[Federal Register Volume 75, Number 109 (Tuesday, June 8, 2010)]
[Notices]
[Pages 32540-32553]
From the Federal Register Online via the Government Publishing 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 determinative of the 

``positive association'' determination VA is required to make. 

Institute of Medicine, Improving the Presumptive Disability Decision-

Making Process for Veterans, at 98 (National Academies Press 2007).

    VA has carefully reviewed the NAS findings and analyses in Update 

2006 and prior reports. For the reasons explained below, VA has 

determined that a positive association does not currently exist between 

herbicide exposure and hypertension, but that Update 2006 does identify 

significant new evidence that warrants careful consideration of 

hypertension on an ongoing basis.

    The finding in Update 2006 of ``limited or suggestive evidence'' 

for hypertension is based primarily upon one new Vietnam Veteran study, 

which NAS found to be significant and consistent with results of other 

lower quality studies. NAS also noted, however, that findings in other 

studies suggested that hypertension is not associated with herbicide 

exposure.

    NAS found that a 2006 study by Kang et al. supported an association 

between herbicide exposure and hypertension. That study assessed the 

incidence of hypertension among 1,499 U.S. Army Chemical Corps (ACC) 

Veterans who handled or sprayed Agent Orange in Vietnam and a control 

group of 1,428 Veterans from the same era who did not serve in Vietnam. 

The study found no significant difference in the rates of hypertension 

between the two groups. However, when analysis was restricted to ACC 

Veterans who served in Vietnam, Veterans who reported having sprayed 

herbicides had a higher incidence of hypertension than those who did 

not report spraying herbicides. Because there is some evidence that 

type 2 diabetes, a condition that may cause hypertension, is associated 

with herbicide exposure, the researchers separately evaluated the risk 

of hypertension in only non-diabetic ACC Veterans and found that 

hypertension was associated with herbicide spraying in non-diabetic 

Veterans.



[[Page 32550]]



    NAS found that this study had several strengths, including its 

focus on one of the most highly exposed Vietnam Veteran cohorts. NAS 

noted that exposure to TCDD was directly measured in one subset of the 

ACC cohort. It also concluded that the study had the merit of 

controlling for established risk factors for hypertension. NAS further 

stated that, although the increased incidence of hypertension among ACC 

sprayers was not large, it was consistent with the existence of several 

other well-established contributors to the development of hypertension.

    NAS noted that one limitation of this study is the potential for 

information bias, inasmuch as the data on hypertension and on herbicide 

spraying were self-reported. The study relied upon information provided 

in telephone interviews in which the Veterans were asked whether a 

physician had ever diagnosed them with hypertension and also requested 

information as to whether they had sprayed or handled herbicides in 

service. NAS felt that the potential information bias was diminished, 

in part, because a patient is more likely to report accurately a 

chronic disorder that requires continuing management, including 

hypertension and diabetes. NAS noted that the researchers did not 

attempt to verify self-reported hypertension by medical-record review, 

but that they did seek to verify self-reports of diabetes and found the 

self-reports verified in 79 percent of cases. NAS also noted the 

potential for misclassification among exposure groups and the possible 

recall bias that could lead to over-reporting of herbicide spraying 

among men who have serious health conditions. NAS noted that, although 

there is evidence that ex-sprayers were more likely to report several 

health conditions besides hypertension, comparison within the ex-

sprayer subgroup according to serum TCDD concentration suggests that 

recall bias does not fully explain the associations.

    NAS noted that selection bias could arise from the cross-sectional 

nature of the study, which accounts for disease prevalence only among 

people in the original deployed and non-deployed ACC cohorts who were 

still alive and participated. NAS concluded, however, that concern for 

that type of selection bias is tempered by the high and nearly equal 

rates of participation by deployed Veterans (72 percent) and non-

deployed Veterans (69 percent), and by the fact that the prevalence of 

hypertension among the non-deployed Veterans (30 percent) was similar 

to that among U.S. men of comparable age (32 percent). NAS stated that, 

despite those data, it remains unknown whether the observed 

relationship of spraying to the prevalence of hypertension is 

equivalent to what one would have observed if the cohort had been 

followed longitudinally. Nonetheless, because the primary population of 

concern to VA is the current living cohort of Vietnam Veterans, the 

findings from the study are particularly relevant.

    NAS stated that the results of the Kang study are consistent with 

those of other studies of Vietnam Veterans, including the other most 

highly exposed cohort composed of Vietnam Veterans who served in 

Operation Ranch Hand. NAS stated that multiple examination cycles of 

the Air Force Health Study (AFHS) of those Veterans have consistently 

reported an increase in the prevalence of hypertension with a doubling 

of serum dioxin concentration. NAS stated that the analyses controlled 

for the major risk factors for hypertension, and diagnosis was 

confirmed with medical-record review. NAS noted that limitations of the 

AFHS studies include the potential for selection bias and the variation 

in the comparison group over examination cycles, but that selection 

bias is reduced, in part, by the relatively high participation rates 

across certain cycles. NAS stated that the Kang study is also 

consistent with three other Veteran studies--a 1996 study of Australian 

Veterans by O'Toole et al., a 1988 study of American Legion Vietnam 

Veterans by Stellman et al., and a 1988 Vietnam experience study (VES) 

by the Centers for Disease Control (CDC)--which NAS characterized as 

reporting ``significant increases'' in the incidence of hypertension. 

NAS noted, however, that only the Kang study controlled for potential 

confounding variables and used an index of herbicide-related exposure.

    NAS noted that there was also evidence weighing against an 

association between herbicide exposure and hypertension. Specifically, 

NAS noted that the key Vietnam Veteran ACC study was not consistent 

with a previous study of herbicide factory workers exposed to TCDD that 

failed to identify a significant association between measured TCDD and 

hypertension after controlling for hypertension risk factors. NAS 

stated that ``[t]he negative findings argue against an association 

between TCDD exposure and hypertension,'' although it noted some 

limitations in the study. Similarly, NAS noted that the ACC study was 

not consistent with another recent environmental study examining the 

prevalence of hypertension in relation to serum concentrations of PCDDs 

and PCDFs in persons residing near a municipal waste dump. NAS stated 

that this study ``showed that serum concentrations of dioxin-like PCDDs 

and PCDFs are not associated with an increased incidence of 

hypertension when major risk factors are adjusted for,'' although NAS 

again noted certain limitations in the study. Accordingly, the report 

identifies significant evidence both for and against an association 

between herbicide exposure and hypertension.

    We agree with NAS that the recent Kang study is a significant 

addition to the scientific literature concerning herbicide exposure and 

hypertension. However, we also note that a number of factors relating 

to that and other positive studies cited by NAS limit the strength of 

the evidence. The Kang study is limited in part because it is based on 

unconfirmed self-reports of hypertension diagnoses. In other reports 

provided to VA, NAS has noted the inherent limitations of studies based 

on self-reports. For example, in a 2007 study of health effects of 

deployment-related stress, NAS noted that some studies had found an 

increase in hypertension related to deployment but that ``because most 

are based on self-reports, not much reliance can be placed on them.'' 

Institute of Medicine, Gulf War and Health, Volume 6, Deployment-

Related Stress and Health Outcomes, at 193 (National Academies Press 

2007).

    In Update 2006, NAS noted that the potential bias of self-reports 

was tempered because people are more likely to accurately recall and 

report a chronic disease requiring continuous management, such as 

hypertension and diabetes, and because the researchers had verified the 

accuracy of 79 percent of the self-reported diagnoses of diabetes. The 

seemingly conflicting views concerning the reliability of self-reported 

hypertension present some difficulty in interpreting the evidence. We 

note that there is some reason to believe that the potential error rate 

in self-reported hypertension may be significant enough to impact the 

study's findings. In its 1994 report on Veterans and Agent Orange, NAS 

explained that in the CDC's 1988 VES study comparing hypertension 

incidence in Vietnam Veterans and non-deployed Vietnam-era Veterans 

``[a] significant difference in self-reported hypertension between the 

groups was reported,'' but that ``there was no significant difference 

in hypertension measured as part of a physical examination in the 

study.'' Institute of Medicine, Veterans and Agent Orange; Health 

Effects of



[[Page 32551]]



Herbicides Used in Vietnam, at 702 (National Academies Press 1994).

    As noted above, the Kang study did find that 79 percent of self-

reported diabetes diagnoses were confirmed by medical record research, 

and it is reasonable to believe that a similar verification rate would 

exist for self-reported hypertension. That finding suggests that most 

self-reports are accurate, but also acknowledges a potentially 

significant margin of misreported diagnoses. The NAS report does not 

address the potential impact that such misreported diagnoses could have 

on the study.

    We note also that the Kang study found no significant difference in 

hypertension between Veterans who served in Vietnam and non-deployed 

Vietnam era Veterans. This factor does not undermine the study's 

finding of an increased risk of hypertension in the most highly exposed 

group, although it might suggest that any association between herbicide 

exposure and hypertension would be limited to certain high levels of 

exposure.

    The other Vietnam Veteran studies cited as consistent with the Kang 

study also have a number of limitations. As noted above, NAS noted that 

several cycles of the AFHS study have consistently reported an increase 

in the prevalence of hypertension with a doubling of serum dioxin 

concentration. However, the AFHS findings as reported in Update 2006 

report increased risks that are relatively small and in most instances 

are not statistically significant. Although the consistent findings of 

increased risk may weigh in favor of an association, the low magnitude 

of the findings and the general lack of statistical significance may 

argue against an association or at least may be viewed as 

indeterminate.

    NAS indicated that the CDC's 1988 VES study found a significant 

increase in the incidence of hypertension in Vietnam Veterans. As noted 

above, however, that finding existed only with respect to self-reported 

hypertension diagnoses, and was not supported by physical examinations. 

Accordingly, in another recent report, NAS characterized the CDC study 

as finding that the prevalence of hypertension was ``not significantly 

higher'' in Vietnam Veterans as compared to non-deployed Vietnam-era 

Veterans. Institute of Medicine, Gulf War and Health, Volume 6, 

Deployment-Related Stress and Health Outcomes at 185 (National 

Academies Press 2007).

    NAS discussed the 1996 O'Toole study in Veterans and Agent Orange: 

Update 1998. The study involved a simple random sample of Australian 

Vietnam Veterans' self-reported health status information in relation 

to the Australian public. The study found a significant increase in 

self-reported hypertension among the Vietnam Veterans. Because the 

study was based on self-reports, it is subject to some of the same 

concerns discussed above in relation to the Kang study. More 

significantly, the results apparently do not control for confounding 

factors. In fact, the study found that the Veterans were significantly 

more likely than the control population to be current or former smokers 

and to report high alcohol consumption. The lack of controls for 

potentially significant risk factors known to exist in the study 

population significantly limits the weight of this study for present 

purposes.

    NAS discussed the 1988 Stellman study in its 1994 Veterans and 

Agent Orange report. That study was also based on self-reports of 

hypertension diagnoses. The report found no significant differences in 

the prevalence of hypertension in Vietnam Veterans and non-deployed 

Vietnam-era Veterans. It did, however, find a significant increase in 

self-reported hypertension in Vietnam Veterans who handled herbicides 

as compared to Vietnam Veterans who did not. NAS noted that the 

conclusions to be drawn from the study are limited by the potential for 

misclassification of exposure and the lack of validation of self-

reported diagnoses. As noted above, the potential for misreporting of 

hypertension diagnoses limits the strength of the reported data on 

association.

    Further, in update 2006, NAS acknowledged that the CDC, O'Toole, 

and Stellman studies did not control for potentially confounding 

variables. These variables may include alcohol or tobacco use, body 

mass index or obesity, and type 2 diabetes. The failure to control for 

confounding factors renders it difficult to draw significant 

conclusions from the reported data. In Update 2006, for example, NAS 

noted that a 2006 environmental study by Chen et al. based on self-

reported data initially found a more than five-fold increase in the 

risk of hypertension associated with elevated serum PCDD and PCDF 

concentrations in persons who lived near municipal-waste incinerators; 

however, when the results were controlled for age, sex, smoking status, 

and body mass index, the results showed that the study population 

actually had a decreased risk of hypertension.

    NAS identified a number of studies finding no association between 

herbicide exposure and hypertension. Among Vietnam Veteran studies, a 

2005 study by Ketchum and Michalek of mortality of Ranch Hand Veterans 

found no significant increase in mortality from hypertension. As noted 

above, although the CDC's 1988 Vietnam Experience Study found a 

significant increase in self-reports of hypertension, physical 

examinations did not show any differences in increased blood pressures, 

which argues against an association.

    The two environmental studies cited by NAS showed no increased risk 

of hypertension. As noted above, the 2006 study by Chen et al. found 

that persons residing for at least 5 years near a municipal-waste 

incinerator and who had elevated serum PCDD and PCDF concentrations did 

not have any increased risk of hypertension. This study has the 

strength of controlling for confounding factors, although NAS noted a 

potential limitation in the lack of information on the criteria for 

diagnosing hypertension. A 2001 study by Bertazzi et al. of mortality 

among persons exposed to TCDD as the result of an accident in Seveso, 

Italy, found no increased mortality due to hypertension.

    Occupational studies identified by NAS generally found no increased 

risk of hypertension in exposed populations. A 2005 study by `t 

Mannetje et al. of mortality rates among New Zealand workers exposed to 

phenoxy herbicides and dioxins found no increased mortality due to 

hypertension. A 1998 study by Calvert et al. of workers exposed at two 

U.S. herbicide factories did not find any significant increase in the 

risk of hypertension. This study controlled for risk factors and 

included exposure information based on serum TCDD levels, although NAS 

noted potential limitations in that some of the information on 

hypertension was based on self-reports and the overall response rate 

was low, which could contribute to selection bias. A 1984 study by 

Suskind and Hertzberg of circulatory disorders among workers at an 

herbicide production plant found no significant differences in rates of 

self-reported hypertension associated with exposure. A 2000 study by 

Kitamura et al. of workers at a municipal-waste incinerator found no 

significant increase in self-reported hypertension associated with 

elevated serum PCDD levels. Several other studies found no significant 

increase in circulatory disorders, including hypertension, in persons 

occupationally exposed to herbicides, but these studies are less 

helpful because they do not specifically isolate findings concerning 

hypertension.



[[Page 32552]]



    The consistently negative findings in the occupational studies 

identified to date is of interest because, as NAS has noted (Update 

2006 at 38), at least in studies of chemical-production workers, the 

magnitude and duration of exposures in occupational studies generally 

would be greater than in Vietnam Veteran studies. Accordingly, if the 

increase in self-reported hypertension observed in the recent Kang 

study is attributable to herbicide exposure, one would expect similar 

findings in occupational studies of herbicide-production workers.

    In summary, the available occupational and environmental studies to 

date have consistently failed to detect a significant association 

between herbicide exposure and hypertension. The available Vietnam 

Veteran studies have produced a mixture of positive and negative 

findings, as well as findings that are essentially indeterminate in 

that they report low-magnitude increases that are not statistically 

significant. The primary evidence in favor of an association is the 

recent study by Kang et al. Other Vietnam Veteran studies reporting a 

significant increased risk of hypertension are limited primarily by 

concern of control for confounding factors. Viewing the evidence as a 

whole and taking into account the considerations discussed above, the 

Secretary has determined that the credible evidence for an association 

between hypertension and herbicide exposure is not equal to nor does it 

outweigh the credible evidence against an association. Therefore, he 

has determined that a positive association does not exist. In view of 

the suggestive findings in the recent Kang study, VA will continue to 

closely monitor further developments regarding the possible association 

between herbicide exposure and hypertension.



Circulatory Disorders



    NAS found that circulatory diseases constitute a group of diverse 

conditions, of which hypertension (addressed above), coronary heart 

disease, and stroke are the most prevalent, that account for 75 percent 

of mortality from circulatory diseases in the United States. The major 

quantifiable risk factors for circulatory diseases are similar to those 

for hypertension and include age, race, smoking, serum cholesterol, BMI 

or percentage of body fat, and diabetes.

    NAS found that reported results of new morbidity and mortality 

studies of the most highly exposed Vietnam-Veteran cohorts (ACC and 

Operation Ranch Hand) were not entirely consistent. NAS noted that ACC 

Veterans who sprayed Agent Orange reported a significant increase in 

the prevalence of heart disease, primarily ischemic heart disease, but 

that the AFHS did not find the prevalence of heart disease, myocardial 

infarction, or stroke to be significantly associated with either 

current or back-extrapolated serum TCDD concentrations in Ranch Hand 

Veterans. NAS stated that one study found a significant increase in 

mortality due to atherosclerotic heart disease in Ranch Hand ground 

crew personnel, but the increase in mortality from circulatory disease 

among all Ranch Hand Veterans based on back-extrapolated serum TCDD was 

not significant.

    NAS also noted that several new occupational studies reported no 

significant increase in risk of circulatory disorders, including 

ischemic heart disease, associated with herbicide exposure; in fact, 

two new studies found that the risk of certain circulatory disorders 

was significantly lower in the exposed populations.

    NAS noted that some previously reviewed studies of herbicide 

factory workers occupationally exposed to TCDD reported findings 

supporting an association between herbicide exposure and heart disease. 

Those findings came primarily from mortality studies in which the 

researchers did not have access to information concerning the impact of 

potentially confounding risk factors. NAS noted that, in the studies 

that did have information on potential confounders, the cardiovascular 

health endpoints were described imprecisely and did not clearly 

distinguish ischemic heart disease from other conditions. Viewing those 

prior studies in relation to the new findings from the studies of ACC 

and Ranch Hand Veterans, some members of the NAS committee felt that 

there was limited/suggestive evidence of an association between 

herbicide exposure and ischemic heart disease. Other members of the 

committee, however, felt that the lack of information on potential 

confounders limited the strength of many of the studies and that the 

evidence remained inadequate or insufficient to determine whether an 

association exists between herbicide exposure and ischemic heart 

disease. For all other types of circulatory disease, the committee 

agreed that the evidence is inadequate or insufficient to determine 

whether there is an association with exposure to the compounds of 

interest.

    Upon consideration of Update 2006 and prior NAS reports, the 

Secretary in May 2008 determined that the then-existing credible 

evidence for an association between circulatory disorders and herbicide 

exposure was not equal to nor did it outweigh the credible evidence 

against an association. Therefore, he determined that a positive 

association was not established at that time. Although Update 2006 

found some evidence supporting an association between herbicide 

exposure and ischemic heart disease, there was also significant 

evidence against an association, including several studies that found 

no significant increased risk of the disease and at least one that 

found a significantly decreased risk. Further, a number of the studies 

reporting a significant increase in mortality due to ischemic heart 

disease were unable to consider potential confounding factors, a 

concern that limits the strength of the reported data.

    As stated previously, based upon the NAS report ``Veterans and 

Agent Orange: Update 2008,'' the Secretary, on October 13, 2009, 

announced his decision to establish a presumption of service connection 

between exposure to herbicides and the subsequent development of hairy 

cell leukemia (HCL) and other chronic B cell leukemias, Parkinson's 

disease, and ischemic heart disease. See 75 FR 14391 (Mar. 25, 2010).



Endometriosis



    In prior reports, NAS evaluated five studies relevant to 

endometriosis. It found that three environmental studies reported no 

increased incidence of endometriosis associated with herbicide exposure 

and that two case-control studies reported elevated odds ratios but had 

very wide confidence intervals that precluded statistical significance. 

In Update 2006, NAS identified two new environmental studies, both of 

which reported significant increases in the incidence of endometriosis 

in the populations exposed to dioxin-like PCBs. NAS noted, however, 

that one of the studies was limited because it was unable to 

differentiate the effects of the dioxin-like PCBs and non-dioxin-like 

PCBs to which the subjects were exposed.

    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 endometriosis.



Effects on Thyroid Homeostasis



    NAS noted that numerous animal experiments and several 

epidemiologic studies have shown that TCDD and dioxin-like compounds 

appear to exert an influence on thyroid homeostasis. Specifically, 

those compounds may



[[Page 32553]]



affect the secretion of thyroid-stimulating hormone (TSH), which 

governs the function of the thyroid gland in secreting the hormones T3 

and T4. In prior reports, NAS noted that several human studies observed 

an increase in TSH levels associated with TCDD exposure, but without a 

corresponding increase in T4 levels, suggesting that the human body was 

able to adapt to any effect on TSH production. In Update 2006, NAS 

noted that, in the newly identified studies of adults, there was lack 

of correlation between dioxin-like compounds and TSH concentrations. 

Likewise, NAS noted that, in the newly identified studies of changes in 

thyroid homeostasis in relation to fetal and infant development, there 

were not significant associations between magnitude of exposure to 

dioxin or dioxin-like compounds and measures of thyroid function. NAS 

concluded that the studies continue to suggest that people were able to 

adapt to changes in thyroid status that might have been induced by 

exposure to TCDD and other dioxin-like compounds.

    NAS concluded that there is inadequate or insufficient evidence of 

an association between exposure to the compounds of interest and 

clinical or overt adverse effects on thyroid homeostasis. Although some 

effects have been observed in humans, the functional importance of the 

changes reported in the studies reviewed remains unclear, because 

adaptive capacity could be adequate to accommodate them.



AL Amyloidosis



    In Update 2006, the NAS found there was limited or suggestive 

evidence of an association between herbicide exposure and AL 

amyloidosis. We are not addressing AL amyloidosis in this Notice 

because a presumption of service connection has been established for 

this disease. VA published a final rule providing a presumption of 

service connection for AL amyloidosis for any Veteran exposed in 

service to an herbicide agent who develops the disease at any time 

after separation from service in the Federal Register on May 7, 2009, 

at 74 FR 21258.



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 2006.'' 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 a positive association with herbicide exposure. 

The Secretary's determinations regarding the diseases discussed in 

Update 2006 are based upon the NAS's identification and analysis of the 

relevant scientific and medical literature in Update 2006, as 

summarized above, and the additional analyses set forth in this notice, 

viewed in relation to prior relevant NAS reports and VA's prior notices 

addressing these matters.

    Taking account of the available evidence and NAS's analysis, the 

Secretary in May 2008 found that the evidence and analysis available to 

VA at that time did not warrant a presumption of service connection for 

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 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 (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. That determination was 

based on a finding that the then-existing credible evidence against an 

association between herbicide exposure and the cited conditions 

outweighed the credible evidence for such an association and that a 

positive association therefore did not exist.



    Approved: May 28, 2010.

John R. Gingrich,

Chief of Staff, Department of Veterans Affairs.

[FR Doc. 2010-13653 Filed 6-7-10; 8:45 am]

BILLING CODE 8320-01-P