**DEPARTMENT OF HEALTH AND HUMAN SERVICES**

**and**

**FOOD AND DRUG ADMINISTRATION**

**NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH**

**convene the**

**[Ranch Hand Advisory Committee Meeting]{.smallcaps}**

***Rockville, Maryland***

***April 30, 2004***

**[Record of the Proceedings]{.smallcaps}**

**TABLE OF CONTENTS**

[Page]{.underline}

Opening Session 1

Approval of Previous Meeting Minutes 2

Update on the Long-Term Studies Meeting 2

Proposal for Future Use of Biological Samples 2

Review of Chapter 1: Introduction 7

Review of Chapter 2: Dioxin Assay/Appendix A 9

Review of Chapter 3: Questionnaire Methodology 9

Review of Chapter 4: Physical Examination/Appendix B 10

Review of Chapter 17: Renal Assessment/Appendix F-9 11

Review of Chapter 9: General Health/Appendix F-1 11

Review of Chapter 6: Quality Control/Appendix D 14

Public Comment Period 14

RHAC Business 15

# Closing Session 16

**DEPARTMENT OF HEALTH AND HUMAN SERVICES**

**FOOD AND DRUG ADMINISTRATION**

**NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH**

**[Ranch Hand Advisory Committee Meeting]{.smallcaps}**

***April 30, 2004***

***Rockville, Maryland***

**[Meeting Minutes]{.underline}**

The Department of Health and Human Services (HHS) and the Food and Drug
Administration (FDA) National Center for Toxicological Research (NCTR)
convened a meeting of the Ranch Hand Advisory Committee (RHAC). The
proceedings were held on April 30, 2004 at FDA's Washington Operations
Office, 5600 Fishers Lane in Rockville, Maryland.

Dr. Michael Stoto, the RHAC Chair, called the meeting to order at 8:19
a.m. He welcomed the participants to the meeting and opened the floor
for introductions. The following individuals were present for the
deliberations.

**[RHAC Members]{.underline}**

Dr. Michael Stoto, Chair

Dr. Paul Camacho

Dr. Ezdihar Hassoun

Dr. David Johnson

Dr. Sanford Leffingwell

Dr. Ronald Trewyn

**[FDA/NCTR Representatives]{.underline}**

Dr. Leonard Schechtman

RHAC Executive Secretary

Ms. Kimberly Campbell

Committee Management Specialist

**[U.S. Air Force Representatives]{.underline}**

Col. Daniel Berry

Dr. Joel Michalek

2Lt. Margaret Montgomery

Lt. Col. Julie Robinson

**[U.S. Air Force Contractors]{.underline}**

Mr. Manuel Blancas

Operational Technologies Corporation

Dr. William Grubbs

Science Applications International Corporation

Dr. Judson Miner

Operational Technologies Corporation

Dr. Maurice Owens

Science Applications International Corporation

Ms. Meagan Yeager

Science Applications International Corporation

**[Guest]{.underline}**

Dr. Richard Atkinson

MedStar Research Institute

[Approval of Previous Meeting Minutes]{.underline}. Dr. Stoto announced
that the previous meeting minutes were distributed to RHAC for review
and comment; the draft was revised based on changes submitted by Drs.
Michalek and Stoto. Dr. Stoto entertained a motion to approve the
previous meeting minutes as modified; a motion was properly made and
seconded by Drs. Trewyn and Leffingwell, respectively. The January 21,
2004 RHAC Meeting Minutes were unanimously approved as modified with no
further discussion.

Dr. Joel Michalek, the Air Force Health Study (AFHS) Principal
Investigator, reported on a meeting he and Dr. Stoto recently attended.
The meeting was sponsored by the U.S. Medicine Institute and focused on
the value of long-term studies. The participants included experts in the
field, Congressional staffers, and high-ranking officials from the Army
and Department of Veterans Affairs (VA). The participants expressed
enthusiasm and showed support for long-term studies and also made
positive comments about the AFHS. Most notably, the Surgeon General of
the Army mentioned that the AFHS and similar studies should be
incorporated into the Department of Defense's (DoD) regular routine of
business.

Col. Daniel Berry, the Aeromedical and Medical Information System
Division Chief, oversees the AFHS in the USAF Human Systems Program
Office. He was pleased to announce that the AFHS has a higher follow-up
rate and more data points than the Framingham study and is recognized as
the world\'s premier epidemiological study. The AFHS is a well-operated
program and is based on solid science. Most notably, the AFHS was one of
only 24 research and development studies that met or exceeded program
goals out of a total of 187 projects. Over the past 21 years, \$125.9
million has been allocated to the AFHS to cover 13,183 physical
examinations, 42,953 records, 26,500 x-rays and 66,597 specimens. The
final AFHS physical examinations were successfully completed on May 5,
2003.

Despite this success, the value of the AFHS is not widely recognized.
Participants are extremely concerned about the termination of the AFHS
and the possibility of data and specimens being lost or destroyed
(specimens are perishable even with refrigeration). Congress is now
attempting to identify a suitable location to house the AFHS data and
specimens and has asked the National Academy of Sciences (NAS) to
conduct a study in this effort. However, the NAS study will only focus
on the disposition of the AFHS data and will not address the issue of
the stored specimens and the use of the data. If no practical purpose
can be identified for the data or specimens before the AFHS terminates
on September 30, 2006, the likelihood of using these valuable study
resources in the future will significantly decrease. Moreover, if no
actions are taken regarding the AFHS data and specimens prior to being
warehoused, they risk being put in indefinite storage, in which case the
samples will eventually deteriorate and chances are that funding for
such storage will eventually be discontinued. Such a scenario will
result in study materials that will never be used again and will never
benefit other similar research activities.

To address these concerns and illustrate the value of using the AFHS
data in the future, Col. Berry suggested that a small "demonstration
study" be conducted and ideally designed as follows. AFHS data would not
be destroyed or depleted. Information stored on computers and maintained
in participants' records would serve as the primary data source. The
majority of each specimen would be preserved since only a small fraction
of a given specimen would be needed. According to Col. Berry, the study
would appeal and be of value to veterans, the military, Congress and
society. Concerns expressed by participants would be addressed since the
AFHS data would be maintained and not lost or destroyed. The
demonstration project would be supported by private dollars or Congress
rather than AFHS funding.

Col. Berry proposed a specific example of such a demonstration project:
using the AFHS data to address the worldwide obesity epidemic. Obesity
has now surpassed smoking as the number one cause of preventable death.
Since 1980, the prevalence of obesity in the United States has doubled
in adults and tripled in children. This trend is continuing to rise
because \~31% of all U.S. adults are now obese with a body mass index
(BMI) of 30 kg/m^2^. The epidemic also affects military personnel and
veterans since more federal dollars are now allocated to health care for
obesity-related problems. Of \$100 billion annually spent on this issue
in the United States, \$51.6 billion is in direct health care costs. The
long-term implications of obesity include cardiovascular problems,
diabetes, cancer and other adverse health effects.

The rapid rise in the prevalence of obesity is not limited to the United
States. China, England, Panama, Paraguay and Sweden have also seen
dramatic increases in obesity over the past 10 to 20 years. Factors
associated with obesity include over-consumption of food, lack of
exercise, stress, neurotransmitters, eating disorders, genetics and
sedentary lifestyles. However, studies have shown that individuals with
reduced food intake and increased exercise eventually begin to regain
weight after the body's metabolism adjusts to the new conditions. The
irregular pattern of obesity does not appear to be completely
explainable based upon behavioral patterns, but may be compatible with
an infectious etiological model.

Col. Berry then presented such an infectious etiological model to
consider as it contemplates use of a demonstration project. Of seven
adenoviruses known to produce obesity in animals, four cause damage to
the central nervous system and three have been shown to cause obesity.
According to Col. Berry, preliminary evidence suggests that a peripheral
mechanism of action may exist. The SMAM-1 is an avian adenovirus that
produces obesity in chickens and is also associated with obesity in
humans. Human adenovirus-36 (Ad-36) has been shown to increase adiposity
and paradoxically reduce serum cholesterol and triglycerides in
chickens, mice and monkeys. Human studies have demonstrated that persons
with Ad-36 antibodies are heavier and have lower serum lipids. Other
research has shown that the prevalence of Ad-36 antibodies was 30% in
obese individuals in the United States and 22% in obese persons in
Australia. Only 10% of non-obese subjects in the United States were
found to be antibody-positive for Ad-36. In two pairs of twins who were
discordant for Ad-36 antibodies, the antibody-positive twins were
heavier and fatter than the antibody-negative twins.

According to Col. Berry, a retrospective study with rhesus monkeys used
an informational database of serum specimens similar to the AFHS
database. After seven years of measuring weight and drawing blood every
six months, all monkeys became Ad-36 positive. The weight decreased 0.04
kg in the year prior to seroconversion, but increased 1.8 kg from
baseline after seroconversion. Serum cholesterol increased \~5 mg/dL in
the year before seroconversion and decreased 35 mg/dL afterwards. Since
an injection of Ad-36 causes infection and weight gain in animals, an
ethical research design must be applied to demonstrate effects in
humans. The human study would test for Ad-36 antibodies to ensure that
no subjects had prior Ad-36 infection. The height and weight of the
eligible cohort would be measured to calculate BMI. Blood samples would
be taken every few years to identify subjects who acquired Ad-36
infection by natural means. Positive Ad-36 antibody tests would be used
to compare weight gain among infected and non-infected subjects.

According to Col. Berry, an Ad-36 research project on humans would
require several years after initiation, but data already gathered during
the AFHS could be used for the demonstration study. Laboratory data
could be reviewed to determine the height and weight of AFHS
participants and a small scraping of fresh frozen plasma specimens could
be tested. The study would be designed to assay for virus antibodies
from all AFHS time periods; correlate changes in weight, serum lipids
and other variables maintained in the database; and leave the AFHS data
intact for future studies.

The importance and benefits of an Ad-36 study would be significant for
various stakeholders. From a research perspective, the project will most
likely lead to an Ad-36 vaccine development program if the findings
conclusively demonstrate that Ad-36 causes obesity in infected persons.
From a military perspective, an Ad-36 vaccine could potentially prevent
or reduce obesity induced by Ad-36 among military personnel, improve
military readiness, reduce the cost of weight management programs funded
by the military, and decrease the need for taxpayer dollars to support
military health care costs directly related to obesity. From a societal
perspective, the study would positively impact the non-military
population since obesity is also a growing problem that affects a large
portion of adults and children in the United States. From an AFHS
perspective, the Ad-36 research project would be extremely rewarding to
participants because their data will be used to benefit other groups.
The study would also demonstrate the value of applying the AFHS
data/specimens to other health studies and increase the likelihood that
specimens will be maintained/preserved for use in the future studies
instead of being destroyed or eternally stored and forgotten.

Col. Berry announced that expertise has already been identified for the
Ad-36 demonstration project. Dr. Richard Atkinson, of MedStar Research
Institute, is a leading researcher in the field of Ad-36 and obesity. He
has expressed a willingness to design the study and collaborate with
USAF in implementing the demonstration project. SpecPro is an Alaska
Native corporation with a successful track record in obtaining
Congressional funding and has already requested support for the study
from Congress. SpecPro has an established relationship with the AFHS
through its history of coding AFHS data.

During discussions with members of the Brooks City-Base Institutional
Review Board (IRB), Col. Berry received favorable feedback on obtaining
approval of the study protocol for the Ad-36 demonstration project.
Additional support was being sought in the form of RHAC approval for the
USAF to proceed with the study.

Dr. Stoto made clarifying remarks to guide the RHAC discussion of the
proposal to use AFHS data for the Ad-36 demonstration project:

1.  As a scientific advisory committee, the RHAC members should only
    focus on the scientific merits of the proposal and not lobby for or
    against any particular study.

2.  The RHAC's role is limited to advising the HHS Secretary; and
    members should review the charter to compare the RHAC's charge to
    regarding its role with respect to the NAS's Congressionally
    mandated study on the disposition of AFHS data.

3.  The members should carefully consider whether the RHAC is now in a
    position to endorse, support or approve the Ad-36 demonstration
    project as the best mechanism for using the AFHS data in the future.
    In particular, several complex issues have not yet been resolved,
    such as informed consent, appropriate sample size, viability of the
    hypothesis, benefits beyond the military population, and the value
    of the study to the scientific community.

4.  The members should consider funding sources other than Congress in
    this effort. For example, specimens and other AFHS data could be
    made available to researchers to make a compelling and scientific
    case to the National Institutes of Health (NIH), other funding
    agencies and research organizations to support the Ad-36
    demonstration project.

Dr. Leffingwell requested additional details on the fraction of
scrapings from the AFHS specimens that would contain stored plasma. Dr.
Atkinson replied that the assays could be conducted with a minimum of
300 microliters of plasma, but 500 microliters would be ideal. If the
project is funded, however, an assay will be developed that will require
smaller quantities of plasma or serum in the range of 10-20 microliters.

Dr. Michalek expressed full support for the proposal, but he cautioned
the RHAC that actions must be taken prior to the termination of the
study on September 30, 2006. Civil service employees, military personnel
and contractors with a wealth of knowledge, experience and expertise in
the AFHS will not be available after the project is concluded. Informed
consent will also play an important role in the time-line of the study.
For example, two years were required to obtain questionnaire responses
from 600 AFHS participants. Dr. Michalek emphasized that the impending
termination date of the AFHS is becoming a source of anxiety in regards
to initiating any new research. The ability to apply the AFHS data to
another research project will be less realistic from a scientific
perspective if no actions are taken over the next few months.

Dr. Atkinson also commented on the short time-line in the context of the
suggestion to consider NIH as a funding source. NIH's grant application
deadlines are February 1, June 1 and October 1 of each year. If the RHAC
tables a decision on the Ad-36 demonstration project until its September
2004 meeting, a proposal could not be submitted to NIH until February 1,
2005 because the October 1 deadline would not be feasible. The proposal
would be reviewed in June or July 2005, but less than 20% of NIH grant
applications are approved in the initial review. Dr. Atkinson
acknowledged that a distinct possibility exists for the AFHS to be
terminated on September 30, 2006 before NIH approves the grant
application for the Ad-36 demonstration project. As a result, he agreed
that other agencies should also be considered as funding sources.

Mr. Maurice Owens, of Science Applications International Corporation
(SAIC), reported that the Veterans Benefits Act of 2003 directed the VA
Secretary to contract NAS or a similar entity to conduct a study on the
disposition of the AFHS data 60 days after the legislation was signed.
The awarded contractor would be given 120 days thereafter to produce a
report. According to this time-line, a report of the findings is due by
June 16, 2004 because the legislation was signed on December 16, 2003.
However, the VA Secretary has not formally contracted NAS to conduct the
study and has not allocated funds for this effort to date.

Dr. Camacho announced that he recently learned NAS maintains Science and
Technology Boards for both the Army and Air Force. Bruce Braun is the
Director of the Army Board and Michael Clark serves in this capacity for
the Air Force. Because Mr. Braun has expressed a great deal of interest
in housing the AFHS data, Dr. Camacho encouraged USAF to follow up on
this contact as a potential source. Dr. Stoto committed to contacting
Dr. Rick Erdtmann, the new Director of the Medical Follow-Up Agency. The
agency is housed in the NAS and maintains databases of veterans' health
for epidemiological studies.

Several RHAC members endorsed and expressed support of using the AFHS
data for the Ad-36 demonstration project as proposed by Col. Berry.
Based on comments by the members during the discussion, Dr. Stoto
confirmed that the RHAC will take the following actions. First, Dr.
Stoto will draft a letter on behalf of the RHAC to HHS Secretary Tommy
Thompson, with a copy to VA Secretary Anthony Principi and Congressional
staffers. Several points will be covered in the letter. USAF made a
presentation to the RHAC on potentially using the AFHS data for an Ad-36
demonstration project. The members agree that the proposal is extremely
promising, but the RHAC is not in a position to make a judgment about
the project, due to its role as a federal advisory committee. Congress
has asked NAS to conduct a study on the disposition of AFHS data, but no
funding has been provided for this effort to date. The RHAC urges the
HHS Secretary to communicate with the VA Secretary to allocate the funds
soon. The draft letter will be circulated to the RHAC membership for
review, comment and approval, finalized and placed on FDA/NCTR
letterhead to be forwarded to the HHS Secretary. \[Following the
meeting, Dr. Stoto determined that it would be more appropriate to
invite Secretary Principi to send a representative to the September
meeting to discuss these issues. A copy of that letter is attached for
the committee members' information.\]

Second, the RHAC charter, NAS charter and other relevant briefing
materials will be distributed to the members prior to the next meeting
to assist the RHAC in its decision-making on the proposal for the Ad-36
demonstration project. Third, efforts will be made to invite an NAS
representative to the next meeting to provide an update on the AFHS
disposition study. The speaker will be asked to discuss funding to
maintain the AFHS samples, necessary staff and other relevant issues.

Dr. Stoto announced that the remainder of the meeting would be devoted
to RHAC's first of three chapter reviews from the AFHS physical
examinations in 2002. RHAC will primarily focus on background chapters
during the first round and will review results chapters during the
second and third rounds. Due to time constraints, he asked the members
to limit the discussion to substantive issues and submit written
editorial comments to Lt. Col. Julie Robinson of the USAF.

Drs. Trewyn and Camacho were charged with the review of Chapter 1. Their
comments along with recommendations by other RHAC members are outlined
below.

> • Clearly describe the composition of the comparison group in Table
> 1-1 to differentiate between dioxin and herbicide exposures.
>
> • Add language on line 95 to emphasize that an unexpected result of an
> increased risk of cancer with years spent in Southeast Asia (SEA) was
> found in the comparison group.
>
> • Provide a breakdown of countries in Vietnam versus other locations
> where the comparison group served.
>
> • Consider the possibility of using AFHS specimens from the 2002
> physical examination to identify potentially significant health
> problems associated with exposure to non-dioxin-contaminated
> herbicides.
>
> • Provide resources for the lay audience since the report is written
> at a highly technical level primarily for epidemiologists, clinicians
> and biostatisticians. For example, create a bibliography, develop a
> glossary of terms, and include a standard one-page summary at the
> beginning of each substantive chapter to explain that the definition
> of dioxin is "TCDD" and four different statistical methods were used.
> Use the "Introduction to Epidemiology" bibliography developed by Dr.
> Stoto as a resource in this effort.
>
> • Incorporate text to reassure readers of the scientific integrity of
> the AFHS by describing quality control procedures, peer review and
> other actions that were taken.
>
> • Insert new text into Section 1.1 to address concerns that may be
> raised by veterans, advocates and other interested groups in the
> future. For example, add language to document that the statistical
> models have been historically used and were also utilized in the AFHS
> for comparison purposes. Include a statement to explain that several
> findings on the comparison group were only recently discovered and the
> new information will be published in the future, such as years in SEA
> as a risk factor for cancer in the control group and no correlation
> between years in SEA and diabetes. Mention that the new publications
> are funded with AFHS dollars. Repeat the new text in the "Future
> Directions" chapter and also cite the web site that lists the upcoming
> AFHS publications.

Dr. Michalek made follow-up remarks to the RHAC's comments on Chapter 1.
The existing AFHS database cannot be used to develop an exposure index
for non-dioxin-contaminated herbicides because day-to-day exposure
records were not available in 1977 when AFHS was designed. The herbicide
tapes are not specific to a particular base or individual. However, new
and more detailed information with the actual date and base where an
individual was stationed during the Vietnam War has been gathered. The
data are currently being maintained by Dr. Jeanne Stellman of Columbia
University and can be used to develop an exposure index for
non-dioxin-contaminated herbicides for the first time. Because the new
information is being used to study Army ground troops rather than Ranch
Hands, Dr. Michalek is attempting to stimulate a discussion with Dr.
Stellman about the benefits of applying these valuable data to the AFHS.

With respect to developing new material for the lay audience, Dr.
Michalek explained that major revisions to the chapter format or any
other changes in the scope of work will need to be considered and
discussed by Program Management. He reminded RHAC that USAF is
developing the report under a contract with SAIC.

Dr. Hassoun was charged with the review of Chapter 2 and Appendix A. Her
comments along with recommendations by other RHAC members are outlined
below.

> • Include a reference to inform readers that a detailed description of
> the method used for the serum dioxin assay can be located in the 1986
> paper by Patterson published in *Annals of Chemistry*.
>
> • Add a sentence to explain that Figure 2-4 illustrates no body burden
> among controls and a body burden among Ranch Hands, which suggests
> exposure to Agent Orange during years in Vietnam.

Dr. Trewyn was charged with the review of Chapter 3; his comment is
outlined below.

> • Change the sentence on line 39 to "All participants were asked
> questions to update their medial histories since their last interviews
> and were reminded of information already reported."

Dr. Johnson was charged with the review of Chapter 4 and Appendix B. His
comments along with recommendations by other RHAC members are outlined
below.

> • Add a statement to clarify that all internists referenced in the
> report are "Board Certified Internists."
>
> • Change "internist with subspecialty in pulmonary disease" in Table
> 4-1 to "pulmonologist" to be consistent with "radiologist" and
> "dermatologist."
>
> • Revise Table 4-2 as follows: change "differential segs" to
> "segmental neutrophil;" change "cubic micra" to either "cubic
> micrometer" or "micron;" change "differential lymphs" to "differential
> lymphocytes;" place "absolute" in the left column under "T & B
> lymphocytes" with the list of other absolutes in the right column; and
> reformat the list of 137 laboratory tests to be consistent with the
> list of 83 laboratory tests in Appendix B.
>
> • Include a statement to confirm that the physical examinations were
> properly administered despite errors in the *Examiner's Handbook*.
>
> • Add language to clarify that the *Examiner's Handbook* was provided
> to SAIC and Scripps Clinic clinicians for guidance only; clinicians
> were actually trained in administering physical examinations with the
> biomedical test plan developed by SAIC. Include the biomedical test
> plan in Chapter 4 or reference the web site where the document can be
> located.
>
> • Add language in parenthesis to the "chemistry" table on line 38 to
> explain whether the rapid plasma reagent card test, fluorescent
> treponemal antibody absorption test or both were conducted to detect
> syphilis.
>
> • Expand "additional QC included the following elements" on line 63 to
> clearly describe standardized data and other quality control
> procedures clinicians used to verify results of the physical
> examinations. Include forms the clinicians used in Appendix B.
>
> • Add language to clarify and expand on the following sentences:
> "Alcohol was prohibited for 24 hours before the first day of the
> examination" on line 86; "They were paid their stipends and reimbursed
> for travel at this time" on line 105;" and "On the first examination
> day, participants were asked to collect their first urine void of the
> day at the hotel" on line 107.
>
> • Change the sentence on line 121 to "the Air Force was provided 35 cc
> of serum and 10 cc of whole."

Dr. Leffingwell was charged with the review of Chapter 17 and Appendix
F-9. His comments along with recommendations by other RHAC members are
outlined below.

> • Clarify the "Statistical Methods" section with the following
> statements. Scheffe's method or a similar procedure is appropriate for
> a restricted setting, but is not suitable for the AFHS. A multiple
> comparison procedure is best used in a control clinical trial where
> primary endpoints and contrasts with placebo and control groups are
> required. Rothman and other current textbooks argue against using the
> Bonferroni method.
>
> • Reformat Table 17-3 to illustrate positive findings only and place
> the remainder of the extensive analysis that shows no significant
> associations in an appendix or newspaper column.
>
> • Provide percentages for the "born \<1942 or [\>]{.underline}1942\"
> dependent variable-covariate associations to illustrate the
> significant correlation with blood urea nitrogen.
>
> • Replicate Dr. Leffingwell's "Table of Significant Results" in
> substantive chapters where numerical differences substantially add
> values beyond the p value. Create the tables as a separate handout or
> supplement to the major report.
>
> • Revise line 247 as follows. Add language to clarify that the text
> refers to an empiric formula estimating creatinine clearance and is
> not an actual calculation. Include a citation to reference that the
> actual formula is from Cockroft-Gault.
>
> • Revise lines 369-373 to note that age and weight may provide a
> different adjustment or additional information to estimate 24-hour
> creatinine generation or excretion as an independent variable. Tabular
> data suggest a positive correlation between race and weight or age.
>
> • Correct the "Cockroft-Gault (52, 53)" citation on line 1088; the
> "References" section lists 52 and 53 as Coresh and Lam, respectively.
>
> • Change the sentence on line 1096 to "The AFHS cutpoints for
> hematuria and pyuria (two cells per HPF) will miss few cases of
> disease, but may cause inclusion of more healthy subjects that would
> result in higher numbers."

Dr. Johnson was charged with the review of Chapter 9 and Appendix F-1.
His comments along with recommendations by other RHAC members are
outlined below.

> • Revise the "Study Summary Results" throughout the chapter because
> these sections are filled with various facts and are difficult to
> read. Include language to explain that the summaries were extracted
> from previous reports.
>
> • Clearly define the terms "direct," "positive," "inverse" and
> "adverse" in the "Results" section.
>
> • Create a boilerplate with standard language to incorporate into each
> clinical chapter.
>
> • Revise the tables to highlight significant p values in bold.
>
> • Incorporate more text into the description of each model to clarify
> the following terms: "Ranch Hands-Initial Dioxin-Unadjusted,"
> "analysis results for log~2~ initial dioxin," "adjusted relative
> risk," "adjusted for BMI," "relative risk for a twofold increase in
> initial dioxin," and "the p value is 0.314 for adjusted relative
> risk."
>
> • Change the sentence on line 150 to "Apart from the AFHS
> examinations, only a few published reports other than those described
> above relate clinical laboratory indices to serum and adipose dioxin
> levels."
>
> • Add "(\>20 mm/hr)" after "erythrocyte sedimentation rate
> abnormalities" on line 168, but delete the phrase in the remainder of
> the chapter to avoid redundancy.
>
> • Add text on line 181 to further explain "the (geometric) mean
> erythrocyte sedimentation rates did not differ significantly."
>
> • Change the sentence on line 215 to "In general, body fat and
> erythrocyte sedimentation rate exhibited significant direct
> associations with initial dioxin."
>
> • Change the sentence on line 234 to "In summary, with the exception
> of erythrocyte sedimentation rate, the data analyzed in the general
> health assessment did not reveal any direct association between
> adverse health effect and herbicide exposure or to body burden of
> dioxin."
>
> • Change the sentence on line 270 to "Longitudinal analyses showed
> that Ranch Hands, particularly the two enlisted strata, had a higher
> percentage of abnormal erythrocyte sedimentation rates relative to
> comparisons."
>
> • Change the sentence on line 273 to "This increased occurrence of
> elevated erythrocyte sedimentation rates in Ranch Hands raises the
> possibility of a subtle inflammatory, infectious or occult malignant
> disease process associated with the body burden."
>
> • Include language to explain that "erythrocyte sedimentation rate" is
> not mentioned again after line 281 because the section was moved from
> the "General Health" to "Hematology" chapter in the 2002 physical
> examinations.
>
> • List the "dependent variables" on line 285.
>
> • Move "weight/(height)^2^\" on line 305 to the end of the sentence on
> line 306.
>
> • Move "(118)" on line 309 to the end of the sentence on line 310.
>
> • Incorporate text at the beginning of the "Dependent
> Variable-Covariate Associations" section to explain the rationale for
> the sentence on line 389: "The highest percentage of participants who
> perceived their health as fair or poor was among nondrinkers." Clarify
> that this association was summarized rather than studied due to its
> importance in interpreting other results.
>
> • Change the sentence on line 432 to "Model 2 explored the
> relationship between the dependent variable and the initial dioxin
> level at the time of potential exposure to dioxin when they began as a
> Ranch Hand."
>
> • Change the sentence on line 443 to "Model 3 created categories of
> Ranch Hands based on the initial dioxin levels and examined the
> relation between the dependent variables and these categories."
>
> • Add more descriptive language to the titles of all models in the
> tables, such as "Self-Perception of Health of Ranch Hands Versus
> Comparisons Unadjusted for Covariates" on line 476 and
> "Self-Perception of Illness in Ranch Hands Versus Initial Dioxin
> Unadjusted for Covariates" on line 478.
>
> • Replace "0.10\" with "0.05\" on line 517 to be consistent with the
> remainder of the report and emphasize the "minimum p value."
>
> • Change the phrase on line 760 to "helped to clarify."
>
> • Change the sentence on line 773 to "However, during the course of
> the AFHS since 1982, self-perception of general health has shown mixed
> results."
>
> • Change the sentence on line 782 to "Officers more often perceived
> their health to be in the "excellent" or "good" categories" to clarify
> that the variation was across subjects and not over time.
>
> • Change the term on line 784 to "various levels of education."
>
> • Revise the text beginning on line 796 to distinguish between the
> entire longitudinal study and the 2002 physical examination only.
>
> • Make the following changes to clearly differentiate between other
> studies or prior follow-up examinations: "a finding similar to results
> reported in earlier phases of this study" on line 802 and "These
> results are generally consistent with earlier phases of this study" on
> line 818.
>
> • Change the sentence on line 847 to "Therefore, more than one-third
> of AFHS participants are at risk for health complications associated
> with obesity." Delete "significant" since the finding was not
> statistically evaluated and has no p value.

Dr. Camacho was charged with the review of Chapter 6 and Appendix D. His
comments along with recommendations by other RHAC members are outlined
below.

> • Incorporate language to clarify that the National Opinion Research
> Center (NORC) specifically developed and designed the
> computer-assisted personal interview system for the AFHS.
>
> • Add another down arrow to Figure 6-2 to illustrate the exit.
>
> • Include a statement in the "Data Completeness Checks" section to
> note that physicians performed the majority of quality control
> measures while participants were at Scripps Clinic, but participants
> were asked to return if necessary.
>
> • Change the sentence on line 130 to "NORC schedulers telephoned the
> 15 participants who should have been asked these questions, but were
> not to collect that information."
>
> • Use either lower case or capital letters to make the following
> titles consistent throughout the chapter: "field manager," "data
> collection task leader," "interviewer," "Air Force researchers" and
> "NORC designers."
>
> • Add language in Appendix D-1 to clarify that lower numbers mean
> better quality control. Include sentences to explain that "high,"
> "medium" and "low" refer to a laboratory quality control measure in
> which manufactured specimens are used to calibrate equipment.
>
> • Revise "No participants felt that the experience was unsatisfactory"
> on line 193 to more strongly emphasize the overall clinic experience.

At the conclusion of the first round of chapter reviews, Dr. Stoto
suggested that the two drafts for each chapter be clearly indicated in
the future with "Draft 1\" or "Draft 2\" in the footer of the document.
The RHAC also agreed that a global change should be made throughout all
chapters by revising tables to replace phrases with complete descriptive
sentences. Overall, the RHAC acknowledged the tremendous effort that has
been devoted to the AFHS and commended USAF and SAIC for developing a
well-written and evidence-based report.

The Chair called for public comments; no attendees responded.

Dr. Stoto announced that the RHAC will conduct its review of the second
set of chapters during the September 2004 meeting; those chapters will
address psychology, hematology, immunology, cardiovascular disease, and
study selection participation/statistical methods. If time permits, the
endocrine chapter may be included in this round as well. For the second
cycle, Drs. Stoto and Camacho will review the statistical methods
chapter and Dr. Hassoun will review the psychology chapter. Ms. Kimberly
Campbell, the Committee Management Specialist, will circulate an e-mail
to the RHAC requesting the expertise of each member. A roster will be
developed based on this feedback to assist Dr. Stoto in assigning
chapters to members for the second review.

Dr. Trewyn suggested that before the RHAC reviews the cancer chapter,
the USAF should revisit this section to determine whether a
statistically significant health effect is present if the comparison
group is divided by personnel stationed in-country versus those
stationed out of country. Dr. Michalek confirmed that new findings to
address this issue will be incorporated into the cancer chapter and will
also be published soon. The new unpublished data show that an SEA effect
on birth defects and diabetes was not seen in the control group.
However, presence in Vietnam was found to be a risk factor for cancer in
the control group and an extremely strong effect on the incidence of
cancer was seen.

Dr. Stoto advised USAF to list the upcoming publications with the new
findings in both the literature review and discussion sections of the
report. Dr. Camacho urged USAF to take proactive measures in addressing
concerns that may be raised by the community in the future. For example,
the report could be revised to clarify that effects on birth defects and
diabetes were not seen when personnel stationed in country and those
stationed out of country were maintained as one comparison group.

Dr. Michalek summarized the RHAC charter in preparation for the members
to make a decision during the next meeting on the proposal for the Ad-36
demonstration project. The charter states that the Assistant to the
President for Domestic Policy directed the establishment of an
interagency workgroup in December 1979 to study possible long-term
health effects. The interagency workgroup recommended that USAF conduct
the study in August 1980 and RHAC was formed in 1981.

The RHAC is charged with advising the Secretary and Assistant Secretary
for Health about the oversight and conduct of the AFHS and providing
scientific oversight of the VA Chemical Corps Vietnam Veterans Health
Study and other studies in which the Secretary or Assistant Secretary
for Health believes involvement by RHAC is desirable. In addition to the
RHAC's purpose and structure, the charter also outlines appropriate
members to serve on RHAC; suitable qualifications of both the Chair and
members; frequency and structure of meetings and public sessions; and
honoraria, meeting minutes and the expiration date.

The next RHAC meeting is tentatively scheduled on September 22, 2004;
several members had a conflict with the date of September 8, 2004 that
was proposed during the previous meeting. NCTR will poll the members by
e-mail to confirm the new date.

With no further discussion or business brought before the RHAC, Dr.
Stoto adjourned the meeting at 12:59 p.m.

I hereby certify that to the best of my knowledge, the foregoing Minutes
of the proceedings are accurate and complete.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Michael Stoto, Ph.D. Date

Chair

Ranch Hand Advisory Committee

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leonard M. Schechtman, Ph.D. Date

Executive Secretary

Ranch Hand Advisory Committee

\*\*\*\*\*\*\*

Complete details of the topics and discussion points addressed by
members of the RHAC and summarized in these minutes are available from
the transcript of the RHAC meeting
[www.fda.gov/ohrms/dockets](http://www.fda.gov/ohrms/dockets) and select
advisory committees.

\*\*\*\*\*\*\*