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Disposition of the Air Force Health Study (2006)

Chapter: 2 Background

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Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

2
Background

This chapter provides background information on a number of topics related to the committee’s charge. It begins with accounts of the development of a military aerial herbicide delivery system and the Operation Ranch Hand spray program during the Vietnam War. The early history of the Agent Orange controversy is then reviewed along with the first studies of Vietnam veterans’ health. A detailed description of the Air Force Health Study (AFHS) follows—its origins, the development of the protocol, identification of the exposed and comparison cohorts, means by which exposure was characterized, collection and analysis of data, results of the research,1 and cost of conducting the study. The Department of Veterans Affairs (VA) compensation policy for health problems deemed to be associated with wartime exposure to herbicides is also outlined. The chapter concludes with a discussion of the Institute of Medicine’s (IOM) comprehensive reviews of the literature regarding adverse health outcomes and herbicide and dioxin exposure, as well as the role of AFHS reports and papers in that work.

This information forms the foundation for many of the committee’s findings, conclusions, and recommendations in succeeding chapters.

DEVELOPMENT OF A MILITARY AERIAL HERBICIDE DELIVERY SYSTEM

It has been said that the seeds of the Agent Orange controversy were planted during World War II (WWII) when the conquest of islands in the Pacific theater

1  

This chapter is not intended to provide a critical review of the research results—a task outside of the committee’s charge—but rather to recap the content of the reports and papers prepared by the investigators over the years.

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

of operations exacted enormous human tolls on the U.S. Army and Marine Corps units mounting first-wave beach assaults (Galston, 2001). At the time, high explosives designed expressly for tree destruction had been used by the military as one tactical option to eliminate the enemy advantage afforded by the dense indigenous vegetation. This tactic was eventually abandoned, as fallen trees could still provide effective cover and concealment for defensive enemy positions along targeted beachheads (Minarik, 1964).

Prior to WWII, the U.S. Army Air Corps had assembled the basic physical apparatus of aerial chemical delivery systems as part of its chemical warfare research and development effort (Buckingham, 1982). Methods for low-altitude application were well beyond preliminary developmental stages, and the atmospheric conditions necessary for the delivery of effective chemical concentrations to targets had also been characterized (Buckingham, 1982). Despite their availability during WWII, aerial chemical delivery systems for herbicide application were not widely implemented in the Pacific theater.2 The technology was, however, employed at many locations including Morotai, Palau, Iwo Jima, and Okinawa in an effort to rid regions of strategic importance of disease-carrying vectors (Cecil, 1986).3 In the 1950s, the British military effectively used aerially disseminated herbicides,4 a fact that did not go unnoticed by U.S. military planners and the State Department as the situation grew more volatile in Southeast Asia (SEA) during the late 1950s and early 1960s (Buckingham, 1997).

By the time President Kennedy took office in 1961, the U.S. military possessed a fairly well-developed arsenal of herbicidal agents. Three years prior to Kennedy’s inauguration, an efficient large-capacity system for the delivery of liquid agents had become standard U.S. Air Force (USAF) inventory (Buckingham, 1982). This system, referred to as the MC-1 Hourglass, comprised a 1,000-gallon tank, pump, and pipe assembly with six nozzles and emergency dumping capabilities (IOM, 1994). The MC-1 was the forerunner of the spray system that was ultimately fitted to the Fairchild C-123s flown in Vietnam.

Meanwhile, in 1959, an H-21 helicopter was successfully used for aerial delivery of herbicides to clear a grove of nuisance sugar maples from an artillery firing range at Camp Drum, New York.5 The herbicide used at Camp Drum was a 50:50 mixture of two phenoxyacetic acids: 2,4-dichlorophenoxyacetic acid

2  

Limited aerial spray tests did occur on some Japanese-controlled islands to demarcate navigation points and to remove dense tropical foliage (Buckingham, 1997).

3  

Vector-borne disease (malaria, dengue, filariasis, and fly-borne dysentery) was the major cause of lost man-hours for the Army Air Corps in the Pacific during WWII. Copper acetate arsenite (Paris Green dust) and dichlorodiphenyltrichloroethane (DDT) were among the insecticides used in the Pacific to destroy adult and larval vector populations (Cecil, 1986).

4  

During the Malayan Emergency (1953–1954) the British used helicopters and some fixed-wing aircraft for successful aerial delivery of sodium arsenate, and later, a mixture of trioxene and diesolene to agricultural targets (Buckingham, 1982).

5  

Known today as Fort Drum.

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

(2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T).6 The herbicide application achieved the desired effect: within one month, treated trees were undergoing abscission (falling) of leaves and significant regrowth was not observed the following year (Warren, 1968).

The organic acid mixture used at Camp Drum was only one herbicidal candidate of more than 1,000 compounds tested during and after WWII at the Army Chemical Corps laboratories at Fort Detrick, Maryland (Midwest Research Institute, 1967). Early synthetic pesticides were mainly inorganic compounds. The emergence of organic compounds as effective herbicidal agents can be attributed to the isolation and ultimate synthesis of compounds during the 1930s that were found to act as chemical messengers (hormones) in plants (Butler, 2005).7 Defoliants are a subclass of herbicides that induce abscission.8 Their application can, but does not necessarily, destroy the entire plant (Buckingham, 1982). Both 2,4-D and 2,4,5-T act as plant hormones, and application of species-appropriate concentrations ultimately induces abscission.

By the end of WWII, 2,4-D had found widespread use in the agricultural and forestry industries. More than 5 million pounds of 2,4-D were produced in 1945 and Weedone, which was released that same year, was the first 2,4-D-containing weed killer marketed in the United States for general use (Cecil, 1986). Both civilian and military WWII-era research efforts led to the same conclusion with respect to chlorophenoxy herbicides: formulations containing a combination of 2,4-D and 2,4,5-T were found to exhibit the most effective level of selective herbicidal activity for both broad-leafed and woody plants.9 Thus, the herbicides used in Vietnam were not novel compounds. Just one year prior to the launch of herbicidal missions in Vietnam, hundreds of thousands of miles of U.S. roads, railways, and utility easements as well as tens of millions of acres of agricultural land had been treated with chlorophenoxy herbicides, an appreciable percentage of which had been disseminated aerially (Buckingham, 1982).

6  

The mixture tested at Camp Drum in 1959 was actually Agent Purple, which was a 50:30:20 mixture of n-butyl 2,4-D, n-butyl 2,4,5-T, and isobutyl 2,4,5-T (Stellman et al., 2003).

7  

Butler (2005) summarizes the history of the development of 2,4-D and 2,4,5-T and the subsequent discovery of 2,3,7,8-tetrachlorodibenzo-p-dioxin as a 2,4,5-T contaminant.

8  

Abscission is typically governed by changes in diurnal cycle duration and occurs when auxin (3-indoleacetic acid) levels increase, ultimately leading to the production of enzymes that digest the structural plant material that secures the leaf to the plant stem. Both 2,4-D and 2,4,5-T trigger this same chain of chemical events (Galston, 2001).

9  

The selectivity of these compounds is based, in part, on leaf surface area in the horizontal plane, meaning horizontally planar leaves make better herbicide collection areas than leaves that grow predominately in the vertical plane (Buckingham, 1982). Selectivity holds true up to a certain threshold concentration (Cecil, 1986) and is also governed by variation in plant growth, absorption, and metabolism rates (Lavy, 1987).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

OPERATION RANCH HAND

The defoliation initiative that eventually became known as Operation Ranch Hand officially began in January 1962 (Buckingham, 1982). Aerial defoliants were used in Vietnam to efficiently clear vegetation providing concealment for enemy movements, bunkers, and other structures (McConnell, 1970). Major supply and communication routes vital to the U.S. mission, and therefore to the safety of U.S. military personnel, were under constant threat of guerrilla ambush as the Viet Cong had in many areas established complex networks of tunnels, caves, and trenches that under the cover of the dense jungle canopy were difficult, if not impossible, to detect from the air. These conditions put U.S. ground forces at a great disadvantage (Cecil, 1986). Defoliant operations in a much-reduced capacity also targeted agricultural concerns considered to be potential food sources for enemy troops.10 Although the Army Corps of Chemical Engineers and the Navy were also involved in defoliant missions,11 the bulk of defoliation efforts in Operation Trail Dust12 were undertaken by a largely volunteer group of Air Force personnel who eventually became known as the Ranch Hands.

In July of 1961, before the Ranch Hands arrived in South Vietnam, the Combat Development and Test Center at Saigon received its first shipments of defoliant chemicals from the United States (Buckingham, 1982) and, beginning in August of that same year, spray tests were conducted by the (South) Viet Nam Air Force using H-34 helicopter dissemination of Dinoxol, Trinoxol, and Concentrate 4813 (Cecil, 1986). Two months earlier, the Office of the Secretary of Defense tasked researchers at Ft. Detrick with a feasibility study of Vietnamese jungle defoliation (Young and Reggiani, 1988). Eighteen spray tests formed the basis of their analyses and in weighing the costs and strategic benefits, researchers determined that the most effective defoliant regimen for the region would involve the application of two distinct classes of herbicides—chlorophenoxy acids and cacodylic acids (Young and Reggiani, 1988).

The original unit, officially named Tactical Air Force Transport Squadron Provisional 1 (Buckingham, 1982) began trial operations in Vietnam in 1962 with three modified C-123 aircraft (McConnell, 1970). The unit initially com-

10  

Farmgate was the operational code name for the food deprivation project (Stellman et al., 2003).

11  

Ground delivery of herbicides also took place to a much lesser degree. Truck- and trailer-mounted sprayer units called “Buffalo” turbines as well as hand-held and backpack sprayers were used for treatment of roadsides and base perimeters (Stellman et al., 2003; Young and Reggiani, 1988). The “brown water Navy” treated the banks of inland rivers (Bullman et al., 1994).

12  

Operation Trail Dust was the code name of the U.S.–Vietnam allied herbicide program and Operation Ranch Hand referred specifically to the C-123 mission (Stellman et al., 2003).

13  

Dinoxol was a 50:50 formulation of butoxyethanol esters of 2,4-D and 2,4,5-T. The active ingredient in Trinoxol was 2,4,5-T. Concentrate 48 (Weedone) contained the ethyl ester of 2,4-D (Cecil, 1986).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

prised six pilots and 12 enlisted personnel (Buckingham, 1982) and was later supplemented with volunteers from Pope Air Force Base (AFB), North Carolina. At Pope AFB, Capt. Carl W. Marshall recruited from a pool of Air Force personnel who had volunteered for an earlier USAF counterinsurgency mission code-named Jungle Jim (Buckingham, 1982). USAF personnel from this pool readily volunteered for the new mission, which had been packaged as a 120-day temporary duty assignment to SEA during which unit members would don civilian attire and fly unmarked aircraft. Potential volunteers were also informed that if captured, the U.S. military would renounce any affiliation with them. Ultimately, six spray aircraft and 69 USAF personnel left for SEA in November 1961 as the first defoliation unit deployment (Buckingham, 1982) and arrived at Clark AFB in the Philippines on December 6. The first three spray-ready planes were ordered to Saigon on January 7, 1962 (Buckingham, 1982) and a shipment of Agents Blue and Purple arrived at Tan Son Nhut Air Base on January 9 (Young and Reggiani, 1988). The initial choice of Agents Blue—a water-soluble liquid containing the active ingredient hydroxydimethylarsine oxide (cacodylic acid)—and Purple—a 50:30:20 mixture of n-butyl 2,4-D, n-butyl 2,4,5-T, and isobutyl 2,4,5-T—was consistent with the recommendation that had been made by Ft. Detrick researchers a year earlier. On January 10, 1962, Ranch Hands flew their first spray mission using Agent Purple. While the application was ineffective—which was later thought to be attributable to the delivery of a suboptimal concentration of herbicide—Ranch Hand crews discovered that the herbicide destroyed the rubber seals of the Hourglass spray system (Buckingham, 1982). Thus, the Ranch Hands, operating under the call signs Cowboy and later Hades,14 were required to develop their own operational tactics tailored to indigenous conditions during their first year in Vietnam. By June 1962, the Ranch Hands were ready to fly their first tactical missions.

In 1968 the Special Aerial Spray Flight received the new unit designation of 12th Special Operations Squadron (McConnell, 1970). Generally, excepting missions associated with Operation Mule Train, Operation Flyswatter, and the Tet Offensive,15 the 12th Special Operations Squadron was engaged exclusively in the execution of defoliant operations. Over time, the unit developed a group persona that, like their mission, made them somewhat unique among their fellow service members. Contrary to initial plans of anonymity, the Ranch Hands wore

14  

In 1966 the 12th Air Commando Squadron moved from Tan Son Nhut to Ben Hoa. The change in call sign accompanied the move (Cecil, 1986).

15  

Operation Mule Train comprised logistical missions in 1962 and 1963, which the Special Aerial Spray Flight supported. Operation Flyswatter missions were carried out to kill malaria-carrying mosquitoes and other insects. The Ranch Hands flew airlift support missions during the 1968 Tet Offensive (Cecil, 1986).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

special insignia as well as purple scarves16 that were a source of controversy17 among USAF commanders and which would eventually come to be recognized as a unit symbol (Cecil, 1986). Like the purple scarf, the Chinese character for purple at the center of the Ranch Hand unit insignia echoed the namesake of one of the earliest herbicide agents used in Vietnam (Cecil, 1986).

Prior to each Ranch Hand mission, a flight mechanic or a crew chief facilitated herbicide loading. Herbicides were not loaded directly from the 18-gauge, 205-liter steel drums that were used for transport by all of the 11 companies18 that manufactured herbicides for the military (Young and Reggiani, 1988). Drums were offloaded from cargo vessels, transported to Ranch Hand unit locations, and then herbicide was transferred from drums to F-6 trailer tanks.19 An assembly of pumps, pipes, and hoses allowed the F-6 to remain stationary during aircraft tank filling. Residuals (2–5 liters per drum) were collected from inverted drums in a drip pan and used to treat base perimeters. It was common for military personnel to utilize discarded drums to fortify defensive positions and to construct barriers (Young and Reggiani, 1988).

Three to six C-123s typically made up a tactical formation (Meek, 1981). When mission20 requirements were at their highest levels between 1967 and 1969, more than 10 C-123s would fly in a single formation (Boyne, 2000; Cecil, 1986). C-123s normally at or above their weight limit were required to fly “low and slow,” typically at 150 feet and 130 knots for targets to be effectively treated. This meant that Ranch Hand aircraft were extremely vulnerable to enemy fire. Early formations flew at an altitude of 3,000 feet on target approach and then went into a 2,500 feet per second dive to the optimum spray delivery altitude of 150 feet. It was soon discovered that the high altitude approach was costing the aviators the element of surprise. A reverse approach was later used and formations would fly as low as 20 feet and then abruptly climb to the optimum spray altitude (Boyne, 2000). Shortly after a ground fire incident that disabled the hy-

16  

The purple scarf became part of the Ranch Hand uniform after a violet scarf had been presented to one of the flight commanders by South Vietnam Prime Minister Nguyen Cao Ky, who had accompanied the Ranch Hands on some of their early missions (Cecil, 1986).

17  

Policy coming from (commander of U.S. forces) General William Westmoreland’s office forbade the wearing of the purple scarves. However, threats made by Prime Minister Ky to close Tan Son Nhut over the wearing of the purple scarves resulted in an exception to the USAF uniform policy for Ranch Hands (Cecil, 1986).

18  

In a class action lawsuit initiated in 2004, more than 30 Agent Orange manufacturers are named (de Sola, 2004).

19  

Each F-6 tank could accommodate approximately 78 drums of herbicide (Young and Reggiani, 1988).

20  

Each single aircraft take-off/landing cycle was termed a sortie; a mission was the collective reference to sorties flown with a common target. A project was all missions related to a specific target (Lavy, 1987; Young and Reggiani, 1988).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

draulic system of one C-123, which controlled the spray pump and herbicide shut-off valve, the decision was made to fly future missions with the rear cargo door open so that if an onboard flare was ignited by incoming fire it could be shuttled out the back door (Buckingham, 1982). Although the open rear door reduced the risk of injury to crew members and of damage to the spray system from internal fire and potential onboard herbicide combustion or leakage, in cases where the hydraulic lines suffered direct hits from enemy fire, the cargo area and flight mechanic could be sprayed with herbicide. Bottles of distilled water were installed in the cargo bay to flush eyes after such events (Buckingham, 1982). The open aft door of the fuselage also allowed the flight mechanic who operated the spray console to drop smoke grenades marking enemy positions for fire-support aircraft (Meek, 1981). Additionally, both cockpit side windows remained open for ventilation during missions (Meek, 1981) and to prevent crew injury resulting from flying Plexiglas shards should a window sustain a direct hit (RHAC, 2000). These operational conditions resulted in a situation where the crews of lead aircraft of the formation were exposed to spray mist carried forward by the internal aft-forward airflow created by the open door and windows. Aircraft in positions other than the lead were not only flying directly into the spray paths of aircraft before them in the formation (Cecil, 1986), but they were also drawing into the fuselage some of their own spray mist (Meek, 1981; Wilcox, 1989).

Other conditions under which Ranch Hands were subject to herbicide exposure included the use of herbicides as hand cleaners (efficient for grease and oil removal), during the removal of debris from nozzles (rubber bits from dissolved seals), and through the maintenance of the herbicide tank valve (the maintenance person was required to actually enter the tank to lubricate the dump valve) (RHAC, 2000).

Flight conditions for the Ranch Hands improved with the introduction of a new spray system and jet-powered aircraft. In July of 1966 the MC-1 Hourglass system was replaced by the A/A45Y-1 spray system (Cecil, 1986). The A/A45Y-1 provided a flow rate of 250 gallons per minute, improved spray pattern evenness, and allowed the entire herbicide payload to be dumped in just 30 seconds in emergency situations (Cecil, 1986). The introduction of the C-123K—the K in the nomenclature referred to the jet version of the C-123—in 1968 reduced hits from enemy fire by 28 percent (Cecil, 1986). This reduction was attributed in part to the greater number of targets that the enemy had to fire at—formation numbers increased to as high as 12 aircraft on some missions (Cecil, 1986). The new jet-equipped C-123Ks had also undergone some structural improvements to better protect the engines from enemy fire and to reduce windshield shattering. They were fitted with larger spray pumps that were able to maintain a constant spray flow rate (3 gallons per acre) during airspeed fluctuations (Cecil, 1986).

By the time that the jet-equipped C-123Ks arrived in 1968, the Ranch Hand mission, technically, had already peaked; mission requirements had steadily in-

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

TABLE 2-1 Herbicides Used in Vietnam Between 1961 and 1971

Herbicide Designation

Years Used

Millions of Gallons Potentially Used in Vietnama

Active Ingredient(s)b,c

Agent Pink

1961; 1965

0.013

n-butyl, isobutyl esters of 2,4,5-T

Agent Green

1961–1965d

0.008

n-butyl ester of 2,4,5-T

Agent Purple

1962–1965

0.499

n-butyl ester of 2,4-D; n-butyl and isobutyl esters of 2,4,5-T

Agent Orange Ie

1965–1970

12.054

n-butyl esters of 2,4-D and 2,4,5-T

Agent Orange II

1968–?

0.948

n-butyl ester of 2,4-D and isooctyl ester of 2,4,5-T

Agent White

1966–1971

5.425

Picloram

Agent Bluef

1962–1971

1.251

Cacodylic acid

aIn some instances procurement records are represented versus spray volumes (Stellman et al., 2003).

bYoung and Reggiani, 1988.

cStellman et al., 2003.

dEstimated to be within the Agent Pink usage time frame.

eThere were two Agent Orange formulas used in Vietnam. The original formula was a 50:50 mixture of 2,4-D and the n-butyl ester of 2,4,5-T. In the formula known as Agent Orange II the isooctyl ester of 2,4,5-T was used. Improved production methods allowed synthesis to occur at lower temperatures, ultimately reducing levels of TCDD contamination in the 2,4,5-T component of Agent Orange II (Stellman et al., 2003).

fTwo herbicides were referred to as Agent Blue. One was a powder (cacodylic acid/sodium chloride mix) and the other was a water-based solution (cacodylic acid/sodium cacodylate) (Stellman et al., 2003).

SOURCE: Adapted from Stellman et al., 2003.

creased through 1967 and then gradually began to decline (Buckingham, 1997). By the end of 1970 President Nixon had issued an order to phase out the herbicide mission (Cecil, 1986). Between 1962 and 1971 Ranch Hands flew 19,977 sorties (IOM, 2003b), and herbicides had been sprayed on nearly 10 percent of the South Vietnamese landmass (Table 2-1) (Alcott, 1995). The last fixed-wing application of herbicides took place on January 7, 197121 (Buckingham, 1982). It has been claimed (Gough, 1986) that the Ranch Hand mission resembled civilian crop-dusting to some degree—both required excellent piloting skills for extremely

21  

The last helicopter application took place on October 31, 1971 (Buckingham, 1982).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

low-altitude flight, but Ranch Hand C-123s were generally dangerously overweight during takeoff, were far less maneuverable than civilian crop dusting aircraft (110-foot wingspan), and when pilots were required to execute the most difficult of maneuvers (60° banks at treetop level), they normally did so under enemy fire (Boyne, 2000). Largely due to the receipt of the Purple Heart, the Ranch Hand unit ended up being the most highly decorated USAF unit in Vietnam (Gough, 1986).

THE AGENT ORANGE CONTROVERSY

Initial Concerns over the Use of Herbicides in Vietnam

As early as 1963 the American public was made aware through media reports of the use of herbicides in Vietnam (Buckingham, 1997). As media coverage continued to draw attention to the potential legal, political, and ethical consequences of the defoliant operations, concerns about ecological and human health impacts were also mounting. The year before the first missions disseminating Agent Orange were flown in Vietnam (March 1965) (Cecil, 1986), the Federation of American Scientists publicly condemned the use of herbicide in Vietnam, marking the beginning of a concerted campaign against U.S. military use of defoliants (Young and Reggiani, 1988). Several scientific organizations petitioned for the cessation of spraying and for the investigation of the short- and long-term consequences of the military’s herbicide use. Under increasing pressure from the scientific community and in response to increasing media coverage of what was rapidly becoming a major domestic controversy, the Department of Defense (DOD) commissioned a series of studies related to herbicide exposure. Two studies were instrumental in the eventual modification of U.S. military policy governing the use of herbicides. The first was a literature survey carried out by the Midwest Research Institute (MRI) that resulted in a recommendation of further Agent Blue (an arsenical) research, but did not specifically address the major herbicidal mixtures (Agents Purple and Orange) used in Vietnam (Butler, 2005). Additionally, the MRI study was not able to draw definitive conclusions regarding the long-term effects of herbicide exposure (Young and Reggiani, 1988).The second study, conducted by Bionetics Research Laboratories under contract from the National Cancer Institute, evaluated the potential teratogenic effects of 2,4,5-T exposure (Galston, 2001). Results from the Bionetics study, reported in 1968, indicated that 2,4,5-T exposure could elicit teratogenic outcomes in some species. In response to these results, as well as increasing media reports implicating Agent Orange as a causative agent for myriad health problems, the use of 2,4,5-T was domestically restricted on April 15, 1970, and the DOD concomitantly suspended 2,4,5-T’s military use (Butler, 2005).

Later that year, Congress requested (Pub. L. 91-441) the National Academy of Sciences (NAS) to form a committee whose task would be to conduct a com-

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

prehensive evaluation of the physiological and ecological impacts of herbicidal operations in Vietnam (NAS, 1974). In their report published in 1974, the committee stated that they could not determine whether exposure to herbicides in Vietnam was responsible for any deleterious health outcomes among war veterans or civilian populations. The committee also noted that when defoliant operations were initiated in Vietnam, it was not widely known22 that the 2,4,5-T stores were contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Records were reviewed from three Saigon hospitals, but no convincing association between birth defects and herbicidal exposure was found.23 The committee, in conclusion, suggested that Congress fund further evaluation of potential adverse ecological and physiological outcomes associated with defoliant operations in Vietnam.

Early Studies of Vietnam Veterans’ Health

In 1979, Pub. L. 96-151 was endorsed by President Carter and required the Veterans Administration—known today as the Department of Veterans Affairs—to conduct studies of adverse health outcomes among Vietnam veterans exposed to TCDD-containing herbicides (Young and Reggiani, 1988). In the same year, the Agent Orange Working Group (AOWG) was established. The AOWG comprised several governmental entities under the executive branch with a vested interest in the health effects associated with exposure to Agent Orange. In 1980, the congressional Office of Technology Assessment (OTA) became an active member of the AOWG, and in 1981 President Reagan incorporated the AOWG into the Cabinet Council on Human Resources, greatly increasing the influence of the AOWG (Young and Reggiani, 1988). By congressional mandate, the VA was required to produce a study protocol within 180 days of the passage of Pub. L. 96-151. The VA failed to meet this deadline, and the protocol that finally made its way to the OTA was declared inadequate. It was not until 1982 that the VA submitted a protocol for review that was approved by the OTA. However, by that time, the AOWG’s priorities had shifted to the study of the Vietnam experience; i.e., in the health status of Vietnam veterans vs. non-Vietnam veterans. This resulted in pressure on the VA to shift from a study of the health effects of Agent Orange to a study of the Vietnam experience. Ultimately, Congress decided to transfer the responsibility for the execution of such studies from the VA to the

22  

German researchers Georg Sorge and Karl Schulz had, in the 1950s, isolated TCDD from 2,4,5-T samples and in 1957 published three papers in scientific journals (in German) relating the occurrence of chloracne with TCDD exposure in occupational settings (Butler, 2005).

23  

The committee did cite in their report the existence of a series of unconfirmed reports of respiratory illness among Montagnard (inhabitants of the highland regions of southern Vietnam) children that warranted further investigation (NAS, 1974).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

Centers for Disease Control (CDC)—known today as the Centers for Disease Control and Prevention.

The CDC, instead of choosing between a study of Agent Orange or the Vietnam experience, decided to conduct both studies (Young and Reggiani, 1988). The Vietnam Experience Study was eventually conducted, but researchers ran into difficulties trying to carry out the Agent Orange Study. In short, the CDC had formulated an exposure index based on the assumptions that all members of a battalion were located at the centroid of the reported locations of their component units and that the entire battalion was considered to be exposed if that “average” location was within 2 kilometers of an active spray tract (OTA, 1983). The OTA rejected the CDC’s proposed exposure model, noting that as the model was designed, it was an inadequate representation of actual troop locations, and as such, could not establish the magnitude of exposure at even the battalion level.24 A year later the CDC developed an assay (Patterson et al., 1987) for measuring serum 2,3,7,8-TCDD levels—hereafter referred to as simply serum TCDD—which presumably could serve as a biomarker of Agent Orange exposure. With the advent of the serum TCDD assay, the CDC conducted the Agent Orange Validation Study to determine the feasibility of an Agent Orange study using both military records and serum TCDD levels as surrogates of in-theater herbicide exposure (VA, 2003). Serum TCDD levels were measured for 696 ground troops who had served in Vietnam and 97 Vietnam veterans who had not served in the theater of conflict. Mean serum TCDD levels were “nearly identical”25 for both groups. Additionally, serum TCDD measures could not be correlated with exposure indices based on existing military records or self-reports of Agent Orange exposure. The CDC, with the assent of the AOWG and the OTA as well as the Science Panel of the Domestic Policy Council, cancelled the planned Agent Orange Study (VA, 2003).26 By the time the CDC Agent Orange study was cancelled, CDC and AFHS investigators had already begun collaboration on a serum TCDD assay pilot study of Ranch Hand sera (RHAC, 2000). A detailed overview of Vietnam veterans’ studies is provided in Appendix E.

24  

The CDC presented as an example a calculated centroid battalion location with an associated range of ~40 kilometers. OTA concluded that it was impossible to know how battalion members were distributed within the circumscribed area and that individuals could have been as far as ~20 kilometers from the centroid (OTA, 1983).

25  

Mean serum TCDD levels were approximately 4 ppt for both groups (CDC, 1988).

26  

A proposed UCLA Agent Orange study was also cancelled as its protocol was deemed inadequate by President Reagan’s AOWG (Cecil, 1986).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

THE AIR FORCE HEALTH STUDY

Origins and Protocol Development

On June 5, 1979, the Washington Post reported27 that a commitment had been made by the USAF in consultation with the White House to study the potential adverse health outcomes of service members involved in Operation Ranch Hand. Five months before the announcement, a class action suit had been filed by the organization Agent Orange Victims International seeking compensation from Dow and other chemical companies for a series of illnesses ranging from cancer to skin disorders that plaintiffs believed to be attributable to Agent Orange exposure (Schuck, 1987). In the midst of a groundswell of controversy surrounding Agent Orange and in partial response to an increasing number of congressional inquiries, in 1979, independent of the mandates of Pub. L. 96-151, the USAF initiated an epidemiologic study of USAF personnel involved in defoliant operations in Vietnam.

On June 6, 1979, the USAF officially began development of its Agent Orange study protocol. The University of Texas School of Public Health in Houston first reviewed the USAF protocol. Following the university’s review, the protocol underwent two additional reviews—first by an USAF scientific advisory board and then by a subcommittee of the Armed Forces Epidemiologic Board. Subsequent to a series of review-prescribed revisions, the NAS was asked by USAF investigators to review the study protocol—version 6 of November 28, 1979 (AFHS, 1982). Although this request does not mark the origins of Academy involvement with Agent Orange (NAS, 1974), it does mark the beginning of the Academy’s association with the USAF’s Agent Orange study.

In December of 1979, the NAS Panel on the Proposed Air Force Study of Herbicide Orange convened to review the proposed protocol, and their final report was issued on May 6, 1980 (NRC, 1980). Within the context of the health, political, and legal goals of the study, as stated by the USAF, the panel’s objective was to assess the scientific merit of the protocol as it related to toxicological, epidemiologic, and statistical relevance and validity. The protocol, as then proposed, was divided into three major study components: a retrospective mortality study, a retrospective morbidity study, and a 5-year prospective follow-up study

27  

The decision by the USAF at the time was contrary to existing Pentagon policy, which can be characterized by Major General Garth Dettinger’s (Deputy Surgeon General of the Air Force) 1978 testimony before the House Veterans Affairs subcommittee where he testified that there was “no evidence of any lasting health damage to anyone” involved in defoliant operations (500 vets, 1978). Prior to the USAF announcement, follow-up study of Vietnam veterans exposed to chemical defoliants had been recommended by the General Accounting Office in their 1979 report conducted at the request of Rep. Bennett M. Stewart (D-IL) on the subject (Herbicide victim study, 1979).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
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of original study participants (Ranch Hand and C-130 cargo crews). In their report, the NAS panel commended USAF investigators on their thorough consideration and acknowledgement of inherent protocol limitations, specifically those imparted by the relatively small size of the exposed cohort (n ≈ 1,200). From its protocol analysis and the methodological weaknesses therein identified, the panel arrived at the following four primary recommendations:

  1. Lengthen the follow-up period beyond the proposed 3- and 5-year points.

  2. Limit outcome measures and focus in greater detail on reproductive outcomes as well as hepatic, nervous system, and immune system dysfunction.

  3. Identify additional subjects (U.S. Army and Marine Corps) for possible inclusion in the cohort.

  4. Revise the protocol, and again, seek outside peer review of the revised protocol.

The panel also discussed potential credibility issues likely to emerge resulting from primary study administration by the USAF. It noted that, while not lacking proficiency as the investigating body, the USAF might generally be considered to be lacking in impartiality.

One minority opinion was included in the final report in which dissent was expressed with panel recommendations regarding the need for major methodological revision of the proposed protocol, but concurrence was stated regarding the recommendations of the panel to investigate reproductive outcomes and to extend the follow-up period.

The NAS protocol review recommendations for the evaluation of reproductive outcomes and extended follow-up period were assimilated into the seventh version of the protocol dated October 8, 1980. The USAF rejected the suggestion of cohort expansion through the inclusion of military members from other branches of service and attributed the issues of suboptimal study power not “to the epidemiologic design, but to the vagaries of history” and postulated that “the Marine group probably received an herbicide exposure three orders of magnitude less than the Ranch Hand cohort” (Lathrop, 1980).28 Four additional protocol revisions over the next 15 months refined information on the study cohorts and expanded discussions of key issues (AFHS, 1982).

The implemented protocol (version 11), which called for a 20-year follow-up of the cohort and up to six physical examination cycles, was completed in January 1982 (AFHS, 1982). By that time, the effort—which was originally called the

28  

In the 1980 NAS protocol review, the panel suggested both Army and Marine Corps members for potential cohort inclusion. A Marine Corps group numbering 5,900 was specifically mentioned as they were known to have been less than one kilometer away from spray tracts on the days that the tracts were sprayed (NRC, 1980).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

FIGURE 2-1 Air Force Health Study time line.

Ranch Hand II Study—had been given its present name: the Air Force Health Study (AFHS). Colloquially, it is referred to as the Ranch Hand Study.

The physical examination cycles correspond to years 1, 3, 5, 10, 15, and 20 of the study. AFHS investigators refer to the 1982 baseline morbidity evaluation as Cycle 1, the first follow-up (1985) as Cycle 2, the second (1987) as Cycle 3, the third (1992) as Cycle 4, the fourth (1997) as Cycle 5, and the fifth (2002) as Cycle 6. Mortality and reproductive studies are reported independent of morbidity follow-ups. Figure 2-1 illustrates the time line of the study and the period of exposure to herbicides for the subjects.

Cohort Enumeration

Cohort enumeration involved the utilization of all governmental assets available to the USAF, including the Social Security Administration, the Internal Revenue Service, and the VA. Location of subjects was determined using existing military records archived at the National Personnel Records Center, St. Louis, Missouri, and the USAF Human Resources Laboratory, Brooks AFB, Texas (AFHS, 1983). For both the mortality and morbidity branches of the study, the exposed population was defined as Ranch Hand personnel (n ≈ 1,269)29 who had served among the C-123 crews—pilot, copilot, navigator, and one spray operator—and the ground support crews—typically enlisted flight-line support personnel—between 1962 and 1971 (AFHS, 1984a). AFHS investigators repeated their awareness of the inherent limitations resulting from the small size of the study population in the baseline report, an issue that had been raised by protocol

29  

AFHS reports are not reliable accounts of the absolute number of “exposed” (Ranch Hand) and “unexposed” (comparison) subjects. These numbers change between reports and over time as further study leads to the reclassification of study subjects.

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

review committees and other involved groups.30 After they reevaluated the feasibility of including personnel from other branches of service in the AFHS, USAF investigators believed it was sound to limit the exposed cohort to Ranch Hands. They asserted “the Ranch Hand group had a much higher level of exposure that was sustained over a prolonged period of time … [implying] that Ranch Hand personnel would be more likely to develop more acute and chronic symptoms … and would manifest them sooner than the other exposed military personnel” (AFHS, 1984a).

The initial eligible comparison group of 23,978 was limited to C-130 crews, each comprising three officers and two enlisted persons. Comparison subjects were generally characterized as nonrisk taking, nonvolunteer, and nonherbicide exposed (AFHS, 1982). They had served in the USAF between 1962 and 1971,31 but had flown cargo, and not defoliant missions, in SEA. They were assumed to be similar to Ranch Hand subjects regarding lifestyle, training profiles, and socioeconomic factors. Comparison subjects were matched to Ranch Hand subjects on age, race,32 and military occupation at a ratio as high as 1:10.33 Military occupation was divided into five categories: officer/pilot, officer/navigator, officer/ other, enlisted/flight engineer, and enlisted/other (AFHS, 1984a).

Individual-level pools of comparison subjects remained assigned to each Ranch Hand for the duration of the study. For the mortality component of the study, Ranch Hand subjects were matched to 5 (of the possible maximum of 10) randomly selected comparison subjects (AFHS, 1983). Subjects for which the cause of death was determined to be combat related were excluded from mortality analyses.34 For the morbidity component, previous health status or history was ascertained for all exposed subjects and comparison subjects. Ranch Hand sub-

30  

The General Accounting Office reported in 1999 that due to the limited statistical power of the AFHS, the “minimum relative risk that would be likely to be detected” for the cohort was 45, 7.5, and 1.7 for liver cancer, prostate cancer, and all-sites cancer, respectively, in 1982. Those minimum detectable relative risks were projected to decrease to 11, 2.0, and 1.37 for liver cancer, prostate cancer, and all-sites cancer, respectively, for 1992 (GAO, 1999).

31  

For the purposes of Agent Orange-related disability compensation, the VA applies an exposure window of “service on active duty in the Republic of Vietnam during the period beginning on January 9, 1962, and ending on May 7, 1975” (VA, 2003).

32  

Ranch Hands were predominately non-Black—98 percent of officers and 92 percent of enlisted (AFHS, 1984a).

33  

Manual review of personnel records in 1981 (after matching had been conducted) revealed that 18 percent (n = 2,208) of the comparison group did not meet study inclusion criteria (AFHS, 1984a). This effectively reduced the matched ratio of Ranch Hand subjects to comparison subjects from 1:10 to 1:8. Investigators reported that the ineligible comparison subjects were “randomly distributed among the matched sets” and were thus removed from the study without the conduct of a random reassignment of matched sets, and replacement comparison subjects were shifted within subsets (AFHS, 1984a).

34  

The health status prior to combat-related death was determined through review of medical records (AFHS, 1984a).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
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TABLE 2-2 AFHS Matching Scheme

Study Component

Subject to Comparison Ratio for Analysis

Comparison Selection, Replacement, and Study Duration

Mortality

1:5

Combat deaths excluded; random selection from maximum pool of 10; vital status ascertained periodically for 20 years

Retrospective Morbidity

1:1

Random selection from subset of 5 of maximum pool of 10; living non-compliant comparisons replaced from remaining pool; replacements not health-matched; deceased comparisons not replaced; cross-sectional survey

Prospective Morbidity

1:1

Random selection from subset of 5 of maximum pool of 10; living non-compliant comparisons replaced from remaining pool; replacements “health-matched;” deceased comparisons replaced; 20 years of observation including family health questionnaires (reproductive outcomes)

SOURCE: Adapted from AFHS, 1982.

jects were matched to the first living and compliant comparison randomly selected from the individual-level mortality pool of five (AFHS, 1984a). If the first selected comparison subject was living, but noncompliant, then another subject was randomly selected from the remaining eligible comparison pool. Retrospective health data were collected for deceased (noncombat related) Ranch Hand subjects and comparison subjects through first-order next-of-kin interviews. Original comparison subjects for the prospective morbidity study were those selected for the retrospective morbidity study, with the addition of replacements for deceased comparison subjects (AFHS, 1982). The impact on study power resulting from loss to follow-up (noncompliant or unlocatable) of original prospective morbidity component comparison subjects was addressed through the replacement of unaccountable or noncompliant comparison subjects with the next eligible comparison35 from the remaining pool of up to 10 (AFHS, 1982). According to the study protocol (AFHS, 1982), replacement comparison subjects were also to be matched on self-reported health perception to original comparison subjects that refused to participate. In the initial (1982) physical examination, replacement comparison subjects were the first willing randomly selected subjects from the available pool (AFHS, 1984a). In the follow-up evaluations, replacement comparison subjects were matched on self-perceived health when possible to refusal or unaccounted-for comparison subjects (AFHS, 2000). The matching schemes for the various components of the study are summarized in Table 2-2,

35  

Eligibility in any cycle reflects eligibility in a previous cycle and not compliance in a previous cycle (AFHS, 2005).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

and AFHS population dynamics for the entire morbidity study are presented in Figure 3-2 of Chapter 3.

Reconstruction of Exposure

While Ranch Hand subjects were considered to be exposed as a group, an exposure index was created to categorize degree of potential exposure to Agent Orange among Ranch Hand subjects. Each Ranch Hand subject was assigned to an exposure category (low, medium, or high) based on a composite exposure score (Ei) defined as the quotient of the number of gallons of herbicides sprayed during a subject’s tour and the number of airmen with the subject’s duties during his tour scaled by a temporally-based TCDD weighting factor (AFHS, 1984a).36

The TCDD weighting factor equaled 1 for post–July 1, 1965 duty and 24 for pre–July 1, 1965 duty. The rationale for it was that the herbicides used in the earlier time period (Agents Pink, Green, Purple, and early batches of Agent Orange) were more heavily contaminated with TCDD than those used thereafter. The derivation of weighting factor is detailed in the baseline morbidity report’s Exposure Index Development chapter (AFHS, 1984a).

Investigators acknowledged the inability of the exposure classification scheme to directly assess exposure at the individual level or any differences in exposure related to variation in or deviation from typical job duties, but adopted it as a working model (AFHS, 1984a). Exposure scores (Ei) were applied differentially to occupational categories to reflect differences in exposure opportunity associated with the performance of typical duties characteristic of each occupational group (Table 2-3) (IOM, 1994).

36  

The TCDD weighting factor equaled 1 for post-1965 duty and 24 for pre-1965 duty. The rationale for the weighting factor was that earlier herbicide formulas (Agents Pink, Green, and Purple) were found to be more heavily contaminated with TCDD (NAS, 1974). The volume distribution of herbicides in Vietnam, on which the exposure model was based, was derived from data contained in the HERBS computer tapes (AFHS, 1984a). The HERBS tapes are computer tapes that contain information on location and time of 9,495 fixed-wing spray missions conducted between 1965 and 1971 (Bullman et al., 1994). The exposure index used in Cycles 1–3 was a modified version of the model in the original protocol as investigators discovered that the data needed for the original exposure index did not exist. Investigators later admitted (ca. 2000) that the assumption that more service personnel in the area would reduce individual exposure was probably not valid and that more individuals in a contaminated area likely meant that more individuals were exposed (RHAC, 2000).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

TABLE 2-3 Calculated Exposure Index

Occupational Group

Exposure Category

Corresponding Gallons of Herbicides (Ei)

Officer

Low

< 35,000

Medium

35,000–70,000

High

> 70,000

Enlisted Flyer

Low

< 50,000

Medium

50,000–80,000

High

> 80,000

Enlisted Ground

Low

< 20,000

Medium

20,000–27,000

High

> 27,000

 

SOURCE: AFHS, 1984a.

The calculated exposure index developed for Cycle 1 was implemented in both the first (1985) and second (1987) morbidity follow-ups. In the Cycle 3 report investigators noted that, as structured, the calculated exposure index “[could] be regarded as only fair” (AFHS, 1987) in its ability to characterize actual exposure to herbicides as they had knowledge of preliminary results from the serum TCDD pilot study.

Assessment of exposure was drastically altered with the advent of a serum TCDD assay developed by the CDC in 1987 (Patterson et al., 1987).37 The assay had a detection limit of 1.25 parts-per-quadrillion (ppq = femtogram or 1 × 10−15) for a 200-g sample (Patterson et al., 1987) and was strongly correlated with adipose tissue TCDD levels. It was weakly correlated with the original calculated exposure index, indicating the potential for the misclassification of exposure using the index (assuming the assay was the better proxy) (AFHS, 1991b). The new assay eliminated the need for the painful surgical extraction of adipose tissue to determine TCDD body burden.38 When “serum dioxin” is referred to in AFHS

37  

CDC and AFHS investigators met in 1986 to discuss the serum TCDD assay pilot study (Michalek, 2000; RHAC, 2000). Eventually, sera samples were collected from 150 Ranch Hand subjects and 50 comparison subjects independent of the 1987 Cycle 3 follow-up physical exam; sera were collected at Red Cross Centers in Atlanta, Cleveland, Los Angeles, and Tulsa (CDC, 1988). Forty-seven AFHS participants had had their serum assayed for the pilot and the Cycle 3 follow-up. These serial measures were used to assess test reliability (RHAC, 2000). The assay is congener specific for 2,3,7,8-tetrachlorodibenzo-p-dioxin and therefore, when TCDD body burden or dioxin are referred to in AFHS reports the reference is to 2,3,7,8-TCDD burden, and not to toxic equivalents.

38  

TCDD can also be measured from lipids in breast milk (Patterson et al., 1987).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

publications, it is actually serum lipid-weight concentration in parts-per-trillion (ppt) and is equal to measured serum TCDD in ppq, which has been corrected for total lipid weight and serum density39 (AFHS, 1991b). When a “current” level is referred to in reports later than the Serum Dioxin Analysis of 1987 Examination Results report (AFHS, 1991b), the value has been extrapolated back to 1987 values based on contemporaneously accepted (by AFHS investigators) TCDD half-life values (AFHS, 1995).40 When “initial” dioxin is referred to in the AFHS, it is based on TCDD levels as determined by assay measurements extrapolated back to a subject’s end of term of service in Vietnam using contemporaneously accepted TCDD half-life estimates (AFHS, 1991b). For the exam cycles that took place after the development of the assay (Cycles 4–6), earlier exposure proxies were replaced with both cohort status (Ranch Hand vs. Comparison) and serum TCDD level—initial or current values.

Data Collection

Data from both the questionnaires and the physical examinations were collected by contracted personnel41 who were blinded to participant exposure status (AFHS, 1982, 1984a, 2005). Data collected during physical examinations comprised indices of health status that encompassed general health, endocrine, pulmonary, immunologic, neurologic, renal, hepatic, hematologic, dermatologic, psychiatric, cancer, and cardiovascular endpoints. Reproductive data pertained to aspects of lineage, gestation, date of birth, birth defect status, maternal/ paternal risk factors, birth outcome, birth weight, and offspring health through age 18 (AFHS, 1982). Questionnaire data included information relating to “demographics, education, occupation, medical history, study compliance, toxic exposures, and reproductive history” (AFHS, 2005). Additional data sources include birth certificates and military personnel and medical (civilian and military) records (AFHS, 1984a). Comprehensive reproductive histories were also ascertained through interviews of current and former wives or partners (AFHS, 1984a). Permission forms for the release of medical data (subject, spouse, and

39  

, where 102.6 is a correction factor for serum density and w is equal to the total lipid weight of the sample (AFHS, 1991b).

40  

Original TCDD half-life estimates were based on data from the 1976 Seveso, Italy, industrial accident (AFHS, 1990).

41  

Louis Harris and Associates, Inc. administered questionnaires and Kelsey-Seybold Clinic, P.A., conducted the physical examinations for the baseline study (AFHS, 1984a). The questionnaire was developed by the National Opinion Research Center, but Louis Harris and Associates, Inc. was awarded the contract for administration of the baseline questionnaire (AFHS, 1984a). Under contract with Science Applications International Corporation, the National Opinion Research Center and Scripps Clinic and Research Foundation, administered all follow-up questionnaires and physical examinations, respectively, for the morbidity study (AFHS, 1987).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

offspring) were administered during or following questionnaire administration (AFHS, 1984a).

All study participants who had completed the questionnaire were invited to participate in the physical examination (AFHS, 1984a). Endpoints measured during the 2 1/2-day physical examination were derived from scientific literature reviews of subject areas (toxicology, chemistry, case reports, and epidemiologic studies) related to chlorophenoxy herbicides and dioxin. The final choice of outcome measures was also influenced by practicality (complexity and length) as well as invasiveness of procedures (AFHS, 1984a).42 The battery of laboratory tests performed at each physical examination changed over time reflecting changes in science and technology (Appendix B). Biospecimens from study participants—serum (all cycles), urine (Cycles 1–3), whole blood (Cycle 6), semen (Cycle 1), and adipose tissue (Cycle 5)—were banked for future analysis (AFHS, 1984a, 1987, 1990, 1991b, 1995, 2000, 2005). It took approximately 10 months to conduct physical exams for all participants; the cost of the exams was estimated as $16 million in 2000 (RHAC, 2000).

Questionnaires were administered by trained professionals in the subjects’ homes for the Cycle 1 evaluation.43 If a subject was new to the study in any of the follow-up cycles, then he and his spouse received the same questionnaire that was administered at the Cycle 1 evaluation. In-home interview administration for subjects new to the study continued through part of Cycle 3 (AFHS, 2005). Beginning in 1987, administration of the baseline questionnaire for new subjects took place at the physical examination site (Scripps Clinic, La Jolla, California). An interval questionnaire was developed for all returning subjects attending follow-up examinations to capture new information and to update existing data. All interval questionnaires were administered at the physical examination site. Beginning with the Cycle 3 examination, computer assisted personal interview (CAPI) systems facilitated the administration of the interval questionnaire as well as any newly administered baseline questionnaires (AFHS, 2005). Questions were added to the interval questionnaire over time to better address pertinent research questions. When a new question appeared on the questionnaire for a particular follow-up cycle, it was included in subsequent questionnaires to establish a longitudinal record for the item (AFHS, 2005). In cases where new questions were not subject to changes over time, only those subjects who had not previously answered the

42  

AFHS researcher Joel Michalek stated in 2000 that Cycle 1 outcomes were based on a list of veteran complaints compiled by the VA (RHAC, 2000).

43  

Any replacement comparison subjects—there were 346 replacement comparison subjects (23 percent of the comparison population) who completed questionnaires at the baseline—contacted after November 1982 (n = 30), were not interviewed by a Lewis Harris and Associates employee (AFHS, 1984a). Baseline questionnaires were administered to these replacement comparison subjects by USAF personnel at the physical examination site (AFHS, 1984a).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

question were queried. A dietary assessment included in the Cycle 4 examination was a one-time query of dynamic variables (AFHS, 2005).44

Mortality data collected (VA,45 SSA,46 IRS,47 and USAF48) throughout the study include date of death and underlying cause of death (primary and secondary) (AFHS, 1983). According to the protocol, all participants were to be encouraged at the first follow-up examination to consent to a government-funded autopsy in the event of their death (AFHS, 1982).49 The overwhelming majority of data and biologic samples collected during the course of the study are archived at the AFHS research facility at Brooks City-Base, San Antonio, Texas.

The primary data sources for the elements of the study are listed in Figure 2-2.

Data Analysis

Morbidity Analyses

Subjective (self-reported) and objective (clinically verified) data were gathered through the questionnaires and during the physical examinations (AFHS, 1987). Analytical tests performed reflected a variety of data types (dichotomous, polytomous, and continuous) and numerous research questions that evolved over time—many in later cycles were generated by the results of previous cycles (AFHS, 1984a). Generally, earlier analyses performed sought to identify differences between Ranch Hand subjects and comparison subjects relating to both subjective and objective endpoints by group and exposure opportunity (AFHS, 1987). For the Cycle 1 evaluation, 190 dependent variables were evaluated for associations with self-reported symptoms, medical signs, and vital status (AFHS, 1984a). The majority of analyses performed on data collected for the Cycle 1 evaluation focused on differences by occupational group and exposure category

44  

An SEA service-based occupational survey was administered to enlisted Ranch Hand subjects only in 1989 (independent of cycle-specific activities) to evaluate the accuracy of the calculated exposure index as judged by the degree of correlation with the serum TCDD assay (Wolfe et al., 1995b).

45  

The VA’s Beneficiary Identification and Record Locator Subsystem (BIRLS) served to locate subjects for whom death benefits had been awarded (AFHS, 1983).

46  

If the Social Security Administration’s Office of Remuneration and Earnings had employer-reported earnings data for a previous calendar year, then a subject was presumed to be living (AFHS, 1983).

47  

The National Institute for Occupational Safety and Health facilitated retrieval of Internal Revenue Service mortality-related data (e.g., living if filing tax return and deceased if listed as such on joint tax return) for AFHS (AFHS, 1983).

48  

USAF personnel, finance, and medical records were used to locate subjects and ascertain vital status (AFHS, 1983).

49  

Tissue samples were to be analyzed at the Armed Forces Institute of Pathology (AFHS, 1982).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

FIGURE 2-2 Data sources for AFHS morbidity study subjects.

SOURCE: M. Yeager, Science Applications International Corporation (SAIC), personal communication, July 13, 2005.

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

(AFHS, 1984a). In the 1985 Cycle 2 follow-up examination, results reported in all major clinical chapters were for differences in subjective and objective outcomes between the Ranch Hand and comparison groups (AFHS, 1987). For purposes of longitudinal comparison, additional analyses of Ranch Hand subjects versus original comparison subjects (Cycle 1) are included in tabulated form in chapter appendixes in the Cycle 2 follow-up report (AFHS, 1987). Cycle 3 analyses reflected the methodology of the previous cycle—characterization of variation in morbidity by group, occupational category, and exposure index ranking (AFHS, 1990). Separate analyses based on the serum TCDD assay (pilot study and Cycle 3 serum collections) data were published in a stand-alone report—Serum Dioxin Analysis of 1987 Examination Results (AFHS, 1991b). In the Cycle 3 follow-up report’s executive summary, readers were cautioned to interpret Cycle 3 results carefully as early indications of assay analyses indicated that the qualitative exposure index was “not a good measure of actual dioxin exposure” (AFHS, 1991b).

Three statistical models were created to evaluate the relationship between dioxin body burden and morbidity (over 300 dependent variables) for the 1987 serum dioxin analyses. In two of the models dioxin body burden among Ranch Hand subjects only was considered. Model 1 was based on initial dioxin values or the estimated body burden (t1/2 = 7.1 years) at the time a Ranch Hand left Vietnam. Model 2 was based on current TCDD body burden. Model 2 analyses mainly involved differences in morbidity outcomes (subjective and objective) by temporal strata (relative to time of service) (AFHS, 1991b). Models 1 and 2 were both conducted under what investigators referred to as the “minimal” (Ranch Hand subjects with less than 10 ppt TCDD body burden [n = 345] were excluded as they were considered not to have been exposed to TCDD in Vietnam) and “maximal” (Ranch Hand subjects with less than 5 ppt TCDD body burden [n = 124] were excluded as they were considered not to have been exposed to TCDD in Vietnam) assumptions (AFHS, 1991b). Under Model 3, differences in health status between Ranch Hand subjects and comparison subjects according to current dioxin levels were evaluated (Table 2-4). The 5 ppt spread between the “un-

TABLE 2-4 Model 3 (Serum Dioxin Analysis of 1987 Examination Results)

Category

Current TCDD Body Burden

Ranch Hand Subjects

Unknown

≤ 10 ppt

Low

15 ppt < TCDD ≤ 33.3 ppt

High

> 33.3 ppt

Comparison Subjects

≤ 10 ppt

 

SOURCE: AFHS, 1991b.

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
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TABLE 2-5 Model 3 (Cycle 5)

Category

Lipid-adjusted Initial TCDD Body Burden

Ranch Hand Subjects

Unknown

≤ 10 ppt

Low

15 ppt < TCDD ≤ 94 ppt

High

> 94 ppt

Comparison Subjects

≤ 10 ppt

 

SOURCE: AFHS, 2000.

known” and “low” Ranch Hand categories was established to ensure clear delineation between the subgroups (AFHS, 1991b).

Six analytical models were used in Cycle 4 (AFHS, 1995). Model 1 contrasted indices of health status between Ranch Hand subjects and comparison subjects. The second model applied to Ranch Hand subjects only and evaluated variation in indices of morbidity according to initial dioxin levels. Model 3 contrasted morbidity of Ranch Hand subjects and comparison subjects by both current and initial TCDD levels. Models 4–6 applied to Ranch Hand health status only and were each based on current TCDD values (Model 4: lipid-adjusted current TCDD; Model 5: whole-weight current TCDD; and Model 6: whole-weight current TCDD adjusted for total lipids) (AFHS, 1995). Changes in percentage of body fat and percentage of body fat at time of duty were treated as covariates in Models 2 and 3 to compensate for the influence of these factors on TCDD half-life value (AFHS, 1995).

The estimated TCDD half-life on which statistical models were based in Cycle 5 changed from the Cycle 4 value of 7.1 years to 8.7 years in Cycle 5 based on then-recent research (Michalek et al., 1996). In the 1992 follow-up, 266 health variables were evaluated using four analytical models (AFHS, 2000). In Model 1, health status was assessed for Ranch Hand subjects and comparison subjects at the group level independent of TCDD body burden. Initial TCDD body burden was the basis for Model 2 and body fat percentage50 was considered a covariate. In Model 3, variation in health outcomes were evaluated for both Ranch Hand subjects and comparison subjects by lipid-adjusted initial TCDD body burden51 category (Table 2-5).

50  

Body fat percentage was calculated using inputs of height and weight. Discrepancies in the database were identified in the 1992 follow-up (Cycle 4) resulting from changes in height over time—a decrease in height of > 5 cm was found to have occurred for more than 85 participants (AFHS, 1995).

51  

“[E]xtrapolated initial dose, assume[s] first-order elimination, I = 4 + (C – 4) × exp(log(2) × t/h), where 4 ppt is considered the median background level of lipid-adjusted dioxin” (AFHS, 2000). The background level of 4 ppt was derived from the results of the Agent Orange Validation Study.

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

TABLE 2-6 Model 3 (Cycle 6)

Category

Lipid-adjusted Initial TCDD Body Burden

Ranch Hand Subjects

Background

≤ 10 ppt

Low

15 ppt < TCDD ≤ 118 ppt

High

> 118 ppt

Comparison Subjects

≤ 10 ppt

 

SOURCE: AFHS, 2005.

Model 4 was based on 1987 serum TCDD values or values from 1992 or 1997 measures extrapolated back to 1987. If a 1992 serum TCDD value was less than 10 ppt, then the measure was not extrapolated back to 1987 levels. Body fat percentage was not a covariate in Model 4.

Analytical models used for Cycle 5 (1997) were applied to Cycle 6 (2002) data analyses with few modifications. The derived initial and 1987 TCDD levels were based on an estimated TCDD half-life of 7.6 years in Cycle 6—this was a change from the half-life estimate of 8.7 years used in the previous cycle—again based on updated research.52 Model 2 in Cycle 6 varied from Model 2 in Cycle 5 in that body mass index was a covariate in Cycle 6 (AFHS, 2005).53 The Model 3 lipid-adjusted initial TCDD low to high cutoff point changed from 94 ppt in Cycle 5 to 118 ppt in Cycle 6 (Table 2-6).

Body mass index also replaced body fat percentage as a covariate in Model 3. The singular change in Model 4 for Cycle 6 was the use of the 7.6-year TCDD half-life value to extrapolate to 1987 serum TCDD levels (AFHS, 2005).

Reproductive Outcomes Analyses

Analyses of reproductive outcomes were focused on potential male-mediated effects and only addressed the offspring of participants for whom serum dioxin measures had been made by 1990 (AFHS, 1992).54 Maternal data (collected from partners) included alcohol, drug, and cigarette use and maternal family histories. Three models were used in the reproductive analyses (AFHS, 1992).55 For the first two models it was assumed that all “Ranch Hands received

52  

TCDD elimination was found to exhibit an inverse relationship with body fat and was also thought to possibly vary by other related factors (Michalek and Tripathi, 1999).

53  

In Cycle 5, body fat (a covariate) was calculated from body mass index (AFHS, 2000).

54  

Reproductive outcomes were reported in the Cycle 1 technical report (AFHS, 1984a). This discussion refers to analytical models used in the stand-alone technical report of reproductive outcomes (AFHS, 1992).

55  

Subjects were limited to one reproductive outcome (Schwartz, 2000).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
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TABLE 2-7 Model 3 (Reproductive Outcomes, 1992)

Category

Current TCDD Body Burden

Background

Comparison with ≤ 10 ppt

Unknown

Ranch Hand with ≤ 10 ppt

Low

15 ppt < Ranch Hand with TCDD ≤ 33.3 ppt

High

Ranch Hand with > 33.3 ppt

 

SOURCE: AFHS, 1992.

a single dioxin dose in Vietnam and only background thereafter” (AFHS, 1992). Model 1 was based on extrapolated initial TCDD level using a half-life of 7.1 years. Model 2 was based on current dioxin levels using the same half-life estimate, and Model 2 also included a “time-by-current dioxin” interaction term (AFHS, 1992). Ranch Hand subjects with current TCDD levels less than or equal 10 ppt (n = 347) were excluded from one set of analyses (using both Models 1 and 2) of reproductive outcomes, and a separate set of analyses (using both Models 1 and 2) were carried out excluding Ranch Hand subjects with less than or equal to 5 ppt (n = 125) (AFHS, 1992). Investigators cited that the “intent of these two analyses was to ‘trap’ the true dioxin versus reproductive outcome relationship between them” (AFHS, 1992). Models 1 and 2 applied only to Ranch Hand reproductive and offspring experience. Model 3 applied to the reproductive outcomes of both Ranch Hand subjects and comparison subjects based on current TCDD ranking (Table 2-7) (AFHS, 1992).

Mortality Analyses

Cycle 1 mortality analyses evaluated all-cause and cause-specific mortality at the group level as well as dose–response trends based on the qualitative exposure index (AFHS, 1983). Ranch Hand mortality was contrasted with that of the study comparison group and three additional external comparison populations: the 1978 U.S. White Male Mortality Experience,56 the DOD Nondisability Retired Life Table, and the West Point Class of 1956. These external comparisons were made to evaluate the “healthy worker effect”57 as well as to identify any

56  

The source of these data was US Department of Health and Human Services: Vital Statistics of the United States 1978 (AFHS, 1983).

57  

The healthy worker effect (confounding) results from the exclusion or out-migration of ill persons from the occupational setting. In the case of the AFHS, this phenomenon could be considered the “healthy soldier effect” whereby AFHS subjects by the nature of the military selection/retention physical examination criteria, would be healthier than the general population.

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
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differences in group mortality experience between Vietnam veterans and other military members (AFHS, 1983). In the first update to this analysis (AFHS, 1984b), Ranch Hand mortality was compared to that of the internal comparison group, active duty USAF personnel, and to the active U.S. Civil Service population (male) in addition to the three external groups used in the Cycle 1. The 1985 update again contrasted Ranch Hand mortality experience with the internal comparison group, the 1978 U.S. White Male Mortality Experience population, the DOD Nondisability Retired Life Table population, the West Point Class of 1956, and U.S. Civil Service population (male) (AFHS, 1985). The 1986 update provided summary counts and death rates for Ranch Hand subjects and comparison subjects stratified by race and military occupation (AFHS, 1986). For the 1989 mortality update, Ranch Hand mortality was compared to that of the matched subsets of five and to the entire internal comparison population (n = 19,101). External comparison populations were not included (AFHS, 1989).

In all mortality analyses conducted prior to 1991, dose–response was evaluated using the Cycle 1 quantified exposure index. This changed when serum TCDD analyses indicated that the index was a poor proxy for Agent Orange exposure (Wolfe, 1989; AFHS, 1991a). However, AFHS investigators chose not to conduct analyses based on TCDD measurements for the 1991 mortality update because they lacked assay data for 91 deceased Ranch Hand subjects and 238 living Ranch Hand subjects (26 percent of the cohort). Instead, military rank and occupation in SEA were considered the most viable surrogates of exposure (AFHS, 1991a). Ranch Hand mortality was contrasted with that of the total comparison population in the 1991 update. The 1993 mortality update included a dose–response assessment based on TCDD measurements on the subset of participants for which this information was available, along with analyses of the entire Ranch Hand and comparison groups stratified by rank and occupation (AFHS, 1993). The methods used in the 1994 and 1996 updates did not deviate appreciably from the analytical methods of the 1993 report (AFHS, 1994, 1996).

Generally, survival curve estimates and standard mortality ratios adjusted for rank (officer versus enlisted), occupation (flyer versus nonflyer), age, birth year, and TCDD level beginning in 1991 are reported in AFHS mortality reports (AFHS, 1991a, 1993, 1994, 1996).

Data analyses are discussed at length in AFHS technical reports. The above summary discussion of AFHS analyses presents only the most basic details of AFHS analyses—major changes made to analytical models over time and changes in TCDD half-life estimates—which along with the discussion of exposure assessment, provide referential context for the discussion of AFHS results. Results and conclusions presented below are the findings of the AFHS and not the conclusions or findings of this committee.

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
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Results

Dissemination of the results of the AFHS has taken place through two primary channels: reports and papers in peer-reviewed journals. Multi-volume reports detailing study methodology and the findings of the clinical assessments have been issued for all six physical examination cycles and for the mortality and reproductive outcomes investigations. These are both posted on the AFHS website (http://www.brooks.af.mil/AFRL/HED/hedb/afhs/reports.html) and available through the National Technical Information Service of the US Department of Commerce (www.ntis.gov). Papers related to study topics have been published in journals covering epidemiologic, medical, toxicological, exposure assessment, and statistical methodology topics since 1980.58

This section briefly summarizes some of the results presented in the AFHS reports. Selected papers produced by the investigators are addressed in the section entitled AFHS Research and the Institute of Medicine’s Veterans and Agent Orange Reports.

Morbidity and Mortality Study Results

Participation in the Cycle 1 evaluation was on a volunteer basis even for personnel on active duty—15 percent of both Ranch Hand subjects and matched comparison subjects were on active duty59 at the time the Cycle 1 study was implemented, and 17 percent of Ranch Hand subjects and 19 percent of matched comparison subjects held Federal Aviation Administration Certificates indicating active participation in the aviation sector (AFHS, 1984a). During protocol development it was estimated that 39 percent of Ranch Hand subjects would participate in the physical examination (AFHS, 1984a). In actuality, 97 percent of Ranch Hand subjects and 93 percent of comparison subjects completed the questionnaire, and 87 percent of Ranch Hand subjects and 76 percent of comparison subjects underwent physical examination (AFHS, 1984a). Flight status,60 age, race,

58  

A list of these papers is provided on the AFHS web site: http://www.brooks.af.mil/AFRL/HED/hedb/afhs/articles.html.

59  

Retired USAF nurse and Yale researcher Linda Spoonster Schwartz testified before the National Security, Veterans Affairs, and Intergovernmental Relations Subcommittee of U.S. House of Representatives that only limited confidentiality was granted to AFHS study participants on active duty (Schwartz, 2000). In November of 1981, study participants received introductory letters in which the issue of confidentiality of medical findings was discussed. In cases where “serious medical findings which impact public health and safety” were discovered during the morbidity study, a committee comprising a specialist physician, a physician of the subject’s choice, a flight surgeon, a legal representative, and a representative from the subject’s professional field would make the final determination as the degree of threat any identified medical condition posed to the public’s health and safety (AFHS, 1984a).

60  

Even minor abnormalities discovered in the course of a physical examination can adversely impact flight status in both the military and civilian sectors (AFHS, 1984a).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
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and military status were said to have influenced participation rates. Questionnaires were administered to noncompliant persons by telephone (AFHS, 1984a) and trends among nonresponders were analyzed (AFHS, 1984a). Higher than expected participation rates resulted in many tasks cited as “undone”61 by the time the Cycle 1 results were reported in 1984, and investigators estimated that the Cycle 1 report represented “100 man-years of in-house work” and the accomplishment of thousands of statistical tests (AFHS, 1984a).

Cycle 1 analyses indicated that at the group level Ranch Hand subjects were found to differ significantly on such outcomes as nonmelanomic skin cancer,62 self-reported neuroses, liver enzymes, and peripheral leg pulses, although many of these differences were not evident after adjusting for age and smoking history (AFHS, 1984a). Inconsistent with what would be expected with TCDD exposure (Cook et al., 1980), no cases of chloracne or evidence of previous occurrence of chloracne was documented. Like chloracne, other diseases associated with TCDD exposure (soft-tissue sarcoma63 and porphyria cutanea tarda) were also not observed to be more prevalent among Ranch Hand subjects. Many of the differences observed between Ranch Hand subjects and comparison subjects were based on self-reported measures (e.g., more Ranch Hand subjects perceived their health to be poor), and those differences that were based on clinical measures were within normal ranges and did not correlate with exposure indices. Investigators concluded as of Cycle 1 that Ranch Hand subjects were not experiencing increased rates of or early onset of diseases under study relative to the comparison population. Ranch Hand mortality was found not to vary by frequency, cause, or age relative to comparison subjects. Minor birth defects (such as birthmarks), neonatal deaths, and physical handicaps were significantly higher among Ranch Hand subject offspring versus comparison offspring. Reproductive results were characterized as “mixed” in the Cycle 1 report (AFHS, 1984a) and were considered “preliminary” as they were subject to verification of records.64

Cycle 2 analyses indicated that cancer, kidney disease, general cardiovascular health, pulmonary disease and function, and hematologic measures did not

61  

Investigators identified five areas as needing further development: database refinement, tailor follow-up examination requirements based on Cycle 1 results, refine exposure index (aerodynamic study of flight conditions), conduct additional statistical analyses and power estimates, and collaborate with other groups with research activities related to herbicides and/or dioxin exposure (AFHS, 1984a).

62  

The influence of sun exposure (UV radiation) could not be evaluated during Cycle 1 analyses, but was slated for evaluation in the Cycle 2 skin cancer evaluation (AFHS, 1984a).

63  

One case of soft-tissue sarcoma was reported among comparison subjects, but diagnosis had not been confirmed at the time of the baseline evaluation, and this case was not included in analyses (AFHS, 1984a).

64  

Reproductive results became a source of controversy, and AFHS investigators were later criticized for the delayed publication (AFHS, 1992) of early reproductive results (GAO, 1999).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

vary significantly by group. The differences in peripheral pulse measures observed in the Cycle 1 evaluation were no longer evident, a change investigators attributed to the requirement of pretest smoking abstinence for the Cycle 2 physical examination. Endpoints for which a significant group difference was observed included lower percentages of body fat among Ranch Hand personnel and a higher proportion of erythrocyte sedimentation rate (ESR)65 abnormalities among Ranch Hand subjects. Rates of self-reported fair or poor health were higher for enlisted Ranch Hand subjects. Ranch Hand subjects had higher rates of basal cell carcinoma as well as higher rates of verified heart disease. Ranch Hand subjects were more likely to self-report abnormalities related to hysteria and social introversion. As was the case in the Cycle 1 evaluation, Ranch Hand personnel were not found to be at increased risk for development of chloracne, soft-tissue sarcoma, or porphyria cutanea tarda. No dose-response pattern was observed based on the calculated exposure index for the included dependent variables. Of the 19 endpoints evaluated in longitudinal analyses, erythrocyte sedimentation rate, Babinski reflex, depression, platelet count, and manual all-pulse index66 indicated changes over time. Changes in ESR were attributed to differences in laboratory procedures between the Cycle 1 and Cycle 2 evaluations.67 Results of psychological tests were mixed: Ranch Hand subjects experienced more psychological abnormalities according to the results of the Cornell Medical Index, but comparison subjects experienced more psychological maladies according to the results of the Halstead-Reitan Neuropsychological Test Battery (AFHS, 1987). Overall, there were slight decreases in group differences between Cycle 1 and Cycle 2.

Mortality analyses from the 1984 update failed to detect statistically significant differences in the mortality experience of Ranch Hand personnel relative to the comparison population or as compared to mortality trends among white males in the U.S. population and DOD retired officers (AFHS, 1984b). Trends in mortality were associated with age: Ranch Hand officers born between 1905 and 1935 were found to have a better mortality experience than comparison subjects and a worse mortality experience than comparison subjects for those Ranch Hand subjects born after 1935 (AFHS, 1984b). Overall, the mortality experience of Ranch Hand ground personnel was less favorable than that of the comparison group, but the difference was not statistically significant.

65  

Erythrocyte sedimentation rate is used to screen for inflammatory or malignant disease. It is not a definitive diagnostic test (Stevens and Mylecraine, 1994).

66  

Both manual palpitation and Doppler technique were used to evaluate pulse (femoral, popliteal, dorsalis pedis, posterior tibial, and radial) quality in Cycle 2 (AFHS, 1987). A longitudinal trend was observed for the manual technique.

67  

The laboratory portions of the baseline examination were conducted by Kelsey-Seybold Clinic, Houston, Texas. For the follow-up examination Scripps Clinic in La Jolla, California, through SAIC conducted lab analyses (AFHS, 1984a, 1987).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

At the time of the 1987 morbidity follow-up evaluation, USAF investigators concluded that the differences in health outcomes between Ranch Hand subjects and comparison subjects were insufficient to attribute trends in adverse health outcomes among Ranch Hand subjects to herbicide exposure (AFHS, 1990). The difference between Ranch Hand subjects and comparison subjects in self-perceived health status was not statistically significant. Recurrent findings were cited in the follow-up. Erythrocyte sedimentation rates continued to be higher for Ranch Hand subjects as a group. Skin cancer incidence remained higher for Ranch Hand subjects. Ranch Hand subjects were more likely to have developed coordination and balance difficulties as well as some psychological disorders. Ranch Hand subjects had more pulse abnormalities—a result observed at the Cycle 1 evaluation, but not at the Cycle 2. At the time the Cycle 2 results were published (1987), one case of soft-tissue sarcoma among Ranch Hand subjects and one case of soft-tissue sarcoma among comparison subjects68 were reported. Additionally, one case of non-Hodgkin’s lymphoma among Ranch Hand subjects had been reported, but not verified (Wolfe, 1989). These cases of soft-tissue sarcoma and non-Hodgkin’s lymphoma were verified and included in the report of Cycle 3 results (AFHS, 1990). Ranch Hand subjects had higher rates (statistically significant) of verified and suspected neoplasms. Ranch Hand subjects were found to be experiencing more coordination abnormalities than comparison subjects, and after controlling for insecticide exposure, a significant increasing trend was observed for coordination abnormalities among enlisted Ranch Hand subjects. Statistically significant trends were observed for sleep disorders, verified psychological disorders, and in scores on two psychological batteries69 (indicators of psychological distress and/or dysfunction). Investigators again noted the lack of chloracne and porphyria cutanea tarda occurrence among Ranch Hand subjects. In summary, investigators stated that as of Cycle 3 there was no evidence of an association between herbicide exposure and increased morbidity among Ranch Hand subjects (AFHS, 1990).

Reevaluation of Cycle 3 data based on TCDD body burden revealed several statistically significant associations for lipid-related abnormalities (cholesterol, high-density lipoprotein [HDL], and cholesterol to HDL ratio) (AFHS, 1991b). Two-hour postprandial glucose, ESR, immunoglobulin A, white blood cell and platelet counts, spirometric indices, benign systemic neoplasms, and decreased testicular size were also directly associated with TCDD body burden. AFHS investigators stated, in summary, that their findings “reveal[ed] a consistent relationship between dioxin [body burden] and body fat,” which they believed begged

68  

The single case of soft-tissue sarcoma was mentioned in the baseline report (AFHS, 1984a). There is some variation in reporting of these cases of soft-tissue sarcoma and non-Hodgkin’s lymphoma among AFHS reports and publications.

69  

The Symptom Checklist-90-Revised and the Millon Clinical Multiaxial Inventory were used as part of the psychological evaluation during the Cycle 3 follow-up (Appendix B) (AFHS, 1990).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

two separate hypotheses: (1) that dioxin causes an increase in body fat, and (2) that body fat modulates TCDD elimination rates (AFHS, 1991b).

As of Cycle 3 (1987), median Ranch Hand (n = 866) serum TCDD level was 12.7 ppt and ranged from no detection to 617.8 ppt. Median comparison (n = 804) serum TCDD was 4.2 ppt and ranged from no detection to 54.8 ppt (AFHS, 1991b). The 1987 TCDD value was considered by AFHS investigators to be the most informative. Subject sera were assayed in Cycles 4–6, but those assays were primarily intended to capture serum TCDD data for subjects whose sera had not previously been assayed. By Cycle 6 TCDD assays were performed for only 12 Ranch Hand subjects (2 percent of Ranch Hand participants) and 94 comparison subjects (8 percent of comparison participants). Table 4-2 recounts the number of assays performed by cycle in Chapter 4.

Cycle 4 analyses indicated that Ranch Hand subjects perceived their health status to be poorer than that of comparison subjects. Investigators noted that this result may have been biased as subjects were aware of TCDD body burden results and thus those with higher levels (Ranch Hand subjects) may have “consciously or subconsciously perceived their health to be poorer than their comparison subjects” (AFHS, 1995). Statistically significant associations were observed between TCDD body burden and percentage of body fat and ESR. Ranch Hand subjects had only a “slightly higher” prevalence of skin neoplasms (both benign and malignant) relative to comparison subjects, which had been found previously to be significant. Risk of neoplastic disease was determined to be similar for both groups. Members of Ranch Hand groundcrews were more likely than members of comparison groundcrews to develop cranial nerve index abnormalities. For the neurological assessment overall, no significant differences were observed between Ranch Hand subjects and comparison subjects, and no exposure-effect trend was evident (AFHS, 1995). TCDD body burden was found to be associated with glucose intolerance. The association was observed in both diabetic and nondiabetic subjects and was also found to exhibit a dose–effect trend. The association was evident longitudinally. While diabetes prevalence did not differ significantly between Ranch Hand subjects and comparison subjects, current dioxin was significantly associated with diabetes onset (AFHS, 1992). Using both the current and initial TCDD body burden models, a statistically significant direct association was observed between TCDD body burden and cholesterol, triglycerides, and the cholesterol-to-HDL ratio as well as for some hepatic enzyme levels (AST, ALT, and GGT)70 among Ranch Hand subjects. TCDD body burden was not found to be associated with any clinical maladies. No statistically significant group differences were found for neoplastic disease and most of the site-specific cancer evaluations found lower relative risks in the cohort subjects in the high

70  

AST: aspartate aminotransferase; ALT: alanine aminotrasferase; GGT: gamma glutamyltransferase (AFHS, 2000).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
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dioxin category than those in the background and low dioxin categories (AFHS, 1995). Deaths due to cardiovascular and digestive disease were significantly increased among Ranch Hand groundcrews (AFHS, 1994). This finding was consistent with the previous three mortality follow-up evaluations (AFHS, 1989, 1991a, 1993). The AFHS cited cardiovascular disease, glucose intolerance, and serum lipid abnormalities as the most highly relevant findings in the Cycle 4 follow-up (AFHS, 1995).

Ranch Hand subjects, and specifically enlisted Ranch Hand groundcrew personnel, continued to report their health as fair to poor with significantly greater frequency than comparison subjects in Cycle 5 (AFHS, 2000). Body fat was found to be directly correlated with TCDD body burden, and the pharmacokinetics of TCDD appeared to differ by body fat percentage (AFHS, 2000). Significant differences in ESR were not observed at the group level, but ESR did correlate with TCDD body burden. Longitudinal analysis indicated that Ranch Hand subjects experienced more ESR abnormalities than comparison subjects over time, and this trend was strongest for enlisted Ranch Hand subjects (AFHS, 2000). Ranch Hand subjects were not at increased risk for malignant neoplastic disease development after 15 years of follow-up, and longitudinal analyses did not suggest a difference in the development of malignancies over time by group status. Enlisted Ranch Hand groundcrews had lower rates of neoplastic disease than comparison subjects. A dose–effect trend between TCDD body burden and neuropathy was observed for peripheral nerve disorders, as verified by medical records review. An increase in prevalence of several neuroses was observed for enlisted Ranch Hand groundcrews. Many significant associations were observed between hepatic enzymes (AST, ALT, and GGT) and serum lipid indices (cholesterol, triglycerides, and HDL) and current TCDD body burden (AFHS, 2000). A history of essential hypertension was found to be directly associated with current serum TCDD values among Ranch Hand subjects, and initial serum TCDD body burden was found to be associated with evidence of myocardial infarction. These findings, along with increased frequency of circulatory-related deaths among nonflying enlisted Ranch Hand subjects, indicated that further evaluation of the relationship between TCDD body burden and heart disease was warranted (AFHS, 2000). Enlisted Ranch Hand groundcrews were found to have a significant increased risk of elevated levels of thyroid stimulating hormone (TSH). Type 2 diabetes prevalence was significantly associated with TCDD body burden. Ranch Hand subjects were also more likely than comparison subjects to require insulin control of their diabetes. Time to diabetes onset was directly associated with current serum TCDD levels among Ranch Hand subjects. Fasting glucose and α-1-C hemoglobin levels were directly associated with current and initial serum TCDD levels, and fasting urinary glucose trended with current TCDD levels. Investigators concluded that there was evidence of an association of either Ranch Hand group/subgroup status or serum TCDD levels (current and/or initial) with diabe-

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

tes, cardiovascular abnormalities, peripheral polyneuropathy, serum lipid abnormalities, and elevation of hepatic enzyme levels.

Analyses of Cycle 6 data revealed increases among enlisted Ranch Hand subjects of reported post-SEA acne occurrence and of post-SEA acne duration. These increases were correlated with current TCDD levels for those subjects who had not reported occurrence of pre-SEA acne (AFHS, 2005). Cardiovascular results varied by model and subgroup. An increased risk of high diastolic blood pressure was observed among Ranch Hand enlisted flyers and Ranch Hand subjects in the high-exposure category (Model 3/initial TCDD). Ranch Hand subjects were more likely to suffer from heart disease than comparison subjects in the enlisted-flyer stratum. Mean platelet count was higher for Ranch Hand enlisted flyers. Among enlisted Ranch Hand groundcrew personnel (Model 1) and Ranch Hand subjects in the low and high initial TCDD categories (Model 3) an increase in abnormal red blood cell morphology was observed. An increase in mean ESR was observed for Ranch Hand subjects in the low and high categories (Model 3). White blood cell count was inversely associated with current TCDD values (Model 4). Associations for diabetes indices varied by statistical model. Ranch Hand subjects were at significantly higher risk of abnormal 2-hour postprandial urinary glucose levels versus comparison subjects (Model 1). Under Model 2, mean fasting insulin and the probability of requiring insulin to control diabetes were directly correlated with initial TCDD, and the time to onset of diabetes was inversely correlated with initial TCDD. The requirement of insulin management of diabetes was also correlated with initial TCDD under Model 3 for the high category. Current TCDD (Model 4) was directly associated with the need for oral hypoglycemic or insulin control of diabetes and inversely associated with time to diabetes onset. Risk of elevated levels of α-1-C hemoglobin was directly associated with current TCDD (Model 4). Mean TSH was significantly higher for Ranch Hand subjects versus comparison subjects as was luteinizing hormone for Ranch Hand officers only versus comparison subjects (Model 1) (AFHS, 2005). The risk of abnormal antinuclear antibody titer increased (Model 2) with initial TCDD level (AFHS, 2005).

Reproductive Study Results

Although rudimentary reports of reproductive outcomes were published in the 1982 (baseline) morbidity report, it was not until 1996 that a comprehensive report of the reproductive experience of the Ranch Hand subjects was published. Cycle 1 results were considered preliminary and were based on maternal reporting only. Medical data collection/verification began for 9,921 conceptions and 8,100 live births one year after the Cycle 1 report was released (AFHS, 1992). Results did not reflect a dose–effect trend under any of the implemented analytical models. For several outcomes—for example, circulatory system disorders and

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
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genital anomalies—rates were greater for children born to Ranch Hand subjects in the low-dioxin categories versus Ranch Hand subjects in the high-dioxin category or the comparison group (AFHS, 1992).

Michalek and colleagues (1998b) evaluated preterm birth, intrauterine growth retardation (IUGR), and infant death in offspring of veterans with quantifiable 1987 or 1992 dioxin measures (Ranch Hand offspring: n = 859; comparison offspring: n = 1,223). Offspring analyses were restricted to singleton live births conceived during or subsequent to the subject’s SEA tour. Ranch Hand offspring were categorized by paternal dioxin level. Subject assay measures greater than 10 ppt, were extrapolated to “initial dioxin” level or to the time of conception. Offspring whose father’s 1987 or 1992 dioxin level—if both were available the 1987 measure was used—was ≤ 10 ppt were assigned to the background. Initial dioxin levels ≤ 79 ppt but >10 ppt were assigned to low, and those > 79 ppt were assigned to the high categories. Children of fathers in the high and background categories were at increased risk of preterm birth. All offspring of Ranch Hand subjects were at increased risk of infant death. Offspring of any category were not at increased risk of IUGR. Evaluation of sex of offspring indicated that offspring sex was not associated with paternal dioxin levels (Michalek et al., 1998c).

In 1998, a follow-up report of reproductive outcomes documented at Cycle 1 was released (AFHS, 1998). According to the follow-up report, which was based on verified reports of reproductive anomalies, statistically significant odds ratios relating to birth defects and neonatal death with respect to paternal service in SEA (pre- versus post-SEA outcomes) were observed (AFHS, 1998), although more than 6,000 negative responses were not subject to records verification. An elevated rate of neural tube defects71 among Ranch Hand offspring was reported in the journal Epidemiology three years before the updated USAF report was released (Wolfe et al., 1995a).

Additional Mortality Study Results

As already noted, a baseline mortality report (AFHS, 1983) and several updates (AFHS, 1984b, 1985, 1986, 1989, 1991a, 1993, 1996) have been published as part of the study. The mortality investigation has also been the subject of three papers in the peer-reviewed literature.

Michalek and colleagues (1990) analyzed cumulative mortality through December 31, 1987. Ranch Hand subjects were similar to comparison subjects with respect to all-cause mortality. Results for unadjusted cause-specific analyses indicated that Ranch Hand subjects did not differ significantly from comparison subjects. After adjusting for rank and military occupation—there were too few non-Caucasian subjects to adjust for race—there were still no significant trends

71  

Three of four neural tube defects identified were cases of spina bifida (IOM, 1996).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
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in mortality. When analyses were adjusted for time since beginning of SEA tour of duty (≤ 5 years), Ranch Hand subjects had experienced a significantly greater than expected number of deaths from external causes, with the overwhelming majority caused by nonmilitary aviation accidents. Unadjusted analyses indicated that more Ranch Hand subjects than comparison subjects had died from diseases of the digestive tract. However, this finding was not statistically significant and was not suggestive of an herbicide effect—the majority resulted from alcoholic liver disease.

In view of the data collected between 1979 and December of 1993, AFHS investigators concluded that there were no significant differences between Ranch Hand subjects and comparison subjects for overall all-cause mortality, nor were any differences in group mortality (officer/enlisted or flyer/nonflyer) evident. No significant differences were observed for cause-specific mortality, excepting an observed increase in deaths due to diseases of the circulatory system among enlisted groundcrew. This finding was again reported in the 1994 mortality update. Mortality results were also published in the American Journal of Epidemiology (Michalek et al., 1998a). This paper reported a greater number of observed Ranch Hand deaths due to digestive disease than expected, but 7 of the 9 observed deaths were due to cirrhosis and hepatic disease. The authors warned that they were not able to control for alcohol consumption in the analysis.

A 20-year update—covering cohort mortality through December 31, 1999—was published in 2005 (Ketchum and Michalek, 2005). That paper reported, for the first time, an elevated relative risk for all-cause mortality among all Ranch Hand veterans. The observed increased risk was driven by outcomes among the enlisted groundcrew (based on 88 deaths in Ranch Hand veterans). When separated by reported cause, death due to circulatory disease in enlisted groundcrew was notable (based on 40 deaths).

Following 20-years’ worth of observation and analysis and the generation of more than 20,000 pages of printed material, investigators stated that “diabetes represents the most important health problem seen in the AFHS” (AFHS, 2005; RHAC, 2000).

Costs

AFHS funding is a line item in the DOD annual budget, where it is referred to as the Ranch Hand II Epidemiology Study. Budgets from Fiscal Year (FY) 2000 (which provides figures back to FY 1998) onward are available online (DTIC, 1999, 2000, 2001, 2002, 2003, 2004, 2005); the committee obtained earlier information from study staff.72 Data, shown in Table 2-8, indicate that costs were the highest in the years where physical examinations took place. For most of

72  

M. Blancas, Air Force Health Study, personal communication, November 4, 2005.

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
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TABLE 2-8 AFHS Budget by Fiscal Year and Exam Cycle

Exam Cycle

Fiscal Year

Fiscal Year $(M)

 

1981

1.30

1

1982

7.00

 

1983

1.00

 

1984

1.40

2

1985

8.50

 

1986

4.80

3

1987

9.10

 

1988

5.50

 

1989

3.10

 

1990

1.40

 

1991

1.50

4

1992

9.70

 

1993

8.90

 

1994

3.70

 

1995

3.20

 

1996

3.00

5

1997

8.80

 

1998

10.22

 

1999

4.12

 

2000

4.18

 

2001

4.18

6

2002

11.29

 

2003

10.07

 

2004

4.65

 

2005

4.77

 

2006

4.19

NOTE: FY 1998–2004 are final amounts; 2005–2006 are estimates.

SOURCES: M. Blancas, Air Force Health Study, personal communication, November 4, 2005; DTIC, 2000, 2001, 2002, 2003, 2004, 2005.

the cycles, these costs are spread over two years. All told, approximately $143 million has been spent or allocated for conducting the AFHS. Study funding is thus provided by direct congressional appropriation and is not at the discretion of the USAF.

The yearly budget justifications include breakouts for major categories of work. These indicate that a total of ~$20.8 million73 was spent or is allocated for

73  

$8.3 million in FY 2002; $7.7 million in FY 2003; $2.3 million in FY 2004; $1.6 million in FY 2005; $0.9 million in FY 2006.

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
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the Cycle 6 physical examinations, questionnaires, and participants’ database, of which ~$16.0 million was in the two years where examinations were being conducted (DTIC, 2003, 2004, 2005). Processing and documentation of the database has averaged ~$2.8 million per year over the past five years’ budgets.

The AFHS FY 2006 budget (DTIC, 2005) includes allocations to perform documentation and organization of the data assets in anticipation of their future disposition:

Continue to process and document examination data. Continue archiving previous cycles’ examination data and digitize and archive the Cycle 6 data as received. Conduct medical records coding and verification of examination database and Cycles 1 through 6 coding…. Prepare for and complete transition or turnover of archives and specimens to designated agencies.

A total of $1,612,000 is assigned to these and other data analysis and support tasks.74 The documentation and organization activities were apparently planned as a routine part of the study’s shutdown and were not related to the Veterans and Agent Orange–series report recommendations concerning the AFHS discussed in the Chapter 1. In Chapters 3 and 4, the committee offers several recommendations regarding how the data assets should be documented and organized. It believes that these activities may well fall under the existing budget items listed above.

Study staffing levels have varied over time; personnel comprised two USAF active duty personnel, 10 federal civil service, and 26 contract employees at the beginning of 2005 (Michalek, 2005). There have also been additional outside personnel associated with analysis and data gathering contracts.

COMPENSATION AND BENEFITS FOR VIETNAM VETERANS

The Department of Veterans Affairs and Public Law 102-4

When illness or injury is related to military service, the VA provides medical care, vocational rehabilitation, and a range of other federal benefits as appropriate to those veterans (or their dependents) whose cases have been declared service connected (Brown, 2005). For injuries and acute diseases with clearly defined causes or exposures, proof of service connection is relatively straight forward, and if a veteran can provide the VA disability rating specialist with the necessary supporting documentation, then benefits are awarded according to the degree of the severity of the disease or injury. The disability rating scheme is based on a graduated scale ranging from 10 to 100 percent. Compensation grants related to

74  

The other tasks specified in the line item were: support of the annual mortality analysis, conduct of data analysis for journals and reports to Congress, and continued maintenance of study’s local area network. An additional $1,677,000 was allocated for data analysis under a separate line item.

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
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environmental or occupational exposures such as Agent Orange represent some of the most difficult disability cases to adjudicate (Brown, 2005). Proof of service connection is far more difficult to establish for longer-latency chronic diseases for which a substantial lapse of time since exposure has occurred. To establish direct service connection the onus is on the veteran to meet minimum VA evidentiary criteria: “evidence of a scientific association,” “evidence of military exposure,” “evidence of exposure magnitude,” and “evidence of temporal plausibility” (Brown, 2005). Claims are decided on an individual basis, and if the evidence indicates that “a veteran’s illness or injury is at least as likely as not to have been caused by the environmental or occupational exposure” (Brown, 2005), then the claim is settled in favor of the veteran or his or her dependents.

Excepting the evidentiary requirements listed above, the VA can grant benefits based on what is known as a presumptive service connection (Brown, 2005). A condition presumed to be connected to military service generally needs to manifest within a prescribed postservice time frame and must result in at least 10 percent disability. Presumptive connection relieves the veteran of the task of meeting the burden of proof75 of service connection. Agent Orange claims proved to be problematic for the VA and veterans seeking compensation, as the nature of exposure at the individual level was largely unknown and the toxicokinetics (relationship between dose and transport to site of toxic activity) and toxicodynamics (mechanisms of toxicants at the site of toxic activity and the downstream functional consequences) of 2,4-D and 2,4,5-T as well as that of TCDD have yet to be fully elucidated (Bier, 2003; Brown, 2005). To expedite the compensation awards process in the case of Agent Orange-related claims, in 1991 Congress placed provisions into Pub. L. 102-4, The Agent Orange Act of 1991. Pub. L. 102-4 required the VA to contract with the NAS to independently review all available scientific data pertaining to the health effects of herbicides used during the Vietnam War (not limited to Agent Orange) and dioxin exposure.76 Although respective NAS committees evaluate the strength of the evidence between specific outcomes and herbicide/dioxin exposure, it is the VA that has the ultimate authority regarding compensation policy and dispensation of awards. The VA is not limited to the input of the NAS, and has its own panel of experts that recommends actions to the Secretary of Veterans Affairs regarding the establishment of presumptive service connection for a particular health outcome. NAS reports consti-

75  

When many veterans separate from service they often retain only the minimum documentation of their service experience—their ETS (end of term of service) orders and their DD214/DD13. They may not possess a complete copy of their medical record. Recovering these documents and reconstructing service experience years and even decades after separation from service can be an onerous task, and veterans may not have access to germane documentation.

76  

Pub. L. 102-4 also called for the IOM to conduct biennial reviews of related material for a follow-up period of 10 years (IOM, 1999). In 2001, Pub. L. 107-103 extended IOM biennial reviews through 2014 (IOM, 2005).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
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tute an important input to this process, but the VA can and has made decisions on other bases.

AFHS Research and the Institute of Medicine’s “Veterans and Agent Orange” Reports

In accordance with Pub. L. 102-4, the VA asked the NAS to form a series of committees to “determine (to the extent that available scientific data permit meaningful determinations)” the following regarding associations between specific health outcomes and exposure to TCDD and other chemical compounds in herbicides:

  • whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemiologic methods used to detect the association;

  • the increased risk of the disease among those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era; and

  • whether there exists a plausible biological mechanism or other evidence of a causal relationship between herbicide exposure and the disease.

In fulfillment of its charge, the first committee given this task assembled a list of health outcomes to evaluate based on an exhaustive literature survey that included more than 6,000 abstracts and articles, 230 of which were epidemiologic investigations. Fourteen of the 230 studies were related to the Air Force Health Study. Thirty-two outcomes or categories of outcomes were identified.

Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (VAO) (IOM, 1994), was the first comprehensive evaluation published under the congressional mandate.

Determinations of health risks related to veterans were based on the appropriateness and strength of statistical association reported in the scientific literature as well as biologic plausibility and mechanistic evidence of or inference to causality77 (IOM, 1994). The strength of the scientific evidence is characterized by a qualitative scale based on criteria first established by the International Agency for Research on Cancer (IARC, 1977):

  • sufficient evidence of an association,

  • limited or suggestive evidence of an association,

77  

While evidence of causality is considered, diseases are classified on the basis of “statistical association, not on causality” (IOM, 1994).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
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  • inadequate or insufficient evidence to determine whether an association exists, and

  • limited or suggestive evidence of no association.78

AFHS mortality and morbidity results were reviewed in great detail with respect to all major disease categories and contributed with varying degrees of influence to the overall knowledge foundation on which the original report of the Veterans and Agent Orange (VAO) series was based. A total of 13 reports and papers were cited (IOM, 1994). Application and interpretation of AFHS results by the committee was limited by the statistical methods and results presentation employed by investigators. The committee noted specifically that inclusion of more Cycle 1 data,79 statement of a priori hypotheses, and greater “exploration of an overall effect” would have improved the clarity and generalizability of AFHS outcomes (IOM, 1994).

Two then-new AFHS publications (AFHS, 1995; Wolfe et al., 1995a) were reviewed in VAO Update 1996 (IOM, 1996). The AFHS 1995 mortality update was one of three studies of “high quality” that led to the addition of spina bifida to the disease category of limited or suggestive evidence of an association. The previously reviewed (IOM, 1994) AFHS 1990 report of increased risk of nonmelanomic skin cancer among Ranch Hand subjects contributed to the category change of skin cancer from limited or suggestive evidence of no association to inadequate or insufficient evidence to determine whether an association exists.

In VAO Update 1998 (IOM, 1999), urinary bladder cancer was upgraded from a condition for which there was limited or suggestive evidence of no association to an outcome for which there was inadequate or insufficient evidence to determine whether an association exists. AFHS findings did not contribute to this change.

78  

Sufficient evidence of an association is declared when “a positive association has been observed between herbicides and the outcome in studies in which chance, bias, and confounding could be ruled out with reasonable confidence.” Limited or suggestive evidence of an association refers to conditions for which “evidence is suggestive of an association between herbicides and the outcome but is limited because chance, bias, and confounding could not be ruled out with confidence.” Inadequate or insufficient evidence to determine whether an association exists is the determination made when “the available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association.” Limited or suggestive evidence of no association describes outcomes for which “several adequate studies, covering the full range of levels of exposure that human beings are known to encounter, are mutually consistent in not showing a positive association between exposure to herbicides and the outcome at any level of exposure” (IOM, 1994).

79  

The committee concluded that—using Models 1 and 2—the “most relevant baseline data” had been excluded from most analyses of the reproductive data and that the committee’s critique of methods used in reproductive analyses could be generally applied to the AFHS (IOM, 1994).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

In 1999, the VA commissioned an evaluation of type 2 diabetes risk by the IOM independent of the biennial VAO updates. The IOM released Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes in 2000. The results of the AFHS Cycle 5 morbidity analyses (AFHS, 2000) related to diabetes and the contents of a paper on the cohort (Longnecker and Michalek, 2000) were reviewed in great detail. Endpoints measured included type 2 diabetes incidence, time to disease onset, severity of disease, and a battery of related laboratory tests. These metrics were analyzed using four different exposure models that were run adjusted and unadjusted for the age, race, military occupation, personality type, body fat, and family history (IOM, 2000). Further analyses carried out at the request of the IOM committee served to strengthen the importance of AFHS results (Personal communication, J.E. Michalek, Air Force Health Study, July 28, 2000). These indicated an increased prevalence of and a decreased time to onset of type 2 diabetes was associated with dioxin exposure among Ranch Hand subjects. Previously VAO-reviewed AFHS material (Henriksen et al., 1997) was also considered in the committee’s conclusion that there was limited or suggestive evidence of an association between herbicide or dioxin exposure and type 2 diabetes (IOM, 2000). Two AFHS papers were cited in the report’s discussion of the biologic plausibility of an association between diabetes and dioxin exposure: Michalek and Tripathi (1999), reporting a compensatory metabolic relation between dioxin and insulin regulation in study participants; and Longnecker and Michalek (2000), finding an apparent association between serum dioxin levels and fasting glucose levels among nondiabetic AFHS comparison group members with less than 10 ppt serum dioxin.

Nine then-new AFHS reports and papers (including those addressed in the type 2 diabetes report) were reviewed in Veterans and Agent Orange: Update 2000 (IOM, 2001). Other than the type 2 diabetes decision, there were no changes to the categorizations of health outcomes from the previous update as the new literature supported existing conclusions.

No new major AFHS reports had been released at the time the next two update reports were published.80 However, a number of journal articles related to AFHS (Barrett et al., 2001; Michalek et al., 2001a,b,c; Steenland et al., 2001) were reviewed in both VAO Update 2002 (IOM, 2003a) and VAO Update 2004 (IOM, 2005; Akhtar et al., 2004; Barrett et al., 2003; Michalek et al., 2003; Pavuk et al., 2003). No changes were made in the strength of evidence categories by either of the IOM committees because, again, new evidence supported existing conclusions.81

A table adapted from VAO Update 2004 (IOM, 2005) is included as Appendix C. It provides, as part of a comprehensive list of the Vietnam veterans’

80  

The Cycle 6 follow-up examination results were not released until July of 2005.

81  

A new health outcome—chronic lymphocytic leukemia—was added in 2002 (IOM, 2003a).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
×

health outcomes literature, summary information on AFHS publications 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. Additional information on, and reviews of, the AFHS reports and papers may be found in the text of the Veterans and Agent Orange reports referenced in the Appendix.

In the period since the Agent Orange Act of 1991 was passed, the AFHS has contributed to the establishment of a presumptive service connection82 for type 2 diabetes in Vietnam veterans and for spina bifida in their offspring. As of September 2004, 191,649 Vietnam-era veterans were receiving compensation for diabetes mellitus (VA, 2005), and 1,187 children of Vietnam veterans were receiving compensation for spina bifida as of September 2005, the majority of which are presumptively connected to Vietnam service (G. Peters, Veterans Benefits Administration, personal communication, September 2, 2005). The Veterans Benefits Administration of the VA does not have complete documentation on the number of Vietnam veterans who have received compensation for conditions recognized as service connected due to their association with herbicide or dioxin exposure.

REFERENCES

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AFHS. 1983. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Baseline Mortality Study Results. Brooks AFB, TX: USAF School of Aerospace Medicine. NTIS AD-A130 793.

AFHS. 1984a. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Baseline Morbidity Study Results. Brooks AFB, TX: USAF School of Aerospace Medicine. NTIS AD-A-138-340.

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As of March 3, 2005, the VA recognized the following diseases as presumptively connected to Vietnam service: chloracne, Hodgkin’s disease, multiple myeloma, non-Hodgkin’s lymphoma, porphyria cutanea tarda, respiratory cancers (lung, bronchus, larynx, and trachea), soft-tissue sarcoma, acute and subacute peripheral neuropathy, prostate cancer, and spina bifida in offspring of veterans (VA, 2003).

Suggested Citation:"2 Background." Institute of Medicine. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. doi: 10.17226/11590.
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The Vietnam War was fought in a jungle environment that provided cover to the enemy and made battlefield observations difficult, so military strategists used herbicides to remove foliage along key roads and waterways, defoliate areas surrounding enemy bases and supply and communications routes, and improve visibility in heavily canopied forests. The last three decades have seen an ongoing debate about the effects of this military use of herbicides and the potential adverse long-term health effects on those who may have been exposed to these herbicides.

In response to these concerns, the Air Force Health Study (AFHS) was created to investigate the potential relationship between the herbicides used and the health problems of those exposed. Disposition of the Air Force Health Study assesses the scientific merit of the AFHS operations and procedures, and makes recommendations for improvement.

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