Approval of Previous
Meeting Minutes. Dr. Leonard
Schechtman, the RHAC Executive Secretary, confirmed that the November 14-15,
2001 meeting minutes were distributed to the members, revised based on RHAC’s
comments, and approved and finalized with the Chair’s signature. The March 13, 2003 meeting minutes were
circulated to the members for review and comment; NCTR is now seeking RHAC’s
approval on this document as well.
Dr. Stoto expressed
concerns about the process of generating meeting minutes. He suggested that draft minutes be made
available to the committee members in a more timely manner. He explained that, in his opinion, rather
than the meeting minutes being a condensed version of a verbatim transcript, it
was preferable to have the document summarize the essence of the deliberations,
organize presentations and discussions by subject, and highlight key
decisions.
Dr. Schechtman indicated
that actions had already been taken to address these issues and that a new
science writer had been contracted to produce verbatim transcripts, to work
with NCTR in developing quality minutes, and to provide those minutes to the
members more promptly. Regarding the
minutes of the previous March 13, 2003 meeting, the RHAC members agreed to
submit their comments and editorial changes to the draft distributed previously
via email, as requested by Dr. Schechtman.
RHAC Membership. Dr. Schechtman informed the committee members of attempts to
obtain a special exception to DHHS policy that limits the service of advisory
committee members, pointing out that the language in the original 1981 charter
stated that members would be invited to serve for the duration of RHAC. Furthermore, he asserted that because of the
approaching (September 30, 2006) termination of the Ranch Hand Study (RHS), the
RHAC efforts that would be involved in completing it’s review of the study
results would be most efficiently carried out if the committee remained intact
with its current knowledgeable, experienced membership. He stated that the significant turnover in
membership at this time could very likely impose a hardship on the efforts of
the RHAC that could jeopardize its efficiency and productivity and impede the
review process as it moves towards closure and resources are no longer
available.
Despite this reasoning, Dr.
Schechtman regrettably announced that the Department had rejected the waiver
request for Drs. Gough and Harrison because both of these members have served
on RHAC for periods that far exceeded the limit imposed on currently allowable
advisory committee terms of service.
However, Dr. Schechtman was pleased to report that DHHS had approved
additional two-year terms for Drs. Camacho, Osei and Sills from February 1,
2004 through January 31, 2006. These
three members have not exceeded the limit on advisory committee terms as
outlined in DHHS policy. In consideration
of his experience on the committee and his familiarity with the RHS, Dr. Stoto
was requested to replace Dr. Harrison as the RHAC; Dr. Stoto has accepted the
position.
Because the attempts at
obtaining a waiver approval were unsuccessful, nominations for new members were
forwarded to DHHS on November 20, 2003.
The two nominees who will fill the vacancies left by Drs. Gough and
Harrison are Dr. Ezdihar Hassoun, University of Toledo and Dr. David Johnson,
Florida Department of Health; they are currently awaiting confirmation.
Dr. Schechtman reminded the
members that he had circulated an e-mail message to RHAC on November 19, 2003
to inform them of these events regarding committee membership. He thanked Drs. Gough and Harrison for their
exceptional efforts and valuable input while serving on RHAC and noted that
they and their energies will be sorely missed.
He confirmed that at a later date, DHHS will formally acknowledge the
outstanding contributions of the two members with a letter of recognition and
plaque.
Dr. Judson Miner, Research
Director of Operational Technologies Corporation, covered the following items
in his status report. First, a contract
will be awarded to the University of California-Davis to continue with adipose
tissue studies and glucose transport mechanism studies. Second, Program Management has received its
budget authority and is not under a continuing resolution. Third, Science Applications International
Corporation (SAIC) is satisfactorily fulfilling the terms of its contract by
revising draft health study chapters based on U.S. Air Force (USAF) comments
and delivering the documents to Program Management on a timely basis. Dr. Miner confirmed that initial draft
chapters with USAF comments, resolved comments and final draft chapters will be
distributed to RHAC for review.
Dr. David Butler, Senior
Program Officer of the National Academy of Sciences (NAS) Institute of Medicine
(IOM), explained that NAS was chartered by Congress in 1863 to serve as an
independent non-governmental institution and advise federal agencies on
scientific issues. IOM was chartered
under NAS in 1970 to specifically focus on medical and public health
issues. To fulfill its charge, NAS
developed a rigorous study process. The
NAS Governing Board Executive Council must review and approve each study. A
committee of volunteer experts is formed to prepare reports based on findings
from literature reviews, public hearings, workshops, written testimony and
other information. Final reports must
undergo external peer review before being publicized.
With respect to veterans’
health, the Agent Orange Act of 1991 instructed the U.S. Department of Veterans
Affairs (VA) Secretary to contract with NAS to conduct research on Agent Orange
related issues. In fulfilling this
mandate, NAS has produced ten exposure assessments and herbicide health effects
reports among Vietnam veterans since 1994.
These studies are available to the public on the National Academies
Press web site. The most recent effort
by NAS related to Vietnam veterans is the Veterans Benefits Act of 2003 that
was signed into law in December 2003.
The new legislation requested that the VA Secretary contract NAS to
conduct a study on the disposition of the RHS; the language also contained five
elements for NAS to address in this research.
First, the scientific merit
of retaining and maintaining medical records, laboratory specimens and other
RHS data beyond the termination date of the RHS in 2006 should be
evaluated. Second, privacy concerns of
veterans, informed consent and other potential barriers to retaining and
maintaining RHS data should be noted.
Third, the need to provide independent oversight of RHS data should be
assessed and a mechanism to provide the oversight, if appropriate, should be
developed. Fourth, the need to extend
the RHS should be evaluated in terms of its potential value, relevance, cost
and the best entity to continue the research.
Fifth, the feasibility of making RHS data available for independent
study should be assessed in terms of the potential value, relevance and cost of
the research.
Dr. Butler pointed out that
the RHS disposition study is speculative at this point because the NAS
Governing Board has not yet approved the project. However, the project is expected to be approved and NAS will then
sign a contract with the VA. A study
protocol and time-line that are consistent with the VA’s Congressional mandate
will be negotiated and outlined in the contract. NAS will then follow its standard study process by forming a
committee, holding public meetings, and gathering information from RHAC, the
VA, veteran service organizations, individual veterans and other interested
sources. NAS will also post progress
reports about the study on its web site.
Several RHAC members noted
issues for NAS to consider while the RHS disposition study is being
conducted. Dr. Gough advised NAS to
consult with the National Institutes of Health (NIH) National Institute of
Aging (NIA). Because the RHS is the
longest and largest longitudinal study of racially-mixed males ever conducted,
NIA will be extremely interested in the disposition of these data. Dr. Stoto added that other NIH institutes
will also be interested in the RHS since the research has led to important
findings on the environment, diabetes and other issues. He urged NAS to publicize the potential
availability of the RHS data and materials to NIH and the broader scientific
community. These agencies can serve as
funding sources for scientists to explore additional research in the
future. Overall, Dr. Stoto remarked
that RHAC will be pleased to provide input to and interact with NAS on the RHS
disposition study.
Dr. Trewyn suggested that
NAS consider Drs. Gough and Harrison as either members of the RHS disposition
study committee or resources in other areas of the project due to their
extensive service on the RHAC and wealth of knowledge about the RHS. Dr. Osei inquired whether NAS will provide
an opportunity for other private institutions to compete in conducting the RHS
disposition study. Dr. Butler clarified
that the only role that NAS will play in the project will be to provide advice
on the disposition of the RHS by addressing the five elements outlined in the
legislation. In general, NAS neither
conducts primary research nor provides funding to support studies performed by
other institutions. However, NAS may
consider a role for organizations to manage RHS samples and other data.
Dr. Harrison acknowledged
that NAS will need to address some important issues during the RHS disposition
study. First, in research projects that
must protect human subjects, obtaining consent from study participants to
utilize samples and other materials after the data have been collected is often
a challenge. Most notably, the
rationale for maintaining data is difficult for many subjects to understand in
retrospect. Second, no technology has been developed to date to maintain
biological samples for an indefinite period of time. The RHS disposition study committee should be mindful of this
issue during its deliberations. Dr.
Joel Michalek, the RHS Principal Investigator, added that >90% of RHS
participants expressed a willingness for their data to be maintained for future
research purposes. Overall, Dr.
Harrison was pleased that NAS was asked to review the RHS and provide sound
scientific guidance on the disposition of data.
Dr. Butler agreed that
these issues are extremely important and will be considered by NAS. To assist in this effort, experts in the
fields of bioethics, long-term management and maintenance of biological
samples, and treatment of human subjects and materials will be asked to
participate in the RHS disposition study.
Dr. Michalek summarized
several components of the RHS to inform RHAC of recent findings.
Serum Dioxin and Four
Biochemical Parameters of Adipose Tissue. Dr. Michalek announced that the study takes an unprecedented
molecular epidemiologic approach and represents the first research on dioxin
and gene expression in humans. The study
is designed to understand whether dioxin is adversely associated with one or
more components of the biochemical pathway leading to diabetes mellitus. The research is based on data collected
during the 1997 physical examination.
Following a factorial design, 650 subjects who were compliant at the
cycle 4 examination in 1992 were randomly selected and asked to provide 12
grams of adipose tissue by liposuction at the cycle 5 examination in 1997. Of the 650 invited subjects, 313 volunteered
and provided specimens.
The original sample size
was reduced due to refusals, insufficient body fat, medications being taken,
medical deferments and an inability to schedule subjects. Body fat, age and diabetic status were used
as criteria to select subjects, while glucose transporter 4 (GLUT4), C-SRC, NFκβ
and C/EBPα were the biochemical parameters measured in the study. The median age of subjects at the baseline
examination was 42 years. Subjects
participating in the 1995 examination were classified as either diabetic or
non-diabetic. However, the diabetic
status of several subjects was reversed in this study to be consistent with the
change in the American Diabetes Association’s (ADA) definition of “diabetic” in
2002. GAPDH was used as a
“housekeeping” gene for normalization to remove the effects of obesity on
messenger RNA.
The study showed the following results. A significant increase was seen in GLUT4
expression among lean non-diabetics in the comparison group, but this change
was not seen in the Ranch Hand group.
GLUT4 increased with dioxin load among lean diabetics in the Ranch Hands
group. Diabetic status was an important
factor and influenced the value of measurements. Log transform values were negatively correlated with percent body
fat at the time of adipose tissue sampling.
This finding suggested that fat droplet size affected messenger RNA
yield. The transformed GAPDH level was
not significantly different between diabetics and non-diabetics. This result indicated that GAPDH would not
introduce artifacts related to diabetes if the gene was used to normalize
others.
Interactions prevented
simple interpretations and an analysis of main effects. The small sample size of 313 subjects did
not allow for a detailed path analysis.
Path analyses are generally used for large data sets >1,000 subjects. Because
a separate path is made and applied to the comparison group. This method would have reduced the cohort to ~120 subjects. Replicating the study with a different
cohort is not possible. Error terms and
other important parameters were not measured, but the study does account for
medications and several other risk factors.
The study contained
complete data for each subject, was performed under strict quality control and
implemented solid follow-up procedures.
The data suggest that dioxin may disrupt the normal diabetic pathway
through an interaction with GLUT4, but additional research is needed to
understand the complex regulatory mechanism of diabetes and other
pathways. The study is currently being
prepared for journal publication.
Dr. Gough pointed out that
the study is based on animal data, but biochemical animal research with dioxin
is performed at much higher doses than those used in human studies. He inquired about the study’s ability to extrapolate
from animals to humans and also questioned whether the complex methods and
analyses will be informative. Dr.
Michalek explained that the study animals were exposed to small dioxin doses of
<0.10 µg/kg/body weight because these ranges were compatible to those
received by Ranch Hands in Vietnam.
Dr. Stoto remarked that the
study provides valuable information in further understanding the causes of
diabetes. However, he strongly
emphasized the need to clearly delineate potential biases in the discussion
section of the paper. For example, the
study reflects complete data only for obese subjects who were not taking
medication. The study also does not
contain a sufficient sample of subjects with high dioxin levels to determine
whether the outcome would have been different.
Moreover, issues related to sample selection may complicate the
interpretation of the findings, which are essentially third-order interactions.
Dr. Osei expressed concern
about the reversals in diabetic status from 1995 to 2002. For example, the data show an increase in
GLUT4, but the gene expression should actually decrease if dioxin produces
diabetes. Exercise, medications or
other variables that influence GLUT4 levels are most likely the cause for the
change in diabetic status rather than the new 2002 ADA definition. He advised the investigators to consider
these factors before conducting pathway analyses.
Dr. Harrison encouraged the investigators to make an
additional correlation in the future. Intracellular feedback mechanisms lead to
changes in messenger RNA levels that reflect changes in protein transcription
or protein levels. The mechanisms then
influence GLUT4 and reduce activity of the gene. He suggested that the investigators review E-Cell, a computer
simulation of glucose metabolism in cells, because the technology may serve as
an innovative and non-statistical mechanism to analyze data. Dr. Michalek confirmed that this issue has
been addressed. A code was written to
run a feedback loop from GLUT4 to PBF and from C/EBPα and NFκβ.
Cancer Prevalence in Comparisons. Dr. Michalek reported that the study focused on an unexpected
trend in the comparison group discovered while assessing cancer incidence among
Ranch Hands. The data showed that
cancer prevalence is adversely related to years of service in Southeast Asia
(SEA) and is not related to dioxin or Agent Orange. Cancer prevalence was determined through December 31, 1999; all
cases were confirmed by record review.
The comparison group included persons who were fully or partially
compliant with any of the five physical examinations. Time to onset was measured from the end of the last SEA tour to
the earliest occurrence of cancer, death or end of follow-up. Cancers that occurred within 15 years of the
last SEA tour were not considered.
All cancer definitions used
in the study were prescribed by the National Cancer Institute Surveillance
Epidemiology End Results (SEER). The
all-site SEER category includes all SEER
cancers. Proportional hazards models were used throughout the study. All-site, respiratory, prostate, digestive
system, and basal and squamous cell cancers were adjusted with specific risk
factors, such as year of birth, race, military occupation, skin reaction to
sunlight, eye color and pack-years of smoking.
Of the 1,785 persons in the cohort, ~50% spent <2.1 years in
SEA. Older age and smoking were
strongly associated with increased years in SEA.
The study showed the
following results. The risk of all-site
SEER, digestive system and prostate cancers significantly increased in the
comparison group based on increased years in SEA. No significant trends were seen for other cancers. The increases appeared to be unrelated to
exposures to dioxin or dioxin-contaminated herbicides. The underlying cause is unknown because no
biomarkers were measured except dioxin; detailed exposure histories are not
accessible; and information on tour locations is not available at this
time. However, the exposures may be
related to water, food or other environmental media, insecticides or other
chemicals, tropical diseases or medications.
A database is currently
being developed to pinpoint the exact locations and dates of SEA tours from
1942-1982. Removal of the 15-year
latency period from the data analysis resulted in increased statistical
significance. Record reviews were
conducted to verify all outcomes and determine dates of cancer onset. The study was performed under rigorous
quality control and will soon be submitted
to a journal for publication.
Dr. Stoto noted the
significant difference in smoking among persons with long and short SEA
tours. On the one hand, the study found
digestive and prostate cancers to be significant, but these sites are not
generally associated with smoking. On
the other hand, a weak trend was seen for respiratory cancer, but this site is
related to smoking. He raised the
possibility of combining cancer sites that are most strongly associated with
smoking to confirm these outcomes.
Dr. Leffingwell suggested that efforts be made to
correlate cancers and sexually transmitted diseases received during Vietnam
tours, such as prostate cancer and human papilloma virus or gonorrhea and
hepatitis B and C. The analysis should
be thoroughly considered, particularly if the liver is the site in the
digestive system with a high rate of cancer.
Dr. Marian Pavuk, an RHS investigator with SpecPro, Inc., reviewed the
literature on this subject. He reported
that of 26 digestive system cancers, one case of liver cancer, six cases of
colon cancers, nine cases of rectum-to-stomach cancers, and three cases of
pancreatic cancers were identified. Due
to the small number of cases, the study could not definitively conclude that an
unusual distribution of digestive system cancers occurred.
Dr. Gough indicated that
efforts to correlate exposures to cancer excesses may be overwhelming since 25%
of the population develops the disease and the cause is very rarely
identified. Dr. Trewyn noted that
chlordane was heavily used in SEA during the Vietnam War and may be related to
the increased cancer risk. Dr. Pavuk
mentioned that blood samples and other stored specimens may be analyzed for the Ranch Hands and comparison veterans to
determine whether DDT, DDE, pesticides or other organochlorine compounds used
in SEA are associated with the cancer trend observed in the study.
Cancer in Air Force
Veterans of the Vietnam War. Dr. Michalek
conveyed that the period of risk in the study was from end of service in SEA to
December 31, 1999. All study outcomes
were confirmed by record review, International Classification of Disease codes
and SEER category definitions. The data
were analyzed in two parts. The
external analysis focused on cancer incidence and mortality versus SEER rates for
U.S. males, while the internal analysis focused on prevalence by dioxin category. To isolate years in which Agent Orange was
most heavily sprayed, both the external and internal analyses were stratified
by presence or absence in Vietnam, amount of time spent in SEA and actual years
in Vietnam.
In the control group, the
data showed a trend and a median of two years in SEA. All-site SEER cancer, melanoma restricted to whites, and prostate
cancer were the covariates used the study.
When the data were stratified according to time served in SEA (with 2
years as the cutpoint), many Ranch Hands who were in SEA 100% of the time were included in the sample. The external sample of 2,965 excluded all
persons with cancer before or during tours of duty, while the internal sample
of 2,438 excluded all persons with a missing dioxin measurement. The study was restricted to whites to allow
a comparison with national rates.
Compared to national rates, significant increases were seen in prostate
cancer and melanoma. Close follow-up at
Scripps Clinic in which Ranch Hands were examined by a dermatologist and doctor
of internal medicine were suggested to account for the apparent increases
observed.
To resolve this issue,
efforts were made to identify cancers that were detected as a direct result of
physicals at Scripps Clinic. A review
of these data showed that Scripps Clinic physicals were responsible for four of
17 melanomas and some cases of prostate cancer in the comparison group. In the period of heaviest spraying, an
increase was seen in prostate cancer among Ranch Hands and controls who were in
SEA during that time. An increase was
seen in melanoma only among Ranch Hands during the Agent Orange period. Using an analysis of Ranch Hands with 100%
of SEA service in Vietnam and controls with 0% time in Vietnam (100%-0%
analysis), standardized incidence ratios (SIRs) for both prostate cancer and
melanoma increased even though the sample size decreased. The dioxin category was analyzed only for
persons who were in SEA <2 years because the data showed that years in SEA
was statistically a confounder.
Stratifying the data on
time spent in SEA showed a significant pattern of increased risk and greater
dioxin body burden among Ranch Hands.
Relative risks in both high and low categories for all-site SEER cancers
reached statistical significance as well.
Using the 100%-0% analysis, a larger relative risk of all-site SEER
cancers also reached statistical significance even with smaller sample
sizes.
In the external analysis,
melanoma increased among Ranch Hands and prostate cancer increased in both cohorts. In the internal analysis, all-site, melanoma
and prostate cancers increased after adjusting for <2 years in SEA in
the high category. All-site cancer
increased using the 100%-0% analysis.
The study will be published on February 11, 2004 in the Journal of
Occupational and Environmental Medicine and has been selected
for continuing medical education training as a model of good epidemiologic research.
Prostate Cancer and
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in USAF Veterans of the Vietnam War. Dr. Michalek reported that the study was designed to specifically
investigate a potential association between TCDD and prostate cancer among USAF
veterans of the Vietnam war. Prostate
cancer affects one of nine men >65 years of age and is the second leading
cause of cancer-related deaths in men.
TCDD is classified as carcinogenic in animals and humans, but the IOM
has only found “suggestive/insufficient” evidence from animal and human studies
to link TCDD to prostate cancer. Data
and biological specimens were collected during six medical examinations from
1982-2002, while serum dioxin was measured during three physicals from
1987-1997.
Ranch Hands and comparisons
who had serum TCDD measurements and were fully compliant to at least one examination were
considered for the study. The study
assumed that at least 20 years passed after initial exposure to TCDD and
development of prostate cancer. In
addition to dioxin level measurements, area under the curve (AUC) was computed
beginning at the end of exposure in Vietnam.
AUC is a metric used in animal studies that is proportional to the
bioavailable dose. For purposes of this
study, AUC was calculated using the average dioxin half-life of 7.6 years. Based on tertiles of the AUC comparison,
Ranch Hands were assigned to low, medium and high categories. Veterans were excluded from the analysis on
the bases of no TCDD measurement, <20 years of follow-up and non-white. The exclusion criteria resulted in a loss of
20 comparisons and eight Ranch Hands.
Proportional hazards models were used to calculate hazard ratios and 95%
confidence intervals.
In comparing the two
groups, age, height, weight, body mass index (BMI), pack-years of smoking and
alcohol use were found to be similar.
The Ranch Hands spent more time in Vietnam, while the comparisons spent
more time in SEA. Increased dioxin
levels were seen among the high AUC category; the full range of 24,569
ppt-years was <50% of exposures to U.S. chemical workers who made
herbicides. An increase was also seen in
cumulative TCDD levels by AUC category.
The comparison group showed a significant trend of increased prostate
cancer risk based on years in SEA, but this trend was not seen in Ranch Hands. The trend in the control group was most
likely due to the cut point of <2 years in SEA.
The study also focused on
age and medical procedures among 47 prostate cancer cases in the comparison
group and 33 cases in the Ranch Hands group.
All of these subjects had prostate cancer more than 20 years after SEA
tours. The analysis found no
association between Gleason scores and AUC categories. The study showed the following results. Without accounting for time spent in SEA, no
increase in prostate cancer risk was seen in the Ranch Hands TCDD
categories. The length of time spent in
SEA increased the risk of prostate cancer in the comparison group, but time
spent in SEA was not associated with TCDD.
A shorter stay in SEA of <2 years and higher TCDD levels
increased the relative risk of prostate cancer in Ranch Hands. The incidence of prostate cancer was found
to be elevated in both the comparison and Ranch Hands groups relative to the
U.S. male population.
The study has been
submitted to a journal for publication, but some aspects of the research may be
modified in the future based on current efforts. Physiologically-based pharmacokinetic modeling is being
introduced to accommodate half-life changes in the Ranch Hands cohort in terms
of time, lipid content and body fat.
The half-life modeling paper has been submitted to the Lancet and
will eventually lead to the development of new initial dose estimates.
Dr. Pavuk further defined
two terms used in the study. A “Gleason
score” measures the stage of prostate cancer with a pathological examination of
prostate tissue obtained through biopsy or surgery at the time of
diagnosis. An “AUC” calculation
reflects length of time of follow-up and from exposure to development of
disease. AUC serves as a better
estimate of cumulative body burden than a single measurement at one time
point. Dr. Stoto clarified that IOM
found “limited/suggestive” rather than “suggestive/ insufficient” data to link
TCDD to prostate cancer.
Dr. Harrison questioned the
methodology of extrapolating to the initial dose without data from the initial
period. He pointed out that all
measurements based on the new half-life study will appear after the initial
slope is removed. Dr. Michalek agreed
with these comments because when RHS data were combined with findings on the
1976 dioxin accident among males in Seveso, Italy, a linear pattern appeared
within three months of initial exposure.
However, a very rapid and highly significant non-linear decrease was
seen before the three-month time period.
Dr. Michalek acknowledged that the study he presented does not account
for the non-linear pattern, but the new analysis will accommodate this finding.
Adjustments for Ethnicity
and Cut Points. Dr. Michalek
reported that the study was conducted in response to two questions submitted by
Dr. Gough. The first issue related to
whether the study results on melanoma would be different if an adjustment was
made for ethnicity. In response to this
question, the analysis assumed that blue-eyed and fair-skinned persons of
Scandinavian or Danish descent would have a much higher risk of melanoma than
individuals with darker skin. The study
was adjusted for self-reported ethnicity in which persons were asked during
physical examinations whether they considered themselves Scandinavian. The sample size of 2,965 persons reflected 1,189
eligible Ranch Hands and 1,776 eligible comparisons.
In the comparison,
background, low and high categories, ~5% of persons considered themselves
Scandinavian. To address these
responses, a new covariate was created and introduced into the melanoma
analysis in which “1" represented Scandinavian descent and “0"
represented other ethnic groups. A
large percentage of persons in the cohort self-reported their ethnic
backgrounds as Irish or French.
Overall, the original conclusions did not change when the covariate of <2
years in SEA was incorporated into the melanoma analysis.
Dr. Gough’s second question
focused on whether the study results would be different if the two-year cut
point was changed. Based on quartile of
years in SEA, the analysis showed trends in year of birth and pack-years of
smoking among the comparison group.
Similar changes were seen for these covariates in the Ranch Hands group
as well. The two-year cut point was
found to be important because ~6% of comparisons who were in SEA up to 2.1
years experienced cancer, but the rate was flat among Ranch Hands. The analysis was unable to explain the
dynamic in the comparison group.
The analysis showed a decreased risk of cancer in the
comparison group among those who were in SEA <2 years. The 100%-0% analysis was used in the study
because years spent in SEA were considered to be a surrogate for length of time
spent in Vietnam or other factors. An
interaction model that included significant years by dioxin and group was found
to be critical to reducing years in SEA.
For purposes of this analysis, “group” was defined as Ranch Hands and
controls. The model showed that the
relationship between dioxin and SEER cancer changed with years in SEA and group, while the main
effects model used in other research was found to be inappropriate for this
study. When the cut point was changed,
the adjustment disappeared and treatment effects in Ranch Hands were more
difficult to detect.
The analysis showed the following results. The association between cancer and dioxin
significantly changed with years served in SEA. The risk of cancer increased with years served in SEA among
comparisons. Increasing the value of
the two-year cut point attenuated the adjustment for confounding. Years served in SEA were a confounder and
may be a surrogate for another factor in the comparison group, but confounding
was controlled by stratification.
Dr. Stoto raised the
possibility of applying another methodology in future studies of
ethnicity. National rates can be reviewed
to identify countries with relative high rates of melanoma, such as England,
Ireland, Scandinavia or Scotland. The
rates could then be grouped for a combined analysis rather than focusing on
country data for Scandinavia only. Dr.
Harrison noted that the ethnicity analysis relied on self-reported data, but
this tool is not reliable in many instances.
Dioxin and Memory Loss. Dr. Michalek announced that the study was designed to determine
whether dioxin and memory loss are adversely associated in Ranch Hands
veterans. The Wechsler Memory Scale
(WMS) was administered to 2,000 persons in 1982 and 2002 to test five
components: immediate and delayed logical memory, associate learning, and
immediate and delayed visual reproduction.
The study was reviewed by NAS and published in Neurotoxicology in
2002, but the 2002 data are preliminary.
Based on the WMS, the data showed a significant deficit in the high
dioxin exposure category on immediate recall.
Significantly lower scores among Ranch Hands in the highest exposure
category relative to comparisons were statistically significant.
The study was adjusted for
military occupation, age, race, years of drinking, marital status, combat
exposure, organic psychotic conditions, other psychoses, neurotic personality,
non-psychotic disorders, substance abuse and use of psychotropic
medications. The study showed a
significant decrease in delayed logical memory among the highest exposure
category, but all other components of the WMS at baseline were not found to be
significant. No significant deficits
were seen in associate learning or immediate and delayed visual reproduction at
baseline in any Ranch Hands category.
In the 2002 WMS data
collected at cycle 6, one subject in the background category and 3-4 comparisons
had missing data. Sample sizes at cycle
6 with complete data included ~1,170 comparisons and a range of 211-351 persons
in the background, low and high categories.
Of persons who completed the WMS at the cycle 6 physical, the mean age
was ~60-65 years; dioxin levels ranged from 3.9-48; and BMI was ~30 for all
categories. Education was obviously an
important indicator of the ability of subjects to complete the WMS. In the comparison, background, low and high
categories, the percentage of subjects who had at most a high school education
ranged from 34%-68%. Education was also
highly correlated with officers versus enlisted personnel. No significant decrements were seen in
immediate and delayed logical memory or associate learning when the analysis was
repeated at cycle 6 and adjusted for age and education.
In comparing cycle 1 in
1982 and cycle 6 in 2002, 200 subjects in the high category had complete
associate learning data at both cycles, while 846 comparisons had complete data
at both cycles. No significant
differences were seen among persons who were fully compliant with both cycles.
The data analysis subtracted baseline values from cycle 6 values because the
subjects were expected to have lower WMS scores in 2002 than 1982. The study has not yet been adjusted for
covariates other than age, but the new data analysis will account for these
factors. Efforts are currently being
made to locate confounders, resolve the visual reproduction analysis and obtain
serum dioxin measurements. At the
present time, no evidence has been generated to support the hypothesis that
dioxin is adversely related to memory deficits in Ranch Hands.
Several RHAC members noted
that the demographics on education are unclear. For example, the data do not show whether subjects completed high
school, attended college or received degrees.
The current analysis combines all persons, such as those without a high
school diploma and those who received a Ph.D.
Dr. Stoto recommended that the demographics on education be clarified with
a cut point of “high school or less.”
He also pointed out that the original findings may contain
false-positives since the new data are not yet adjusted for years in SEA or
other covariates.
Dioxin and Syndrome X. Dr. Michalek reported that the study resulted in a published case
definition of “Syndrome X.” The term is
defined as three or more of the following conditions at the cycle 6 examination
in 2002: a waist circumference of
>102 cm; a triglycerides level of >150 mg/dl; a high-density
lipoprotein cholesterol level of <40 mg/dl; high blood pressure or a
diagnosis of hypertension; or a fasting glucose level of >110 mg/dl
or a diagnosis of diabetes based on ADA criteria. The case definition was published in NIH’s Third Report of the
National Cholesterol Education Program.
The study focused on
whether dioxin and Syndrome X are adversely associated in Ranch Hands. Recent data gathered by Scripps Clinic in
2002-2003 were used for the analysis.
The sample size reflected 1,086 comparisons and 775 Ranch Hands. Of the total cohort, only 89 subjects were
excluded due to missing dioxin measurements.
Demographics on age, birth year, race, military occupation and
pack-years of smoking were similar to other RHS data. Other covariates that were more important for this study were
similar among comparisons and Ranch Hands:
~11 median years of drinking; a family history of diabetes of ~20%; a
family history of hypertension of ~40%; and a remarkable risk of Syndrome X of
~42%. Similar to other RHS data, dioxin
exposure increased in the high category.
The data showed a
significant increase in the risk of Syndrome X in the high exposure category
and a significant trend after adjusting for covariates. The study could not explain the cause for
the significant deficits of Syndrome X and hypertension in the background
category. Syndrome X was not adjusted
for BMI since this variable is included in the model, but incorporating BMI
into the hypertension analysis was found to attenuate the result. The study concluded that dioxin may be
adversely associated with Syndrome X, but additional research in this area is
needed; other confounders need to be considered and measured; and exposures
need to be accurately classified.
Dr. Osei noted that the 42%
rate of Syndrome X in the study is much higher than the national average of
25%. He indicated that the larger
percentage is most likely due to the study population of males only.
Lt. Col. Julie Robinson, of the USAF, reiterated that the
RHS protocol and funding will end on September 30, 2006. USAF has developed cost estimates and
several options for the end of the RHS, including taking no further action or
conducting another physical examination.
USAF’s entire time-line to complete the protocol by September 30, 2006
was distributed to RHAC, but Lt. Col. Robinson highlighted some of the key
activities. The final Institutional
Review Board report is scheduled for July 2006. USAF is requesting that RHAC review 12 chapters during its
meetings in April, September and November 2004. The members will receive three documents for each chapter: an initial draft from SAIC to USAF;
resolutions to comments by USAF and SAIC; and a revised second draft based on
the comments. Some chapters will
contain appendices for RHAC to review as well.
To date, RHAC has received
two initial draft chapters, an instruction sheet, an explanation of the
attachments, and contact information for Lt. Col. Robinson. USAF hopes to provide RHAC with a total of
five of the 12 chapters by mid-February 2004 and will make every effort to
distribute chapters to the members at least two months prior to meetings. Each chapter was written by lead and
alternate writers who are all from Scripps Clinic; the list of writers was
distributed to RHAC. The literature
research was conducted by an
SAIC subcontractor. USAF plans to
submit articles to peer-reviewed journals up until January 1, 2006; any
remaining reports will be transformed into USAF technical documents.
Dr. Stoto saw the benefit
in prioritizing chapters for RHAC to review based on USAF need or other
factors. Dr. Harrison advised RHAC to
identify consultants with appropriate expertise to provide assistance in
reviewing the chapters. Dr. Trewyn
raised the possibility of using former RHAC members as consultants for the
chapter reviews. Dr. Schechtman
confirmed that he would contact the Committee Management Office to determine if
former members can serve as consultants to advisory committees. He planned on reporting his findings to RHAC
as soon as possible.
The Chair called for public
comments; no attendees responded.
April 30, September 8 and
November 3, 2004 were tentatively scheduled for the next three meetings; NCTR
will poll the members by e-mail to confirm these dates.
Lt. Col. Robinson presented
a certificate to Ms. Barbara Jewell, in absentia, to recognize her as an
official member of the Air Force Health Study Crew. Prior to Ms. Jewell’s recent retirement, she served as the RHAC
Committee Management Specialist for 14 years and was extensively involved with
RHAC and the RHS. She made outstanding
efforts in coordinating RHAC meetings, developing agendas and providing other
support. The certificate was given to
Dr. Schechtman to be forwarded to Ms. Jewell.
With no further discussion
or business brought before RHAC, Dr. Harrison adjourned the meeting at 1:27
p.m.
I hereby certify that to
the best of my knowledge, the foregoing Minutes of the proceedings are accurate
and complete.
___________________ ________________________________
Date Michael
Stoto, Ph.D.
Chair
Ranch
Hand Advisory Committee
___________________ ________________________________
Date Leonard
M. Schechtman, Ph.D.
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
and select advisory committees.
˜˜˜˜˜˜˜˜˜˜˜
