.e., infertility, spontaneous abortion, neonatal 

or infant death and stillbirth in offspring of exposed people, low 

birth weight in offspring of exposed people, birth defects (other than 

spina bifida) in offspring of exposed people, childhood cancer 

(including acute myelogenous leukemia) in offspring of exposed people; 

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 2006 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 2006 report. Information 

regarding additional relevant studies is stated in VA's prior notices 

following earlier NAS reports, and generally will not be repeated here.

    This notice relates only to the Secretary's May 2008 determination 

based on a 2006 report of the National Academy of Sciences (NAS) and 

prior NAS reports. Subsequent to the Secretary's May 2008 

determination, NAS in 2009 issued a further report discussing 

additional evidence concerning Veterans and Agent Orange. Based on that 

2009 report, VA in March 2010 proposed to establish presumptions of 

service connection based on herbicide exposure for three conditions 

(Parkinson's disease, ischemic heart disease, and b-cell leukemias). 

See 75 FR 14391 (Mar. 25, 2010). The discussion in this notice does not 

in any way affect those proposed presumptions, but merely explains the 

basis for the Secretary's prior May 2008 decision, as required by law.



FOR FURTHER INFORMATION CONTACT: Thomas Kniffen, Chief, Regulations 

Staff, Compensation and Pension Service, Veterans Benefits 

Administration, Department of Veterans Affairs, 810 Vermont Avenue, 

NW., Washington, DC 20420, (202) 461-9725.



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 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 2 years 

(as measured from the date of the first report) for a 10-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 findings and analyses of the NAS and aspects of the 

relevant studies, including the magnitude and the statistical 

significance of the findings, their capability of replication, and 

whether that study will withstand peer review.



[[Page 32542]]



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 effects.



Scope of This Notice



    NAS issued its seventh report, entitled ``Veterans and Agent 

Orange: Update 2006'' (Update 2006), on July 27, 2007. As required by 

law, this notice explains a determination made by the Secretary in May 

2008 that then-existing evidence, as summarized in Update 2006, did not 

warrant a presumption of service connection for several specific 

diseases. Among other things, this notice conveys the Secretary's 

determination that the evidence and analysis in Update 2006 and prior 

reports did not provide a basis for establishing presumptions of 

service connection, based on herbicide exposure, for movement disorders 

(including Parkinson's disease), ischemic heart disease, and leukemia 

(other than chronic lymphocytic leukemia).

    Subsequent to the May 2008 determination that is the subject of 

this notice, VA in 2009 received another NAS report, entitled 

``Veterans and Agent Orange: Update 2008.'' Based on the 2009 report, 

the Secretary of Veterans Affairs has determined that presumptions of 

service connection based on herbicide exposure are now warranted for 

Parkinson's disease, ischemic heart disease, and b-cell leukemias, and 

VA published a proposed rule in the Federal Register of March 25, 2010 

(75 FR 14391) to establish such presumptions. We emphasize that nothing 

in this notice affects the Secretary's more recent determination, based 

on additional evidence and analysis by NAS, to establish presumptions 

of service connection for those three diseases. The Secretary's May 

2008 determinations are set forth here merely for the purpose of 

providing public notice of those determinations as required by statute.



Update 2006



    Consistent with its prior reports, NAS in Update 2006 found that 

there was ``sufficient evidence of an association'' between herbicide 

exposure and five categories of diseases in Veterans. VA has previously 

established presumptions of service connection for each of these 

diseases. See 38 CFR 3.309(e). NAS, in Update 2006, categorized certain 

health outcomes to have ``limited or suggestive evidence of an 

association.'' This category is defined to mean that evidence suggests 

an association between exposure to herbicides and the outcome, but a 

firm conclusion is limited because chance, bias, and confounding could 

not be ruled out with confidence. Health outcomes placed in the 

``limited or suggestive evidence of an association'' category are 

laryngeal cancer; cancer of the lung, bronchus, or trachea; prostate 

cancer; multiple myeloma; early-onset transient peripheral neuropathy, 

prophyria cutanea tarda; type 2 diabetes (mellitus); and spina bifida 

in offspring of exposed people. VA has previously established 

presumptions of service connection for each of these diseases, see 38 

CFR 3.309(e), with the exception of spina bifida, for which VA pays a 

monetary allowance under 38 CFR 3.814. NAS, in Update 2006, 

additionally categorized AL amyloidosis and hypertension as having 

limited or suggestive evidence of an association. VA recently 

established a presumption of service connection for AL amyloidosis. See 

74 FR 21258 (May 7, 2009).

    NAS, in Update 2006, categorized certain health outcomes as having 

inadequate or 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. The health outcomes that met this category are: 

Cancers of the oral cavity (including tongue), pharynx (including lips 

and tonsils), or nasal cavity (including ears and sinuses); cancers of 

the pleura, mediastinum, and other unspecified sites within the 

respiratory system and intrathoracic organs; esophageal cancer; stomach 

cancer; colorectal cancer (including small intestine and anus); 

hepatobiliary cancers (liver, gallbladder, and bile ducts); pancreatic 

cancer; bone and joint cancer; melanoma; non-melanoma skin cancer 

(basal cell and squamous cell); breast cancer; cancers of reproductive 

organs (cervix, uterus, ovary, testes, and penis; excluding prostate); 

urinary bladder cancer; renal cancer; cancers of brain and nervous 

system (including eye); endocrine cancers (thyroid, thymus, and other 

endocrine); leukemia (other than CLL); cancers at other and unspecified 

sites; neurobehavioral disorders (cognitive and neuropsychiatric); 

movement disorders (including Parkinson's disease and ALS); chronic 

peripheral nervous system disorders; respiratory disorders; 

gastrointestinal, metabolic, and digestive disorders (changes in liver 

enzymes, lipid abnormalities, and ulcers); immune system disorders 

(immune suppression, allergy, and autoimmunity); ischemic heart 

disease; circulatory disorders (excluding hypertension); endometriosis; 

effects on thyroid homeostasis; certain reproductive effects, i.e., 

infertility, spontaneous abortion, neonatal or infant death and 

stillbirth in offspring of exposed people, low birth weight in 

offspring of exposed people, birth defects (other than spina bifida) in 

offspring of exposed people, and childhood cancer (including acute 

myelogenous leukemia) in offspring of exposed people.

    The Secretary's determination that there is not a positive 

association between herbicide exposure and the diseases addressed in 

this notice is based upon the NAS's 2006 review and analysis of the 

relevant scientific evidence as summarized below, the additional 

analyses provided in this notice, and NAS's and VA's previous analyses 

of the scientific and medical literature set forth in earlier Federal 

Register notices at: 59 FR 341 (Jan. 4, 1994), 61 FR 41442 (Aug. 8, 

1996), 64 FR 59232 (Nov. 2, 1999), 66 FR 2376 (Jan. 11, 2001), 67 FR 

42600 (Jun. 4, 2002), 68 FR 27630 (May 30, 2003), 72 FR 32395 (May 20, 

2007).



I. Cancer



Cancer of the Oral Cavity, Pharynx, or Nasal Cavity



    NAS found that the new occupational studies of cancers of the oral 

and nasal cavities or pharynx were generally small and so yielded 

unstable estimates of risk. Integration of the evidence on this set of 

cancers is challenging because different studies group cases 

differently. Two studies of agricultural pesticide applicators found 

significant decreases in certain oral cancers rather than excess risk 

associated with exposure. Studies on Australian Vietnam Veterans showed 

some increases in risk, but the results were not adjusted for 

cigarette-smoking or alcohol use, both of which are known risk factors.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and in previous reports, NAS concluded that there was inadequate 

or insufficient information to determine whether there is an 

association between herbicide exposure and oral, nasal, and pharyngeal 

cancers.



Lip Cancer



    NAS evaluated lip cancer as a separate entity for the first time in



[[Page 32543]]



Update 2006 and found that the available studies suffered from certain 

limitations. Some studies had very low specificity with respect to 

exposure to the compounds of interest. NAS noted that these studies 

defined exposure status almost exclusively in terms of occupation, and 

even the determination of occupation usually could not be regarded as 

rigorous.

    Other studies used computer techniques to link records in 

comprehensive databases, such as those matching entries in tumor 

registries with compendiums of national censuses. NAS noted that these 

studies amass large samples that may have the effect of inflating 

power. Such investigations are useful for generating hypotheses, but 

NAS noted that suggestive findings must be replicated by studies with 

more refined designs that are capable of gathering more extensive 

information about the subjects to use in adjusting for confounders.

    NAS further noted that the certainty of the diagnostic categories 

culled directly from death certificates or other databases may be 

questionable and that diagnoses of lip cancer might overlap with non-

melanoma skin cancers in the sources from which the information was 

gathered for the studies discussed.

    NAS also noted the studies in question did not adjust for smoking 

and sunlight exposure, as would be necessary before inferring that 

agricultural chemicals played a role in any observed association in an 

occupational group.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and lip cancer.



Tongue Cancer



    NAS also evaluated tongue cancer as a separate category for the 

first time in Update 2006, and concluded that interpretation of the 

evidence on tongue cancer is constrained by the grouping of data on 

them with data on other oral cancers. Most of the studies with 

information on this specific tumor site observed only a small number of 

cases and therefore had unstable estimates of risk.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and tongue cancer.



Tonsil Cancer



    NAS noted that there is a paucity of findings specifically related 

to tonsil cancer, because of the extreme rarity of this type of cancer 

and its occurrence in an anatomic region whose cancers are generally 

grouped fairly idiosyncratically. That the tissue type developing into 

a neoplasm at this location might generate a carcinoma, a lymphoma, or 

a sarcoma has further constrained NAS's ability to assemble a 

meaningful body of evidence addressing risk factors for this unusual 

type of cancer. NAS noted that further research, such as a case-control 

protocol, would be needed to evaluate whether tonsil cancer is 

associated with exposure to the herbicides used in Vietnam.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and tonsil cancer.



Cancer of the Pleura, Mediastinum, and Other Unspecified Sites Within 

the Respiratory System and Intrathoracic Organs



    NAS's default category for any health outcome for which no 

epidemiologic research findings have been recovered has always been 

``inadequate evidence'' of association, which in principle is 

applicable to specific cancers. Cancers of the pleura, mediastinum, and 

other unspecified respiratory cancers are rarely reported individually 

and are not as yet seen for the chemicals of interest, reflecting the 

paucity of information. NAS concluded there is inadequate or 

insufficient information to categorize such a disease outcome.



Esophageal Cancer



    NAS noted that previous updates did not review the risk of 

esophageal cancer separately. In Update 2006, NAS concluded that the 

epidemiologic studies of esophageal cancer to date yielded no evidence 

of an increased risk associated with the compounds of interest, 

although updates of the health status of the Australian Vietnam 

Veterans presented an interesting but non-significant pattern of 

increased risk of esophageal cancer. No toxicologic studies provide 

evidence of biologic plausibility of an association between the 

compounds of interest and tumors of the esophagus.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and esophageal cancer.



Stomach Cancer



    NAS found that the risk of stomach cancers had not been reviewed 

separately in previous updates. Among the newly reviewed studies, only 

one reported a significant relationship, which was between stomach 

cancer and the rather non-specific exposure of being a forestry worker. 

The NAS noted some evidence of biologic plausibility in animal models, 

but concluded that the epidemiologic studies to date do not support an 

association between exposure to the compounds of interest and stomach 

cancer.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and stomach cancer.



Colorectal Cancer



    NAS found that previous updates had not reviewed the risk of 

colorectal cancers separately. In Update 2006, NAS found no evidence to 

suggest an association between the compounds of interest and colorectal 

cancer in the epidemiologic studies reviewed to date. The only 

significant increase in intestinal cancers noted in Update 2006 was a 

reported result concerning cancer of the small intestine based on cases 

in two exposed people. NAS explained that this is a very uncommon tumor 

and was reported in Update 2006 with the more common cancers of the 

large intestine and rectum for completeness of coverage. NAS found no 

evidence of biologic plausibility of an association between exposure to 

any of the compounds of interest and the development of tumors of the 

colon or rectum. NAS concluded that the available evidence does not 

support an association between the compounds of interest and colorectal 

cancer.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and colorectal cancer.



Hepatobiliary Cancers



    For Update 2006, NAS found that no new reports of a definitive link 

between exposure to the compounds of interest and hepatobiliary tumors 

were found. One study suggested a reduced risk of hepatic cancers in 

Veteran populations, and one suggested an increased risk of cancer of 

the gallbladder among forestry



[[Page 32544]]



workers. However, given the relatively low incidence of hepatobiliary 

cancers in Western populations, NAS concluded that the evidence from 

epidemiologic studies remains inadequate to link the compounds of 

interest with hepatobiliary cancer.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and hepatobiliary cancer.



Pancreatic Cancer



    NAS noted that one study reported increased rates of pancreatic 

cancer among Australian Vietnam National Service Veterans, but that the 

findings could be associated with increased rates of smoking and cannot 

be attributed to exposure to the compounds of interest. NAS noted that 

other reports have been largely negative.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and pancreatic cancer.



Bone and Joint Cancer



    NAS reviewed results of several pertinent studies published since 

the previous update. The studies either reported a non-significant 

increase in risk of bone and joint cancer, observed too few events to 

estimate relative risk (RR) adequately, or did not present data that 

sufficiently linked observed results to specific compounds of interest 

to this report. NAS concluded that the new results add little to the 

previous body of results that, taken together, do not indicate an 

association between exposure to the compounds of interest and bone 

cancer.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and bone and joint cancer.



Skin Cancer-Melanoma



    NAS found that new occupational studies were small and could not 

provide stable estimates of RR associated with herbicide exposure. NAS 

stated that the evidence from a number of studies of occupational and 

environmental populations is inconsistent, but that significant 

associations have been demonstrated in some studies of populations with 

well-characterized exposures to the compounds of interest. NAS noted, 

however, that the evidence of an association with melanoma in these 

studies may be limited by the possibility of bias or chance. Further, 

NAS noted that positive findings of a study of Australian Vietnam 

Veterans are limited by internal inconsistency, and that an increase in 

mortality reported by the Centers for Disease Control and Prevention 

Vietnam Experience Study is consistent but too small to be considered 

significant.

    NAS stated that the results of the Air Force Health Study (AFHS) 

have long been anticipated as the most directly pertinent to the 

experience of US Vietnam Veterans, so NAS was impressed by recent 

reports of a strong dose-response relationship between serum TCDD 

concentrations and melanoma in this population. Some members of the 

committee were concerned, however, that the findings of the AFHS have 

not been presented in a complete and systematic fashion. Further, NAS 

noted that the two recent Ranch Hand studies are based on diagnoses 

rendered up to 1999 and 2003, respectively, but that there is some 

indication that more recent melanoma diagnoses among the control 

subjects greatly exceeds that of the Ranch Hands, which might produce 

quite different results. NAS therefore endorses further evaluation and 

longitudinal analysis of the entire data set on cancer outcomes 

generated in the important AFHS population. NAS noted that, despite the 

findings in the AFHS study, there was a persisting concern that there 

was little suggestion of an association in other relevant populations.

    After extensive deliberation concerning new evidence and the 

results of studies reviewed in previous updates, NAS was unable to 

reach consensus as to whether the evidence concerning an association 

between herbicide exposure and melanoma met the criteria for being 

considered limited or suggestive or whether this health outcome should 

remain in the inadequate or insufficient classification primarily 

because the suggestive findings are almost exclusively from the AFHS, 

whose final data on both the Ranch Hand and comparison subjects have 

not yet been analyzed in a satisfactory and uniform manner.

    As indicated in prior NAS reports and reiterated in Update 2006, 

occupational and environmental studies generally have not found a 

significant increase in the risk of melanoma associated with herbicide 

exposure, and the few significant findings are limited by 

methodological concerns. In its 2004 report, NAS noted that a 2004 

study by Swaen et al. of herbicide applicators in the Netherlands 

reported a significantly increased incidence of all skin cancers, but 

the data were limited because they could not distinguish the effects of 

herbicide exposure from the significant confounding factor of sun 

exposure, which was likely to be common among herbicide applicators. In 

its 1996 update, NAS also noted that one occupational study of Danish 

herbicide-production workers reported a significant increased incidence 

of melanoma, but because of the small number of cases (4) and the lack 

of adequate information in the study, it was not considered to provide 

evidence of an association.

    Although recent analyses of the Ranch Hand Veterans provides some 

evidence of an association, as noted in Update 2006, the evidence 

overall continues to weigh against an association. Occupational 

exposures, particularly among herbicide-production workers are 

ordinarily expected to exceed in duration and magnitude the types of 

exposures that would be seen in Vietnam Veteran populations. As NAS 

noted in Update 2006, the general lack of significant findings in 

occupational studies is a relevant consideration in interpreting the 

more recent findings concerning the Ranch Hand Veterans. Additionally, 

based on the indications in Update 2006 that more recent data 

concerning the Ranch Hand population could affect the findings of the 

recent studies suggests that further inquiry is needed before 

definitive conclusions can be drawn regarding the significance of those 

findings.



Skin Cancer--Basal-Cell and Squamous-Cell Cancer (Non-Melanoma)



    NAS found that the new results demonstrate only a small RR that is 

not statistically significant, and the dose-response relationship also 

is not statistically significant.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and basal-cell or squamous-cell cancer.



Breast Cancer



    NAS reviewed several new studies concerning breast cancer in Update 

2006 and, with one exception, found that they did not provide evidence 

supporting an association between breast cancer and herbicide exposure. 

NAS found that recent results from the Agricultural Health Study (AHS) 

cohort



[[Page 32545]]



generally do not support the hypothesis that exposure to the compounds 

in Agent Orange increases breast-cancer incidence or mortality in 

women, although exposure to the specific compounds of interest was not 

specified. NAS noted that recent studies of environmental exposure 

found null associations, but that the exposures in some cases were of 

questionable relevance. NAS further noted that two studies of 

organochlorine concentrations in adipose tissue failed to find any 

evidence of increased risk in association with higher adipose 

concentrations; in fact, the more relevant study found the risk in the 

highest tercile of dioxin concentrations in breast fat was lower than 

in the lowest tercile of dioxin concentrations, although not 

significantly so.

    NAS found that one study published since the last update does 

provide some evidence of an association between exposure to 2,4-D and 

breast-cancer risk in female farm workers in California. The study is 

limited by lack of detailed information on potential confounding 

factors and lack of evidence of a dose-response relationship, but it is 

large and the investigators were able to estimate individual exposures 

by linking work histories to an extensive database on pesticide use.

    NAS considered the new information in the context of the cumulative 

data from studies reviewed in previous updates. NAS found that the 

results of four prior studies lend support to the hypothesis that there 

is an association between breast cancer and exposure to the compounds 

of interest. However, each study has limitations or weaknesses that 

keep its conclusions about the association in question from being 

definitive.

    NAS noted that the recent data from a 2005 study by Mills and Yang, 

although not persuasive in themselves, lend additional weight to an 

association between the relevant herbicide exposures and breast-cancer 

risk. This study has reasonable size and relatively specific exposure 

information but is limited chiefly by the data available to control for 

confounding. Some members of the committee considered the body of 

evidence as a whole to be suggestive of an association; for others, the 

few modestly positive results associated with a diversity of exposures 

suggested chance findings rather than a coherent picture. Further 

laboratory and epidemiologic work on this association should be 

pursued.

    The main reason for the unresolved division in the NAS opinion 

concerning the adequacy of the available evidence to support an 

association between breast cancer and exposure to the components of the 

herbicides sprayed in Vietnam was differing individual views about the 

specificity and relevance of the studied exposures for the population 

of primary concern to the committee, Vietnam Veterans. Overall, the 

committee was impressed by the positive results from earlier studies 

reviewed, but several members considered this a very small sample upon 

which to anchor an association. The degree to which the profile of 

chemicals contributing to total toxicity equivalency in the more 

positive epidemiologic studies differed from that of Vietnam Veterans 

diminished the conviction of some members that these results 

constituted fully relevant evidence.

    After extensive deliberation concerning the new evidence and the 

results of studies reviewed in previous updates, NAS was unable to 

reach consensus as to whether the evidence of an association between 

exposure to the compounds of interest and breast cancer met the 

criteria for being considered limited or suggestive or whether concerns 

about chance, bias, and confounding remained so substantial that breast 

cancer should remain in the inadequate or insufficient classification.

    Relatively few studies provide evidence of a positive association 

between herbicide exposure and breast cancer. As NAS noted, most of the 

recent studies do not support an association, although some of the 

studies are of questionable relevance and thus would not provide strong 

evidence against an association. Of the five positive studies 

identified by NAS, two are limited by potential confounding factors. As 

noted above, the 2005 study by Mills and Yang lacked data to control 

for confounding. A 2001 study by Revich et al. found an increased 

mortality from breast cancer among persons exposed to dioxins from 

working in or residing near a chemical plant, but the potential for 

confounding exists because the subjects were exposed to a number of 

other toxic chemicals. One of the positive studies, a 2000 Vietnam 

Veteran study by Kang et al., reported an increase in breast cancer 

among female Vietnam Veterans, but the result was not statistically 

significant. The other two studies showed positive results, although 

the NAS noted some limitations related to study size and relevance of 

exposures. Although those studies provide some supportive evidence, the 

overall weight of the current evidence does not support an association 

between herbicide exposure and breast cancer.



Cancers of the Female Reproductive System



    NAS found that two analyses of the same cohort found increased 

incidence of and mortality from ovarian cancer in women who had been 

engaged in pesticide application. The weight of those studies for the 

present purposes is limited by the lack of detail on chemical exposures 

and the absence of data that would allow for control of confounding. 

Future studies of ovarian cancer should be watched carefully, 

particularly studies that use biomarkers of exposure or more detailed 

chemical-exposure histories.

    On the basis of its evaluation of the evidence in Update 2006 and 

in previous reports, NAS has concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and uterine, ovarian, or cervical cancer.



Testicular Cancer



    NAS found that the evidence from epidemiologic studies is 

inadequate to link herbicide exposure and testicular cancer. The 

relative rarity of this cancer makes it difficult to develop risk 

estimates with any precision. Most cases occur in men 25-35 years old, 

and men who have received such a diagnosis could be excluded from 

military service; this could explain the slight reduction in risk 

observed in some Veteran studies.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and testicular cancer.



Bladder Cancer



    NAS found that available analyses of an association between 

exposure to the compounds of interest and bladder-cancer risk are 

characterized by low precision because of the small numbers, low 

exposure specificity, and lack of ability to control for confounding. 

No new data have emerged since Update 2004 to alter the conclusion that 

the cumulative evidence of such an association is inadequate or 

insufficient.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and bladder cancer.



Renal Cancer



    NAS found that available analyses of an association between 

exposure to the



[[Page 32546]]



compounds of interest and renal-cancer risk are limited by the small 

number of cases and lack of exposure specificity. No new data have 

emerged since Update 2004 to alter the committee's conclusion that the 

evidence is inadequate or insufficient to determine whether there is an 

association.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and renal cancer.



Cancer of the Eye and Orbit



    NAS found that most of the epidemiologic studies of findings on eye 

cancer alone reported few or no cases, were of low power, and had 

statistically non-significant results. The studies with the largest 

numbers of cases did not indicate significant increases in risk 

associated with herbicide exposure. Some analyses of the Australian 

Vietnam Veterans showed excess risk, but it was probably due to excess 

exposure to UV radiation, which was not adjusted for. It should be 

noted that eye cancer is sometimes reported in a combined category with 

brain cancers.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and eye cancer. Any future findings for this 

cancer site will be tracked with results on brain cancer.



Brain Cancer



    NAS found that since Update 2004, several relevant studies have 

been identified, including cohort and case-control designs. Many 

studies rely on surrogate indicators of exposure, such as occupational 

titles, but several studies estimated exposure to one or more of the 

compounds of interest on the basis of a job-exposure matrix or self-

reported exposure history. Most used cancer-registry data with a high 

degree of diagnostic certainty. However, each study has limitations or 

weaknesses that keep its conclusions about the association in question 

from being definitive.

    Most of the relevant prior cohort studies do not show substantial 

risk differences from the null hypothesis, but this may reflect the 

limited power of the cohort method to identify risk differences in rare 

diseases, such as brain cancer. However, with the accumulation of 

findings that deviate from consistency with the null hypothesis, the 

present committee can no longer retain the original VAO committee's 

conclusion that the available evidence is suggestive of no association.

    On the basis of detailed evaluation of the epidemiologic evidence 

from new and previously reported studies of populations with potential 

herbicide exposure, NAS concluded that the categorization in prior 

updates (limited or suggestive evidence of no association) should be 

revised to inadequate or insufficient to determine whether there is an 

association between herbicide exposure and brain cancer and other 

nervous system cancers.



Endocrine Cancers



    Update 2006 is the first to consider endocrine cancers as 

constituting a separate cancer type. NAS found several relevant studies 

that show low thyroid-cancer incidence and cancer mortality in various 

populations. The studies assessed exposure to one or more of the 

compounds of interest although the metrics often were based on 

surrogate indicators or self-reported exposure. Some of the cohort 

studies used cancer-registry data with a high degree of diagnostic 

certainty. Several of the studies show somewhat increased risks of 

thyroid or other endocrine cancers in association with the compounds of 

interest. The two studies with any indication of statistical 

significance both had mixed results. The authors were conducting 

analyses on large samples whose exposure was no better characterized 

than ``agricultural worker'' on a death certificate or census response, 

whereas in a third study, the risks of endocrine cancers were lower in 

phenoxy herbicide workers who also had exposure to TCDD. Most showed no 

substantial risk differences in association with the compounds of 

interest. Many of the studies had very small numbers of cases, and 

their limitations preclude risk estimation. There were no significant 

findings in Vietnam-Veteran studies. Thus, the studies reviewed do not 

provide sufficient evidence to determine whether there is an 

association between exposure to the compounds of interest and thyroid 

cancer.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and thyroid or other endocrine cancers.



Leukemia (Other Than CLL)



    NAS found that the new studies did not provide any new evidence of 

an association between exposure to the compounds of interest and 

leukemia.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that, at the time of Update 

2006, there was inadequate or insufficient evidence to determine 

whether there is an association between herbicide exposure and 

leukemias other than CLL.



Acute Myelogenous Leukemia



    NAS found that taken together, the occupational, environmental, and 

Veteran studies are limited by the paucity of reports related to the 

types of leukemia and to acute myelogenous leukemia (AML) in 

particular. In concluding its review of the available findings related 

to the occurrence of AML in Veterans exposed to the herbicides sprayed 

in Vietnam, NAS notes the finding in Update 2000 of limited or 

suggestive evidence of an association between exposure to the compounds 

of interest and AML in the children of Vietnam Veterans and the 

reversal of the finding in the report on AML. The recognition of an 

error in a key publication and new information on the illness resulted 

in reclassification of AML in children to inadequate evidence to 

determine whether there is an association.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and AML.



Cancers at Other and Unspecified Sites



    NAS' default category for any health outcome for which no 

epidemiologic research findings have been recovered has always been 

``inadequate evidence'' of association, which in principle is 

applicable to specific cancers. Cancers at other and unspecified sites 

are rarely reported individually and not as yet seen for the chemicals 

of interest, reflecting the paucity of information. NAS concluded there 

is inadequate or insufficient information to categorize such a disease 

outcome.



II. Reproductive and Developmental Effects



Fertility



    NAS found that although there is much evidence of the biologic 

plausibility of disruption of male and female fertility by exposure to 

the chemicals of interest, there continues to be a lack of substantive 

epidemiologic data that demonstrate any association in human 

populations.



[[Page 32547]]



    On the basis of its evaluation of the evidence reviewed in Update 

2006, NAS concluded that there is inadequate or insufficient evidence 

of an association between herbicide exposure and altered hormone 

concentrations, menstrual-cycle abnormalities, decreased sperm counts 

or sperm quality, and sub-fertility or infertility.



Spontaneous Abortion



    NAS found that no additional information was available to the 

committee responsible for Update 2006 to motivate changing the 

assessment of the last two committees. Given the age of the Vietnam-

Veteran cohort, it is highly unlikely that additional information on 

this outcome among the population will appear.

    In Update 2006, NAS concluded that paternal exposure to TCDD is not 

associated with risk of spontaneous abortion and that insufficient 

information is available to determine whether an association exists 

between the risk of spontaneous abortion and maternal exposure to TCDD 

or either maternal or paternal exposure to 2,4-D, 2,4,5-T, picloram, or 

cacodylic acid.



Stillbirth, Neonatal Death, and Infant Death



    NAS found that the study reviewed for Update 2006 did not find 

significant associations between the relevant exposures and rates of 

infant or fetal deaths. The study was limited in that exposure was 

based on environmental concentrations of dioxin and individual exposure 

data were not obtained. Furthermore, several risk factors that could 

confound associations between exposure and outcome were not assessed.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and stillbirth, neonatal death, or infant 

death in offspring of exposed people.



Low Birth Weight and Preterm Delivery



    NAS found that the three studies reviewed in Update 2006 did not 

find an association between exposure to the compounds of interest and 

the risk of low birth weight or prematurity. The two new weakly 

significant findings may simply be spurious results arising among many 

comparisons; a modest increase in average birth weight would not be 

construed as an adverse effect, and the small decrease in average 

gestation is of questionable biologic importance. Although the results 

overall suggest a lack of an association, they should be interpreted 

with caution because of some methodologic limitations, such as a long 

recall period in the cohort study and exposure misclassification in the 

environmental studies.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and low birth weight or preterm delivery in 

offspring of exposed people.



Birth Defects (Other Than Spina Bifida)



    NAS found only one new occupational study of birth defects and 

exposures to the chemicals of interest, and the information generated 

was too sparse to provide additional insights into the risks of birth 

defects. Birth defects were addressed indirectly by a new environmental 

study, which found an association between residence in the areas with 

the highest soil dioxin concentrations and deaths before the first 

birthday due to any congenital abnormality, but this relationship did 

not carry over to deaths occurring in the first month or in the first 

week of life.

    Only one study addressed birth defects among the offspring of 

female Vietnam War Veterans, who overall constitute fewer than 10,000 

of the roughly 3 million U.S. Vietnam Veterans. NAS noted that, in 

general, the relatively small number of offspring among Vietnam 

Veterans seriously restricts the ability to detect statistically 

significant increases in specific birth defects. In addition, as the 

offspring of Veterans become older, the risk of diseases stemming from 

congenitally transmitted defects that alter normal physiologic 

function, such as endocrine and reproductive function, merits 

increasing attention.

    Another study reported a substantially greater strength of 

association between exposure to Agent Orange and birth defects in the 

studies of Vietnamese populations than in those of non-Vietnamese 

populations. The non-Vietnamese study populations consisted of Vietnam 

Veterans, who were almost exclusively men, whereas the Vietnamese 

populations had a much greater likelihood of maternal exposure. This 

study also conducted subgroup meta-analyses based on presumed exposure 

intensity. Meta-analytic methods are the best approach to assessing the 

overall import of the studies of exposures to the chemicals of interest 

and the risk of specific birth defects. However, the numbers of cases 

reported were too small to allow meta-analysis of specific types of 

birth defects.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and birth defects (other than spina bifida) 

in offspring of exposed people.



Childhood Cancer



    NAS found that the studies reviewed for this update did not find 

significant associations between the relevant exposures and childhood 

cancers. As with other outcomes in the offspring of Vietnam Veterans, 

the small number of these rare childhood cancers expected among the 

circumscribed number of Vietnam Veterans would seriously hinder 

detection of any actual increases. NAS reviewed newly available 

occupational and environmental studies but found the value of these 

studies to be limited by the questionable reliability of self-reported 

exposures or other factors.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and childhood cancers in offspring of 

exposed people.



III. Neurologic Disorders



Neurobehavioral (Cognitive and Neuropsychiatric) Disorders



    NAS found that there is not consistent epidemiologic evidence of an 

association between neurobehavioral disorders (cognitive or 

neuropsychiatric) and Agent Orange exposure. Difficulties in case 

identification and diagnosis, misclassification of exposures because of 

a lack of contemporaneous measures, subject ascertainment and selection 

bias, and uncontrolled confounding from many comorbid conditions are 

common weaknesses in the studies reviewed. The variability of the test 

results over time, the weak and inconsistent associations, and a lack 

of consistent dose-response relationships also detract from evidence of 

an association between the compounds of interest and neurobehavioral 

disorders.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide



[[Page 32548]]



exposure and neurobehavioral disorders (cognitive or neuropsychiatric).



Movement Disorders, Including Parkinson's Disease



    NAS found that epidemiologic studies have pursued various 

occupational exposures as potential risk factors for Parkinson's 

disease; pesticide use is among those receiving the most attention, but 

it has rarely been possible to isolate the effects of selected chemical 

herbicides, because exposures often are mixed and assessments usually 

are retrospective, relying on such broad categories as ``ever exposed 

to any pesticide,'' which is not considered informative for this 

report. In addition, reported associations have been inconsistent, and 

only rarely has evidence supported dose-response relationships. Thus, 

the data are weakened for the committee's purposes by persistent 

methodologic limitations and by the lack of specificity for the 

compounds of interest.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that, at the time of Update 

2006, there was inadequate or insufficient evidence to determine 

whether there is an association between herbicide exposure and 

Parkinson's disease.



Peripheral Neuropathy



    NAS found that epidemiologic studies that used appropriate 

comparison groups and standard techniques for diagnosis and assessment 

of exposure have not demonstrated consistent associations between 

exposure to the compounds of interest and the development of peripheral 

neuropathy. Several reports have shown no significant association, and 

in the reports that did indicate an association, chance, bias, or 

confounding could not be ruled out with confidence. In particular, 

diabetes might confound the results, inasmuch as many of the subjects 

with neuropathy also had diabetes, which is a known cause of 

neuropathy. Controlling for the effects of diabetes is a technical 

challenge because there is evidence of an association between diabetes 

and exposure to at least one of the compounds of interest; in many 

cases, diabetes could be in the causal pathway that links exposure and 

peripheral neuropathy.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and delayed or persistent peripheral 

neuropathy.



IV. Other Health Effects



Respiratory Disorders



    NAS found that results of the new studies of mortality from 

nonmalignant respiratory diseases do not support the hypothesis that 

herbicides increase mortality from them. The results of one study 

showed a positive association, although it is based on only nine deaths 

in the high-exposure area, and this finding could have been due to 

chance or misclassification of causes of death. More important, 

although it recognizes that mortality studies are limited by small 

numbers of events and misclassification of causes of death, especially 

respiratory conditions, NAS does not believe that scientific 

conclusions can be based on health outcomes that are defined vaguely, 

for example, by combining a wide array of disparate respiratory health 

outcomes into one large category.

    Two new cross-sectional studies have reported positive associations 

between exposure and the prevalence of various chest conditions. The 

nonspecificity of the types of respiratory conditions reported in one 

of the two studies makes it exceedingly difficult to draw any 

conclusions regarding specific respiratory conditions, and the lack of 

observed association with serum TCDD concentrations also argues against 

the existence of an association. The issue of nonspecificity is key to 

interpreting this study. The results of a second study were weakened by 

a definition of ``wheeze'' that was very broad and included any episode 

in the year before administration of the questionnaire. Further, only 

28 percent of subjects reporting this symptom also reported having 

asthma or atopic conditions.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and the respiratory disorders specified.



Immune-System Disorders (Immune Suppression, Allergy, and Autoimmunity)



    NAS found that TCDD is a well-known immunosuppressive agent in 

laboratory animals. Therefore, one would expect that exposure of humans 

to sufficiently high doses would result in immune suppression. However, 

several studies of various measures of human immune function have 

failed to reveal consistent correlations with TCDD exposure, and no 

detectable pattern of increased infectious disease has been documented 

in Veterans exposed to 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.

    Epidemiologic studies have been inconsistent with regard to TCDD's 

influence on IgE production in humans (Update 2004). No animal or human 

studies have specifically addressed the influence of TCDD on autoimmune 

disease. One study of post-service mortality associated with various 

causes showed no increase in deaths of Vietnam Veterans that could be 

attributed to immune-system disorders.

    Few effects of phenoxy herbicide exposure on the immune system have 

been reported in animals or humans, and clear association between 

phenoxy herbicide exposure and autoimmune or allergic disease has not 

been found.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and immune suppression, allergy, or 

autoimmune disease.



Lipid and Lipoprotein Disorders



    NAS found that previously reviewed literature showed inconsistent 

changes in serum lipids or lipoproteins after exposure to the compounds 

of interest, and in most cases the sample sizes were insufficient to 

support any conclusions. The recent report on Ranch Hand Veterans shows 

that serum TCDD concentrations are positively associated with serum 

triglycerides; however, even in Ranch Hand Veterans with the highest 

TCDD exposure, the mean serum triglyceride concentration (130 mg/dL) is 

well below that considered to be abnormal (250 mg/dL). It is notable 

that the Ranch Hand Veterans with abnormally high serum triglycerides 

tend to be those with the highest TCDD exposure.

    Hypertriglyceridemia is considered to be a major risk factor for 

acute pancreatitis when serum triglyceride concentrations exceed 1,000 

mg/dL, and there is some evidence that it is an independent but weak 

risk factor for ischemic heart disease at concentrations over 150 mg/

dL. More commonly, however, high serum triglyceride concentrations 

(150-500 mg/dL) are considered to be a consequence of other underlying 

diseases, particularly diabetes mellitus and metabolic syndrome, and 

hypertriglyceridemia is a



[[Page 32549]]



well recognized marker of these diseases, especially when associated 

with low high-density lipid (HDL) concentrations.

    The VAO committee responsible for type 2 diabetes concluded that 

there was limited or suggestive evidence of an association between type 

2 diabetes mellitus and exposure to herbicides in Vietnam. Although the 

latest Ranch Hand study adjusted the RR of hypertriglyceridemia for 

smoking and body-mass index (BMI), it failed to account for the 

presence of diabetes mellitus. Diabetes mellitus is strongly associated 

with hypertriglyceridemia, as discussed above, so it is plausible that 

the increased percentage of Ranch Hand Veterans with abnormally high 

serum triglycerides may be a consequence of diabetes mellitus. In that 

regard, the percentage of all Ranch Hand Veterans with a diagnosis of 

diabetes mellitus (about 23 percent) could include the percentage with 

hypertriglyceridemia (about 13 percent).

    Hypertriglyceridemia itself was not considered a health outcome for 

Update 2006, but it was recognized that its presence may indicate the 

emergence of a more significant health concern, metabolic syndrome. 

Metabolic syndrome is characterized by obesity, high triglycerides 

(over 150 mg/dL), low HDL (under 40 mg/dL), hypertension (over 130/85 

mm Hg), and high fasting plasma glucose or diagnosed diabetes mellitus. 

As noted above, NAS previously concluded that there is suggestive 

evidence of a link between exposure to herbicides in Vietnam and type 2 

diabetes mellitus, whereas the Update 2006 has concluded that there is 

suggestive evidence of a link between exposure to herbicides in Vietnam 

and hypertension. Thus, an increasing number of Vietnam Veterans may be 

exhibiting at least three of the diagnostic criteria for metabolic 

syndrome: Hypertriglyceridemia, diabetes mellitus, and hypertension. It 

will be important to analyze the incidence of those individual outcomes 

as potential components of a larger disease syndrome.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and lipid or lipoprotein disorders.



Gastrointestinal, Metabolic, and Digestive Disorders (Changes in Liver 

Enzymes, Lipid Abnormalities, and Ulcers)



    In Update 2006, NAS noted there is no evidence that Vietnam 

Veterans are at greatly increased risk for serious liver disease, and 

reports of increased risk of abnormal liver-function tests have been 

mixed. Although increased rates of gastrointestinal disease have not 

been reported, the possibility of a relationship between dioxin 

exposure and subtle alterations in the liver and in lipid metabolism 

cannot be ruled out.

    On the basis of its evaluation of the evidence reviewed in Update 

2006 and in previous reports, NAS concluded that there is inadequate or 

insufficient evidence to determine whether there is an association 

between herbicide exposure and gastrointestinal and digestive diseases.



Hypertension



    In Update 2006, NAS concluded that there was ``limited or 

suggestive evidence of an association between exposure to the compounds 

of interest and hypertension.'' Prior NAS reports concluded that there 

was inadequate or insufficient evidence to determine whether there was 

an association between exposure to herbicides and any cardiovascular 

diseases, including hypertension. Because Update 2006 suggests that the 

evidence for an association between herbicide exposure and hypertension 

is stronger than at the time of prior reports, hypertension warrants 

close consideration.

    As an initial matter, it must be noted that the NAS finding of 

``limited or suggestive evidence of an association'' does not imply any 

view by NAS as to whether the scientific evidence establishes a 

``positive association'' between herbicide exposure and hypertension 

within the meaning of 38 U.S.C. 1116(b). The NAS category of ``limited 

or suggestive evidence'' is defined to mean that ``[e]vidence suggests 

an association between exposure to herbicides and the outcome, but a 

firm conclusion is limited because chance, bias, and confounding could 

not be ruled out with confidence.'' Update 2006, at 11. NAS has 

explained that, ``[f]or example, a well-conducted study with strong 

findings in accord with less compelling results from populations with 

similar exposures could constitute such evidence.'' Id. In contrast, 

the ``positive association'' standard in 38 U.S.C. 1116(b)(1) and (3) 

directs VA to determine whether ``the credible evidence for the 

association is equal to or outweighs the credible evidence against the 

association.'' In making that determination, VA must consider the NAS 

reports and any other available evidence and must consider, with 

respect to scientific studies, ``whether the results are statistically 

significant, are capable of replication, and withstand peer review.'' 

38 U.S.C. 1116(b)(2). As NAS noted in a 2007 report, ``the IOM limited/

suggestive category covers a broad range of epidemiological evidence 

from relatively weak to strongly suggestive,'' and the NAS 

characterization thus cannot be viewed as determ