Impact of Revised Airborne Exposure Limits on Non-Stockpile Chemical Materiel Program Activities (2005)

The Centers for Disease Control and Prevention (CDC) established airborne exposure limits (AELs) in 1988 for sarin (GB), tabun (GA), and VX (Federal Register, 1988). The nerve agent GB is the most studied of these three agents; very little experimental information is available for GA and VX. Thus, in developing AELs for these three agents, experimental data on the induction of mild effects (miosis¹) were used to establish the AELs for GB and relative potency factors were used to establish the AELs for GA and VX.

The actual method of deriving the 1988 CDC worker population limit (WPL)² of 1 × 10⁻⁴ mg/m³ and the general population limit (GPL) of 3 × 10⁻⁶ mg/m³ (Table 3-1) was not specifically documented in the 1988 Federal Register or in the 1987 CDC meeting transcript “Safe Disposal of Lethal Chemical Agents.” Mioduszewski et al. (1998) reported that the 1988 AELs for GB were based on recommendations proposed by McNamara and Leitnaker (1971) using a combination of acute human exposure data as well as acute animal pharmacokinetics data to predict cumulative effects of GB exposure in humans. The AELs recommended in 1988 for VX were based on the estimated relative potency of VX and GB reported by Reutter et al. (2000).

The CDC-recommended 1988 GPL for GB was 3 × 10⁻⁶ mg/m³ for a TWA over 72 hours (Table 3-1). This AEL was calculated to be 30-fold less than the 1988 WPL. The CDC did not establish a short-term exposure limit (STEL) or an immediately dangerous to life or health (IDLH) limit in 1988. The potency of GA is considered to be equal to that of GB, so the AEL values for GA are the same as those for GB (Federal Register, 2003a).

The AELs for VX were based on its potency relative to that of GB. In 1988, the CDC assumed that VX was 10 times more toxic than GB and recommended a WPL (i.e., TWA) of 1 × 10⁻⁵ mg/m³ (Table 3-1) (Federal Register, 1988).

However, it recommended that the GPL (3 × 10⁻⁶ mg/m³) for VX be the same as that for GB based on the limited technical capabilities of the air monitoring equipment available in 1988. STELs and IDLHs were not established for VX in 1988.

In 2003, the CDC revised the AELs for GA, GB, and VX. The revised GB WPL (3 × 10⁻⁵ mg/m³) and the GPL (1 × 10⁻⁶ mg/m³) (Table 3-1) were one-third of the 1988 values (Federal Register, 2003a). These new limits were based not on new experimental data for humans or animals but on an additional uncertainty factor of 3 that the CDC wanted to account for individual variability. For VX, the CDC adjusted the relative potency factor from 10 to 12 to reflect increased toxicity compared with GB and applied a modifying factor of 3 to account for an incomplete data set, resulting in a total composite adjustment of 36 for VX. Applying these factors resulted in a VX WPL of 1 × 10⁻⁶ mg/m³ and a calculated GPL of 3 × 10⁻⁸ mg/m³. However, CDC then adjusted the calculated GPL for VX upward, by a factor of 20, to 6 × 10⁻⁷ mg/m³ based on the technical capabilities of latter-day air-monitoring methods (Federal Register, 2003a). The CDC justified this by saying it could be expected that any exposure would be identified and corrected within 3 days (72-hour TWA).

STELs and IDLH limits were derived in 2003 for GA, GB, and VX. A STEL of 1 × 10⁻⁴ mg/m³ was set for GA and GB while a STEL of 1 × 10⁻⁵ mg/m³ was set for VX (Table 3-1) (Federal Register, 2003a). A STEL is an acceptable exposure for 15 minutes for unprotected workers.³ For GA and GB, such exposures should not occur more than four times per day, and at least 60 minutes should elapse between successive exposures. For VX, STEL exposures should occur no more than once a day (Federal Register, 2003a).

Several issues surrounding the CDC’s 1988 and 2003 AELs for GA, GB, and VX deserve consideration. The CDC based its 2003 recommendations on several sources of information:

• Comments from expert scientists,

• Risk assessment approaches used by regulatory agencies and other organizations, and

• Information provided in recent U.S. Army evaluations of AELs for chemical warfare agents.

The CDC used the U.S. Environmental Protection Agency (EPA) conventional reference dose concentration risk assessment methodology for developing the AELs (Federal Register, 2003a). The CDC says that this methodology is conservative and does not reflect a change in the understanding of demonstrated human toxicity by these agents nor does it redefine that understanding. The CDC also indicated that no overt adverse health effects had been noted in association with the 1988 recommended exposure limits.

The EPA’s risk assessment methodology is used to promulgate reference dose concentrations for airborne chemicals—that is, airborne exposure limits—for general (including sensitive) populations over a lifetime (70 years).⁴ The EPA has also developed and now manages a mechanism for establishing short-term emergency exposure limits for airborne chemicals. The process functions through the National Advisory Committee to Establish Acute Exposure Guideline Levels (AEGLs) for Hazardous Substances.⁵ AEGL values define exposures to airborne chemicals intended to protect the general public (including sensitive individuals) after single exposures ranging from 10 minutes to 8 hours. The proposed short-term AEGLs were reviewed by a National Research Council committee and ultimately issued as a National Academy of Sciences publication (NRC, 2003). EPA has not, however, developed long-term reference dose concentrations for nerve agents GA, GB, and VX. Since the CDC’s recommended STELs are for a 15-minute exposure, the WPLs for 8 hours per day, and the GPLs for a lifetime based on a 24-hour TWA (albeit not one-time exposures), some of the AEGL methodology could be directly applicable to the Army for emergency responses. For

instance, the AEGL-1 for GB was derived using recent experimental vapor exposure data based on miosis in rats and nonhuman primates as well as historical data for miosis in human volunteers (Mioduszewski et al., 2002), while the AEGL-2 was based on miosis, dyspnea, and red blood cell cholinesterase inhibition in human volunteers (Baker and Sedgwick, 1996). The recommended 1-hour AEGL-1 for GB is 2.8 × 10⁻³ mg/m³ and the 1-hour AEGL-2 is 3.5 × 10⁻² mg/m³, while the 8-hour AEGL-1 for GB is 1 × 10⁻³ mg/m³ and the 8-hour AEGL-2 is 1.3 × 10⁻² mg/m³ (Table 3-1).

Developing long-term AELs for the nerve agents results in a fairly low calculated degree of confidence, because there are no long-term inhalation exposure data for humans and only limited animal data. For humans, almost all exposures have been for less than 60 minutes, many for only 5 or 10 minutes. The CDC used a 40-minute human study with miosis as the health end point to develop nerve agent STELs, WPLs, and GPLs. Thus, the CDC extrapolated over time from a 40-minute exposure to develop the 8-hour WPL and the GPL (Federal Register, 2002). The AEGL-1, on the other hand, was derived using recent rat and marmoset data on the presence of miosis during 4-5 hours of vapor exposure and historical human experimental data for 20-minute vapor exposures. The methods used by the CDC and the National Advisory Committee/NRC to develop AELs incorporate degrees of uncertainty and interpretive judgment. Both methods evaluated the quality and weight of evidence of the data and applied standardized uncertainty factors to establish AELs.

The CDC used a factor of 12 to represent the potency of VX compared with that of GB. The factor 12 was based on a 1971 study by Calloway and Dirnhuber that measured miosis in rabbits (Calloway and Dirnhuber, 1971). A modifying factor of 3 was also applied to account for what was considered a sparse data set, resulting in a total composite adjustment factor of 36 between the calculated exposure limits for GB and VX (Federal Register, 2003a).

The AEGL values for VX were developed by applying a relative potency factor of 4 between GB and VX based on human experimental and animal oral and intra-arterial/intravenous administration of GB and VX with the same critical end point—a 50 percent reduction in red blood cell cholinesterase activity (NRC, 2003). A further uncertainty factor of 30 (1 for interspecies, 10 for intraspecies, and 3 for a sparse VX data set) was applied, resulting in a 1-hour AEGL-1 of 1.7 × 10⁻⁴ mg/m³ and a 1-hour AEGL-2 of 2.9 × 10⁻³ mg/m³, with the 8-hour AEGL-1 being 7.1 × 10⁻⁵ mg/m³ and the 8-hour AEGL-2 being 1 × 10⁻³ mg/m³ (Table 3-1). Thus, the two exposure limits—AELs and AEGLs—were derived using different routes of exposure (oral vs. inhalation) and health end points (red blood cell cholinesterase vs. miosis). This example demonstrates that occasionally different scientific data, exposure concentrations, and/or health end points can be selected as points of departure for risk assessment.

The CDC-recommended STELs for GB and VX are 1 × 10⁻⁴ mg/m³ and 1 × 10⁻⁵ mg/m³, respectively. The VX STEL was adjusted from a calculated 4 × 10⁻⁶ mg/m³ to 1 × 10⁻⁵ mg/m³ (not to occur more than once per day) based on the technical capabilities of existing air monitoring technologies (Federal Register, 2003a).

A question now arises about the extent to which the 2003 CDC-recommended AELs, which are lower than the 1988 CDC AELs, will impact human health. Since the 2003 WPLs and GPLs for GB were lowered by an uncertainty factor of 3 to account for individual variability (Federal Register, 2003a), the 2003 WPLs for GA and VX, which were derived from the WPL for GB, were automatically reduced by the same factor, 3. For VX, however, an additional modifying factor of 3 was applied to account for a sparse database, resulting in a 10-fold total decrease in the WPL from 1988 (1 × 10⁻⁵ mg/m³) to 2003 (1 × 10⁻⁶ mg/m³). The 2003 GPL for VX (6 × 10⁻⁷ mg/m³ ), on the other hand, represented a reduction by a factor of 5 of the 1988 GPL (3 × 10⁻⁶ mg/m³). The factor 5 was used to obtain a value that would be protective for humans and yet measurable by currently available monitoring methods (Federal Register, 2002). The CDC clearly states that the lower 2003 AELs do not reflect a change in or a refinement of its understanding of the demonstrated human toxicity of these agents and were not derived from new or additional scientific data on the toxicity of these nerve agents in humans or animals, and that no overt adverse health effects have been associated with the exposure limits recommended in 1988. Rather, they were a result of using updated and minimally modified risk assessment assumptions (Federal Register, 2003a) and, as such, added a layer of safety (conservatism) to the 1988 recommended AELs that have so far been protective for humans.

The U.S. Army currently sets alarm levels for near-real-time (NRT) monitors used to detect airborne nerve agents in non-stockpile and stockpile sites at 0.20, 0.50, or 0.70 of the 1988 WPL (which the Army refers to as “TWA”). In general, the non-stockpile program uses 0.70 as the alarm level, unless required by permit to use a lower alarm level. Thus, for GB and GA, 1988 WPL (TWA) concentrations at which NRT monitors alarm range from 2 × 10⁻⁵ mg/m³ (for an alarm level of 0.20) to 7 × 10⁻⁵ mg/m³ (for an alarm level of 0.70). The new 2003 WPL for GB and GA is 3 × 10⁻⁵ mg/m³. For VX, 1988 WPL (TWA) concentrations at which NRT monitors alarm range from 2 × 10⁻⁶ mg/m³ (for an alarm level of 0.20) to 7 × 10⁻⁶ mg/m³ (for an alarm level of 0.70). The new 2003 WPL for VX is 1 × 10⁻⁶ mg/m³.

The newly developed STELs (Federal Register, 2003a) are numerically equivalent to the 1988 WPLs (TWAs), that is, 1 × 10⁻⁴ mg/m³ for GB and GA and 1 × 10⁻⁵ mg/m³ for VX. For this reason, the readout from an NRT system for

monitoring at the new STELs is the same as the readout from the system would be if it were being used for the 1988 WPLs (TWAs), regardless of the alarm level set point.^6,7

The 1988 WPLs (numerically equivalent to the 2003 STELs) has been confirmed by the CDC to protect humans from the toxic effects of these agents (Federal Register, 2003a). If the Army used NRT systems (e.g., MINICAMS) to monitor at the 2003 WPLs for GB and set the alarm level to 1.00 WPL (as allowed by the CDC if certain conditions are met), then the alarm level for GB would be 3 × 10⁻⁵ mg/m³ versus 2 × 10⁻⁵ mg/m³ for an alarm level set at 0.20 of the 1988 WPL (TWA). Thus, it would appear that NRT monitors could be used to monitor at the 2003 WPL for GB and GA. It should be noted, however, that several problems arise if the alarm level is set at 1.00 WPL, as discussed in Chapter 4 of this report. It should also be noted that the accuracy required for a 1.00-WPL challenge of an NRT monitor is +25 percent with 95 percent confidence and that there is no accuracy requirement for challenges of NRT monitors at a fraction of an AEL (for example, at a concentration reading of 0.20 TWA). Thus, the comparison presented in this paragraph is tenuous at best.

If the Army used NRT systems (e.g., MINICAMS) to monitor at the 2003 WPLs for VX and set the alarm level to 1.00 WPL (as allowed by the CDC, if certain conditions are met), then the alarm level for VX would be 1 × 10⁻⁶ mg/m³ versus 2 × 10⁻⁶ mg/m³ for an alarm level set at 0.20 of the 1988 WPL (TWA). Thus, it may be possible to use NRT monitors to monitor at the 2003 WPL for VX. Once again, however, it should be noted that several problems arise if the alarm level is set at 1.00 WPL.

CDC’s objective in developing AELs was to protect the health of workers and others who could be exposed to nerve agents. Monitors must be capable of demonstrating the effectiveness of engineering/administrative controls and work practices and ensuring that excursions of agent concentrations above the AELs, if they occur, are detected in a timely manner. The difficulty presented by the situation at non-stockpile sites such as Newport is the pragmatic need to monitor at a level that minimizes background interference yet ensures, with a high degree of confidence, that the AELs are not exceeded.

The overall intention, and difficulty, of developing AELs for the nerve agents is to reach a balance between protecting

humans from the health effects of these highly toxic chemicals and yet being able to adequately monitor above detection limits and against background interference to ensure safety with a reasonable degree of confidence.

Because all three forms of mustard (H, HD, and HT) are chemically and toxicologically related and can be treated as a single compound, they will be referred to as either sulfur mustard or HD in this section (Federal Register, 2003b).

The 1988 CDC-recommended worker population limit (WPL) for HD was 3 × 10⁻³ mg/m³, while the general population limit (GPL) was 1 × 10⁻⁴ mg/m³ (Table 3-2). These AELs were determined to be substantially below concentrations at which adverse health effects have been observed for mustard agent (Federal Register, 1988) and have proven to be protective of human health (Federal Register, 2003b).

The 2004 CDC-recommended interim occupational AELs (WPL and STEL) for HD are the same as those that were recommended by the U.S. Army Center for Health Promotion and Preventive Medicine (CHPPM) in 2000. The CDC recommended a WPL⁸ of 4 × 10⁻⁴ mg/m³ (Federal Register, 2004). This AEL was based on both short-term human data and long-term animal data. The critical human study incorporates an exposure concentration of 0.06 mg/m³ for 8 hours a day for 3 consecutive days adjusted to a 5-day occupational work week using a factor of 3/5, resulting in a lowest observed adverse effect level (LOAEL)⁹ of 0.036 mg/m³.

The uncertainty factors applied were 3 to extrapolate from a LOAEL to a no observed adverse effect level (NOAEL),¹⁰ 10 to extrapolate from short-term to long-term exposure, and 3 to accommodate additional uncertainties inherent in using acute exposure data and a small number of subjects, for a total uncertainty factor of 100 (Federal Register, 2004; U.S. Army, 2000b).¹¹

In 2004, the CDC also recommended a new GPL of 2 × 10⁻⁵ mg/m³. This value was established using a single 10-hour human exposure of 0.1 mg/m³ and adjusting the 10-hour exposure to 24 hours and the 1-day exposure to 7 days, resulting in a LOAEL of 6 × 10⁻³ mg/m³. A composite uncertainty of 300 was applied to the LOAEL: 3 to account for individual human variability, 3 to extrapolate from a LOAEL to a NOAEL, 10 to extrapolate from short-term to long-term exposure, and 3 to adjust for chemical-specific or study-specific uncertainties not dealt with by the standard uncertainty factors (Federal Register, 2004).

The CDC recommended a 2004 STEL of 3 × 10⁻³ mg/m³ for one occurrence per day. The STEL was calculated by two approaches: the time-adjusted LOAEL approach and the probit and logistics approach (Federal Register, 2004; U.S. Army, 2000b). A total uncertainty of 10 was used in the time-adjusted LOAEL approach: 3 to extrapolate from a LOAEL to a NOAEL and 3 to extrapolate from short-term exposure data.

The CDC recommended the 2004 immediately dangerous to life or health (IDLH) level to be 0.7 mg/m³ (Federal Register, 2004), not to exceed 30 minutes of exposure. It was stated in the 2003 Federal Register that the IDLH of 0.70 mg/m³ was derived by CDC’s National Institute for Occupational Safety and Health (NIOSH) in accordance with structured NIOSH protocol (Federal Register, 2003b).

The 2004 recommended AELs for sulfur mustard were based on the following sources of information:

• Comments by scientific experts,

• Latest available scientific data and technical reviews,

• Exposure and risk assessment approaches, and

• CDC’s understanding of current risk management practices associated with the U.S. Army’s chemical agent demilitarization program.

The AELs proposed by the CDC reflect realistic management practices associated with chemical demilitarization and do not necessarily apply to other conceivable exposure scenarios (Federal Register, 2004).

Sulfur mustard is listed as a Part A carcinogen by the National Toxicology Program (DHHS, 2004) and as a Group 1 carcinogen by the World Health Organization’s International Agency for Research on Cancer (IARC, 1987). The CDC sulfur mustard GPL is a 12-hour TWA that reflects the typical sampling times used in the stockpile program. The CDC considers that its 2004 GPL of 2 × 10⁻⁴ mg/m³ meets carcinogenicity protection levels by keeping exposures below thresholds of significant risk (Federal Register, 2003b).¹² Nevertheless, it recommends that its 2004 AELs should be considered as interim values pending better understanding of the cancer potency of sulfur mustard (Federal Register, 2004).

Acute exposure guidelines (AEGLs) have also been developed for sulfur mustard agent (HD). The AEGLs were developed for a one-time exposure ranging from 10 minutes to 8 hours. AEGL-1 and AEGL-2 are defined in the preceding section on nerve agents. The AEGL-1 values established for sulfur mustard are 6.7 × 10⁻² mg/m³ for a 1-hour exposure and 8 × 10⁻³ mg/m³ for an 8-hour exposure (NRC, 2003). The 1-hour AEGL-2 is 1 × 10⁻¹ mg/m³ and the 8-hr AEGL-2 is 1.3 × 10⁻² mg/m³. The AEGL-1 levels were based on conjunctival injection and minor discomfort with no functional decrement in human volunteers, while the AEGL-2 levels were based on well-marked generalized conjunctivitis, edema, photophobia, and eye irritation in human volunteers. An intraspecies uncertainty factor of 3 was applied in developing the AEGL-1, while a composite uncertainty factor of 10 (3 for intraspecies and 3 to accommodate potential onset of long-term ocular or respiratory effects) was applied in developing the AEGL-2. The 2004 CDC WPLs and GPLs for sulfur mustard were reduced approximately 10-fold from the 1988 recommended values (Table 3-2). The 2004 AELs were derived using newer risk assessment methods and some additional toxicity data. However, the CDC stated there is no empirical evidence that the 1988 AELs for sulfur mustard are not protective of human health (Federal Register, 2003b). Thus, there does not appear to be any major change in health impact between the 1988 and 2004 WPLs and GPLs. The CDC also recommended a STEL and an IDLH limit in 2004 but did not do so in 1988 (Federal Register, 2004). The CDC did, however, state as follows: “Given the uncertainty in the risk assessment regarding cancer potency, reduce exposures to sulfur mustard to the lowest practicable level” (Federal Register, 2004, p. 24167).

The committee finds merit in the Army’s adoption of the 2003 CDC-recommended STEL to replace the 1988 WPL. The 1988 WPL was used as the basis for NRT workplace monitoring and has been protective of worker health (Federal Register, 2003b). The new NRT workplace monitoring level is based on the new STEL, which is the same numerically as the old WPL and will be equally protective.

Finding 3-1: The committee concurs with the non-stockpile program’s plans to replace the CDC 1988 WPLs with the 2003/2004 STELs for NRT monitoring.

Recommendation 3-1: PMNSCM should continue with its plans to replace the CDC 1988 WPLs with the 2003/2004 STELs for near-real-time monitoring.

The revised AELs do not reflect any change in agent toxicity. Workers, communities, and the environment were sufficiently protected under the old AELs. The revised AELs are, however, more stringent and more in line with how these standards are established for other air toxins. This standardization should help ensure the continued safety of workers, communities, and the environment since the revised AELs are more stringent and will result in a reexamination of all aspects of the protection of these populations and the environment.

The revised AELs, including the WPL, the GPL, and the IDLH, do not offer any clear quantitative risk advantage vis-à-vis the 1988 AELs. The 2003/2004 AELs are slightly more conservative than the 1988 AELs, but both are low enough that any quantitative comparison between the two is over-whelmed by the uncertainty in the current understanding of low dose effects. Further, the impacts of chronic exposures are difficult to assess owing to a lack of data.

This lack of demonstrable risk benefit is consistent with the position the CDC took when it announced the new AELs:

The revision of the AELs has significant impacts on the operations at chemical agent demilitarization sites, training facilities, and laboratories. In accordance with U.S. Army guidance (2004b), the Army’s monitoring program must change such that an extra level of chronic monitoring at the WPL is introduced. Other areas are also affected, such as safety and emergency response procedures, medical monitoring programs, marking and handling of contaminated materials, release of contaminated materials, and handling, treatment, and storage of waste (U.S. Army, 2004b). It is possible that some improvements in worker risk and operations will result from implementing the revised AELs. These benefits will probably come from a fresh look at operating procedures rather than from the change in AEL values.