5
Value of the AFHS Research Assets

The previous three chapters of this report provide a detailed description of the Air Force Health Study (AFHS) (Chapter 2), and address the current state of the study’s medical records and other study data (Chapter 3) and specimens (Chapter 4). This chapter summarizes and builds on that foundation to draw conclusions regarding the scientific merit of retaining and maintaining the data assets of the AFHS, and the advisability of further study of such records, data, and specimens. It also addresses privacy and security concerns related to the retention and maintenance of the AFHS data assets.

SCIENTIFIC MERIT OF THE DATA ASSETS

Based on the information contained in Chapters 24 and the additional details presented below, the committee has reached the following findings:

The AFHS Data Assets Are Unique: No Other Epidemiologic Dataset on Vietnam Veterans Contains as Detailed Information Over as Long a Time Period

Subjects in the AFHS morbidity study have undergone up to six cycles of detailed physical examinations and questionnaire data collection over a 20-year period. Physical examination data sources include blood draws, urine and semen collections, skin and fat biopsies, stool smears, spirometry, chest X rays, electrocardiograms, dermatology and peripheral vascular examinations, neurological assessments, psychological testing, and myriad other clinical endpoints. Subjects



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Disposition of the Air Force Health Study 5 Value of the AFHS Research Assets The previous three chapters of this report provide a detailed description of the Air Force Health Study (AFHS) (Chapter 2), and address the current state of the study’s medical records and other study data (Chapter 3) and specimens (Chapter 4). This chapter summarizes and builds on that foundation to draw conclusions regarding the scientific merit of retaining and maintaining the data assets of the AFHS, and the advisability of further study of such records, data, and specimens. It also addresses privacy and security concerns related to the retention and maintenance of the AFHS data assets. SCIENTIFIC MERIT OF THE DATA ASSETS Based on the information contained in Chapters 2–4 and the additional details presented below, the committee has reached the following findings: The AFHS Data Assets Are Unique: No Other Epidemiologic Dataset on Vietnam Veterans Contains as Detailed Information Over as Long a Time Period Subjects in the AFHS morbidity study have undergone up to six cycles of detailed physical examinations and questionnaire data collection over a 20-year period. Physical examination data sources include blood draws, urine and semen collections, skin and fat biopsies, stool smears, spirometry, chest X rays, electrocardiograms, dermatology and peripheral vascular examinations, neurological assessments, psychological testing, and myriad other clinical endpoints. Subjects

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Disposition of the Air Force Health Study were asked to provide their medical records, as well as those of their children (up to age 17), their present partner, and any previous partner. These hard copy records were duplicated and exist as part of AFHS data assets. In addition, questionnaires were administered eliciting information on education; employment; income; marital and fertility history; child and family health; health habits; recreation, leisure, and physical activities; toxic substances exposure; military experience; and wartime herbicide exposure. In all, 2,758 subjects participated in at least one cycle exam. In addition, reproductive data were gathered and coded on 9,921 conceptions and 8,100 live births. The mortality component of the study has followed for nearly 25 years more than 20,000 Vietnam War-era veterans who served in Southeast Asia. More than 86,000 biologic specimens have been collected over the course of the study; approximately half of these are serum. Blood was collected in all six cycles and serum stored; stored semen is available only from Cycle 1 (1982), and urine is available only from Cycles 1–3 (1982, 1985, and 1987). In the last (sixth) cycle, whole blood was also stored. Chapters 3 and 4 detail the data and specimens collected over the course the study. Participation rates in the morbidity study have been relatively high, particularly among the Ranch Hands. Of the 1,208 Ranch Hands eligible at the time of the baseline examination, 1,045 (87 percent) took part. Although participation has dropped over time—from 85 percent at Cycle 2 to 74 percent at Cycle 6—the relatively high participation rates suggest that there may not be substantial selection biases in the cohort. Selection bias would exist, for example, if subjects with a health outcome differentially dropped out by exposure status. Among refusal subjects at Cycle 6, 5.4 percent of Ranch Hand refusals cited health reasons as their barrier to participation. Among comparison subjects, 5.1 percent of original comparisons and 5.4 percent of replacement comparisons refused to participate due to health reasons (AFHS, 2005). Passive refusal (non-response to invitation) rates were higher for comparison subjects versus Ranch Hands. The committee notes that the rate of attrition over time is high enough to potentially introduce other sources of bias, and that the introduction of such biases could compromise the internal validity of the study. However, it also notes that AFHS participation rates are comparable to those commonly observed in other longitudinal epidemiologic studies. All told, the AFHS has more data points and a higher rate of follow-up than the Framingham Heart Study, according to a USAF representative (RHAC, 2004). Approximately $143 million has been spent or allocated for collecting, managing, and analyzing these materials. Although several other epidemiologic studies of Vietnam veterans have been conducted, few have longitudinal data or have collected and analyzed any biologic samples. Two ongoing studies—the VA Normative Aging Study (Bell et al., 1972; Bossé and Spiro, 1995; MAVERIC, 2001) and the Vietnam Era Twin

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Disposition of the Air Force Health Study Registry (Henderson et al., 1990; Goldberg et al., 2002; Seattle ERIC, 2005)—collect similar but less comprehensive data and specimens from U.S. veterans, some of whom had wartime service in Vietnam.1 It is beyond the scope of the committee’s work to synopsize and review the epidemiologic literature on Vietnam veterans. However, Veterans and Agent Orange: Update 2004 (IOM, 2005a) and earlier reports in the Veterans and Agent Orange (VAO)—series (IOM, 1994, 1996, 1999, 2000, 2001, 2003) provide details on them. A table adapted from VAO Update 2004 is included as Appendix C. It contains a comprehensive list of the Vietnam veterans’ health outcomes literature and indicates in which volume of the VAO report series a review may be found. The table includes information on the type of study, a summary description of the topics addressed, and the size of the study population. It also contains a listing of AFHS publications reporting epidemiologic results through 2004. In brief, the table and VAO supplementary materials indicate that very few prospective morbidity studies with a broad set of health outcomes have been conducted. In addition, in most of these studies only self-reported health outcomes were obtained. The study most similar to the AFHS—an investigation of health outcomes among U.S. Army Chemical Corps2 specialists—shares many of AFHS’ limitations (a relatively small cohort of veterans with atypical exposures) and has much less detailed information on its subjects. Even in studies of particular health outcomes—most typically, forms of cancer—data were not obtained through direct examination of subjects, although physicians’ records were sometimes consulted to verify self-reported diagnoses. It must be noted that the AFHS cohort is a relatively small sample that is not representative of the US male population at large or of Vietnam veterans. This does not preclude its use in studies of issues beyond those involving exposure to the herbicides employed in the Vietnam War. However, it does mean that the results of such studies must be appropriately qualified and their limitations forthrightly discussed. Most “occupational” cohorts have similar limitations and researchers have developed means of dealing with these issues in their work. The Data Collected by the AFHS Appear to Be of High Quality and the Specimens Appear to Be Well Preserved The committee did not perform a comprehensive review of all AFHS data and specimens. However, the survey conducted by a subcommittee during a May 2005 site visit to the study’s San Antonio, Texas home led it to conclude that 1   Additional detail on these two studies is provided in Chapter 6. 2   The US Army Chemical Corps were responsible for the storage, preparation, and spraying of herbicides using hand equipment and H-34-type helicopters (Kang et al., 2001). They conducted spray operations such as defoliation around Special Forces camps; clearance of perimeters surrounding airfields, depots, and other bases; and small-scale crop destruction.

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Disposition of the Air Force Health Study these materials were collected, coded, documented, and stored in a manner consistent with best practices at the time they were obtained. All information collection and laboratory analysis activities were subjected to rigorous quality control procedures. These procedures are most recently documented in the quality control chapter of the Cycle 6 final report (AFHS, 2005). Earlier reports chronicle the procedures used in analogous chapters. The procedures were intended to ensure that data were properly recorded, coded, and entered into SAS databases. Information was subjected to validity checks, missing and outlying values were investigated and verified, and subjective observations (clinical impressions in medical exams, for example) were reviewed. The working groups that visited the site found that requested data could be extracted from SAS datasets and that randomly chosen specimens could be retrieved and appeared to have been properly stored. Details of their findings are contained in the interim letter report of the committee (IOM, 2005b) and are also covered in Chapters 3 and 4 of this report. The interim letter report also offered several recommendations for documenting and organizing the data assets in a form and format that would facilitate easy access to their contents. Analysis of the AFHS Data Assets Has Contributed to the Literature Addressing the Health of Vietnam Veterans In Spring 2005, Institute of Medicine (IOM) staff undertook a survey of citations to papers produced by AFHS investigators. Science Citation Index was used to determine the number and title of papers that referenced any one of 45 papers published in peer-reviewed scholarly publications addressing the results of analyses of AFHS data assets. A total of 733 citations were found. Of these, 273 (37 percent) were self-citations, that is, a citation in which the citing and the cited paper had at least one author in common.3 The remaining 460 (63 percent) were from other authors. Seven AFHS papers account for the majority of these citations by other authors (301 of the 460, or 65 percent). They address TCDD half-life/pharmacokinetics (159 citations), diabetes (58), and other health outcomes (84). Table 5-1 provides additional details on these papers. Although this analysis does not yield any information about the quality of the cited paper or the context in which it was cited, it does yield a rough idea of the extent to which AFHS research has attracted the notice of the scientific community. AFHS data and biospecimens have had a particular influence on scientific understanding of the pharmacokinetics of TCDD and its half-life4 in humans be- 3   Given that AFHS is a longitudinal study, it is de rigueur for later publications by the investigators to reference earlier work. 4   Half-life refers to the amount of time it takes to reduce the original concentration of an analyte by 50 percent within a circumscribed compartment such as serum or plasma.

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Disposition of the Air Force Health Study TABLE 5-1 AFHS Papers with the Greatest Number of Citations by Other Authors AFHS Paper Topic Total Citations Citations by Other Authors Pirkle et al., 1989 Serum dioxin half-life 110 80 Wolfe et al., 1990 Veterans’ health status 88 56 Michalek et al., 1996 Pharmacokinetics of TCDD 65 44 Henriksen et al., 1997 Serum dioxin and diabetes mellitus 54 37 Wolfe et al., 1994 Serum dioxin half-life 37 35 Wolfe et al., 1995 Paternal serum dioxin and reproductive outcomes 43 28 Longnecker and Michalek, 2000 Serum dioxin and diabetes mellitus 24 21 cause there are so few longitudinal studies that have collected serum from an exposed population. Within two years of the development of a serum TCDD assay, Pirkle and colleagues published estimates of TCDD half-life based on serial measures (collected 1982 and 1987) for 36 Ranch Hand subjects using a first-order kinetics model. Subsequent analyses (Caudill et al., 1992; Wolfe et al., 1992; Michalek et al., 1992; Wolfe et al., 1994; Michalek et al., 1996; Michalak et al., 1998; Michalek and Tripathi, 1999; Michalek et al., 2002; Emond et al., 2005) of AFHS data and the application of earlier AFHS findings (Warner et al., 2005) have served to refine TCDD half-life estimates with respect to elapsed time since exposure as well as the influence of body fat, the handling of nondetects and truncation of extrapolated values. In conjunction with studies of other exposed populations (Piacitelli et al., 2000; Steenland et al., 2001; Aylward et al., 2005), a revised two-compartment open pharmacokinetic model was subsequently developed. While the serial nature of AFHS TCDD data have enabled them to significantly impact half-life estimates, the data are limited by the length of elapsed time between exposure and assay. Additionally, they cannot inform half-life estimates for TCDD-exposed females, for whom longer half-lives have been observed (Aylward et al., 2005). AFHS reports and papers have also had an influence on the determinations of Institute of Medicine committees charged with evaluating the strength of the scientific evidence regarding exposure to the herbicides used in the Vietnam War and adverse health outcomes. As noted in Chapter 2,5 AFHS research was cited 5   Chapter 2 contains the committee’s discussion of this topic in the section entitled AFHS Research and the Institute of Medicine’s “Veterans and Agent Orange” Reports.

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Disposition of the Air Force Health Study as influential in their decisions regarding spina bifida in the children of Vietnam veterans and type 2 diabetes among Vietnam veterans. The IOM committee responsible for Veterans and Agent Orange: Update 1996 (IOM, 1996), while acknowledging the limitations imparted by the small population size, cited AFHS as one of three studies of “relatively high quality” that influenced their determination of limited/suggestive evidence of an association between spina bifida and paternal herbicide exposure. Based in part on the committee’s finding, spina bifida compensation legislation (Section 421 of Public Law 104-204, Title 38) was proposed in July 1996 and signed in September 1996 (IOM, 1999). This legislation altered the US Code to include dispensation of benefits to offspring of Vietnam veterans born with spina bifida (excluding spina bifida occulta). The VA’s subsequent implementation of the legislation in September 1997 (62 FR 51274-96) marked the first time that VA benefits had been extended to affected offspring based on paternal exposure. An IOM committee assembled in 1999 at the behest of the VA conducted a review of the scientific literature related to type 2 diabetes and herbicide and dioxin exposure. This committee’s report, Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000) discusses AFHS research at length and cites it among the information that was influential in its finding that there was limited/suggestive evidence of an association between exposure to herbicides and/or dioxin and type 2 diabetes. The VA subsequently classified type 2 diabetes as a “presumptive condition” for in-country Vietnam veterans, allowing persons with the disease to seek benefits without showing specific proof of a relationship between their service and the condition. No figures are available on the impact of this program, but a 2001 VA press release indicated that the cost of the benefit was projected to be $3.3 billion over the first five years of its availability, based on the assumption that approximately 220,000 veterans would be receiving benefits (VA, 2001). There has been relatively little collaboration between AFHS and outside investigators. However, some studies have been conducted. As noted elsewhere in the report, AFHS researchers and a team from the National Institute of Dental and Craniofacial Research collaborated on a study of silver-mercury amalgam fillings and adverse health outcomes, with a specific focus on neurological morbidity (Kingman et al., 2005). Sleep disturbances among Ranch Hand subjects were evaluated in a collaborative effort between AFHS and Texas Tech University researchers. Questionnaire data from participants of Cycles 3 and 4 were used to evaluate the nature and frequency of reported sleep disorders. Researchers hypothesized that dioxin somehow targets arousal mechanisms and thereby interferes with normal sleep patterns. Results of this research have been submitted for publication; they were presented in draft form in a June 2005 meeting the Ranch Hand Advisory committee (Liu et al., 2005).

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Disposition of the Air Force Health Study Investigators at University of California-Davis conducted a glucose transport study using 313 adipose tissue samples collected in conjunction with the Cycle 5 physical examination. This molecular epidemiology study matched samples from 313 AFHS volunteers to comparisons recruited from outside the cohort. The molecular markers selected included glucose transporter 4 (GLUT4), an adiposity index, an inflammation marker (NFκB), a signal messenger for toxic action of dioxin, and a housekeeping gene used as a normalization standard. The results of this study have not been published, but preliminary findings are available (RHAC, 2005). Other efforts have involved the provision of AFHS subjects’ biospecimens to other institutions for use in various assays. In 1984, 200 sera samples were sent to the University of Cincinnati for Strongyloides stercoralis antibody testing. Duke University and the University of Virginia each received 4 AFHS sera specimens in 1993 for an immunology related study. Nearly 700 sera specimens have been sent to the CDC, in addition to those sent for the standard AFHS morbidity study TCDD assays, for Legionella antibody testing and TCDD half-life studies (addressed above). The committee also identified an instance where data derived from publicly available AFHS reports were combined with other data and analyzed. Researchers compared the prevalence of chronic disease and behavioral risk factors among AFHS study participants (Cycles 1–5; Ranch Hand and comparison subjects) to a subset of age, race, and education-level comparable participants of the National Health and Nutrition Survey (Pfizer, 2005). Any future on the AFHS data assets is likely to attract the attention of those involved with veterans’ health policy because so few epidemiologic studies have been conducted on Vietnam veterans, and almost none on veterans with quantified TCDD body burden. FUTURE POTENTIAL OF THE DATA ASSETS The completion of the Cycle 6 physical examinations marked the end of major data gathering activities planned by the AFHS before the currently scheduled termination date of the study in 2006.6 However, investigators, contractors, and collaborators continue to analyze data and specimens and publish results. Since the beginning of 2005, the Cycle 6 final report has been released, four papers have been published in peer-reviewed journals (Ketchum and Michalek, 2005; Kingman et al., 2005; Pavuk et al., 2005a,b), and several more are under submission or in preparation. These include a study using longitudinal data being prepared under contract by Science Applications International Corporation (SAIC, 2005). 6   The study continues to conduct periodic mortality updates.

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Disposition of the Air Force Health Study It is clear that these remaining analyses will only scratch the surface of possible scientific hypotheses that can be investigated. Even in the absence of new health outcome information, the AFHS data assets could be used to examine myriad health questions. The committee does not have specific recommendations regarding the type of hypotheses that should be pursued. Rather, should the assets be made available to the scientific community, it believes that these details are best left to the investigators who propose to carry out the work. The committee offers, below, some possible topics for future work to illustrate the richness of the data and to indicate possible avenues for research. Researchers Can Reanalyze Outcomes Examined by the AFHS Using Different Assumptions and Approaches Than Have Been Applied to Date The AFHS was initiated to investigate the possible long-term health effects of wartime exposure to herbicides in Vietnam veterans. The study has, by and large, maintained the analysis protocols and assumptions established at its initiation. These include the use of rather basic means of characterizing herbicide exposure7 and the application of data from replacement subjects when original matched comparisons were unable or unwilling to participate in later cycle exams. It is outside the scope of this report to provide detailed critical analysis of these assumptions. However, it is axiomatic that different assumptions might yield different results concerning the association between herbicide or dioxin exposures and health outcomes. Advances in both knowledge and technology also allow new and more sophisticated analyses to be conducted. For example, the research of Stellman and colleagues (Stellman et al., 2003a,b; Stellman and Stellman, 2004) has recently yielded a far more detailed understanding of which herbicides were applied where and when, and how dioxin contamination of the 2,4,5-T-based herbicides changed over time. This information could possibly be used to refine exposure assessment models for dioxin-contaminated herbicides and separately factor exposure to non-dioxin-contaminated herbicides.8 Preliminary research suggests the calendar period of service in-theater, the number of days that spraying took place during that service, and the time spent in Southeast Asia—all previously unfactored surrogates of dioxin exposure—are effect modifiers in analyses of Ranch Hand veterans’ postservice health outcomes (Michalek, 2005). 7   The “Reconstruction of Exposure” section of Chapter 2 describes the various means used to characterize herbicide exposure in the cohort. Most analyses use either an exposure surrogate based on wartime occupation or a categorical variable based on a serum dioxin level measured—at minimum—some 16 years after the last exposure. 8   Such analyses were proposed in a 2004 AFHS presentation before the Ranch Hand Advisory Committee (RHAC, 2004).

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Disposition of the Air Force Health Study When a Ranch Hand subject’s comparison was unavailable for a cycle exam, AFHS study protocol dictated that a new comparison be selected from that person’s pool of matched (on age, race, and military occupation) potential comparisons. In Cycles 2–6, when feasible, the new replacement comparison was matched to the unavailable comparison on self-perceived health status—excellent, good, fair, or poor. The replacement of noncompliant comparison subjects during the course of the 20 years of follow-up introduces major complexities into the survival analyses of the comparison group. AFHS chose to treat replacements as identical to originals for the purpose of analyses. However, there is no reason why this assumption has to be maintained and more complex approaches—taking into account the specific times of entry into the comparison cohort, for example—could be explored. Further studies could be accomplished under novel or modified matching strategies, or by excluding replacement comparison subjects. The cohort’s repeated examinations and questionnaires have introduced time-dependent variables into the dataset, and there are correlations among these measurements. These data offer a valuable opportunity to explore how trends in risk factors influence the development of various diseases. Only in recent years has adequate statistical software become available to handle this situation, creating the opportunity for a number of longitudinal analyses that would have been difficult to perform in earlier years.9 New Analyses Can Be Performed on the Existing Medical Records and Other Study Data That Examine Questions That Were Not Addressed in the AFHS AFHS analyses focused on the influence of herbicide or dioxin exposure on health outcomes. However, data were collected on a wide range of potential influences on disease and health and a number of health outcomes not addressed in the AFHS reports could be studied with these data. Some of these may not be directly related to herbicide exposure but may still be important for furthering knowledge about veterans’ health and the natural history and risks of disease. For example, one could investigate associations between occupational exposures to chemical agents, dusts, and fumes and levels of pulmonary function. At each of the six cycles, subjects were asked about their occupational history.10 9   As of late 2005, a longitudinal analysis of AFHS data was underway. 10   It should be noted that, in Cycle 1, the coding was contracted to Louis Harris and Associates, Inc.; for Cycles 2–6 occupational and industrial codes were attributed by the NORC. The coders were not trained industrial hygienists, and the reliability of the coding has not been verified. For Cycles 1–4, the 1980 Census Alphabetical Index of Industries and Occupations was used, and for Cycles 5 and 6 the 1990 Census revision was used. These facts would have to be accounted for in any analyses using occupational data.

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Disposition of the Air Force Health Study Subjects were asked about the jobs they held since the last examination, up to a maximum of five jobs. These were coded to the Bureau of the Census’ North American Industry Classification System and Occupation Classification System. In addition, self-reported exposure to a number of agents was elicited, including dates and frequency of exposure, the reason for leaving employment, and use of personal protective equipment. Separately, pulmonary function measurements (FEV1 and FVC) were measured during all physical exams except Cycle 2.11 To ascertain whether occupation affects pulmonary function, analyses using hierarchical linear models (for example) could be undertaken. Appendix B lists, in tabular form, endpoints that were analyzed in one or more physical exam cycles. Many of the table entries represent multiple endpoints (e.g., the SCL90 battery is a 90-question psychological test that counts as one entry in Table B-3). With myriad variables collected during at least one exam cycle, the potential for investigating various associations is great. Other forms of study design such as nested case–cohort and case–control studies may be appropriate for such research. And in some of these studies, it may be desirable to limit the study group to only the Ranch Hands or only the comparison group. Advances in Biospecimen Analysis Technology and Science Can Be Employed to Conduct Studies That Were Not Contemplated in the AFHS Protocol A report by RAND describes the breadth of tissue banking in the United States, thought to span thousands of collections and over 300 million specimens in 1999 (Eiseman and Haga, 1999). These include several massive collections such as the National Pathology Repository at the Armed Forces Institute of Pathology (AFIP), which holds over 12 million wet tissue specimens from more than 2.8 million subjects (AFIP, 2005) and the Coriell Cell Repositories, which maintain nearly a million vials of cryopreserved cells and over 120,000 cell cultures (Coriell Institute for Medical Research, 2005). Although these and other specimen holdings represent much larger and wider populations, the biological samples collected in the AFHS are a distinctive resource because of the depth of the accompanying detailed information from the physical exams, clinical measurements, and questionnaires. The serial nature of the physical exam data and variety of specimen types from individual subjects (sera, whole blood, urine, and semen) are also strengths. Clinical and biomarker measures include over 210 parameters with over 60 measured at all six cycles (Appendix B, Table B-14). 11   The Cycle 2 exam report stated that pulmonary function studies were not performed “[b]ecause of the essentially negative pulmonary analyses from the baseline examination” (AFHS, 1987).

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Disposition of the Air Force Health Study Storage conditions maintained by the AFHS are adequate for some future analyses of the specimens.12 Examples include element analysis, standard blood chemistry, steroid hormones, fatty acids, and lipoproteins. Among the potential future uses of these samples are studies of biomarkers of exposure to environmental agents in the Vietnam theater—as was the study of serum 2,3,7,8-tetrachlorodibenzo-p-dioxin as a biomarker of exposure to Agent Orange—or exposures to other environmental hazards (Ryan et al., 2004). Studies of biomarkers of response or susceptibility in relation to health endpoints studied in the AFHS are also possible. The whole blood collected during Cycle 6 would be an excellent source of DNA for possible genetic studies (Kelly and Woolley, 2005; Sun et al., 2005), including whole genome scans. It is also possible to obtain sufficient DNA from stored serum samples for limited genotype analysis. Thus, although it is unlikely that genetic studies were contemplated at the beginning of the AFHS, they are now feasible. Other changes in technology (Hirsch et al., 2003; Chou et al., 2005) and the availability of new methods (Shevkoplyas et al., 2005) have made possible uses of the specimens that would not have been feasible—or imagined—when the study protocol was written. For example, serum proteomics was unknown 10 years ago. Studies are now examining specific patterns of proteins detectable in stored sera and their utility in the early diagnosis of disease, and in identifying therapeutic targets and disease response markers (Figeys, 2003; Domon and Broder et al., 2004; Chen et al., 2005; Srivastava et al., 2005). Additional examples of potential future analyses are listed below.13 Polychlorinated biphenyl, polychlorinated dibenzofuran, and polychlorinated dibenzo-p-dioxin congeners that, like 2,3,7,8-TCDD, bind to the aryl hydrocarbon (Ah) receptor can be measured from sera and evaluated (TEQs) for associations with observed health outcomes (Warner et al., 2005). Polymorphisms are known to exist in many of the genes involved in response to dioxin such as cytochrome P4501A1 (Huang et al., 2002) and the Ah receptor (Chan et al., 2004). DNA isolated from stored whole blood or serum and genotyped would allow the investigation of gene–environment interactions in response to dioxin (Landi et al., 2005). 12   Chapter 4’s discussion of obstacles to retaining and maintaining the specimens indicates that there are some analytes that require different methods of handling and preservation than those employed in the AFHS in order to ensure analytic viability. This precludes conducting certain types of tests in the future. 13   It should be noted that the committee has not researched in-depth whether these could feasibly be applied to the AFHS specimens.

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Disposition of the Air Force Health Study There is limited data on oxidative stress biomarkers over time. Sera and urine samples could be used for studies that investigate changes in these biomarkers, polymorphisms in oxidative stress genes, and their relation to disease outcome (Lenaz et al., 1999; Shertzer et al., 2004). Sperm samples could be used for analysis of DNA adducts and possible levels of environmental chemicals (Horak et al., 2003). Serum inflammatory markers and polymorphisms in inflammation-related genes can be studied in relation to several psychiatric illnesses (Kahl et al., 2006). Although highly susceptible to degradation, RNA can be extracted from whole blood and sera stored at –80°C using polymerase chain reaction (PCR) methods (Paoli, 2005) to explore the progression to cancer, diabetes, or other diseases in relation to dioxin and other factors (M.T. Landi, National Cancer Institute, personal communication, April 16, 2005). Many of these newer technologies have very small sample requirements, making them applicable to the AFHS repository. As biospecimen analysis technology and science are rapidly evolving, more opportunities are likely to become available in the coming years. Additional considerations in the future use of specimens, including consent issues, are discussed in Chapter 6. Although the AFHS specimen collection may be physically amenable to newly developed analytical technologies, the application of stored specimens to research interests in disciplines such as disease pathology, epidemiology, and genetics is firmly anchored to the existence of and quality of the associated subject records. Therefore, although pertinent aspects concerning the disposition of various AFHS resources are addressed separately in this report, the value of the collective AFHS resource (biomaterial and data holdings) exceeds the value of the sum of its component parts. The Study’s Period of Analysis Can Be Expanded Through Follow-Up of the Cohorts Using Publicly-Available Information When the AFHS was originally designed, the investigators as well as various reviewers felt that 20 years of follow-up would be adequate to document major adverse effects of wartime exposure to herbicides (AFHS, 1982). However this time period may be insufficient to detect effects that may take several decades to develop. The average subject age at the first examination cycle in 1982 was about 44 years; in 2005 it is approximately 67. Chronic diseases are occurring more often among study participants and mortality has increased as the population has aged. The latest AFHS mortality update (Ketchum and Michalek, 2005) reported an elevated relative risk for all-cause mortality among all Ranch Hand veterans and a statistically significant increase in the risk of death from circulatory system diseases among veterans with the highest serum dioxin levels. If confirmed by

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Disposition of the Air Force Health Study further follow-up, these trends could have implications for health monitoring of the study’s participants and possibly for compensation decisions regarding Vietnam veterans in general. Appendix D of this report presents a calculation of the expected number of deaths over the next 10 years among the participants of the morbidity study. These calculations were made under the assumption that statistical bias was not present. Whether or not such bias will be an issue in any future analyses will depend on the outcome being examined and the characteristics of the population for whom data are available.14 The rough estimates presented in the appendix suggest that, even in analyses limited to the subjects who participated in one or more cycle exams, the AFHS cohort is large enough to detect moderate to large associations in future mortality analyses of health outcomes of potential interest to Vietnam veterans. The vital status of the AFHS cohort can be updated periodically without too much difficulty or expense using the National Death Index (NDI). The NDI (2005) provides information on underlying and contributing causes of death, coded to various revisions of the International Classification for Diseases (ICD), so that continuing follow-up of the cohort can be carried out expeditiously. It should be noted, though, that there are inherent limitations regarding the accuracy of certain underlying causes of death reports in the NDI—particularly, noncancer outcomes. It may also be possible to follow up on other endpoints through the use of administrative databases—for example, examining cancer incidence through record linkage with U.S. state tumor registries or hospital discharges through Medicare and private insurance health plans. However, such work would be more difficult because there is no central data source comparable to the NDI. The committee did not investigate this in detail, but the feasibility of this approach depends, among other factors, on the extent to which subjects reside in states where there are cancer registries and whether they participate in a federal or private health provider program that systematically collects relevant information. Nevertheless, data acquisition using administrative databases in future years could increase the statistical power of analyses for some outcomes that have been identified as being possibly related to exposure to herbicides or dioxin. Other outcomes related to the health of veterans and new questions regarding aging in the population could also be explored. Additional Follow-Up of Health Outcomes in AFHS Participants Can Be Carried Out There are several mechanisms for acquiring additional morbidity data on AFHS participants if a decision is made to actively maintain the cohort. New 14   Selection bias, for example, could be a factor if the participation rate of subjects with a particular health outcome depended on their herbicide exposure status.

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Disposition of the Air Force Health Study general physical examinations of the cohort are one means. However, as noted in Chapter 2, these are highly resource-intensive exercises, costing more than $20 million for examinations, specimens’ analysis, questionnaire administration, coding, and other database activities in Cycle 6. Epidemiologic studies of other cohorts, including veterans’ cohorts, have used more focused data gathering. These include surveys conducted by mail, phone, or on the World Wide Web (with or without independent verification of information through contact with physicians), contracting with local health professionals to administer limited physical exams, and establishing central sites for examinations in cohort population centers or at events where groups of participants gather, such as veterans service organization annual meetings. Such data collection could involve the entire cohort or subgroups with particular characteristics of interest to the researchers (only veterans with a confirmed polyneuropathy, for example). The range of such studies is limited only by the initiative and imagination of potential investigators and their ability to identify funds to conduct the work. For example, one association that has been found in the AFHS is a relationship between exposure to Agent Orange and type 2 diabetes. As the incidence of diabetes increases with age, it may be useful to reexamine this association or other age-related health outcomes. Assuming that the number of new cases increases as the study population ages, it will become increasingly more likely that underlying exposure–response patterns will be detected, should they exist. If detected, thorough analysis of such patterns may require the collection of additional data. One cost-effective method to gather simple, yet substantial, additional data would be to administer questionnaires to living subjects and surrogate respondents to obtain physician diagnoses and treatments administered, notably antiglycemic therapies. This kind of questionnaire follow-up also reduces the burden placed on unwell subjects to attend complex health evaluation sessions and hence is less likely to be subject to differential participation due to health status. Other postservice influences could be investigated as well, including diet (which was surveyed in the Cycle 4 questionnaire) and occupational and leisure activities (which would serve as indicators of sedentary and active lifestyles). A major strength of the AFHS is its longitudinal component and therefore investigations of associations with outcomes such as diabetes across time can provide some picture as to whether drop outs are influencing study results. The committee believes that the data in this study are probably sufficient to evaluate selection bias through various sensitivity analyses. Any further collection of data would entail establishing a mechanism for contacting study subjects in a manner that would be respectful of their privacy and of ethical and legal constraints.15 Chapter 6 touches on this issue in the context of the committee’s discussions of options for further study and consent issues. 15   Goldberg et al. (2002) describe one such mechanism that is in place for gathering data from participants in the Vietnam Era Twins Registry.

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Disposition of the Air Force Health Study There is very little scientific literature on the long-term effects of herbicide or dioxin exposure so any further follow-up of the cohort—if pursued—would add to the medical knowledge base on this topic, whether or not specific health impacts were identified. PRIVACY AND SECURITY CONCERNS RELATED TO THE RETENTION AND MAINTAINANCE OF THE AFHS DATA ASSETS As noted in the interim letter report (IOM, 2005b) and Chapters 3 and 4, the committee has concluded that the present state of the documentation and organization of the AFHS medical records, other study data, and laboratory specimens is an obstacle to retaining and maintaining these materials after the currently scheduled termination date of the study. Several recommendations intended to address these obstacles were offered. The committee was also charged with evaluating whether the retention and maintenance of these assets raise any “privacy concerns.” It interpreted this component of the charge to cover what the public health and research communities generally refer to as ethical, legal, and social issues (ELSI) considerations. Any disposition of the resources of the AFHS must address the related but distinct requirements of privacy, confidentiality, and security. Though often used interchangeably, these terms have distinct legal and ethical meanings as they relate to health information (Hodge, 2004). Health information privacy refers to an individual’s right to control the acquisition, uses, or disclosures of his or her identifiable health data. Confidentiality, which is closely related, refers to the obligations of those who receive information to respect the privacy interests of those to which the data relate. In a legal sense, duties of confidentiality arise from specific relationships (e.g., doctor and patient, or researcher and subject). From an ethical perspective, health information privacy rights (grounded in individual autonomy) include a corresponding duty of confidentiality that others must adhere. Security is altogether different. It refers to technological or administrative safeguards or tools to protect identifiable health data from unwarranted access or disclosure. Maintaining information security is becoming increasingly complex in the modern era of digitized exchanges of health information within a national electronic information infrastructure (Hodge et al., 1999). To the committee’s knowledge, there have been no breaches of security in the AFHS. Once the study reaches its scheduled end date of September 30, 2006, there are three possible destinies for its data assets: destruction, retention by the AFHS as part of an extension of the study, or transfer to some other custodian(s). Proper destruction of the data or samples would eliminate further privacy, confidentiality, and security concerns; transferring these resources to one or more new custodians would pose challenges and raise questions regarding the informed consent of the participants. The committee believes such ELSI considerations must play a central role in decisions regarding the future disposition of the AFHS; it does not,

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Disposition of the Air Force Health Study however, believe that any would necessarily prevent further study. ELSI considerations thus are addressed in Chapter 6 in the context of the committee’s recommendations for further study. CONCLUSIONS AND OBSERVATIONS On the basis of its review of AFHS reports, its site visit to the study facility, the scientific literature, and other information presented in this and previous chapters, the committee has reached the following conclusion: There is scientific merit in retaining and maintaining the medical records, other study data, and laboratory specimens collected in the course of the Air Force Health Study after the study’s currently scheduled termination date. Although it was not part of its evaluation of their scientific merit, the committee notes that the AFHS data assets were obtained at a considerable cost to the government and represent a substantial investment in time and dedication by the study’s subjects. Of course, past investment in a project does not justify future investment in it. The committee believes, though, that it is important to acknowledge that such great expenditures of taxpayer funds and participants’ effort should not be treated casually, especially when it is possible to derive additional societal benefit from them. The committee further concludes that: Privacy concerns and related ethical, legal, and social issues are not an intrinsic obstacle to retaining and maintaining the AFHS medical records, other study data, and laboratory specimens after the currently scheduled termination date of the study. However, attention to such concerns and issues must play a central role in decisions regarding the future disposition of these data assets. As there is scientific merit in retaining and maintaining these assets and the committee believes that the identified obstacles are surmountable, the committee concludes that: Further study of the AFHS medical records, other study data, and laboratory specimens is advisable. The potential value and relevance of extending the study of the AFHS data assets rests in the application of the results of future research on the assets. This research could encompass: reanalysis of the herbicide or dioxin exposures and health outcomes examined by the AFHS using different assumptions and approaches than have been applied to date; new analyses of the medical records and other study data that examine questions that were not addressed in the AFHS; new studies of the collected biospecimens that take advantage of advances in technology and science to conduct analyses that were not contemplated in the AFHS protocol;

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Disposition of the Air Force Health Study expansion of the study’s period of analysis through follow-up of the cohorts using publicly available information; and additional follow-up of health outcomes in AFHS participants. As already noted in Chapters 2 and 3, the AFHS dataset has several weaknesses that may limit its utility as a means of evaluating the health impacts of exposure to Agent Orange. These include the inherently small size of the cohort, lack of any biomarkers of herbicide exposure other than 2,3,7,8-TCDD, little information on subjects’ locations in-theater, unavailability of a detailed exposure history, and possible herbicide exposures in the comparison population. The reproductive outcomes and mortality-only components of the study have larger sample populations but far less detailed data on the subjects. It would thus be a mistake to view the committee’s conclusions here as an indication that the AFHS data assets are a definitive source of information on the topic of Vietnam veterans’ health—they are not. Instead, the data and specimens are pieces of evidence that can be put to use in the effort to understand the determinants of good and ill health in Vietnam veterans and to address other scientific questions. REFERENCES AFHS (Air Force Health Study). 1982. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides: Study Protocol, Initial Report. Brooks AFB, TX: USAF School of Aerospace Medicine. SAM-TR-82-44. AFHS. 1987. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. First Follow-up Examination Results. 2 vols. Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-87-27. AFHS. 2005. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 2002 Followup Examination Results. Brooks AFB, TX: Epidemiologic Research Division. Armstrong Laboratory. AFRL-HE-BR-SR-2005-0003. AFIP (Armed Forces Institute of Pathology). 2005. National Pathology Repository. [Online]. Available: http://www.afip.org/Departments/repository/npr.html [accessed Nov. 9, 2005]. Aylward LL, Brunet RC, Carrier G, Hays SM, Cushing CA, Needham LL, Patterson DG Jr, Gerthoux PM, Brambilla P, Mocarelli P. 2005. Concentration-dependent TCDD elimination kinetics in humans: toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort. Journal of Exposure Analysis and Environmental Epidemiology 15:51–65. Bell B, Rose CL, Damon A. 1972. The Normative Aging Study: An interdisciplinary and longitudinal study of health and age. Aging and Human Development 3:5–17. Bossé R, Spiro A III. 1995. The Normative Aging Study. In Maddox G, ed. Encyclopedia of Aging. 2nd ed. New York: Springer Press. Pp. 688–690. Caudill SP, Pirkle JL, Michalek JE. 1992. Effects of measurement error on estimating biological half-life. Journal of Exposure Analysis and Environmental Epidemiology 2:463–476. Chan CY, Kim PM, Winn LM. 2004. TCDD-induced homologous recombination: the role of the Ah receptor versus oxidative DNA damage. Mutation Research 563(1):71–79. Chen R, Pan S, Brentnall TA, Aebersold R. 2005. Proteomic profiling of pancreatic cancer for biomarker discovery. Molecular and Cellular Proteomics 4(4):523–533. Chou PH, Chen SH, Liao HK, Lin PC, Her GR, Lai AC, Chen JH, Lin CC, Chen YJ. 2005. Nanoprobe-based affinity mass spectrometry for selected protein profiling in human plasma. Analytic Chemistry 77:5990–5997.

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Disposition of the Air Force Health Study Pfizer, Inc. 2005. Pfizer Health Publications: Pfizer Facts—the health profile of United States Air Force Retirees: 1982–1997. [Online]. http://www.pfizer.com/pfizer/download/health/pubs_facts_airforce.pdf [accessed January 12, 2006]. Piacitelli L, Marlow D, Fingerhut M, Steenland K, and Sweeney MH. 2000. A retrospective job exposure matrix for estimating exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. American Journal of Industrial Medicine 38(1):28–39. Pirkle JL, Wolfe WH, Patterson DG, Needham LL, Michalek JE, Miner JC, Peterson MR, Phillips DL. 1989. Estimates of the half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Vietnam veterans of Operation Ranch Hand. Journal of Occupational and Environmental Medicine 27(2):165–171. RHAC (Ranch Hand Advisory Committee). 2004. Certified Verbatim Transcript: Ranch Hand Advisory Committee Meeting, April 30, 2004. [Online]. Available: http://www.fda.gov/ohrms/dockets/ac/04/transcripts/2004-4041t1.doc [accessed December 4, 2005]. RHAC. 2005. Record of the Proceedings. Ranch Hand Advisory Committee Meeting, Department of Health and Human Services, June 10, 2005, Rockville, Maryland. [Online]. Available: http://www.fda.gov/ohrms/dockets/ac/05/minutes/2005-4146m1.htm [accessed February 10, 2006]. Ryan L, Huang W, Thurston SW, Kelsey KT, Wiencke JK, Christiani DC. 2004. On the use of biomarkers for environmental health research. Statistical Methods in Medical Research 13(3): 207–225. SAIC (Science Applications International Corporation). 2005. Longitudinal Summary. [Online]. Available: http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4146s1_03_SAIC%20Response.pdf [accessed October, 25 2005]. Seattle ERIC (Epidemiologic Research and Information Center). 2005. Seattle ERIC Home Page. [Online]. Available: http://www.eric.seattle.med.va.gov/ [accessed October, 24 2005]. Shertzer HG, Clay CD, Genter MB, Chames MC, Schneider SN, Oakley GG, Nebert DW, Dalton TP. 2004. Uncoupling-mediated generation of reactive oxygen by halogenated aromatic hydrocarbons in mouse liver microsomes. Free Radical Biology and Medicine 36(5):618–631. Shevkoplyas SS, Yoshida T, Munn LL, Bitensky MW. 2005. Biomimetic autoseparation of leukocytes from whole blood in a microfluidic device. Analytic Chemistry 77(3):933–937. Srivastava S, Srivastava RG. 2005. Proteomics in the forefront of cancer biomarker discovery. Journal of Proteome Research 4(4):1098–1103. Steenland K, Deddens J, and Piacitelli L. 2001. Risk assessment for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) based on an epidemiologic study. American Journal of Epidemiology 154(5): 451–458. Stellman SD, Stellman JM. 2004. Exposure opportunity models for Agent Orange, dioxin, and other military herbicides used in Vietnam, 1961–1971. Journal of Exposure Analysis and Environmental Epidemiology 14(4):354–362. Stellman JM, Stellman SD, Christian R, Weber T, Tomasallo C. 2003a. The extent and patterns of usage of Agent Orange and other herbicides in Vietnam. Nature 422(6933):681–687. Stellman JM, Stellman SD, Weber T, Tomasallo C, Stellman AB, Christian R. 2003b. A geographic information system for characterizing exposure to Agent Orange and other herbicides in Vietnam. Environmental Health Perspectives 111(3):321–328. Sun G, Kaushal R, Pal P, Wolujewicz M, Smelser D, Cheng H, Lu M, Chakraborty R, Jin L, Deka R. 2005. Whole-genome amplification: relative efficiencies of the current methods. Legal Medicine 7(5):279–286. VA. 2001 (May 8). Rules Published for VA’s Diabetes-Agent Orange Benefits (press release). [Online]. Available: http://www1.va.gov/pressrel/aodiab01.htm. [accessed February 10, 2006]. Warner M, Eskenazi B, Patterson DG, Clark G, Turner WE, Bonsignore L, Mocarelli P, Gerthoux PM. 2005. Dioxin-like TEQ of women from the Seveso, Italy, area by ID-HRGC/HRMS and CALUX. Journal of Exposure Analysis and Environmental Epidemiology 15(4):310–318.

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Disposition of the Air Force Health Study Wolfe WH, Michalek JE, Miner JC, Rahe A, Silva J, Thomas WF, Grubbs WD, Lustik MB, Karrison TG, Roegner RH. 1990. Health status of Air Force Veterans occupationally exposed to herbicides in Vietnam. I. Physical health. Journal of the American Medical Association 264(14): 1824–1831. Wolfe WH, Michalek JE, Miner JC, Pirkle JL, Caudill SP, Needham LL, Patterson DG Jr. 1992. Dioxin half-life in veterans of Operation Ranch Hand. Organohalogen Compounds 10: 239–242. Wolfe WH, Michalek JE, Miner JC, Pirkle JL, Caudill SP, Patterson DG Jr, Needham LL. 1994. Determinants of TCDD half-life in veterans of Operation Ranch Hand. Journal of Toxicology and Environmental Health 41(4):481–488. Wolfe WH, Michalek JE, Miner JC, Rahe AJ, Moore CA, Needham LL, Patterson DG Jr. 1995. Paternal serum dioxin and reproductive outcomes among veterans of Operation Ranch Hand. Epidemiology 6(1):17–22.