Grantee Research Project Results
1998 Progress Report: Reproductive Health, Serum Dixon, and P450 Genes in Vietnam Veterans
EPA Grant Number: R825817Title: Reproductive Health, Serum Dixon, and P450 Genes in Vietnam Veterans
Investigators: Sweeney, Anne , Wun, Chuan-Chuan , Symanski, Elaine , Denison, Michael , Cooper, Sharon , Wu, Xifeng , Junco, Deborah del
Institution: The University of Texas at Houston
EPA Project Officer: Aja, Hayley
Project Period: November 19, 1997 through November 18, 2000 (Extended to November 30, 2002)
Project Period Covered by this Report: November 19, 1997 through November 18, 1998
Project Amount: $874,195
RFA: Issues in Human Health Risk Assessment (1997) RFA Text | Recipients Lists
Research Category: Human Health
Objective:
In the 1996 update by the Institute of Medicine's Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides, it was concluded that there was "limited/suggestive evidence" of an association between paternal herbicide exposure and spina bifida in the offspring of male Vietnam veterans. Much of the concern is with regard to the dioxin contamination present in herbicides used during the Vietnam War. Dioxin exposure, however, is not limited to Vietnam veterans and a "safe threshold" for dioxin exposure has never been established for the U.S. general population. The contradictory findings of previous research relating dioxin and adverse reproductive effects may be due in part to the absence of a genetic susceptibility component to identify high-risk subpopulations. The proposed case-control study is designed to test the hypothesis that the interaction between parental P450 genotype and dioxin exposure increases the risk of neural tube defects (NTDs), using Vietnam era veterans as the study population.Progress Summary:
Our research protocol has been approved by the following agencies or individuals: the Environmental Protection Agency (funding agent), the Department of Veterans Affairs, Admiral Elmo R. Zumwalt, Jr. (ret., U.S. Navy), the Agent Orange Coordinating Council, the Vietnam Veterans of America, the Spina Bifida Association of America, the Association of Birth Defect Children, the National Association of Public Health Statistics and Information Systems (NAPHSIS), the National Center for Health Statistics (NCHS), the State Vital Statistics Offices of Alabama and New Jersey and the Houston Shriner's Hospital.
We have acquired a data file of over 2.7 million unique records of Vietnam Veterans from the Department of Defense (Defense Manpower Data Center in Monterey, California). The data file includes women Vietnam Veterans who, to our knowledge, have never been offered the opportunity to have their blood tested for the presence of environmental toxins. To our knowledge, our study will also be the first to offer Vietnam Veterans (male or female) the opportunity to have their blood tested for genetic susceptibility to environmental toxins.
Along with the States of Alabama and New Jersey, 43 other vital statistics "registration areas" have approved our initial request (made through the NCHS) to acquire parent identifiers from the birth and death certificates of offspring reported to have neural tube defects. The total number of vital statistics registration areas is 55: all 50 States plus New York City, Washington D.C., Guam, Puerto Rico, and the Virgin Islands. Approvals from California, Connecticut, Florida, New York City, Pennsylvania, Rhode Island, Virginia and Washington are pending review of standardized applications.
To date, we have received no refusals from any Registration Area for death certificate data. Although the State of Illinois has no problem with our request for death certificate data, the Deputy State Registrar, Mr. Steve Perry, told us in a telephone conversation that Illinois is now denying researchers any access to birth certificate data without prior consent from the mother. The basis for the denial is a lawsuit (Jane Doe II vs. Lumpkin). We believe that there may have been some misunderstanding as to the aggregate, not individual nature of our proposed use of the birth certificate data. We have asked Mr. Perry to provide us more information on the basis for the denial. The lawsuit has apparently never been appealed. We are aware of a ruling on a 1983 appellate case in the State of Kansas that may be relevant here. In that lawsuit against the Kansas Department of Health and Environment, the use of birth certificate data (i.e., to ascertain the presence of birth defects) was upheld as serving the Public's best interest. The estimated size of the population of Vietnam Veterans residing in Illinois is large. Because we do not wish to deny certain groups of Vietnam Veterans the opportunity to participate in this research, we are preparing a letter for appeal to the head of the Illinois State Health Department, Dr. John R. Lumpkin, M.D., M.P.H.
To date, NCHS has sent us computerized certificate numbers and other data elements that will enable us to extract the necessary parent information from 60,000+ original death and birth certificates archived within the vital statistics offices of the 45 participating registration areas. We have also submitted standardized applications as required by the States of Texas, Maryland and Massachusetts for review of our policies for the protection of human subjects prior to the release of any personal identifiers. We expect many if not most of the other registration areas will also require some form of additional assurance or clearance before they release the actual parent identifiers to us. Within a week, we will be mailing out each State's listing of certificate numbers along with our protocol and assurances for the protection of human subjects and compliance with the Privacy Act.
From our communications with NCHS and with the various registration areas, we have determined that natality and fetal death databases predating 1989 did not always identify specific birth defects like spina bifida or anencephaly. Between 1962 and 1989, the standard birth certificate and fetal death certificate forms in use had a place for the birth attendant to "write in" or "describe" specific birth defect(s) if present. However, in processing a completed birth certificate for vital statistics reporting purposes, data entry staff (of the NCHS and of some States) input only the presence (yes) or absence (no) of a birth defect, and not the diagnostic code to identify the specific defect. The situation is more complicated for fetal death certificates in that NCHS has no available listing of certificate numbers or causes of fetal death prior to 1989. Despite the fact that open spina bifida and anencephaly are among the most common birth defects and easily recognized at birth, there is considerable variability among and within the vital statistics registration areas with regard to diagnosis, nosology, data entry and data storage over time. Some States have birth defects registries that should enable us to maximize ascertainment. Unfortunately, most of the birth defects registries were not established until the 1980s. The high degree of regional and temporal variability will necessitate State- and time period-specific procedures to acquire parent identifiers for affected stillbirths and surviving offspring born before 1989. We have proposed to conduct a "pilot test" of different cost-conservative approaches to the ascertainment of affected stillbirths and surviving offspring using the vital statistics databases of the State of Texas. Texas is a reasonable site for the pilot test because of its large population size and the considerable variability in its vital statistics data resources over time. In addition, Texas is estimated to have one of the largest populations of Vietnam Veterans and the Texas Vital Statistics Office (in Austin) is within driving distance of our Houston research offices. Our proposal to begin the pilot studies is currently under review and we are awaiting word from the State Vital Statistics Registrar.
Dr. Fran Murphy of the Department of Veterans Affairs (VA) has agreed to facilitate our access to the VA's national listing of over 600 veterans who have reported the birth of offspring with neural tube defects. Access to this list is important to ensure that all Vietnam Veterans (or their families) who might be eligible for and interested in participating in this study will have the opportunity to do so. It is our understanding that the VA originally acquired a list of 600 Vietnam veteran parents from the Spina Bifida Association of America (SBAA). We have also spoken with Ms. Susan Liebold who directed the development of the SBAA registry of Vietnam veteran parents. Ms. Liebold was very helpful in explaining how the registry was developed. We understand that the VA is now adding to the list Vietnam Veterans (or their families) who have recently applied for new VA benefits. The Secretary of the VA authorized the new benefits in response to a 1996 report by the Institute of Medicine (IOM) of "limited/suggestive evidence" for an association between Vietnam Veterans' exposure to Agent Orange and the occurrence of neural tube defects in their offspring. At Dr. Murphy's request, we have provided copies of our full protocol and IRB approvals for her review, and we are awaiting her response.
Future Activities:
- Because we know of no complete listing of all the veterans who served in Vietnam, we are exploring the use of an automated index of all veterans' archived military records maintained by the National Personnel Records Center (NPRC) in St. Louis, Mo. The NPRC index is a fairly exhaustive listing of veterans separated from military service since before World War II. The data elements are limited to the veteran's name, registration or file location number, military service number and branch of the military. Unfortunately, there are no indicators for veterans' dates of service or locations of service. Despite these limitations, a previous study of post-traumatic stress disorder in returning Vietnam Veterans (the National Vietnam Veterans' Readjustment Survey or NVVRS) was able to draw representative samples of Vietnam Veterans from the NPRC database. In drawing samples of veterans, the NVVRS used the unique registration numbers that NPRC assigned to each veteran's file upon receipt of his/her records following the veterans' official separation. NPRC assigns the registration numbers in chronologic order, and certain series of numbers were used for veterans separated between 1962 and 1975. We plan to use the NPRC index and its chronologic assignment of registration numbers to help fill in gaps in the DoD listing of Vietnam Veterans. Dr. del Junco gained experience in using the DoD Vietnam Veteran database and the NPRC database while constructing the National Registry of Women Veterans (NRWV). Dr. del Junco's working copy of the NPRC index is currently stored at the VA's Automation Center in Austin, TX. Dr. del Junco's NPRC data files are being copied to magnetic tapes that can then be consolidated onto dedicated hard drives for faster processing at UTSPH.
- Dr. Murphy also offered to facilitate our access to the VA's roster of Vietnam Veterans. We know that the DoD's Environmental Support Group (ESG) created the original listing of Vietnam Veterans (~2.7 million) and that the list is considered incomplete. However, we do not know whether the VA has added veterans to the ESG listing. Several years ago, the VA established a registry of Vietnam Veterans who apply for VA benefits with health concerns relating to possible Agent Orange exposure. We do not know the degree of overlap between the VA Agent Orange Registry and the DoD ESG listing. At one time, Dr. Han Kang, head of the VA's Environmental Epidemiology Office and a member of the Steering Committee for the NRWV, described plans to acquire listings of Vietnam Veterans from the 20 or so States that had offered bonuses to returning Vietnam Veterans. Dr. Kang indicated that he would use the bonus listings to help fill in gaps in the ESG database. We plan to follow up on this issue with Dr. Murphy to ensure that we do not inadvertently exclude known Vietnam Veterans from our study sampling frame. This is an important concern as it has been reported that Vietnam Veterans who may have had significant cumulative herbicide exposure were excluded from previous research on this topic.
- We are exploring available probabilistic matching algorithms to match veteran identifiers with "possible parent" identifiers. We are looking into site licensing options for the commercially available software, (e.g., "MatchwareJ"). The site licenses are very expensive, ($6,000) but we may be able to negotiate a cooperative sharing arrangement through the Texas State Health Department which has MatchwareJ site licenses for two of their ongoing programs: ImmTrac (which tracks childhood immunizations) and the Texas Cancer Registry. Alternatively, we may be able to negotiate a subcontract with NCHS's National Death Index (NDI) which has developed its own matching algorithm based on the individual's first and last names and month and year of birth. Again, we will opt for the most cost conservative and effective approach.
- To aid in our efforts to reconstruct individual veterans' lifetime exposure to herbicides and other environmental agents containing dioxin, we have contacted Dr. Jeanne Mager Stellman at Columbia University. In June 1998 the IOM awarded Dr. Stellman and her husband, Dr. Steven D. Stellman, a $5 million grant to continue their work in developing models to estimate individual herbicide exposure during the Vietnam Conflict. The Stellmans will also be examining the long-term health consequences of herbicide exposure to the civilian population of Vietnam (http://www.columbia.edu/cu/record/23/24/17.html). Dr. Stellman indicated that she was eager to talk with us at length and would be contacting us in a few days.
- To gain additional insight into veterans' exposure and war-time experiences, we have reviewed reports of the congressional hearings on "Links Between Agent Orange, Herbicides, and Rare Diseases" between 1989 and 1990. We will also be reviewing special library collections of Vietnam War materials available in Texas. The collections are located at the Texas State Library in Austin (Archives Division, Texas Veterans Agent Orange Assistance Program files), Texas Tech in Lubbock (Center for the Study of the Vietnam Conflict), and Texas A & M Universities at College Station (Ranch Hand Collection).
- The PCR equipment has arrived and Dr. Xi-Feng Wu and her research assistant are making preparations for the nation-wide shipment of blood samples to her laboratory and for the genetic assays.
- We are developing a web site for interested veterans, their families, researchers and other interested individuals to review for background information about this research and for periodic project updates. We expect the web site to be up and running by December.
- We have applied for a toll free telephone number so that interested veterans, their families and study participants can get their questions about this study answered.
- We have drafted a 2-page questionnaire on military and reproductive histories that will be mailed to the sample of 10,000 Vietnam Veterans to recruit eligible study participants. In developing the questionnaire form, we have reviewed previous reproductive health survey forms developed by the Centers for Disease Control, the Semiconductor Industry Association, the VA and the New York State Department of Health among others. Our questionnaire will be printed by the National Computer Systems (NCS) in a "bubble" format that can be computer-scanned to avoid data entry errors. Because both the DoD and VA have traditionally used NCS forms in collecting health information, we hope that most of the veteran respondents will be familiar and comfortable with this format. If any veterans need assistance in completing the forms, we will provide our toll free telephone number for their convenience.
- We are scheduled to attend the VVA Board Meeting in Washington D.C. on the morning of October 16th, 1998. We will be providing the Board more information about our study, our toll free telephone number (for interested veterans and their families) and our web site information. We will also request the Board's assistance in disseminating this information to the VVA membership across the Nation.
- We are also scheduled to meet with Admiral Zumwalt on October 16th. We have invited Admiral Zumwalt to present a lecture to the students and faculty of the UTSPH as part of the UTSPH colloquium series in January 1999.
Journal Articles:
No journal articles submitted with this report: View all 3 publications for this projectSupplemental Keywords:
RFA, Health, Scientific Discipline, Toxics, Genetics, Epidemiology, Chemistry, pesticides, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, genetic susceptability, Biology, dioxin, sensitive populations, Vietnam veterans, spina bifida, P450 genes, exposure, human exposure, genetic polymorphisms, environmentally caused disease, human susceptibility, reproductive health, herbicides, dioxin exposure, genetic susceptibilityProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.