Post-Vietnam Dioxin Exposure in Agent Orange-Contaminated C-123 Aircraft (2015)

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TCDD: Physicochemical Properties and Health Guidelines

Of the components and contaminants of the several herbicides used by the US military in Vietnam, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) stands out as having the greatest toxic potency. It was an unintended contaminant of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), one of the phenoxy herbicides comprising Agent Orange (AO) and also Agents Pink, Green, and Purple (IOM, 2014). TCDD, or dioxin, is the most toxic of the polychlorinated dibenzo-pdioxin (PCDD), dibenzofuran (PCDF), and biphenyl (PCB) congeners. Several of the PCDD, PCDF, and PCB congeners share TCDD’s major mechanism of action in producing several adverse health conditions by binding to the aryl hydrocarbon receptor (AHR), but at a fraction of its potency. Toxic Equivalency Factors (TEFs), where the TEF of TCDD has a value of one, have been assigned to these congeners providing the basis for a summary metric that expresses the total “dioxin-like activity” in a mixture of chemicals, referred to as its Toxicity Equivalency Quotient (TEQ). The exceptionally high proportion of TEQs accounted for by TCDD itself in AO formulations (compared to other TCDD-containing mixtures) can serve as a chemical “signature” of these herbicides used by the military in Vietnam. After the Vietnam War, analyses of residual herbicide stocks found that contamination by the TCDD congener specifically ranged from less than 0.05 parts per million (ppm) up to almost 50 ppm, averaging 2–3 ppm (NRC, 1974; Young et al., 1978). Consequently, the TCDD contaminant of AO has been regarded as the primary reason for health concerns associated with exposure to the herbicides used in Vietnam, and so it is the committee’s focus.

The committee reviewed those physical and chemical properties of TCDD that would influence its persistence in the C-123s that had been used in ORH, its availability for contacting the US Air Force (AF) Reservists when they worked

inside these planes, and its presence in samples gathered considerably later. To establish a standard for putting the Reservists’ exposures in context, the committee assembled existing health exposure guidelines for TCDD and considered the assumptions underlying them. These topics are discussed in this chapter.

PHYSICOCHEMICAL PROPERTIES OF TCDD IN THE INDOOR ENVIRONMENT

2,3,7,8-TCDD is a persistent organic pollutant and stable in the environment (EPA, 1992; IOM, 2011). It has very low water solubility and is typically removed from water and soil surfaces by photolysis and volatilization. The photolysis half-life at the water’s surface has been estimated to range from 21 hours in summer to 118 hours in winter. The volatilization half-life from the water column of an environmental pond has been estimated to be 46 days; however, when the effects of adsorption to sediment are considered, the volatilization model predicts an overall volatilization removal half-life of over 50 years. Photodegradation on terrestrial surfaces may be an important transformation process. Volatilization from soil surfaces during warm conditions may be a major removal mechanism. The persistence half-life of TCDD on soil surfaces may vary from less than 1 year to 3 years, but half-lives in soil interiors may be as long as 12 years. Photodegradation is responsible for removal of TCDD from many surfaces (Karch et al., 2004). This phenomenon would be largely responsible for the failure to detect TCDD on the exteriors of the C-123s, but it would not be a major function on the aircraft’s interiors, where flux toward equilibrium among media would be expected to dominate, with removal by airflow.

The physicochemical properties of a compound provide the scientific basis for determining how and to what extent a chemical may come into contact with the “outer boundary of a human,” the final step required for exposure to occur as defined by the US Army’s Center for Health Promotion and Preventive Medicine (CHPPM, 2009). Thirty-year-old residues deposited on a surface might be assumed to be effectively chemically inert as purported by the VA (http://www.publichealth.va.gov/exposures/agentorange/locations/residue-c123-aircraft/scientific-review.asp; accessed August 21, 2014) on the basis of reports from Young and Young (2012, 2013b). In fact, however, semi-volatile organic compounds (SVOCs), such as TCDD, are in constant flux around equilibrium.

Prior to reviewing past interpretations of the available sampling data, it is worthwhile to explore the theoretical distribution of TCDD and other SVOCs in the indoor environment and relate this to the exposure potential for AF Reserve personnel who served on C-123s that had formerly sprayed defoliants in Vietnam. The committee subscribes to the concepts related to fugacity as described in Weschler and Nazaroff (2008) that provide a holistic and dynamic view of multimedia transfer of these chemicals. These concepts can be summarized as follows:

1. Equilibrium partitioning of SVOCs between liquids, gas-phase air, airborne particles, dust on surfaces, residues or films on surfaces, and humans, governs the fate and transport of these chemicals.
2. With a saturation vapor pressure of 3.9 × 10⁻¹² atm, TCDD is classified as an SVOC (where SVOCs are defined as having vapor pressures between 10⁻¹⁴ and 10⁻⁴).
3. Indoor surfaces have films (i.e., a mix of organics, inorganic ions, water, and particles) that interact with gas-phase SVOCs; it is likely that these films play a larger role than bare surfaces in transport and exposure.
4. Most indoor environments are dynamic, resulting in exchanges in mass across compartments that are nearly continuously in flux.

From these concepts we can assume that a satisfactory sampling scheme would involve multiple media types (such as air, residue or films, and dust). If it is present in one medium, an SVOC like TCDD would be expected to partition into other environmental compartments, as has been demonstrated for the SVOCs phthalates inside a stainless steel chamber (Liang and Xu, 2014). Processes (such as ventilation and cleaning) may remove chemicals from one compartment; however, if a reservoir exists, over time dynamic partitioning will likely replenish the chemical to a state of equilibrium.

The nature of films that can harbor organic chemicals on nonporous surfaces has been established on glass (Liu et al., 2003) and on metal surfaces (Wallace et al., 2014). Together, these articles demonstrate that, in environments where there are organic materials, an organic film will coat the types of inert surfaces (i.e., metals, glass, and plastic) that are found inside aircraft. The thickness of the film will depend on the type of organic material present (for example, skin oils and greases used or present in aircraft), temperature, and time since the surface was cleaned by some process such as heating, wiping, or solvent treatment. The organic film then serves as both a source from which SVOCs will emanate and a medium into which they will be absorbed in an equilibrium process.

Exposures to herbicide and TCDD residues in the C-123s could occur via three pathways: dermal, inhalation, and ingestion. The characterization of external exposure for each pathway needs to incorporate the concentrations in the relevant media that reach a body boundary, the frequency of that contact, and the duration of the contact. Those data, when coupled with the transference or uptake into the body can provide an internal exposure or dose.

The principle that SVOCs (including TCDD) migrate “downhill” along thermodynamic gradients is generally accepted by physical chemists (Mackay, 2001) and the exposure assessment community (Bennett and Furtaw, 2004; Weschler and Nazaroff, 2008). The former Operation Ranch Hand (ORH) C-123s were contaminated with TCDD, and the AF Reservists were “downhill” when inside the planes. As a consequence, they would have been exposed to TCDD, but the magnitude of the doses they received are quite uncertain.

EXISTING HEALTH GUIDELINES FOR TCDD EXPOSURE

Screening guidelines are derived as standards for assessing whether further action is appropriate for a particular situation because of the possibility of adverse health outcomes of any sort in a group. They are not meant to predict the number of adverse events that will be observed, but are intended to be protective of a broad range of activities and sensitivities.

Although TCDD is a naturally occurring combustion product, it has never been an intended product of any industrial process. Consequently, although dioxin guidelines have been developed by expert bodies such as the US Environmental Protection Agency (EPA) and the World Health Organization (WHO) in an effort to protect the general population from harmful levels of intake from environmental sources, TCDD itself has not been a common target of occupational regulation.

In the past, PCBs were purposefully handled in industrial settings and became of increased concern as the adverse consequences of dispersed and combusted PCBs following transformer fires came to light. This necessitated development of re-entry standards for fire-impacted buildings. The recognition that most of the toxicity of PCBs and also furans results from specific congeners that share the AH-receptor mechanism of action with TCDD with a lower degree of potency has permitted development of a unified measure of toxic potency for dioxins, PCBs, and furans. Exposure standards for these chemicals have been set in terms of TEQs, which are the summed TEFs weighted by the measured amount of their associated congener in a particular analyzed sample.

Various agencies and other groups have proposed guidelines for exposure to TCDD and dioxin-like chemicals through different routes. The recommended surface and air concentrations are guidelines for total intake. A surface contamination guideline assumes that the surface is the source of direct dermal exposure and possibly indirect ingestion and inhalation uptake that would provide a specified total intake, while a TCDD air guideline assumes that air is the sole source of TCDD. When there are multiple sources of exposure, the allowable uptakes from surfaces and from air need to be modified so that the corresponding guideline for total uptake is not exceeded.

All of the TCDD guidelines in Table 2-1 are for a weighted sum of different congeners and are expressed in terms of TEQs. Results in terms of TEQs were not presented for all the interior C-123 samples but, as demonstrated in the 1994 sampling of “Patches” (USAF, 1994), the vast majority of TEQs measured in samples from C-123 aircraft are derived from their TCDD content alone, as is characteristic of exposures derived from AO. As a result, exposure limits in terms of TEQs provide an appropriate standard for comparison with TCDD samples drawn from the interior of the C-123 aircraft that had sprayed herbicides in Vietnam.

Like estimation of the amount of exposure experienced, estimation of the dose–response portion of the risk assessment calculations entails many sources of

TABLE 2-1 Available Guidelines Concerning Exposure to TCDD

NOTES: ADI, acceptable daily intake; ATSDR, Agency for Toxic Substances and Disease Registry; CSF, cancer slope factor; EPA, Environmental Protection Agency; JECFA, Joint FAO/WHO Expert Committee on Food Additives; kg-time, body weight of exposed individual over specified time period; LADD, lifetime average daily dose; LOAEL, lowest-observed-adverse-effect level; MRL, minimal risk level (daily human exposure that is likely to be without appreciable risk of adverse, noncancer effects over a specified duration of exposure—ATSDR); NOEL, no-observed-effect level; NRC, National Research Council; OEL, occupational exposure limit; PTI, provisional tolerable intake; RfD, reference dose (estimate with uncertainty spanning about an order of magnitude of a daily exposure likely to be without appreciable risk of deleterious noncancer effects during a lifetime); TDI, tolerable daily intake; TLV, threshold limit value; TWA, time-weighted average.

uncertainty. Although determination of an agent’s toxicity to humans is the objective, the numerous uncontrolled factors involved in epidemiologic results (which underlie conclusions concerning association reached in the IOM’s Veterans and Agent Orange series) dictate that results of laboratory experiments are most often used. The estimates of toxic potency underlying the guidelines referred to by the committee in assessing concern about the exposure of the AF Reservists who used C-123s that had sprayed herbicides in Vietnam have been derived from controlled animal studies. TCDD guidelines based on noncancer outcomes most often have been based on developmental effects, but a reduction in semen quality among young men exposed during the Seveso industrial accident (Moccarelli et al., 2008) was a determining factor in the noncancer reference dose (RfD) derived in a decades-long process (EPA, 2012).

For cancer outcomes (which are recognized among the adverse health effects associated with TCDD), the once generally accepted assumption of low-dose linearity dictates that some increase in risk is associated with any exposure—down to infinitesimal amounts that would be inconsequential. The resulting guideline, which is intended to protect against the occurrence of any cancer, will generally result in a lower concentration of the substance being regarded as safe than would be determined for a noncancer endpoint. For noncancer adverse effects (several of which are also on TCDD’s generally accepted list of adverse outcomes), it has been thought that there is some level of exposure below which no toxic response would occur. It is now thought that such “threshold” dose–response models may also be applicable to certain mechanisms of toxicity that contribute to carcinogenesis. TCDD’s AHR-mediated mode of biological activity, shared by other dioxin-like chemicals, appears to fit in this category. Small increments in exposure in a “threshold” situation do not pose a health threat if total exposure to agents with the mechanism of action in question is well below the estimated point of inflection in the dose–response curve. However, when “background” exposure experienced by the general public is still very close to “tolerable” daily intakes (TDIs in Table 2-1), a modest increment in exposure from an additional source can move an individual’s total up to a level at which adverse effects are plausible.

The TCDD exposure guidelines (see Table 2-1) are of three types:

• those expressed in terms of daily TCDD intake (from all routes) per body weight (pg/kg-d),
• those expressed as an air concentration (pg/m³), and
• those expressed in terms of surface contamination (ng/m²).

Most of these surface contamination and air guidelines were derived for protection of office workers working in TCDD-contaminated buildings, and utilize exposure scenarios and assumptions pertaining to work practices of office workers, such as breathing rates, rate of contact of hands and arms with contaminated surfaces, percent of contaminant transferred to hands or arms after surface

contact, etc. Each of the guidelines involves assumptions intended to ensure that keeping surface concentrations below the guideline would protect the health of a group. These health-protective assumptions increase the likelihood that, even if the guideline were exceeded, there may be no observable health effect in any individual in a population at risk. Screening levels are developed as a preliminary means of establishing whether health risks are sufficiently plausible that further investigation is needed, but for ORH C-123s and AF Reservists the information at hand is all there will ever be for decision making.

Guidelines developed for protection of the general public from exposure to TCDD and dioxin-like chemicals (focused on ingestion of food that has incorporated environmental contamination) are not directly applicable to evaluating the occupational exposures of the AF Reservists. They are, however, of interest in providing insight into cumulative lifetime intakes regarded by expert bodies such as EPA, the Agency for Toxic Substances and Disease Registry, and WHO, as falling at the borderline of acceptable. The committee found that, although no guideline was a perfect match for the experience of the AF Reservists, the reentry standards expressed in terms of surface loading are most applicable for this situation.

Because fires involving PCB-containing equipment can release TCDD and PCB-related combustion products into the environment in toxicologically relevant concentrations, such fires are the basis for numerous federal and state regulatory and other actions designed to reduce human harm. EPA’s “Transformer Rule” under Toxic Substance Control Act (40 Code of Federal Regulations, Part 761), for example, is a requirement to reduce hazards associated with combustion by-products or contaminants of PCBs in the transformers.

In 1988, the National Research Council’s (NRC’s) Committee on Toxicology, organized a Subcommittee on Dioxin that provided recommendations regarding acceptable contamination concentrations for TCDD to protect worker health upon re-entry into an office building after a transformer fire (NRC, 1988). At the time of the NRC report, four states (California, Louisiana, New Mexico, and New York) had TCDD surface concentration guidelines for worker re-entry after transformer fires in office buildings (see Table 2-1). For example, the NRC Subcommittee considered the recommended exposure guidelines put forth by the New York State Department of Health’s risk assessment (Kim and Hawley, 1985) to be adequate for protecting long-term office workers from the harmful effects of dioxin. The New York guidelines were derived in part with a no-observed-effect level (NOEL)-safety factor approach, giving an assumed negligible likelihood of non-cancer health effects in humans. The TCDD guidelines of 10 pg/m³ in air and 25 ng/m² on surfaces correspond to a 2 pg/kg allowable daily intake over a 30 year exposure period for a 50-kg office worker. The upper bound on lifetime cancer risk associated with the New York TCDD guidelines is 2 × 10⁻⁴.

In Technical Guide 312 (TG 312) the Army Center for Health Promotion and Preventive Medicine (CHPPM, 2009) derives TCDD surface wipe screening

levels (SWSLs) for long-term office workers. The screening level assumes exposure to contaminated surfaces through dermal contact and absorption, incidental ingestion by hand-to-mouth behaviors, and inhalation through breathing resuspended particulates. The upper bound cancer risk is set to 1 × 10⁻⁶ for a 70-kg office worker over a 10-year exposure duration. Environmental samples with concentrations above the 3.5 ng/m² SWSL for TCDD would be an indication for a more thorough health risk assessment for the site with more specific exposure parameters. A comparison of observed surface concentrations to the calculated TG 312 guidelines does not definitively distinguish between “safe and unsafe” environmental conditions, nor is an exceedance an “absolute predictor” of adverse health effects. Another military surface loading guideline was found in an AF interpretation of the sampling data (USAF, 2009b). It was said to be 22 ng/m², but should have been 1.1 ng/m² if it had correctly factored in the more sensitive dermal pathway as it was alleged to do (see discussion of Table 4-1).

In addition, after identifying dioxin as one of six contaminants of potential concern, the World Trade Center Indoor Air Task Force Working Group (WTC, 2003) went on to establish residential re-entry guidelines for each of these substances. To protect against a cancer risk of 10⁻⁴ for 70-kg adults living in a residence fulltime for 30 years, guidelines of 1 pg/m³ indoor air was set for inhalation and 2 ng/m² in settled dust for dermal absorption and ingestion.

The guidelines for surface loading seem to be most applicable to the occupational situation this committee is evaluating. Also, almost all the usable TCDD sampling results happen to be measurements from surface wipes. These screening guidelines in TEQs for surface loading range from 1 to 25 ng/m², including the 3.5 ng/m² derived by CHPPM and the 22 ng/m² (or more correctly, 1.1 ng/m²) guideline from the 2009 AF report. It is interesting to note the trend in these guidelines toward increasing stringency with the passage of time, a larger body of epidemiologic and experimental results, and improving understanding of the underlying biologic processes.