The objective of this exposure assessment is to estimate the type and magnitude of exposures to the 15 pesticides of potential concern (POPCs), containing 12 different active ingredients, that servicemembers may have been exposed to during deployment. The exposure assessment evaluates the potentially-exposed population only, which is a subpopulation of the deployed population. Investigators have combined the results of the exposure assessment with toxicity data to characterize risk in Section B.5,  Risk Characterization.

The movement of a pesticide active ingredient from the source to a human receptor is described in terms of an exposure pathway. A complete exposure pathway consists of all four of the following elements:

• a source and mechanism for pesticide active ingredient release,
• an environmental transport medium,
• an exposure point, and
• a human receptor and a feasible route of exposure at the exposure point.

Investigators have determined that each of the 15 pesticide formulations retained for detailed evaluation in the exposure assessment were associated with one or more completed pathways during deployment.

Investigators developed three to six exposure scenarios for each of the 15 POPCs for detailed evaluation in the pesticide exposure assessment. Table 19 presents a general description of all exposure scenarios evaluated for the POPCs. "Detailed" evaluation means that investigators used the specific scenarios and quantitative methods to estimate human intakes (doses); however, there is a moderate to high level of uncertainty associated with many of the exposure factors used to make the estimation. Wherever possible, investigators developed KTO-specific assumptions; otherwise investigators used standard generic EPA assumptions.

EPA’s Office of Pesticide Programs (OPP) commonly conducts similar risk assessments in order to decide how to regulate pesticide products. OPP seeks to develop realistic exposure scenarios, and has developed highly detailed, sophisticated, and validated exposure models, in order to estimate doses. The models, which have been developed using an abundance of actual field monitoring data, can be used to make estimates for actual or hypothetical situations where monitoring data do not exist. Many of these models are incorporated into the following two sources:

• EPA: Pesticide Handlers Exposure Database (PHED) Surrogate Exposure Guide.^[128]
• EPA: Standard Operating Procedures (SOPs) for Residential Exposure Assessments.^[129]

Both sources have extensive applicability in estimating potential pesticide formulation exposures to Gulf War veterans. The HRA discusses PHED in more detail later in the exposure assessment.

While it is impossible to identify and evaluate all exposure scenarios which actually occurred, the HRA develops exposure scenarios that are representative of the range of exposures. Each exposure scenario is associated with the low exposure level, medium exposure level, or high exposure level. These exposure levels are hypothetical, depending entirely on the assumptions presented for each throughout the HRA.

Table 19. General description of exposure scenarios

In many cases, pesticide formulation exposures during deployment would have been very similar to exposures normally occurring in the US at the time. On the other hand, there were certainly conditions existing some of the time that would have contributed to higher-than-normal, or otherwise unusual exposures for some servicemembers. Mass delousing does not occur domestically. Azamethiphos is not registered for use in the US. Most people in the US do not live under relatively primitive conditions in sweltering regions of extreme pest infestation, which require intensive and sustained control measures. Symptomatic pesticide formulation exposures (i.e., overexposures), however, appear to have occurred rarely by all accounts.

Investigators evaluated the low-, medium-, and high-exposure levels for each POPC, although doses were not always calculated for low and medium levels. The exposure levels are defined by the exposure factors selected, such as the volume of the formulation used each day. Some exposure factors, such as assumed body weight, are the same for all three exposure levels. The degree of overall conservatism increases as one moves from low exposure to high exposure. We applied, as much as possible, the following guidelines for selection of exposure factors:

• Low-exposure group. The nominal 5^th percentile exposure factors derived from the survey. The nominal 10^th percentile exposure factors derived from the interviews. The nominal 10^th percentile exposure factors or low-end values available from published sources.

• Medium-exposure group. The average exposure factors derived from the interviews. The nominal 50^th percentile exposure factors or mid-range values derived from the survey and published sources.

• High-exposure group. The nominal 95^th percentile exposure factors derived from the survey. Nominal 90^th percentile exposure factors from interviews. The nominal 50^th percentile exposure factors or mid-range values available from published sources. The nominal 50^th percentile published values or other mid-range values are used in the high exposure group in order to minimize unreasonably high bias per EPA^[142] recommendation. EPA believes that this approach avoids compounding many conservative assumptions to produce a highly unlikely or impossible exposure estimate.

The rationale for incorporating a few 50^th percentile exposure factors for the high exposure group is based on an understanding of cumulative probabilities. Assuming all percentile values are reliable, the probability that any individual was at or above the 90^th percentile value for a single exposure factor is about 10%. As the number of such factors increases, the probability that an individual was at or above the 90^th percentile values in all cases decreases dramatically. In other words, such an occurrence is extremely unlikely.

One exception to the selection of percentile values are the assumptions regarding the wearing of PPE by pesticide applicators. In general, investigators assumed that the low-exposure group wore the most PPE, and that the high-exposure group wore the least. So, for example, the 90^th percentile for percent of servicemembers wearing PPE is associated with the highest level of protection, but serves as the basis for the low exposure group PPE assumption. The PPE percentile values are not used directly in the calculation of doses, as the algorithms do not accommodate this factor, and, due to the shortcomings in the relevant data from the PM exposure interviews, they can only be used qualitatively to indicate the level of PPE use. In short, investigators assumed that all individuals within an exposure group (e.g., low exposure) wore the same components of PPE, such as gloves and respirators.

The results for the medium-exposure group are the most reliable in this HRA. The "high-exposure group" is equivalent to what is commonly referred to as the "reasonable maximum exposure" (RME) receptor group, which likely applies to a small number of individuals. The EPA has typically used the RME level for decision-making purposes in the regulatory setting. The results for the low and high-exposure groups are less reliable than those for the medium-exposure group, due to generally greater uncertainty surrounding the associated assumptions in the former groups. While the EPA is interested in what might happen in the future, we are particularly interested in what most likely happened in the past.

As used here, a "nominal" 10^th percentile value is the point below which approximately 10% of the values from the associated sample distribution fall. A nominal 50^th percentile value is the point below which approximately 50% of the values from the associated sample distribution fall. A nominal 90^th percentile value is the point below which approximately 90% of the values in the associated distribution fall. However, the sample data arise from the years-old recollections of veterans, and the exposure factors thus derived may not be accurate values for the relevant veteran subpopulations.

One important factor that impacted pesticide formulation use was the prevailing pest pressure or the perceived pest threat (and any associated threat of disease). "Pest pressure" is directly related to the active pest population in the vicinity. If the active pest population was very large, then the pest pressure was high, and would most likely have been associated with a high level of pesticide product use, if pesticide products were available. Usually, the pest threat was tied to time of year and location. For example, fly populations were worse in August than they were in January, and servicemembers were more susceptible to flies if they were quartered in temporary shelters in rural locations versus permanent shelters in urban locations. "Urban" denotes a moderately to highly developed area, normally having a high human population density. "Rural" denotes a relatively undeveloped area, normally having a low human population density. In the scenarios described later in the exposure assessment, each pesticide exposure level is associated with an assumed level of pest pressure. A low exposure level would equate to minimal pest populations and low levels of pesticide use due to time of year and/or location, while medium and high levels would have corresponding moderate and high levels of pesticide use.

Another important distinction between exposures is whether they occurred during application or whether they occurred following application ("post-application exposures"). Application here includes mixing, loading, and applying pesticide products. People may experience exposure during application and/or post application.

Other factors impacting exposure level include the level of PPE used by applicators, and for post-application exposure, whether the applications were made outdoors or indoors. In cases where PPE should have been used, investigators assumed that the low-exposure applicators donned appropriate PPE, and high-exposure applicators did not. Investigators assumed that medium-exposure applicators either did or did not don appropriate PPE, depending on the information provided by the PM interviews. Investigators also assumed that post-application exposures occurred outdoors for the low- and/or medium-exposure group, and indoors for the medium- and/or high-exposure group (depending on our information). While investigators did not evaluate applicators who wore PPE at the high-exposure level, it is safe to conclude that, in a given case, the estimated dose for them would lie between the dose at the medium-exposure level (wearing PPE) and the dose at the high-exposure level (without PPE). In a few selected cases which we examined, a person not protected by PPE would typically receive 10 times the inhalation dose and 10 to 100 times the dermal dose versus a person protected by appropriate PPE. In some cases, however, BDUs may have afforded significant dermal protection, perhaps more so than is reflected in some HRA assumptions.

Investigators grouped the 15 formulations evaluated in the exposure assessment based on similarities in designated uses, application, and/or exposure scenarios, as shown in Table 20.

Table 20. Formulations evaluated in the exposure assessment

1.  Exposure Point Concentrations

For the pesticide formulations considered in the HRA, the most common routes of exposure are dermal contact and inhalation. For this exposure assessment, investigators calculated exposure point concentrations (EPCs) only when they evaluated the oral route of exposure, and when they conducted air modeling to estimate the air concentrations of pesticide active ingredients. Otherwise, investigators calculated doses by other means, as described in the following subsection. EPCs are the concentrations of POPCs in a given medium to which a receptor may be exposed at a specific location known as the "exposure point."

2.  Human Intakes

Per EPA recommendation, investigators calculated one type of dose for the evaluation of potential noncarcinogenic effects, and another for the evaluation of potential carcinogenic effects.^[143] For evaluation of noncarcinogenic effects, we calculated doses for the day of application; that is, we did not reduce the doses by averaging over time. In contrast, for evaluation of carcinogenic effects we calculated lifetime average daily doses (LADDs). Thus, the LADD is always substantially lower than the dose calculated to evaluate noncarcinogenic effects. All doses in the HRA, whether for noncarcinogenic effects or carcinogenic effects, are expressed in units of mg active ingredient per kg body weight per day (mg/kg/d). Intakes for carcinogenic effects are averaged over a lifetime since risk of cancer is accrued over a lifetime. In any case where investigators calculated a dose for the evaluation of noncarcinogenic effects, they calculated at least the high dose. Investigators calculated low and medium doses in most cases; however, if investigators deemed the low and/or medium dose inconsequential, they only calculated the high dose. Investigators calculated a LADD based on the medium exposure level only, where possible; they used the high exposure level in cases where they did not evaluate the medium exposure level.^[144]

As used in the HRA, the term "consequential" means of sufficient magnitude to potentially affect the outcome of the health risk assessment. A "consequential exposure" is known or likely to be greater than or equal to one-tenth of any relevant risk-based threshold such as a reference dose (see Section B.4,  Toxicity Assessment). The term "inconsequential" means of insufficient magnitude to potentially affect the outcome of the health risk assessment. An "inconsequential exposure" is known or likely to be less than one-tenth of any relevant risk-based threshold such as a reference dose.

Investigators initially identified all plausible scenario/route combinations of consequential exposure (Tables 21 and 22), and calculated doses for them as described throughout the exposure assessment. In some cases, investigators evaluated both application and post-application together as the contribution of one so far exceeded the other. This is explained in detail later for each formulation. Evaluation of potential carcinogenic effects is indicated only for those pesticide active ingredients having an appropriate carcinogenic slope factor (see Section B.4,  Toxicity Assessment). The most common routes of exposure are the dermal and inhalation routes; the oral route is relevant in only a few cases.

Table 21. Summary of application scenarios and exposure routes evaluated

Table 22. Summary of post-application scenarios and exposure routes evaluated

The types of doses calculated in the exposure assessment are as follows:

Doses for noncarcinogenic effects:

• PDR_D = potential dose rate for dermal contact
• AD_D = absorbed dermal dose
• PDR_I = potential dose rate for inhalation exposure
• PDR_O = potential dose rate for oral exposure

Doses for carcinogenic effects:

• LADD_D = lifetime average daily dose via dermal contact (absorbed dose)
• LADD_I = lifetime average daily dose via inhalation exposure (potential dose)
• LADD_O = lifetime average daily dose via oral exposure (potential dose)

The HRA expresses dermal doses for the evaluation of noncarcinogenic effects as both potential dose and absorbed dose. In general, these two types of doses, for any route of exposure, are defined as follows:

• Potential dose. The amount of pesticide active ingredient contained in material ingested, air breathed, or bulk material applied to skin.^[145]

• Absorbed dose. The amount of pesticide active ingredient penetrating across the absorption barriers (exchange boundaries) of a test organism or human (same as "internal dose").^[146]

Either one of these may be used to characterize risk, as appropriate, depending on the type of toxicity value identified (see Sections B.4,  Toxicity Assessment and B.5,  Risk Characterization). The HRA presents the inhalation and oral doses for evaluation of noncarcinogenic effects only as potential doses, as this is appropriate for the available toxicity values. The HRA presents the LADD for dermal exposure only as an absorbed dose, because this is appropriate for the available slope factors (see Section B.4,  Toxicity Assessment). The HRA presents the LADDs for inhalation and oral exposure as potential doses, as appropriate for the available slope factors.

To convert a potential dose to an absorbed dose for dermal exposure, it is first necessary to find an appropriate chemical-specific dermal absorption factor (ABS). The ABS represents the fraction or percentage of the pesticide active ingredient which can be expected to pass through the skin into the body. Then the HRA calculates the absorbed dose as follows: potential dose x ABS = absorbed dose.

All equations used to calculate doses are described in the following subsections. All the exposure factors used in the equations are described as well. There are three exposure factors used throughout the HRA, and investigators assume the following:

• Body weight (BW) is 70 kg^[147] for all receptors. The value of 70 kg is the value most commonly used for adults (males and females combined) in EPA risk assessments over the past 15 years or so.

• A human lifetime is 70 years.^[148] This is the value most commonly used in EPA risk assessments over the past 15 years or so. The value for lifetime used for averaging time (AT) in the equations is 25,550 days (i.e., 70 years x 365 days).

• The inhalation rate (IRA) is 1.6 m³/h, which is the EPA-recommended value for adult short-term exposures during moderate activities.^[149] This inhalation rate takes into account that troops were engaged in a variety of activities over the course of the average day ranging from light activities to heavy activities.

Investigators selected the value of 70 kg for body weight because it is close to the mean adult weight for males and females combined, and because of the precedent for its use. Investigators considered using alternative values, but concluded this could introduce additional complications, have only a small effect on the estimates, and provide only a slight improvement in accuracy. The potential alternatives include 1) using the actual mean of 71.8 kg for males and females combined, and 2) evaluating females separately from males, and using mean BW values of 65.4 kg and 78.1 kg, respectively.^[150] Since some toxicity values, such as cancer slope factors, are derived by EPA based on an assumption of 70 kg BW, this would require adjusting slope factors accordingly. Evaluating males and females separately adds another layer of complication to an already complicated risk assessment. The main reason for considering a separate evaluation for males and females would be to better address sex-specific toxicity endpoints; however, sex-specific endpoints are of minor importance for the pesticide dose analysis, and 93% of the relevant population is male.^[151]

Exposure duration (ED) types are defined here as follows:

• acute/subacute: exposures lasting <2 weeks,
• subchronic: exposures lasting 2 weeks to 180 days, and
• chronic: exposures lasting >180 days.

One source defines acute exposure as lasting less than 1 day, and subacute as lasting 1 month or less.^[152] The subchronic and chronic exposure durations are adapted from EPA guidance.^[153,154]

Most pesticide product exposures during the Gulf War were acute/subacute and subchronic; however, there were probably a small number of chronic exposures as well. In some cases there are varying acute/subacute, subchronic, and chronic toxicity values, and investigators combined the assumed exposure duration with the appropriate toxicity value.

In the following subsections, there are six possible exposure scenarios for each formulation: one scenario for each of three exposure levels for application exposure, and one scenario for each of three exposure levels for post-application exposure. Investigators evaluated the high-exposure scenarios in detail in all cases for application and/or post-application exposure; however, they did not evaluate lower-level exposure scenarios if they concluded that the lower-level scenarios are inconsequential. For example, if investigators concluded that lower-level exposure scenarios provided little or no opportunity for contact with the pesticide active ingredient, such exposures were not quantified.

As part of risk characterization (Section B.5,  Risk Characterization), investigators added together the risks due to multiple scenarios, exposure routes, and formulations in some cases, as justified by the evidence, to estimate cumulative risks.

3.  Pesticide Handlers Exposure Database

The Pesticide Handlers Exposure Database (PHED) is used to estimate exposure to pesticide workers (applicators).^[155] PHED is a huge database of actual field monitoring data that provides dermal and inhalation exposure estimates based on type of pesticide product and application method, which are not chemical specific. Thus, a PHED user can identify appropriate scenarios to estimate exposure for many different pesticide active ingredients. EPA has reviewed the exposure data in PHED for scientific integrity and has graded the data based on analytical quality assurance.^[156] Besides the PHED computer program software, there are a number of related PHED hard-copy documents. Of the latter, investigators used the PHED Surrogate Exposure Guide in conducting the exposure assessment. The data listed in the PHED Guide are associated with varying levels of confidence based on numbers of replicates and data quality as described in the PHED Guide. The levels of confidence listed are: high, medium, and low, and are included in the footnotes to the present exposure assessment.

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