III. CYCLOSARINS TOXICOLOGICAL PROFILE
Also developed in Germany during World War II, cyclosarin (GF; cyclohexyl methylphosphonofluoridate; CH3PO(F)OC6 H11) is an acutely toxic, relatively nonpersistent nerve agent similar to GB. The United States has not produced GF in significant volumes, and its chemistry and toxicity are less well explored than sarins (Rosenblatt, 1996). GF has been considered a potential threat agent and was identified in remnants of rockets detonated at Khamisiyah. The following paragraphs discuss the limited toxicity data available on GF. The plume to which forces possibly were exposed consisted of sarin and cyclosarin. Tab B-I lists cyclosarins general chemical properties.
A. Fate and Transport
Evaporating about 20 times slower than GB or water (DAMS, 1990), GF is much less volatile and has a higher Log Kow and Log Koc (partition coefficients used to estimate organic chemicals distribution between n-octanol and water and soil and water, respectively) than GB and therefore is not released into the atmosphere as readily. Like sarin, GFs hydrolysis products, hydrofluoric and cyclohexylmethylphosphonic acids, are less toxic than their parent compound. Although GF is considerably less volatile than GB, it is unlikely to persist for more than a few days in an unprotected environment (DAMS, 1990).
B. Acute Effects
Cyclosarins mechanism of action is similar to sarins, that is, AChE inhibition (Clement, 1994; Gray and Dawson, 1987; Koplovitz et al., 1996; Hill and Thomas, 1969; Coleman et al., 1968). When inhaled, cyclosarin reportedly is less toxic than GB in rats and mice, similarly toxic in rabbits, and 6 to 12 times less toxic than soman in non-human primates (Clement, 1991, 1994; Koplovits, 1996; Coleman et al., 1968; DHHS, 1987). GF is approximately four times more toxic than GB by dermal exposure (OATSDNCB, 1997), most likely because it is a less volatile, more lipid soluble.
Clement (1991, 1994) reported a subcutaneous LD50 in mice of 243 µg/kg, compared to 170 µg/kg for GB. Signs of nerve agent poisoning after exposure were typical of those observed with nerve agent poisoning, including profuse salivation, straub tail, intense tremors progressing to convulsions, and death from respiratory arrest. The author noted that rigor appeared more rapidly after death from GF than after death by GB or soman; the clinical significance, if any, of this finding is unclear. Significant differences between oxime-induced reactivation of GF- and GB-inhibited AChE also were reported. These differences are not relevant to the current evaluation, but they are significant both militarily and clinically.
Clement (1994) also evaluated the combined toxicity of GB and GF in mice. The combined LD50 was intermediate between those of GF and GB, indicating combining the two nerve agents did not result in synergism. Mice were observed to have typical signs of nerve agent poisoning. The ED50 values for various oximes against the GF-and-GB combination were between those found for the individual agents.
Koplovitz et al. (1996) evaluated the toxicity, pathology, and treatment of GF poisoning in male rhesus monkeys. The intramuscular LD50 was determined at 46.6 µg/kg compared with an LD50 of 22 µg/kg for sarin (DHHS, 1987). The monkeys were observed to have typical nerve agent poisoning symptoms, and 11 of 12 animals in the acute toxicity (dose-finding) group convulsed. The primary neural lesions in the acute toxicity group occurred in 4 of 12 animals, ranged from focal minimal to severe, and consisted of neuronal degeneration and necrosis and spinal cord hemorrhage. Animals administered five times the LD50 but treated with atropine, pyridostigmine, and either 2-PAM or HI6 oxime all lived and had minimal nervous system changes. The primary non-neural lesions were degenerative cardiomyopathy and skeletal muscle degeneration, both of which have been recognized in other anticholinesterase toxicities (Singer et al., 1987; Petrali et al., 1984). Koplovitz et al. (1996) also reported LD50 GF doses of 224 µg/kg intra-muscular in mice and 56.5 µg/kg subcutaneous in guinea pigs. Others have reported acute subcutaneous LD50 values for GF in guinea pigs (110 µg/kg), hamsters (130 µg/kg), mice (400 µg/kg), rats (225 µg/kg), and rabbits (100 µg/kg) (DHHS, 1987).
C. Chronic Effects
Although toxicity data for GF are sparse, the effects of chronic exposure to this agent are expected to be similar to GB. Clements (1994) study found GF somewhat less toxic than GB in similar species and routes of exposure. Other studies have reported GFs toxicity intermediate between sarin and soman (Koplovitz et al., 1996; Coleman et al., 1968). GFs higher dermal toxicity appears to result from increased absorption, largely due to lower volatility.
Like those resulting from sarin exposure, Koplovitz et al. (1996) described neural lesions in non-human primates after exposure to convulsive doses of GF at one to five times the LD50. These lesions were described as less severe and at a lower incidence than those observed with soman exposure.
a. Organophosphate-induced Delayed Neuropathy. Vranken et al. (1992) showed GF inhibits NTE in vivo. However, as previously discussed, NTE inhibition is useful only for preliminary evaluation of organophosphorus esters potential to induce OPIDN. This enzymes role in initiating OPIDN is not understood, and the EPA neurotoxicity protocol requires supporting histopathologic evidence (Ecobichon, 1996). Several organophosphates, including sarin, soman, and tabun, can inhibit NTE. Yet exposed animals do not develop OPIDN, except at extraordinarily high doses (Ecobichon, 1996; Johnson et al., 1985; Lotti, 1992; Marrs, 1993). No data were found to suggest GF causes OPIDN at the subclinical dose levels relevant to this evaluation.
b. Behavioral and Psychological Effects. Studies examining the behavioral and psychological effects of GF exposure are unavailable. However, based on observations with organophosphorous pesticides and other nerve agents and the similar mechanism of action, behavioral and psychological effects would be expected to occur with exposure to high or at least symptomatic GF doses. Similar to the toxicodynamics observed with GB, GFs behavioral and psychological effects should correlate with percent inhibition of AChE and presumably have a biologically significant threshold.
c. Electroencephalographic Changes. There are no reports of GF-induced EEG changes. However, GF may produce EEG alterations similar to those of sarin. Any EEG changes induced by GF exposure most likely would correlate with increased dose and decreased ChE activity and likely would have a biologically significant threshold.
Koplovitz et al. (1996) observed GF-induced cardiomyopathy in 3 of 12 monkeys at convulsive doses (approximately 1 LD50) and reported reversible to irreversible skeletal muscle lesions in 4 of 12 of these animals. The authors reported the cardiomyopathy and skeletal muscle lesions as milder and less frequent than in animals receiving similar LD50 of soman. No data suggest exposures to low GF doses would result in cardiomyopathy or skeletal muscle lesions.
3. Carcinogenicity, Genotoxicity, and Mutagenicity
Similar to other G agents, GF would not be expected to be carcinogenic, mutagenic, or teratogenic. Organophosphate nerve agents are not recognized as carcinogens. Goldman et al. (1987) reported GB is not genotoxic or mutagenic. No data currently are available to suggest that GF is carcinogenic, genotoxic, or mutagenic.
4. Developmental and Reproductive Effects
There are no human or animal data on GFs reproductive and developmental effects. Generally, organophosphates are not considered to have significant reproductive effects. Several studies in laboratory animals indicate sarin does not have developmental or reproductive effects, even at dose levels that are maternally toxic (Opresko et al., 2001; Perrotta, 1996).
IV. RECOMMENDED SARIN AND CYCLOSARIN EXPOSURE GUIDELINES
The first step in developing an exposure guideline for a given chemical is to assess toxicity to determine (1) if a chemical agent can increase the incidence of a particular adverse health effect and whether that effect is likely to occur in humans, and (2) the relationship between the dose of an agent received and incidence of adverse health effects (typically called the dose-response or dose-effect) (EPA, 1989). Well-conducted epidemiological or human toxicological studies are considered the most convincing evidence of human risk. In developing guidelines, well-designed animal studies, particularly if data are available for two or more species, are considered an adequate surrogate for human data. Supporting data (e.g., metabolic and other pharmacokinetic studies providing insights into mechanisms of action) and studies using cell cultures or microorganisms providing information about an agents potential for biological activity can provide valuable information and may be useful as screening tools (EPA, 1989). The existing recommended sarin guidelines are based on both animal and human data. The general population and occupational exposure levels were set to protect the public, including sensitive populations, and workers from adverse effects due to chronic sarin exposure.
DHS believes that it is appropriate to use the general population exposure guidelines with modifications, because this is not a lifetime exposure. Even though the military population more closely approximates that of US workers, consisting of generally healthy people, than a general population, which includes the very young, old, and infirm, in using the general population limit (GPL), DHS is using the most reasonable upper bound. However, no existing guidelines were developed for the exposure and health situations of concern in this assessment. As noted previously, the exposure conditions, if any, at Khamisiyah involved very low levels occurring over a short time (a few days) and the possible health outcomes would occur several years after exposure. As noted below, the available guidelines are limited to sarin; cyclosarin exposure guidelines are unavailable.
A. Using Toxicity Data in Setting Exposure Guidelines and Assessing Risk
Sound human toxicity data often are absent and may be neither practical nor ethical to obtain. Most often, uncontrolled human data on high-dose exposures are available from accidental or deliberate poisonings. Well-designed, controlled studies involving low-dose exposures to GB and GF are unavailable. A toxicologist is interested in the effects of precisely these types of lowdose and/or chronic exposures when establishing workplace or general population exposure guidelines, or reference doses and reference concentrations, in assessing risk. Tables B-II-1, B-II-2, and B-II-3 in Tab B-II summarize GB and GF acute lethality data and GB toxicity data.
In lieu of adequate human data, scientists perform studies in animals and in vitro to predict how these chemicals might affect humans. Well-designed animal studies in several species provide the foundation for approval processes for agencies such as the EPA and Food and Drug Administration. Since human data are not always available for the agents under consideration, in vivo and in vitro toxicology data are frequently used in establishing guidelines.
In setting exposure guidelines, safety factors are included to compensate for uncertainties and variability and to ensure protection of the applicable human population. It is important to remember that these guidelines are developed to protect worker and general public health, not to assess possible effects in an exposed population. The currently understood physiological effects of low-level exposure at Khamisiyah cannot be measured retroactively. However, most people could experience levels somewhat higher than the exposure guidelines without having adverse effects, as building in a safety margin intends.
B. Existing Sarin Exposure Guidelines
Existing occupational and general population guidelines for sarin are derived from no-adverse-effect levels and levels known to produce the mildest detectable effects. The exposure conditions are extrapolated to chronic (i.e., long-term) exposures and safety margins were incorporated into the guidelines. The first noticeable effect of a low dose of sarin vapor is miosis. At about the same exposure level, other mild symptoms, including runny nose, tightness of the chest, and eye pain, may occur (McNamara and Leitnaker, 1971). As previously noted, virtually all patients treated after the Tokyo subway sarin attack manifested local symptoms including miosis and other eye effects, rhinorrhea, and frequently coughing and tightness in the throat (Masuda et al., 1995; Yokoyama et al., 1996; Kato et al., 1996).
The Department of the Army requires medical monitoring of all its personnel who routinely work with nerve agents and have a risk of exposure. In the event that an individuals RBC-ChE activity level drops below 75% of his or her baseline value, the affected individual must be removed from further actual or possible nerve agent exposure. Such individuals are not permitted to return to work until their RBC-ChE has reached at least 80% of baseline and they have been asymptomatic for at least one week (DA, 1990). In a year-long study, Sidell (1992) showed RBC-ChE activity varies by 11% and 16% in unexposed men and women, respectively. The study showed the RBC-ChE recovery rate in exposed persons is approximately that of erythrocyte turnover, about 1% per day. Sarin preferentially inhibits RBC-ChE compared with plasma ChE (80 to 100% versus 30 to 50%) (Grob and Harvey, 1957). Systemic effects in humans generally occur when RBC-ChE is inhibited by 75 to 80%. The clinical significance of small ChE decreases or slight miosis, other than as a marker for exposure, has not been demonstrated.
As determined from observations of experiments with human volunteers, the sarin dosage producing first noticeable effects such as miosis is approximately 1 mg-min/m3 (DAMS, 1990; McNamara and Leitnaker, 1971), an exposure rate approximately 70 to 100 times lower than the possibly fatal exposure rate (Mioduszewski et al., 1998; DA, 1990). As previously discussed, the mg-min/m3 terminology reflects a cumulative exposure concentration over time. The milligrams of sarin per cubic meter of air are multiplied by the number of minutes of exposure to calculate a persons exposure dosage. Therefore, a person exposed to a lower air concentration of sarin would have to be exposed for a longer period of time to achieve the same effects as a higher-concentration, shorter-term exposure. However, this relationship holds only within reason; if the concentration is low enough and/or the time long enough, one person may never receive the same dosage as another because the kinetics of detoxification and recovery prevent accumulation. See Section III, "Dose-Response Assessment," Paragraph C.
McNamara and Leitnaker (1971) reported a cumulative dosage of 0.5 mg-min/m3 as the no-effect level at which fewer than 1% of a human population likely would show the mildest symptoms (e.g., miosis, runny nose, or tightness of the chest). It has been estimated that less than an average of 1% ChE depression would occur at this exposure level (McNamara and Leitnaker, 1971). Kinetic data indicate this dosage may accumulate with a daily exposure of 0.05 mg-min/m3. In contrast, the lethal concentration to 50% of a test population (LCt50) and the incapacitation concentration for 50% of a test population (ICt50) in humans were estimated to be approximately 70 to 100 mg-min/m3 and 35 to 70 mg-min/m3, respectively (McNamara and Leitnaker, 1971; Mioduszewski et al., 1998). The LCt50 was derived from data from animal experiments extrapolated to humans. The ICt50 was derived from experiments with human volunteers and lab animals. The precise exposure dosage required to produce a particular effect in humans depends on many factors, including activity level and respiratory absorption (affected by many parameters), and detoxification and elimination rates.
C. Sarin Occupational and General Population Exposure Guidelines
Different exposure guidelines for possible industrial contaminants typically are recommended for occupational settings and the general population. The US Army and CDC similarly recommend occupational and general population guidelines for nerve agents, including GB. Table B-1 presents these exposure guidelines and briefly describes the underlying data from which they were derived. The occupational (worker population limit or WPL) and general population limits (GPL) were developed to address chronic (i.e., lifetime) exposures. Therefore, the table discusses the short-term exposure limits (STELs) and originally calculated acute exposure guideline levels (AEGLs) recommended by Mioduszewski et al.(1998) and derived occupational AEGLs (AEGLos).
1. Guidelines for Occupational Exposure to Sarin (Workers Without Respiratory Protection)
The US Army and CDC recommend an air concentration guideline of 0.0001 mg/m3 averaged over an eight-hour workday (Table B-1) for a WPL (CDC, 1988). A person exposed for eight hours at the occupational guideline thus would receive a maximum estimated exposure dose of sarin of 0.048 mg-min/m3 (DHS, 1997a). The air concentration for the occupational guideline was calculated based on data from experiments with human volunteers and kinetic studies of ChE depression and recovery that determined a no-effects level of 0.5 mg-min/m3 (McNamara and Leitnaker, 1971). Workers should not develop even the mildest symptoms, including detectable ChE changes, at or below this guideline. Thus, if a worker were exposed to this maximum allowable concentration for 8 hours per day, 40 hours per week, for a working lifetime (i.e., 40 years), no adverse effects should result (McNamara and Leitnaker, 1971; CDC, 1988).
Table B-1. Summary of applicable occupational exposure guidelines and derived guidelines for sarin
Air Concentration (mg/m3)
|8-hour exposure day, 40 hours per week over a lifetime||CDC, 1988|
|Maximum safe concentration for single 1-hour exposure||McNamara and Leitnaker, 1971|
|Maximum safe concentration for single 8-hour exposure||McNamara and Leitnaker, 1971|
|Proposed STEL TWA; 15-minute exposures of 0.03 mg-min/m3; maximum 4 per day (1-hour total)||Mioduszewski et al., 1998|
|Derived from 30-minute AEGL-1||Mioduszewski et al., 1998|
|Derived from 1-hour AEGL-1||Mioduszewski et al., 1998|
|Derived from 4-hour AEGL-1||Mioduszewski et al., 1998|
|Derived from 8-hour AEGL-1||Mioduszewski et al., 1998|
McNamara and Leitnaker (1971) also recommended a maximum safe concentration (MSC) for a single 1-hour exposure of 0.001 mg/m3 (0.06 mg-min/m3) and an MSC for a single 8-hour exposure of 0.0003 mg/m3 (0.15 mg-min/m3).
In reviewing the basis for these occupational guidelines in 1988, CDC concluded the occupational guideline would adequately protect worker health from even long-term exposure to sarin at the guideline limit (CDC, 1988). Recently, Mioduszewski et al. (1998) reviewed the adequacy of the existing occupational and general population exposure guidelines for sarin and derived additional STELs and AEGLs. Based on endpoints other than ChE inhibition and kinetics (i.e., threshold effects), Mioduszewski et al., (1998) concluded that the existing occupational and general population limits were sufficiently protective and recommended short-term occupational and acute general population guidelines.
2. General Population Guidelines
The US Army and CDC recommend an airborne concentration level of 0.000003 mg/m3 as the general population guideline (McNamara and Leitnaker, 1971; CDC, 1988). A person exposed for 72 hours at the general population guideline would receive a calculated maximum exposure of sarin of 0.01296 mg-min/m3 (OSA, 1997a). This exposure guideline applies to non-workers, including sensitive subpopulations. The general population exposure guideline for sarin was derived by taking the occupational guideline for sarin, as described in the previous section, and applying another safety factor to protect the most sensitive subpopulations (e.g., infants, the elderly, those with health conditions, or persons who have genetic variation in their cholinesterase activity) (McNamara and Leitnaker, 1971). This safety factor is considered adequate to protect even sensitive individuals exposed at the general population guideline limit from any symptom. The Department of the Army (1990) also has proposed a general population ceiling value (the maximum exposure concentration at any time, for any duration, which in practice is the average concentration occurring over the minimum time required to detect the specified concentration) of 0.0001 mg/m3.
In reviewing the evidence for the occupational and general population guidelines in 1988, CDC concluded, "Even long-term exposure to sarin at these guidelines would not create any adverse health effects," nor would resistance to organophosphorus pesticides measurably decrease (CDC, 1988). A recent US Army ERDEC review (Mioduszewski et al., 1998) recommended retaining the general population guideline of 0.000003 mg/m3.
3. Recommended Short-Term Exposure Limits and Acute Exposure Guideline Levels
Because applying chronic (lifetime exposure) guidelines to low-level acute exposures is inappropriate (it over-estimates the possible exposures by comparing a lifetime guideline to a maximum possible exposure of 72 hours), US Army ERDEC (Mioduszewski et al., 1998) reviewed their occupational STEL and AEGL-1 recommendations and the supporting data (Table B-1).
The American Conference of Government Industrial Hygienists defines a STEL as a "15-minute time-weighted average (TWA) exposure that should not be exceeded at any time during a workday even if the 8-hour TWA is within the threshold limit value (TLV). Exposures above the TLV-TWA up to the STEL should be no longer than 15 minutes and should not occur more than four times per day. There should be at least 60 minutes between successive exposures in this range. An averaging period of other than 15 minutes may be recommended when this is warranted by observed biological effects" (Mioduszewski et al., 1998).
US Army ERDEC (Mioduszewski et al., 1998) recommended a GB STEL of 0.002 mg/m3 (0.12 mg-min/m3) (Table B-1) based on a human study suggesting a LOAEL of 0.06 mg/m3 for 40 minutes (2.4 mg-min/m3). The limit was adjusted for ventilation rate and exposure time and incorporated safety factors. US Army ERDEC (Mioduszewski et al., 1998) assumed that the possibility of exposure might occur multiple times over a working lifetime.
According to the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGLHS) (1997):
AEGLs represent short-term threshold or ceiling values intended for the protection of the general public, including susceptible or sensitive individuals, but not hypersusceptible or hypersensitive individuals. The AEGLs represent biological reference values for this defined human population and have been developed for each of four exposure periods of 30 minutes, 1 hour, 4 hours, or 8 hours. The AEGL-1 biological endpoint is the airborne concentration of a substance at or above which it is predicted that the general population, including susceptible, but excluding hypersusceptible individuals, could experience notable discomfort. Airborne concentrations below the AEGL-1 represent exposure levels that produce mild odor, taste, or other sensory irritations.
Federal and state agencies may adopt AEGLs for chemical emergency programs (Mioduszewski et al., 1998).
US Army ERDEC (Mioduszewski et al., 1998) recommended a GB general population 30-minute, 1-hour, and 4-hour AEGL-1 of 0.0024, 0.0012, and 0.0003 mg/m3, respectively. Calculating an 8-hour AEGL-1 using this methodology results in a value of 0.00015 mg/m3. US Army ERDEC based its recommendations on acute human exposure to GB vapor (0.05 mg/m3 for 20 minutes; 1.0 mg-min/m3) in which between 1 and 3 subjects out of 14 volunteers reported mild symptoms including headache, eye pain, rhinorrhea, tight chest, cramps, and nausea. The LOAEL was scaled for time and ventilation, and the AEGL-1s were conservatively calculated using a linear model (versus the nonlinear model the NAC/AEGLHS recommended); and added a safety factor of 10 to account for a general populations increased sensitivity compared to the military volunteer population used in the critical study. An occupational AEGL (AEGLo) can thus be derived from the recommended AEGL-1s by multiplying by a factor of 10, providing 30-minute, 1-hour, 4-hour, and 8-hour AEGLos of 0.024, 0.012, 0.003, and 0.0015 mg/m3, respectively .
4. Existing Cyclosarin Exposure Guidelines
No regulatory guidelines for GF exist. Since the occupational and general population guidelines for GB are based on inhalation concentrations and both GB and GF have similar toxicity when inhaled, GB's exposure guidelines reasonably should apply to GF exposure.
5. Deriving Reference Doses and Reference Concentrations
EPA commonly estimates a toxic chemicals potential long-term effects by using Superfund methodology, in which EPA compares a chronic reference dose (RfD) to an actual or calculated exposure dose. The RfD is "an estimate (with uncertainty spanning perhaps an order of magnitude or greater) of a daily exposure level for the human population, including sensitive subpopulations, that is likely to be without appreciable risk of deleterious effects during a lifetime" (EPA, 1989). A chronic oral reference dose (RfDo) for sarin is now under review (Opresko et al., 2001); a chronic reference concentration (RfC) is now under development. No chronic RfD or RfC exists for cyclosarin, nor do subchronic or short-term RfDs or RfCs exist for either sarin or cyclosarin.
Chronic RfDs and RfCs similarly are specifically developed to protect from long-term (as a Superfund program guideline, seven years to a lifetime) exposure to a compound (EPA, 1989). Simplified, an RfD is developed by identifying the critical toxicological study and determining the no observed adverse effects level (NOAEL) or LOAEL, incorporating factors such as the dynamics of the respiratory system and its diversity across species (EPA, 1989). Uncertainty factors (generally multiples of 10) and a modifying factor then are applied to account for the uncertainty inherent in the extrapolation from the available data.
Chronic RfDs and RfCs are derived from chronic and subchronic animal toxicity data. For example, the chronic RfDo for sarin was developed based on the results of a 90-day subchronic gavage study in rats (Table B-II-3) (Bucci and Parker, 1992). The LOAEL was 0.075 mg/kg/day of sarin, adjusted to 0.054 mg/kg/day for 7 days per week exposure. The endpoint was a statistically significant decrease in RBC-ChE in male rats. No other statistically significant dose-dependent signs of toxicity were observed at any dose levels (up to 300 µg/kg/day). Five uncertainty factors and a modifying factor were used in deriving the RfD: uncertainty factors of 10 for sensitive subpopulations, 10 for animal-to-human extrapolation, 3 for subchronic-to-chronic extrapolation, 3 for LOAEL-to-NOAEL extrapolation, and 3 for database incompleteness, and a modifying factor of 1 for default value. If greater than 1, the modifying factor value reflects a professional assessment of additional uncertainties (e.g., data quality). Therefore, the RfDo = (0.054 mg/kg/day)/(10 x 10 x 3 x 3 x 3 x 1) = 0.02 µg GB/kg/day.
The RfDo is not suitable for this risk assessment because the forces exposure was from inhalation rather than ingestion. But it is appropriate to use this kind of approach to derive an inhalation RfCi for sarin (the RfC for sarin is not yet available). However, previous risk assessments, such as for chemical agent incinerators, have used the general population exposure limit as a surrogate for the inhalation RfC (UDEQ, 1996). Therefore, if using this method, the RfC (mg/m3) = GB general population guideline (mg/m3) = 0.000003 mg/m3.
The EPA developed Superfund
methodologies to address risks associated with low-level, long-term (lifetime)
exposures to hazardous waste, not risks from short-term exposure to acutely
toxic agents. As EPA states, "The chronic RfDs described above pertain
to lifetime or other long-term exposures and may be overly protective if used
to evaluate the possibility for adverse health effects resulting from substantially
less-than-lifetime exposures" (EPA, 1989). Moreover, Superfund methodology
sets levels to protect human health and the environment, not to assess whether
an effect actually could have occurred due to a possible exposure. Although
developing a chronic RfD may not be altogether suited for assessing the risk
associated with short
-term exposure to a nerve agent vapor
such as may have occurred around Khamisiyah, it is an approach to deal with
the possibility for long-term effects of low-level exposure.