DEPARTMENT OF
HEALTH AND HUMAN SERVICES
FOOD AND DRUG
ADMINISTRATION
Ranch Hand
Advisory Committee Meeting
Meeting
Minutes
The Department of Health and Human
Services (HHS) and the Food and Drug Administration (FDA)
Dr.
Approval of Previous Meeting
Minutes. Dr. Stoto announced that the previous
meeting minutes were distributed to RHAC for review and comment. The draft minutes were revised based on
changes he submitted to FDA prior to the meeting and comments made by Dr. Joel
Michalek, the Air Force Health Study (AFHS) Principal Investigator, for
scientific accuracy. Dr. Trewyn
noted three additional changes for the record. On page 7, the first bullet should end
with “significant cancer results” and the remainder of the text should be
deleted. On page 7, the fourth
bullet should be changed to “... and other herbicides used in
Dr. Stoto entertained a motion to
approve the minutes as modified; a motion was properly made and seconded by Drs.
Trewyn and Camacho, respectively.
With no further discussion, the November 19, 2004 RHAC Meeting Minutes
were unanimously approved with the changes submitted into and noted for the
record.
Dr. David Butler, of the National
Academy of Sciences (NAS), provided RHAC with a status report of this
effort. The Department of Veterans
Affairs (VA) was mandated by Congress to conduct the study and allocated funds
to NAS to address five primary elements:
1.
The scientific merit of retaining
and maintaining medical records, other data and laboratory specimens collected
during the course of AFHS should be evaluated.
2.
The existence of privacy concerns or
other ethical and logistical obstacles to retaining and maintaining AFHS
materials, data and laboratory specimens should be identified.
3.
Advice should be given on providing
independent oversight of AFHS medical records, other materials and further study
of the records, data and specimens.
The mechanism for providing such oversight should also be outlined if
further studies are conducted.
4.
Recommendations should be made on
the potential value and cost of extending the study and the most appropriate
federal or non-federal entity to continue the study.
5.
Guidance should be given on making
laboratory specimens that have been collected available for independent
research. This advice should
include the value, relevance and potential cost of the
research.
To address the five elements, NAS
formed an expert committee with extensive knowledge in environmental and
occupational medicine, health effects related to Agent Orange, epidemiology,
biostatistics, bioethics, privacy issues and SAS database management. A subcommittee was also established to
conduct a site visit of the AFHS research facilities. The NAS committee held a meeting in
February 2005 and a workshop in April 2005 to obtain its formal charge from the
VA, review the process to gather data, and discuss the five elements of the
study. Speakers at the April 2005
workshop represented diverse groups, including federal agencies and the
veteran’s community.
The NAS committee will convene its
final meeting and workshop in June 2005 to gather additional information from
experts on issues related to privacy concerns and the use of data by outside
researchers. Representatives of
federal agencies with experience in these areas will describe lessons learned to
ensure efforts are not duplicated.
NAS expects to release the report of the AFHS disposition study in the
fall of 2005, but more information can be obtained in the interim at or .
Prior to its release, the report of the AFHS disposition study will be reviewed by several persons whose identities will be unknown to the NAS committee. The reviewers’ comments will be addressed and a coordinator will examine responses by the NAS committee for accuracy. Dr. Butler confirmed that RHAC will be given copies of presentations from the April 2005 workshop and will also be notified about the release of the report of the AFHS disposition study.
Dr. Stoto clarified that his
presentation during the April 2005 NAS workshop reflected his personal opinions
and not the respective positions of the U.S. Air Force (USAF), RHAC, NAS or his
employer. His remarks focused on
the purpose, design and endpoints of AFHS; the relatively high exposure to
dioxin among AFHS subjects; currently available data; AFHS research results; the
impact of continuing the AFHS; and consent to use AFHS records and
materials. Dr. Stoto’s position
about the disposition of AFHS is as follows.
Research that is underway should be
completed and relatively inexpensive efforts to monitor mortality of the
subjects should be continued.
Retaining and maintaining AFHS data and materials and providing
researchers with access to these data will be extremely valuable. However, due to the age of the subjects
and the amount of information previously gathered, it is unlikely that much will
be learned from performing additional physical examinations.
Although designed for a narrow
purpose, the wealth of data and materials that have already been gathered by the
APHS means that future research with these data materials could address the
health effects of herbicides and dioxin in veterans; environmental and
occupational exposures and other aspects of military health; more general
chronic disease risks; the normal aging process, and other issues. It is likely that if they knew about the
existence of these data and materials, researchers with expertise in these and
other fields could obtain funding through the regular processes at the National
Institutes of Health and other public and private institutions, and conduct
creative and innovative studies using the AFHS data and materials.
The NAS study is intended to
identify the potential benefits of this material to future researchers, as well
as the costs and logistical issues involved with maintaining access to
them. One specific issue that will
have to be addressed is informed consent.
During the last round of examinations, ~96% of subjects were willing to
give their consent for records and materials to be used in “Agent Orange and
military health studies” and 3% for “Agent Orange only.” Only 1% of subjects were not willing to
give their consent. The subjects
were not asked about other uses of the data.
The RHAC agreed that despite the
25-year history of AFHS, new findings are still being discovered and this issue
should be strongly emphasized to the NAS committee. Other comments by RHAC on the AFHS
disposition study are outlined below.
•
Identify specific elements of the AFHS disposition study for RHAC to
collectively endorse. For example,
RHAC could develop and submit a formal statement to the NAS committee on the
importance of maintaining valuable AFHS data for future studies and the benefits
of re-analyzing existing data with new information or different
methodologies. RHAC’s previous
letters to NAS or Dr. Stoto’s presentation during the April 2005 NAS workshop
could be used as the basis for RHAC’s formal position statement on the AFHS
disposition study.
•
Outline a specific process if the NAS committee recommends that AFHS
laboratory specimens be made available to independent researchers. For example, specimens should not be
examined as individual submissions.
Instead, materials should be accessible in a batch mode with applications
considered during an appropriate time period. This approach will provide material
handlers with better knowledge of the strengths and limitations of AFHS
data.
•
Explore the possibility of establishing a fair and independent oversight
body to systematically examine different methodologies that have been applied in
other research projects. Use this
approach to increase credibility of the AFHS disposition study. For example, different levels of access
or restrictions could be placed on specific data components rather than the
entire data set because some studies will not require samples or identification
of personal information. Data can
also be protected by running statistical analyses from the database rather than
releasing raw data/information to researchers.
•
Ensure that the Census Bureau and
Dr. Butler confirmed that he would
provide the NAS committee with RHAC’s June 2005 meeting minutes or its formal
position statement on the AFHS disposition study if the members decided to
develop this document. He
encouraged RHAC to contact him at afhs_study@nas.edu.
Dr. Stoto,
With respect to other reports, USAF
awarded a contract to SAIC to develop a paper on the overall history of
AFHS. A statement of work is now
being written for the longitudinal study that is expected to be completed before
AFHS is concluded on
Dr. Stoto will assign each RHAC
member specific sections of the summary report to review prior to the November
2005 meeting. An outline and
description of the document were distributed to RHAC; comments from the members
are outlined below.
•
Change the title from “longitudinal summary” because the document will
serve as a summary report rather than a longitudinal
study.
•
Do not use “statistically significant” because this term will not be
understandable to a broad audience.
Provide clear details in the “description of the writing strategy”
section on items the reader should expect to review in the summary
report.
•
Include a paragraph that specifically focuses on the strengths and
weaknesses of the AFHS. Use this
text to strengthen credibility of the AFHS, particularly in the veteran’s
community. For example,
insignificant results for cancer and other health outcomes may become much more
important when existing data are assessed, grouped or re-analyzed with different
or new methodologies.
•
Expand on existing efforts to ensure the history, controversy and other
issues related to the AFHS are transparent and accurately captured. For example, engage political scientists
or sociologists while developing the summary report. Contact Dr. Camacho to obtain
information on a previous literature review of the political and social aspects
of the AFHS.
•
Establish a clear process to identify statistical and clinical
significance. For example, many
potential problems can be avoided by analyzing inconsistencies among or between
officers, enlisted personnel, and other AFHS subgroups.
•
Explore the possibility of including unpublished data in the summary
report as well as recently released papers which may contain important new
findings.
•
Include text to clarify that additional efforts will be undertaken and
new data related to the AFHS will be released in the
future.
Dr. Fumio Matsumura, of the
University of California-Davis, presented results from a new field of
epidemiological science that is designed to increase the sensitivity of
detecting biological effects and provide a logical basis for empirically
observed correlations. A molecular
epidemiology study was conducted in the AFHS cohort. A total of 313 volunteers *Ranch Hands
(RHs) and carefully matched comparisons) donated adipose samples for the
study. The molecular markers
selected included glucose transporter 4 (GLUT4), an adiposity index, an
inflammation marker (NFĸB), a signal messenger for toxic action of dioxin, and a
housekeeping gene used as a normalization standard.
The molecular epidemiology study was
designed with several strategies.
The statistical power was increased by dividing each service group into
four quartiles according to the level of dioxin residues. Statistically significant correlations
between molecular marker expressions and dioxin residues were identified. Positive correlations between dioxin and
combinations of all marker ratios were located. Relationships between the ratio of GLUT4
and NFĸB (G:N ratio) and dioxin were analyzed. Subgroups that were most affected by
dioxin were identified. The
hypothesis of the similarity between the diabetogenic effect of TCDD and obesity
was tested. The relationship
between the G:N ratio and recent changes in body fat was studied. Fasting glucose was used as a diabetes
marker. Relationships among G:N
ratio, percent of body fat and dioxin residue levels were
identified.
The following conclusions were
reached in the molecular epidemiology study. The G:N ratio was found to be the best
marker to detect diabetogenic effects of obesity and genetic risk factors. Some subgroups were found to affect the
pattern of correlations. The use of
the quartile approach was found to be justifiable because the same results could
be obtained through other methods.
Obese and lean subgroups were shown to respond differently to
dioxin.
Dioxin exposure was found to make
non-diabetic RHs more susceptible to diabetogenic influences of obesity. The G:N ratio among non-diabetic
subjects was found to be negatively correlated to obesity, but an opposite trend
was seen among diabetic subjects.
The G:N ratio was found to be a reliable marker of diabetes because of
its high correlation to fasting glucose levels. Fasting glucose levels were found to be
directly affected by dioxin and a sensitive marker in detecting diabetogenic
effects of obesity.
Dioxin was found to act as a
diabetogenic risk factor among
Dr. Michalek described three unique
aspects of the molecular epidemiology study. First, the study is the only body of
research in the world in which a contaminant was measured in both the control
and index groups. Second, ~98% of
both the control and exposed groups were measured for dioxin by the same
laboratory. Third, the study is the
only body of research that exists on adipose markers in humans related to
dioxin.
The Chair opened the floor for
public comments; no attendees responded.
Dr. Michalek conveyed that the AFHS
is most likely the best epidemiologic study ever conducted and is based on some
of the most solid data ever collected in humans. The government launched the AFHS in 1979
and is continuing to commit resources to ~30 years of effective follow-up. The AFHS was designed with an
unprecedented scope, quality and consistency to answer sensitive questions, but
the study contains several limitations.
The AFHS is an extremely complex research effort due to the lack of
dosimetry data to determine when service personnel were exposed to chemicals in
Summary of the 2002 Air Force Health
Study Follow-up Physical Examination Report. Of 1,951 persons given physical
examinations in 2002, 777 were RHs and 1,174 were comparisons. Statistical models were used to address
uncertainties in AFHS. Model 1
focused on differences between RHs and controls on any measure of health. Model 2 focused on connections between
health and initial doses estimated in RHs while serving in
Findings were:
-
Body mass index (BMI) increased with
dioxin.
-
No remarkable results were found to
relate dioxin or herbicide exposure to cancer.
-
A mixed pattern of associations did
not indicate an overall relationship between adverse neurological health and
herbicide or dioxin exposure.
-
No psychological outcome measures
were found to be associated with herbicide or dioxin exposure.
-
The risk of abnormally high
triglycerides was increased in RH enlisted ground crew in the high dioxin
category.
The frequency and occurrence of
reported acne after service in Southeast Asia (SEA) were increased in RH
enlisted ground crew in the high dioxin category. No association was seen between dioxin
and skin lesions indicated by dermatologists during the physical
examination. An inconsistent
pattern of associations was seen between different measures of cardiovascular
health and dioxin or herbicide exposure.
The risk of death from cardiovascular disease was found to be
significantly increased among RH enlisted ground crew. A corresponding association was not seen
in the analysis of veterans with dioxin assay to support the mortality
outcome.
-
Associations were not found to
indicate adverse relationships between hematological health or renal function
and dioxin or herbicide exposure.
-
An association was seen between
adult onset diabetes and dioxin or herbicide exposure.
o
The risk of acquiring type 2
diabetes and taking insulin was increased among RHs with high dioxin
levels.
o
The risk of abnormally high
hemoglobin A1c increased with dioxin.
-
No consistent or interpretable
association was seen between any measure of immune function and dioxin or
herbicide exposure in the cohort.
-
Similar results of no consistent or
interpretable association between dioxin or herbicide exposure and pulmonary
function were seen.
The AFHS is a unique study due to
adjustments made for diabetes and cancer risk factors, including age, BMI,
family history, occupational exposure outside of USAF, exposures to metals and
chemicals, skin reaction to sunlight, eye and hair color, and smoking history in
pack years. Overall, no significant
group differences between RHs and controls were seen for any disease outcome in
the AFHS.
Publication:
Diabetes. The diabetes results were published in
Epidemiology in 1997. The
risk of adult onset type-2 diabetes increased with dioxin among RHs. The time to diabetes onset decreased and
diabetes severity increased with dioxin.
However, no difference was seen between RHs and controls in the overall
prevalence of dioxin. This
contradictory result produced a “check mark” pattern in which RHs with high
dioxin levels had a greater risk than controls and RHs with low dioxin levels
had a lesser risk than controls.
Attempts were made to statistically model the check mark pattern, but
these efforts were not published.
Current Research:
Diabetes. New analyses of dioxin and
diabetes were performed in both Cycles 5 and 6 with adjustments for risk factors
of days of spraying, calendar period of spraying, and last year of service from
1962-1970. The total number of
individuals in the data set who were available for analysis was 3,049. However, the actual sample size was
2,469 because individuals were excluded based on a diagnosis of diabetes prior
to service in Vietnam or SEA, non-compliance with at least one physical
examination and no dioxin levels.
Persons who
served in
The diabetes analysis showed that
persons who served in SEA prior to 1969 had higher dioxin levels than those
whose last year of service was after 1969.
This finding supports the hypothesis that herbicides were more
contaminated with dioxin earlier rather than later in the war. The risk factor of calendar year of
service led to a fairly remarkable outcome of reversing the pharmacokinetics of
dioxin. These data were the only
body of evidence in the world that could be used to make this assessment in
humans because RHs are the only cohort with extensive measurements of dioxin and
other risk factors related to service in
A relationship was seen between
number of days of spraying and body burden of dioxin. No significant increased risk of type-2
adult onset diabetes was seen without adjusting for calendar year of service and
number of days of spraying because these risk factors change the relationship
between dioxin and diabetes. Other
unknown factors may also be important, particularly by incorporating information
from daily spray records to further refine the diabetes
analysis.
-
Cancer. The cancer results were published in the
Journal of Occupational and Environmental Medicine in 2005. Associations between cancer and dioxin
were not evident in simple main effects models. Years of service in SEA were found to be
a risk factor for cancer in comparisons.
Associations between cancer and dioxin were seen after stratification by
years of service in SEA and the proportion of time spent in
The time to onset for veterans
without cancer was the date of the last physical examination plus two years or
the date of death. Cancer was
determined by a review of medical records of death certificates. All analyses were performed with
proportional hazards models adjusted for known risk factors. Individuals who were compliant to at
least one physical examination were included in the analysis. The total number of individuals who were
available for analysis was 3,049, but the actual sample size was 2,583. Persons were excluded based on cancer
prior to service in
The stratified analysis for cancer
had several limitations. The entire
cohort was not examined and the last year of service in the RH unit was
stratified as 1968 or prior. The
relative risk became stronger in earlier years and suggested an exposure effect
on dioxin in cancer, but the number of subjects became smaller due to fewer
persons in SEA during the early years of the war. Years of service in SEA was found to be
a risk factor for all-site SEER cancer in the control group and required an
adjustment for the length of time comparisons were in SEA. Different types of cancer were
combined. However, the stratified
analysis was strengthened with the inclusion of operational information outside
of p values, such as days of spraying and last year of
service.
The results showed that individuals
who served in SEA earlier rather than later in the war had higher dioxin
levels. This finding supported the
hypothesis that herbicides were indeed more heavily contaminated during this
time period. A relationship was
seen between days of spraying and body burden of dioxin among RHs. No association was seen between all-site
SEER cancer and dioxin without adjusting for days of spraying or last year of
service in SEA because these risk factors served as effect modifiers. A significant trend of an increased risk
of cancer was seen in the entire cohort of 788 persons when adjustments were
made for days of spraying, service during or prior to 1968 and whites only. No significant results were seen in the
high-dioxin category with the model 3 analysis and inclusion of
dioxin.
Relative risks increased in RHs when
comparisons with a long duration of time in SEA were excluded. A significant trend of an increased risk
of cancer was seen when the factors of days of spraying, service during or prior
to 1968, and less than two years of service in SEA were combined. The risk factor of days of spraying
alone was not found to relate to cancer in the control group or provide
sufficient information to detect an exposure effect on cancer in RHs. A significant group difference in cancer
was not seen after these adjustments, but a significant increase in the risk of
cancer in RHs was detected.
Overall, a significant association was found between cancer and dioxin
and a unexpected relationship was seen between cancer and years of service in
SEA in the control group.
- Sleep
Disorders. The sleep disorder analysis was
submitted to Environmental Health Perspectives and is currently being
considered for publication. The
analysis serves as the first effort to measure sleep disorders and dioxin in the
same subjects. Sleep questionnaires
were administered to AFHS participants in 1987 and 1992. The analysis was restricted to
individuals who were compliant to the 1987 or 1992 physical examinations; used
the model 3 dioxin category analysis; and applied “insomnia” and “para-insomnia”
as defined in the literature. Risk
factors used in the analysis were consistent with other components of AFHS
research.
The results showed adverse health
effects related to dioxin exposure and sleep disorders. Significant increases in sleep
complaints, disabling daytime fatigue, daytime sleepiness and insomnia were
reported among veterans in low- and high-dioxin categories compared to controls
after adjusting for risk factors.
Overall, dioxin was found to target arousal regulation and interfere with
sleep.
Some
•
Use other published findings in addition to the AFHS to make the Cycle 6
report more valuable, beneficial and sensitive to the
•
Analyze AFHS data in the future with different methodologies to identify
important associations between dioxin and other adverse health effects, such as
birth defects, heart disease and hypertension.
•
Examine Agent Blue with cacodylic acid and other non-dioxin compounds to
detect additional adverse health effects.
•
Refine the specificity of the analyses by incorporating other molecular
markers.
•
Delay publication of the AFHS summary report to include data from the new
cancer, diabetes and sleep disorder analyses.
•
Design the AFHS summary report to be open and transparent by explicitly
stating that positive results were found in non-AFHS research and valuable
information other than the history of the AFHS can be obtained from these
data.
•
Clearly outline the strengths and limitations of the AFHS in the summary
report.
Dr. Michalek and Col. Fox made
several follow-up remarks to RHAC’s discussion. USAF extensively reviewed all comments
on the Cycle 6 report that RHAC made during meetings or submitted in
writing. All of the suggested
revisions could not be incorporated, but the current version reflects most of
the changes. Most notably, a
preface was included that explains other findings in the published literature
may not agree with the Cycle 6 report.
The document has been submitted for public release clearance. A press release should be
forthcoming.
The Centers for Disease Control and
Prevention (CDC) is currently analyzing AFHS sera for dioxin-like chemicals in
~700 samples to strengthen the overall exposure assessment and clarify existing
patterns. The new analysis may
also lead to inaccurate exposure classifications of AFHS participants in terms
of being comparisons or having background, low or high dioxin levels. .
.
Longitudinal Report (Summary
Report). Publication of the AFHS
summary report may not be able to be delayed to incorporate data from the new
cancer, diabetes and sleep disorder analyses. However, the document could perhaps be
revised to emphasize that these data have been collected. Moreover, the new diabetes analysis will
soon be submitted to a journal and may be published prior to the November 2005
RHAC meeting. Dr. Michalek compiled
data from the new diabetes, cancer and sleep disorder analyses into a manuscript
and submitted a proposal for USAF to allocate funding to complete the
paper. The USAF is in negotiation
with SAIC on publication support and Dr Michalek’s two proposals are under
review.
Dr. Schechtman announced that the
next two RHAC meetings will be held on
•
The Cycle 6 follow-up physical examination report, update on its
release.
•
Dr. Michalek’s draft diabetes paper.
•
The AFHS summary report.
•
Report of the IOM AFHS disposition study.
•
The SAIC paper on the history of AFHS.
•
Update on the CDC analysis of all dioxin-like chemicals and
congeners.
•
Overview of USAF’s methodology to unfreeze portions of samples from all
six cycles, perform analyses for ~100 chemistry values, and determine if the
samples are viable from 1982 and thereafter.
Based on preliminary time-lines for
these agenda items according to input from NAS, SAIC and USAF, RHAC agreed that
no meeting should be held in September 2005 and the November 2005 meeting should
perhaps be extended to 1.5 days.
Dr. Schechtman noted that based on FDA’s availability, the meeting should
be convened on November 18, 10 or 3, 2005 in this order of preference. RHAC indicated that its first choice
would be a meeting on
Dr. Stoto thanked the speakers for
their informative presentations, RHAC for its valuable input, USAF, and FDA for
making logistical arrangements for the meeting.
With no further discussion or
business brought before RHAC, Dr. Stoto adjourned the meeting at
I hereby certify that to the best of my knowledge, the foregoing Minutes
of the proceedings are accurate and complete.
___________________
________________________________
Date
Michael A. Stoto, Ph.D.
Chair, Ranch Hand Advisory Committee
___________________
________________________________
Date
Leonard M. Schechtman, Ph.D.
Executive Secretary,
Ranch Hand Advisory Committee
ATTACHMENT
1
List of
Participants