This chapter provides background information on the current population of Vietnam veterans, the military use of herbicides during the Vietnam War, how different groups of veterans were exposed to the herbicides and how that exposure can be characterized, and the determination of risks due to that exposure. It condenses and updates some of the information presented in chapters 2 (Evaluating the Evidence) and 3 (Exposure to the Herbicides Used in Vietnam) of Veterans and Agent Orange: Update 2014 (NASEM, 2016a), which contain more detailed descriptions of the topics under discussion.
Although the conflict ended more than 40 years ago, there are a substantial number of Vietnam veterans who are still living and who, because of herbicide exposure in Vietnam, may have a higher risk than the general public for various negative health effects. The exact number of U.S. military personnel who served in Vietnam is unknown because deployment to the theater was not specifically recorded in military records. Estimates range from 2.6 million to 4.3 million (see Table 2-1), depending on which dates are used to define the Vietnam era and which areas are included in the Vietnam theater of operations (that is, Laos, Cambodia, Vietnam, and the surrounding waters). Approximately 7,500 American women are thought to have served in Vietnam (VA, 2017a). The lack of a comprehensive or official roster of U.S. Vietnam veterans has made it much more difficult to conduct epidemiology studies of health trends in this group of
|Reference||Definition of Service||Time Period||N (millions)|
|DoD (1976)||Vietnam||1/1/65 – 3/31/73||2.6|
|Fischer et al. (1980)||Vietnam||8/64 – 6/75||3.8|
|VA (1985)||Vietnam theater||8/4/64 – 5/7/75||2.7|
|Kulka et al. (1988)||Vietnam theater||8/64 – 5/75||3.1|
|DoD (1976)||Vietnam theater||1/1/65 – 3/31/73||3.4|
|BLS (1990)||Vietnam theater||8/64 – 5/75 (males)||3.7|
|Fischer et al. (1980)||Vietnam theater||8/64 – 6/75||4.3|
|BLS (1990)||Vietnam era||8/64 – 5/75 (males)||7.9|
|VA (1985)||Vietnam era||8/4/64 – 5/7/75||8.3|
|DoD (1976)||Vietnam era||8/4/64 – 1/27/73||8.7|
NOTE: BLS, Bureau of Labor Statistics; DoD, Department of Defense; VA, Department of Veterans Affairs.
military personnel or to track their survival. However, Australian, New Zealand, and South Korean militaries did keep registries of personnel who were deployed to Vietnam.
Beginning in 1990, the Bureau of Labor Statistics used its Current Population Surveys to generate several estimates of the number and age distributions of deployed and non-deployed male Vietnam-era veterans in the civilian population. The 1990 Survey estimated that the number of surviving deployed Vietnam veterans was 29.0% of living male Vietnam-era veterans and 32.7% of surviving non-deployed veterans (Cohany, 1992; NASEM, 2016a).
In 2018, VA estimated that approximately 5,978,000 Vietnam-era veterans (deployed and non-deployed, defined as dates of service from August 1964 to April 1975) were living (VA, 2018c). The committee notes that current information on overall mortality in U.S. Vietnam veterans themselves has been elusive. The most recent reliable information was obtained in the 30-year update of mortality (through 2000) based on the Vietnam Experience Study (Boehmer et al., 2004). The study reported that mortality among the deployed veterans was approximately 9% higher than among the non-deployed veterans. A follow-up study of a random sample of 1,000 Australian Vietnam veterans selected from Australia’s comprehensive roster of 57,643 service members deployed to Vietnam found that mortality among Vietnam veterans was 11.7% through 2004 (O’Toole et al., 2010). This estimate of mortality among Australian veterans is slightly higher than but comparable with what was reported among Americans in the Vietnam Experience Study. The most recent update on mortality among female U.S. Vietnam veterans stated that at the end of 2010, 20.2% of the deployed women in the cohort had died compared with 24.6% of those who remained in the United States (Kang et al., 2014a). However, there are considerable differences
in mortality profiles between men and women, and the information provided by Kang and colleagues may not necessarily apply to the majority of American Vietnam veterans who are male. VA informed the committee that an updated mortality study was underway as of 2017 (Davey, 2017), but no results were available at the time the committee completed its work.
Military use of herbicides in Vietnam took place from 1962 through 1971. Specific herbicides were selected based on tests conducted in the United States and elsewhere that were designed to evaluate defoliation efficacy (IOM, 1994; Young and Newton, 2004). Four compounds were used in the herbicide formulations in Vietnam: 2,4-dichlorophenoxyacetic acid (2,4-D); 2,4,5-trichlorophen-oxyacetic acid (2,4,5-T); 4-amino-3,5,6-trichloropicolinic acid (picloram); and dimethylarsinic acid (DMA, or cacodylic acid). These herbicides were used to defoliate inland hardwood forests, coastal mangrove forests, cultivated lands, and zones around military bases. Whereas the chlorinated phenoxy acids 2,4-D and 2,4,5-T persist in soil for only a few weeks, picloram is much more stable and can persist in soil for years, and cacodylic acid is nonvolatile and stable in sunlight (NRC, 1974). More details on the herbicides used are presented in Chapter 4.
However, other toxic compounds were also present in these herbicide formulations. Specifically, polychlorinated dibenzo-p-dioxins (PCDDs), which includes 75 different congeners that vary by the number and placement of the chlorine atoms, can be formed during the manufacture of 2,4,5-T and the half-lives of these in subsurface soil may exceed 100 years (Sinkkonen and Paasivirta, 2000). One contaminant of particular concern is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). This compound is an unintentional byproduct of the production of 2,4,5-trichlorophenol (NRC, 1974). The structures of the chemicals of interest (COIs) identified above are shown in Figure 2-1.
Herbicides were identified by the color of a band on 55-gallon shipping containers and were called Agent Pink, Agent Green, Agent Purple, Agent Orange, Agent White, and Agent Blue. Table 2-2 shows the herbicides used in Vietnam by color code name and summarizes the chemical constituents, concentration of active ingredients, years used, and estimated amount sprayed, based on original and revised estimates. Two different formulations of Agent Orange were used in the course of military operations in Vietnam. All agents were liquid except Agent Blue, which was used in powder form in 1962–1964 and as a liquid in 1964–1971. Agent Pink, Agent Green, Agent Purple, Agent Orange, and Agent Orange II all contained 2,4,5-T and were contaminated to some extent with TCDD. Agent White contained 2,4-D and picloram. Agent Blue (powder and liquid) contained cacodylic acid.
|Code Name||Chemical Constituentsa||Concentration of Active Ingredienta||Years Useda||Amount Sprayed|
|VAO Estimateb||Revised Estimatea|
|Pink||60% n-butyl ester, 40% isobutyl ester of 2,4,5-T||961–1,081 g/L acid equivalent||1961, 1965||464,817 L (122,792 gal)||50,312 L sprayed; 413,852 L additional on procurement records|
|Green||n-butyl ester of 2,4,5-T||—||1961, 1965||31,071 L (8,208 gal)||31,026 L on procurement records|
|Purple||50% n-butyl ester of 2,4-D, 30% n-butyl ester of 2,4,5-T, 20% isobutyl ester of 2,4,5-T||1,033 g/L acid equivalent||1962–1965||548,883 L (145,000 gal)||1,892,733 L|
|Orange||50% n-butyl ester of 2,4-D, 50% n-butyl ester of 2,4,5-T||1,033 g/L acid equivalent||1965–1970||42,629,013 L (11,261,429 gal)||45,677,937 L (could include Agent Orange II)|
|Orange II||50% n-butyl ester of 2,4-D, 50% isooctyl ester of 2,4,5-T||910 g/L acid equivalent||After 1968||—||Unknown; at least 3,591,000 L shipped|
|White||Acid weight basis: 21.2% triisopropanolamine salts of 2,4-D, 5.7% picloram||By acid weight, 240 g/L 2,4-D, 65 g/L picloram||1966–1971||19,860,108 L (5,246,502 gal||20,556,525 L)|
|Blue, powder||Cacodylic acid (dimethylarsinic acid) sodium cacodylate||Acid, 65% active ingredient; salt, 70% active ingredient||1962–1964||—||25,650 L|
|Blue, aqueous solution||21% sodium cacodylate + cacodylic acid to yield at least 26% total acid equivalent by weight||Acid weight, 360 g/L||1964–1971||4,255,952 L (1,124,307 gal||4,715,731 L)|
|Total, all formulations||—||—||—||67,789,844 L (17,908,238 gal)||76,954,766 L (including procured)|
Estimates of TCDD Concentrations and Amounts of Herbicides Sprayed
TCDD concentrations in individual herbicide shipments were known to vary between batches and between manufacturers, but the concentrations were not recorded (FAO/UNEP, 2009; Young et al., 1976). In 1974, domestic manufacturing standards for 2,4,5-T required that TCDD not be present at more than 0.05 parts per million (ppm) (NRC, 1974). Tests of TCDD concentrations were conducted in stocks of Agent Orange that remained after the conflict that had been returned from South Vietnam or had been procured but not shipped. The concentration of TCDD in these samples ranged from less than 0.05 ppm to almost 50 ppm, and averaged 2–3 ppm in two sets of samples (NRC, 1974; Young et al., 1978). Later work by Stellman et al. (2003a) resulted in substantial revisions of the earlier estimates of TCDD contamination in the herbicide formulations. The researchers concluded that the mean TCDD concentration in Agent Orange was closer to 13 ppm than to the earlier estimate of 3 ppm. Using their revised estimate, the researchers proposed that 366 kilograms of TCDD was likely applied in Vietnam between 1961 and 1971.
Several studies have attempted to estimate the amount of herbicides sprayed in Vietnam. Through the National Academies of Sciences, Engineering, and Medicine (“the National Academies”), one committee used records gathered from August 1965 through February 1971 and calculated that about 18 million gallons (about 69 million liters) of herbicides were sprayed from helicopters and other aircraft over an area of about 3.6 million acres in Vietnam over that time period (NRC, 1974). This estimate does not include the amount of herbicides sprayed on the ground to defoliate the perimeters of base camps and fire bases or the amount sprayed by Navy boats along river banks.
A revised analysis of spray activities and of the exposure potential of troops emerged from a study overseen by a committee of the Institute of Medicine (IOM, 1997, 2003a,b). That work yielded new estimates of the amounts of military herbicides used in Vietnam from 1961 through 1971 (J. M. Stellman et al., 2003a). The investigators reanalyzed the original data sources used to develop herbicide-use estimates in the 1970s and identified errors that had inappropriately removed spraying missions from the dataset. They also added new data on spraying missions that took place from 1961 to 1965. Finally, a comparison of procurement records with spraying records found errors that suggested that additional spraying had taken place but had gone unrecorded at the time. The new analyses led to a revision of the estimates of the amounts of the agents applied, as indicated in Table 2-2, as well as of the concentration of TCDD-containing herbicides. The new research effort estimated that about 77 million liters were applied, which is about 9 million liters more than the previous estimate.
The lack of accurate estimates of chemical exposures experienced by U.S. military personnel who served in Vietnam has significantly hindered
the epidemiological study of the health effects associated with herbicides and TCDD. For example, some military personnel stationed in cities or on large bases may have received little or no herbicide exposure, whereas troops who moved through defoliated areas soon after treatment may have been exposed through many pathways, including skin contact (directly or indirectly through clothing), direct (through contaminated foodstuffs) or indirect (through hand-to-mouth contact) ingestion, or via contaminated water (drinking, bathing, or immersion during operations). The lack of records regarding individual behaviors and locations combined with the lack of contemporaneous chemical measurements and the lack of a full understanding of the movement and behavior of the defoliants in the environment greatly reduces the ability to conduct the exposure assessments that are necessary for ascertaining the association between the COIs and health effects among Vietnam veterans.
Consequently, most studies have focused on populations that had well-defined tasks that brought them into contact with the agents. These populations primarily include Air Force personnel involved in fixed-wing aircraft spraying activities (often referred to as Operation Ranch Hand) and members of the U.S. Army Chemical Corps. The exposures of ground troops are difficult to define, so this group has not been studied as intensively. In accordance with Congress’s mandated presumption of herbicide exposure of all Vietnam veterans, Veterans and Agent Orange (VAO) committees have treated Vietnam-veteran status as a proxy for herbicide exposure when more specific exposure information is not available.
Military personnel who came into direct contact with the herbicidal chemicals through mixing, loading, spraying, and clean-up activities had relatively high chemical exposures. The precise number of U.S. military personnel who handled herbicides directly is not known. However, two groups have been identified as high-risk subpopulations among veterans: Air Force personnel involved in Operation Ranch Hand and members of the Army Chemical Corps. Additional units and individuals handled or sprayed herbicides around bases or communication lines. For example, Navy river patrols were reported to have used herbicides to clear inland waterways, and engineering personnel used herbicides to remove underbrush and dense growth when constructing fire-support bases. At the time, the herbicides used in Vietnam were not thought to present an important human health hazard, so few precautions were taken to prevent the exposure of personnel (GAO, 1978, 1979). Thus, military personnel did not typically use chemical-protective gloves, coveralls, or protective aprons, and dermal exposure almost certainly occurred in these populations in addition to exposure by inhalation and other routes.
Operation Ranch Hand
Air Force personnel who participated in Operation Ranch Hand were the first Vietnam-veteran population to receive special attention with regard to herbicide exposure. The Air Force Health Study (AFHS) was a longitudinal, prospective epidemiologic study initiated by the Air Force in 1979. Its purpose was to determine whether Air Force personnel who had participated in Operation Ranch Hand had experienced adverse health outcomes as a result of their service. The study protocol had three components: a retrospective mortality study, a retrospective morbidity study, and a 20-year prospective follow-up study.
The 20-year prospective follow-up study identified 1,242 Ranch Hands who were individually matched on age, race, and military occupation to comparison subjects who served in the Air Force between 1962 and 1971 and who were stationed in and flew cargo operations elsewhere in Southeast Asia during the Vietnam conflict but had not been exposed to tactical herbicides. The comparison group was assumed to be similar to the Ranch Hands regarding lifestyle, training profiles, and socioeconomic factors. The study itself consisted of six comprehensive exams that began with a baseline exam in 1982 and occurred thereafter in years 3, 5, 10, 15, and 20 of the study. A comprehensive set of clinical measurements and observations were made, and biological specimens (serum, whole blood, urine, semen, and adipose tissue) were obtained and preserved during the exams. In all, 2,758 individuals participated in at least one exam cycle. Data collection and analysis for the formal study was completed in 2006 (IOM, 2015).
Exposure among Ranch Hands and the comparison group was evaluated by objective measurements of TCDD in serum samples drawn in 1987 or later, and serum TCDD concentrations were often used as the primary exposure metric for epidemiologic classification in the AFHS (AFHS, 1991a; Kern et al., 2004; Michalek et al., 2001a, 2003; Pavuk et al., 2003). Pavuk et al. (2014) examined the serum concentrations of several dioxins and dioxin-like chemicals in serum samples gathered in 2002 from 777 Ranch Hands and 1,173 AFHS comparison subjects. While the median serum TCDD levels were more than twice as high in the Ranch Hands as in the comparison veterans (5.0 and 2.2 pg/g, respectively), no substantial differences were found between these groups for the other COIs. Additionally, the authors compared serum dioxin levels in AFHS participants with data collected by the National Health and Nutrition Examination Survey (NHANES) during 2001–2002 in U.S. civilian men of the same age range. The Ranch Hands had serum concentrations of dioxins that were similar to those found in the civilians except for TCDD, where the Ranch Hand mean level of 9.5 pg/g lipid was more than three times the NHANES mean level of 2.5 pg/g lipid. This demonstrates the specificity of the dioxin exposure experienced from contact in Vietnam with military herbicides.
Additionally, several methods for estimating the herbicide exposure of members of the cohort were developed based on questionnaires that focused on such factors as the number of days of skin exposure, the percentage of skin area exposed, and the concentration of TCDD in the different herbicidal formulations (Michalek et al., 1995). Overall, serum TCDD was generally elevated among airmen whose jobs involved more frequent handling of herbicides, but there was no clear demarcation between the distributions of serum TCDD concentrations in the Ranch Hands and those in the comparison group (AFHS, 1991a). A more detailed discussion of the study design and exposure measurement methods used in the AFHS can be found in Chapter 5.
As illustrated by Figure 2-2, the median TCDD levels in veterans who had worked in Operation Ranch Hand were higher than those measured in their own comparison group or in ground troops. The TCDD concentrations found in the controls were of the magnitude of a few parts per trillion (ppt), which are in the range of contemporaneous background levels. Herbicide production workers, by contrast, have serum TCDD levels that are about an order of magnitude higher, and individuals who resided near the site of the industrial explosion in Seveso, Italy, had serum TCDD levels that are about two orders of magnitude higher (Pirkle et al., 1995).
Army Chemical Corps
Members of the Army Chemical Corps used hand-operated equipment and helicopters to conduct smaller-scale operations, including defoliation around special-forces camps; clearing of the perimeters of airfields, depots, and other bases; and small-scale crop destruction (NRC, 1980; Thomas and Kang, 1990; Warren, 1968). Studies of health effects related to herbicide exposure in this population were first conducted in the late 1980s (Thomas and Kang, 1990). A small feasibility study of deployed and non-deployed Vietnam-era veterans from within the Army Chemical Corps found an association between veterans reporting having sprayed herbicides and higher serum TCDD concentrations (Kang et al., 2001); this finding was confirmed in a follow-up study of a larger fraction of the cohort (Kang et al., 2006). Modeling efforts (Ross et al., 2015a,b) have also found that higher exposures were probably experienced by those involved with mixer, loader, and applicator activities than by bystanders because the former were generally in closer proximity to and had more frequent contact with the herbicides.
Other Groups of Herbicide Handlers
Other veteran populations also handled herbicides during their service in Vietnam, although probably to a small degree. For example, as part of Operation PACER IVY, Air Force personnel who were separate from, but who were also assisted by, the Ranch Hands and Army Chemical Corps were responsible for removing stocks of Agent Orange from Vietnam to Johnston Island in the central Pacific Ocean (Young, 2009). As part of the operation, procedures included the identification of unused herbicides, the transport of the identified herbicides to a central location in Vietnam for relabeling, and re-drumming for about half of the barrels before shipment. Most of the relabeling, repackaging, and handling of Agent Orange during PACER IVY was overseen and conducted by contractors from China, local residents, and the Vietnam military, so exposure to U.S. military personnel was likely low. However, there were spills of Agent Orange in the re-drumming and storage areas, which contaminated surrounding soils and asphalt (Young, 2009), and these have been suggested as possible sources of exposure.
Other possible points of contamination for Vietnam-era veterans include defoliation tests conducted in South Vietnam as part of Project AGILE; ports in the United States that served as embarkation points for shipping of Agent Orange to Vietnam; storage locations on Johnston Island, where contamination could have occurred from the re-drumming and maintenance of drums that contained Agent Orange; and at-sea incineration of Agent Orange as part of Operation PACER HO (Young, 2009). Because the Army of the Republic of Vietnam was responsible for the handling, transport, and storage of herbicides from the time it was delivered to Vietnam until it was loaded onto Ranch Hand aircraft, Young
asserts that the herbicide exposures of Allied troops during these procedures may have been negligible.
Given the widespread, long-term use of herbicides in Vietnam, it is reasonable to assume that many military personnel were inadvertently exposed to the COIs. In contrast with government reports and veterans’ testimony about exposure (CDC, 1989b; GAO, 1979), Young et al. (2004a,b) used data from unpublished military records and environmental-fate studies to argue that ground troops had little direct contact with herbicide sprays and that TCDD residues in Vietnam had low bioavailability. They also argued that direct exposures of ground troops were relatively low because herbicide-spraying missions were carefully planned and because spraying occurred only when friendly forces were not in the target area.
To resolve the issue, numerous attempts were made in the 1980s to characterize the herbicide exposures of ground troops in Vietnam (CDC, 1988a; Erickson et al., 1984a; NRC, 1982; S. D. Stellman and J. M. Stellman, 1986; S. D. Stellman et al., 1988a). Those efforts combined self-reports of contact with herbicides or military service records with aerial-spray data to produce a measure of the opportunity for exposure (discussed in greater detail later in this chapter). The search for a way to validate this method led to the development of exposure biomarkers in veterans. Initial studies measured concentrations of dioxin in the adipose tissue of veterans (Gross et al., 1984; Schecter et al., 1987), and dioxin concentrations in adipose tissue were then linked to dioxin concentrations in blood (Kahn et al., 1988). The Centers for Disease Control and Prevention’s (CDC’s) Agent Orange Validation Study measured TCDD concentrations in blood serum from a relatively large sample of Vietnam veterans and other Vietnam-era veterans (CDC, 1989a) but did not find a statistically significant difference in mean serum TCDD concentrations between the groups. The mean values in each group were about 4 ppt (CDC, 1988a). However, the long lag time between exposure and the serum measurements (about 20 years) leads to questions regarding the accuracy of exposure classification based on serum concentrations. The first VAO committee cautioned that serum TCDD measurements that are collected years after the potential exposure occurred should not be regarded as a “gold standard” or as a fully accurate measure of herbicide exposure because each COI has a different biological half-life. More details on the metabolism of the COIs are presented later in this chapter.
Brown Water Navy
Navy riverine units (or the “Brown Water Navy”) are known to have used herbicides while patrolling inland waterways (IOM, 1994).1 It is generally acknowledged that estuarine waters became contaminated with herbicides and dioxin as a result of shoreline spraying and runoff from spraying on land, particularly in heavily sprayed areas that experienced frequent flooding. Thus, military personnel who did not serve on land could have been among those exposed to the chemicals during their service in Vietnam.
Blue Water Navy
Dioxin exposure among personnel who served offshore but within the territorial limits of the Republic of Vietnam has also been of concern. It has been hypothesized that in addition to possibly experiencing drift from herbicide-spray missions, personnel on ships that converted seawater by distillation may have been exposed via drinking water. Those concerns were heightened by the findings of an Australian study that showed that TCDD could be enriched in a simulation of the potable-water distillation process that was used on U.S. Navy and Royal Australian Navy ships during the Vietnam War era (Muller et al., 2002). The National Academies convened the Blue Water Navy Vietnam Veterans and Agent Orange Exposure Committee to address that specific issue; its report found that there was inadequate information to determine the extent of exposure experienced by Blue Water Navy personnel, but that there were possible routes of exposure (IOM, 2011b).
Vietnam Military and Civilians
Although studies of the residents of Vietnam are not directly relevant to the committee’s task, a summary is provided because these studies may inform possible routes of exposure in U.S. military forces, future epidemiologic studies, and the development of risk-mitigation policies. Researchers have attempted to characterize the herbicide exposure of residents of Vietnam in the process of trying to assess adverse reproductive and other outcomes (Constable and Hatch, 1985). Some researchers compared residents of South Vietnam with residents of unsprayed North Vietnam, others compared South Vietnam residents who lived in sprayed and unsprayed villages as determined by observed defoliation, and other researchers compared women from North Vietnam married to veterans who had served in South Vietnam with women whose husbands had not in order to evaluate reproductive and pregnancy outcomes. Few studies have provided information
1 E. R. Zumwalt, Jr. 1993. Letter to the Institute of Medicine Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides regarding draft version of the IOM chapter on the U.S. military and the herbicide program in Vietnam, May 20.
Armitage et al. (2015) indirectly estimated dermal exposure from direct over-spray and long-term dietary exposures in South Vietnam using an aerial dispersion model coupled with a chemical fate and transport model and additional models. The investigators concluded that people in the upland forests of South Vietnam did not commonly experience highly elevated exposures. Dwernychuk et al. (2002) evaluated dioxin contamination around former air bases in Vietnam. The researchers collected environmental and food samples, human blood, and breast milk from residents of the Aluoi Valley of central Vietnam and identified locations where relatively high dioxin concentrations existed in soil and water systems. Soil dioxin concentrations were particularly high in areas (termed “hot spots”) around former airfields and military bases where herbicides were handled. Other hot spots included depots of chemical defoliants, air bases used for defoliant spray missions, and areas where chemical defoliants were used extensively. People have since inhabited the areas in and around many former air bases and depots, which have become the focus of studies of environmental contamination and bioaccumulation. For example, studies of poultry raised by Vietnam residents currently living in hot spots have found that dioxin total toxic equivalent (TEQ) levels in poultry eggs are more than twice the adult exposure guideline set by the World Health Organization (WHO) and more than five times the child guideline (Hoang et al., 2014) and that the dioxin content per unit of fat mass in the muscle and liver of the poultry also exceeded the WHO guidelines (Banout et al., 2014).
Publications reviewed in earlier updates have reported environmental concentrations and human body burdens of dioxins in various areas throughout Vietnam (Brodsky et al., 2009; Feshin et al., 2008; Hatfield Consultants, 2009a,b; Nhu et al., 2009; Saito et al., 2010; Tai et al., 2011) and have found pervasive exposure to dioxins more than 50 years after the Vietnam War. Dioxin concentrations in breast milk reflect the residence location of the mothers, with levels and TEQs being elevated in areas where herbicides were sprayed or stored during the war.2 Another study compared men who had lived in and around the Phu Cat airbase for 50 years or more with men who lived in the unsprayed Kim Bang district of Ha Nam Province in North Vietnam (Manh et al., 2014). Men currently living in the vicinity of the Phu Cat air base have a greater body burden of dioxin than those who spent time in areas that had been the target of herbicide spraying (a geometric mean TEQ of 41.7 pg/g lipid in men who spent time closest to the air base, versus ~29 pg/g lipid for those in two nearby sprayed areas).
2 For example, Tai et al. (2011, pp. 6629–6630) reported that “[t]he total toxic equivalents of 2,3,7,8-substituted PCDDs/PCDFs in breast milk of mothers living in the hot spots, and the sprayed and unsprayed areas were 14.10 pg/g lipid, 10.89 pg/g lipid, and 4.09 pg/g lipid for primiparae and 11.48 pg/g lipid, 7.56 pg/g lipid, and 2.84 pg/g lipid for multiparae, respectively, with significant differences in the values among the three areas.”
Military personnel of the Republic of Korea served in Vietnam during 1964–1973. The Korean Veterans Health Study is a large epidemiological study of more than 114,000 South Korean veterans who served in Vietnam. Several publications from it, including one on how exposure metrics were derived, have been reviewed by prior VAO committees. A more detailed discussion of exposure measurement methods used with this cohort is found in Chapter 5.
Other nations also sent military personnel to assist the South Vietnam military. Reports on the morbidity and mortality of Australian Vietnam veterans have been published on different groups of service members who deployed to Vietnam. These groups include military and some nonmilitary personnel of both sexes who served on land or in the waters of Vietnam from May 23, 1962, to July 1, 1973. However, the comprehensive studies are limited to male members of the military, and most of the analyses focus on men who served in the defense forces—the Army (41,084), the Navy (13,538), and the Air Force (4,570). Objective measures of exposure were not collected, and deployment to Vietnam is generally considered a surrogate of exposure.
A total of 3,394 men and women from New Zealand served in Vietnam between 1962 and 1971, 36 of whom were killed in action or died of wounds or accidents. A cohort of 2,783 living male veterans has been followed prospectively using the New Zealand Veterans Affairs and National Health Index. The 23 women who served in Vietnam were excluded because analyses by sex would not have sufficient statistical power to rule out chance findings. As with the Australian cohort, objective measures of exposure were not collected, and deployment to Vietnam is considered a surrogate of exposure.
Previous volumes of the VAO series and later chapters of this report provide citations to research on these populations as appropriate.
The development of a means of characterizing the exposure of individual Vietnam veterans has long been a prime objective of researchers who are interested in refining epidemiologic investigations of health outcomes in this population. Serum TCDD levels might have been a very useful proxy for harmful exposures to all the components of the herbicides used by the U.S. military in Vietnam had they been measured both before and after deployment; however, these data were not collected. Since over time metabolic processes would have reduced the initial chemical concentrations by many half-lives, collecting new samples would not provide valuable information about exposures that occurred during the Vietnam War even among individuals who were likely highly exposed, such as some of the Ranch Hands. For example, serum TCDD measurements taken in 2002 from the Ranch Hands were still sufficiently elevated to distinguish exposed and unexposed
veterans at the group level. However, TCDD has a half-life of about 7.6 years, and the half-lives of the other COIs are considerably less. With the passage of several decades, serum concentrations decrease exponentially, and newly drawn serum samples are thus unlikely to be useful metrics for assessing health outcomes in surviving Vietnam veterans, occupational cohorts, or Seveso residents. The factors influencing TCDD’s half-life are discussed in Chapter 4.
The consideration of records detailing the herbicide spray missions has provided another approach to deriving individual-specific exposure estimates. Two models—a proximity-based Exposure Opportunity Index (EOI) model and an aerial spray distribution model (explained and contrasted below)—have been proposed for estimating the exposure of Vietnam veterans. However, to date only a few studies (which are addressed in detail later in the chapter) have used these exposure assessment methodologies to study the health of Vietnam veterans.
Other National Academies reports have addressed the issue of exposure assessment in military environments, pointing out both the challenges of gathering good contemporaneous information and the desirability of such data for assessing service members’ and veterans’ health and well-being (IOM, 2000a; NRC, 2000a,b).
Methodologic Issues and Considerations in Exposure Assessment
The focus of this section is on three key methodological issues that complicate the development of accurate exposure estimates in the Vietnam-veteran population and the other study populations discussed in this report: the latent period between exposure and disease, exposure misclassification, and exposure specificity.
The temporal relationship between exposure and disease is complex and often difficult to define in studies of human populations. Many diseases do not appear immediately after exposure. Cancers, for example, might not appear for many years after exposure. The latency period refers to the amount of time between an initiative event, such as a toxic exposure, and the manifestation of the clinical disease. For many disease processes the latency period is not known. If the latency period is underestimated, the effect of the exposure of interest on health outcomes will not be captured by epidemiological methods. Exposures can be brief (acute) or occur over a longer period of time (chronic). At one extreme, an exposure can be the result of a single event, as in an accidental poisoning. At the other extreme, a person exposed to a chemical that is stored in the body may continue to experience “internal exposure” for years even if exposure from the environment has ceased.
Exposure misclassification in epidemiologic studies can affect estimates of risk. In a case-control study, this would be a situation in which the reported measurement of exposure in either the cases or the controls (or sometimes in both cases and controls) is incorrect (classifying a person who was not exposed as having been exposed, for example). Non-differential exposure misclassification occurs if the probability of exposure misclassification is the same in both cases and controls. If this happens, then the estimated association between disease and exposure is biased toward the null value. In other words, one would expect the true association, if it exists, to be stronger than the observed association. Differential exposure misclassification occurs if the probability of misclassification is different between cases and controls. If this occurs, then the estimated association can be biased in either direction, either toward the null value or away from the null value. Then the true association, if it exists, might be stronger or weaker than the observed association.
When exposure is classified into more than two levels, the slope of a dose–response trend is not necessarily attenuated toward the null value even if the probability of misclassification is the same in the two groups of subjects being compared. Therefore, the observed trend in disease risk among the several levels of exposure may be either an overestimate or an underestimate of the true trend (Dosemeci et al., 1990). Greenland and Gustafson (2006) discussed the effects of exposure misclassification on the statistical significance of the result and demonstrated that if one adjusts for exposure misclassification when the exposure is represented as a binary variable, the resulting association is not necessarily more significant than in the unadjusted estimate. That result remains true even though the observed magnitude of the association might be increased.
The Update 2014 committee was concerned about the strong degree of misclassification associated with publications concerning various health outcomes authored by researchers who categorized exposure based on a variable in a patient’s electronic medical record indicating whether the individual was “exposed to Agent Orange” (Ansbaugh et al., 2013; Q. Li et al., 2013). Likewise, several studies of VA health care–user populations have been identified that continue to define exposure on the basis of that indicator in the medical record. That variable conveys a degree of authenticity that this and the prior committee strongly suspected is unmerited because there is little documentation about the source of information used to make this classification—deployment status, entry on the Agent Orange Registry, the veteran’s self-report, a physician’s observation that the patient has a condition presumed to be service-related, results of serum TCDD measurements performed on some patients, or perhaps some other criterion. Regardless, none of these approaches offers a reliable method of determining whether an individual was truly exposed to herbicides (above some unspecified level) or yields a method that can be applied uniformly to all veterans using the VA medical system, who themselves are a self-selected subset of veterans. The current committee concurs
with the Update 2014 committee’s concern that these publications do not adequately discuss the reliability of their exposure metric.
The evaluation of the findings of studies of persons exposed to components of the herbicides sprayed in Vietnam requires some decisions about their relative contributions to the VAO project’s evidentiary database. Only a few herbicidal chemicals were used as defoliants during the Vietnam conflict: esters and salts of 2,4-D and 2,4,5-T, cacodylic acid, and picloram in various formulations. TCDD as a contaminant of 2,4,5-T is also of import. The committee recognizes that in real-world conditions, exposure to TCDD virtually never occurs in isolation and that there are hundreds of similar compounds to which humans might be exposed, including other PCDDS, polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs). Human exposure to TCDD is almost always accompanied by an exposure to one or more of the other compounds, but the exposure of Vietnam veterans to substantial amounts of the other chemicals relative to the exposure to TCDD has not been documented. Studies that analyzed for dioxin-like PCDF and PCB congeners and expressed the results in terms of TEQs have also been considered since Update 1998.
Among the various chemical classes of herbicides that have been identified in published studies reviewed by the committee, phenoxy herbicides, particularly 2,4-D and 2,4,5-T, are directly relevant to the exposures experienced by U.S. military forces in Vietnam. On the basis of the assumption that compounds with similar chemical structure may have analogous biologic activity, information on the effects of other chemicals in the phenoxy herbicide class—such as 2-(2,4,5-trichlorophenoxy) propionic acid (fenoprop or Silvex), 2-methyl-4-chlorophenoxyacetic acid (MCPA), 2-(2-methyl-4-chlorophenoxy) propionic acid (mecoprop, MCPP), and 3,6-dichloro-2-methoxybenzoic acid (dicamba)—has been factored into the committee’s deliberations with somewhat less weight (see Figure 2-1).
Many scientific studies reviewed by the current and prior committees report exposures to broad categories of chemicals rather than to those specific chemicals. Many studies have examined the relationship between exposure to “pesticides” and adverse health outcomes, while others have used the category of “herbicides” without identifying specific chemicals. A careful reading of a publication often reveals that none of the COIs contributed to the exposures of the study population, so such studies could be excluded from consideration. Chapter 3, Evaluation of the Evidence Base, contains a detailed discussion of inclusion and exclusion criteria for the studies reviewed in the current update.
Modeling Herbicide Exposure in Vietnam
Two models have been used to estimate exposure to herbicides experienced by ground personnel in Vietnam: the EOI and AgDRIFT®. The models have different purposes; the EOI model was specifically developed to estimate herbicide exposure potential to persons on the ground on the basis of data on aerial spray history and troop locations, whereas AgDRIFT® is a modification of a model developed by the U.S. Forest Service that predicts agricultural pesticide ground concentrations based on variables related to dispersal, drift, and deposition. The AgDRIFT® model thus does not consider troop-location data, nor is it specific to exposures in Vietnam.
Exposure Opportunity Index Model
Following from recommendations contained in the first VAO report (IOM, 1994), VA asked the National Academies to issue a request for proposals seeking individuals and organizations to develop historical exposure-reconstruction approaches suitable for epidemiologic studies of the herbicide exposure of U.S. veterans during the Vietnam War (IOM, 1997). A team of researchers in Columbia University’s Mailman School of Public Health was awarded the contract for the Characterizing Exposure of Veterans to Agent Orange and Other Herbicides in Vietnam project. Several sources of information concerning spraying activities and information on the locations of military units assigned to Vietnam were integrated into a database. The resulting EOI model (J. M. Stellman and S. D. Stellman, 2003) generates individualized estimates (EOI scores) of the exposure potential of troops who served in Vietnam.
Mobility factor analysis, a technique used for studying troop movement, was developed for use in reconstructing herbicide-exposure histories. The analysis is a three-part classification system for characterizing the location and movement of military units in Vietnam. It comprises a mobility designation (stable or mobile), a distance designation (usually in kilometers) to indicate how far a unit might travel in a day, and a notation of the modes of travel available to the unit (by air, by water, or on the ground by truck, tank, or armored personnel carrier). A mobility factor was assigned to every unit that served in Vietnam.
The data were combined into a geographic information system (GIS) for Vietnam. Herbicide-spraying records were integrated into the GIS and linked with data on military-unit locations to derive individual EOI scores. The results are the subject of reports by the contractor (J. M. Stellman and S. D. Stellman, 2003) and the Committee on the Assessment of Wartime Exposure to Herbicides in Vietnam (IOM, 2003a,b). A summary of the findings on the extent and pattern of herbicide spraying (Stellman et al., 2003a), a description of the GIS for characterizing exposure to Agent Orange and other herbicides in Vietnam (Stellman et al.,
2003b), and an explanation of the EOI model based on that work (S. D. Stellman and J. M. Stellman, 2004) have been published in peer-reviewed journals. In those publications the researchers argued that it is feasible to conduct epidemiologic investigations of veterans who served as ground troops during the Vietnam War. The National Academies later issued a report that examined the feasibility of using the EOI model (IOM, 2008). The report concluded that “despite the shortcomings of the exposure assessment model in its current form and the inherent limitations in the approach, the committee agreed that the model holds promise for supporting informative epidemiologic studies of herbicides and health among Vietnam veterans and that it should be used to conduct studies” (p. 2). This model has since been used in analyses of the Korean Veterans Health Study (Yi and Ohrr, 2014; Yi et al., 2014b).
Ginevan et al. (2009a,b, 2014, 2015) proposed the use of the AgDRIFT® Tier III forestry model for estimating the deposition of herbicides via aerial spraying as alternative to the EOI model. They suggested that dermal exposure through both direct deposition and post-application transfer from foliage could be derived from application information such as aircraft speed and altitude, from nozzle characteristics, and from droplet evaporation and environmental parameters such as canopy density, canopy roughness, and crosswind speed. The authors did not consider exposures resulting from contact with soil and dust or through inhalation because they considered these routes to be negligible (Ginevan et al., 2009a; citing Driver et al., 1989; Gunther et al., 1977; Nadal et al., 2004). However, subsequent reviews of the methodology underlying the authors’ analyses (S. D. Stellman and J. M. Stellman, 2014, 2015) found several weaknesses that call the results by Ginevan et al. into serious question.
Part of the committee’s charge—derived from the text of Public Law 102-4—was to determine, to the extent permitted by the available scientific data, the increased risk of disease among veterans exposed to herbicides or the contaminant TCDD during service in Vietnam. Estimating the magnitude of risk of each particular health outcome among herbicide-exposed Vietnam veterans requires quantitative information about the dose–time response relationship for the health outcome in humans, information on the extent of herbicide exposure among Vietnam veterans, and estimates of individual exposure. Vietnam veterans were exposed to other agents and stressors—such as tobacco smoke, insecticides, therapeutics, drugs, diesel fumes, alcohol, hot and humid conditions, and combat—that may increase or decrease the ability of chemicals in herbicides to
produce a particular adverse health outcome. Few, if any, studies either in humans or in experimental animals have examined those interactions.
As mentioned earlier in this chapter, most health studies of Vietnam veterans were hampered by relatively poor measures of exposure to herbicides or TCDD and by other methodological problems. Most of the evidence on which the findings regarding associations are based, therefore, comes from studies of people exposed to TCDD or herbicides in occupational and environmental settings rather than from studies of Vietnam veterans. The committees that produced the first VAO report and the updates found that the body of evidence was sufficient for reaching conclusions about statistical associations between herbicide exposures and health outcomes but that the lack of adequate data on Vietnam veterans themselves complicated the consideration of this part of the charge.
Although some groups had well-documented high exposures of herbicides (such as participants in Operation Ranch Hand and Army Chemical Corps personnel), most Vietnam veterans had lower exposures to herbicides and TCDD than did the subjects of many occupational and environmental studies (see Figure 2-2 from Pirkle et al., 1995). The committees responsible for the first VAO report and the updates have concluded that in general it is impossible to quantify the risk posed to veterans by their exposure to herbicides in Vietnam.
After decades of research, the challenge of estimating the magnitude of potential risk posed by exposure to the COIs remains intractable. The requisite information is still not available despite concerted efforts to use modeling to reconstruct likely exposure from records of troop movements and spraying missions (J. M. Stellman and S. D. Stellman, 2003; S. D. Stellman and J. M. Stellman, 2004; J. M. Stellman et al., 2003a,b), to extrapolate from agricultural models of drift associated with spraying (Ginevan et al., 2009a; Teske et al., 2002), to measure serum TCDD in individual veterans (Kang et al., 2006; Michalek et al., 1995), and to model the pharmacokinetics of TCDD clearance (Aylward et al., 2005a,b; H. L. Chen et al., 2006; Emond et al., 2004, 2005, 2006). Additionally, there is still uncertainty about the toxicity and health effects of the specific COIs. Prior committees have thought it unlikely that additional information or more sophisticated methods would permit any sort of quantitative assessment of Vietnam veterans’ increased risks of particular adverse health outcomes that are attributable to exposure to the chemicals associated with herbicide spraying in Vietnam. Even if one accepts an individual veteran’s serum TCDD concentration as the best available surrogate for overall exposure to Agent Orange and the other herbicide mixtures sprayed in Vietnam, not only is it nontrivial to make this measurement, but the hurdle of accounting for biologic clearance and extrapolating to the proper timeframe remains. Accordingly, the lack of exposure estimations for Vietnam veterans will likely remain a hurdle to epidemiologic studies, and unless this issue is resolved, the potential for additional epidemiologic studies to yield improved information regarding the specific question of whether an association exists between herbicide exposure and health outcomes will remain limited.