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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 7 Evaluation of the Army's Interim Reference Dose and Slope Factor For Sulfur Mustard Sulfur mustard is a chemical-warfare agent. It is classified as a vesicating agent because of its ability to cause blisters on exposed skin. Sulfur mustard is the chemical-warfare agent present at most stockpile and nonstockpile munition sites in the United States and it territories. At the request of the U.S. Army, Oak Ridge National Laboratory (ORNL) conducted a health risk assessment of sulfur mustard. The assessment included a detailed analysis sulfur mustard's physical and chemical properties, environmental fate, toxicokinetics, mechanism of action, animal and human toxicity, and carcinogenicity (see Appendix E, Health Risk Assessment of Sulfur Mustard, ORNL 1996). On the basis of that assessment, ORNL proposed a reference dose (RfD) of 7 × 10-6 mg/kg of body weight per day for noncancer health effects and a slope factor (SF) of 9.5 per mg/kg per day for the carcinogenic potency of sulfur mustard. The Army's Surgeon General accepted ORNL's proposed RfD and SF as interim exposure values until an independent evaluation of the proposed RfD and SF was conducted by the National Research Council (NRC). This chapter contains the NRC's independent assessment of the scientific validity of the Army's interim RfD and SF for sulfur mustard.
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents EVALUATION OF THE ARMY'S INTERIM RFD DERIVATION OF THE ARMY'S INTERIM RFD The Army's interim RfD for sulfur mustard is 7 × 10-6 mg/kg per day. ORNL (1998) calculated that value on the basis of the lowest oral dose of sulfur mustard that produced forestomach lesions (epithelial acanthosis, which is an increase in the thickness of the stratum spinosum of the epithelial tissue of the forestomach) in rats. The lowest-observed-adverse-effect level (LOAEL) for that effect was 0.03 mg/kg per day in a two-generation reproductive study (Sasser et al. 1989a). In that study, male and female rats were administered sulfur mustard for 5 days per week for 15 weeks, daily for 3 weeks, and 4 days per week for 3 weeks. Because of this discontinuous dosing protocol, ORNL adjusted the LOAEL (LOAELadj) to calculate the doses for continuous exposures. That adjustment was done by calculating the total dose administered during the different exposure protocols: 0.03 mg/kg per day × 5 days × 15 weeks = 2.25 mg/kg. 0.03 mg/kg per day × 7 days × 3 weeks = 0.63 mg/kg. 0.03 mg/kg per day × 4 days × 3 weeks = 0.36 mg/kg. The combined dose over the 21-week exposure period was 3.24 mg/kg. That value was divided by the total number of days (147 days) during the exposure period to yield a LOAELadj of 0.022 mg/kg per day. The RfD for sulfur mustard was calculated to be 7 × 10-6 mg/kg per day by dividing the LOAELadj by 3,000, the product of the uncertainty factors and the modifying factor selected by ORNL. APPROPRIATENESS OF THE CRITICAL STUDY The critical study used by ORNL for deriving the RfD for sulfur mustard was a two-generation reproductive study (Sasser et al. 1989a) in which Sprague-Dawley rats (20 males and 27 females per group) were intragastrically intubated with sulfur mustard dissolved in sesame oil at concentrations of 0.03, 0.1, and 0.4 mg/kg per day. Males and females were dosed for 5 days per week for 15 weeks, including 13 weeks before
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents and 2 weeks during the mating period. Female rats were also dosed for 7 days per week during the 3-week gestation period and 4 days per week during the 3-week lactation period. No significant adverse effects on reproductive performance or fertility were found at any dose through two consecutive generations. Dose-related epithelial acanthosis of the forestomach was observed in both sexes; the incidence of acanthosis was 0 of 94 in the controls, 71 of 94 in the low-dose group, 89 of 94 in the mid-dose group, and 94 of 94 in the high-dose group. In addition, benign forestomach lesions (squamous papillomas) were observed in 8 of 94 and 10 of 94 rats in the mid-dose and high-dose groups, respectively. Because acanthosis was described as mild at the lowest dose of 0.03 mg/kg per day, that dose was considered by ORNL to be the LOAEL for the study. As described earlier, that value was adjusted for a discontinuous exposure regimen to 0.022 mg/kg per day, and ORNL used the adjusted value to calculate the RfD. The subcommittee considered other possible studies, such as those of Hackett et al. (1987) and McNamara et al. (1975). The study by Hackett et al. (1987) was a teratology study in which rats and rabbits were intragastrically intubated with sulfur mustard. For rats, maternal toxicity and teratogenic effects were observed at all doses tested (0.5, 1.0, and 2.0 mg/kg per day); for rabbits, there was no evidence of teratogenic effects at any of the doses tested (0.4, 0.6, and 0.8 mg/kg per day) but maternal toxicity was observed at the two highest doses. Dosing lasted only a few days (10 days for rats or 14 days for rabbits) in the Hackett et al. (1987) study compared with the 21 weeks in the Sasser et al. (1989a) study. The study by McNamara et al. (1975) was an inhalation study using rats, mice, rabbits, guinea pigs, and dogs; therefore, equivalent oral doses could only be estimated from the data. Because of that, the subcommittee considered the study to be inappropriate for deriving the RfD for sulfur mustard. Furthermore, inhalation of sulfur mustard resulted in lesions to the skin and eyes, which would not be expected from oral exposure. The subcommittee also reviewed the Institute of Medicine's (IOM 1993) evaluation of the health effects of mustard gas and found no other relevant studies with respect to derivation of the RfD. The subcommittee concurs with ORNL that the two-generation reproductive study (Sasser et al. 1989a) was the most appropriate of the available studies for calculating the RfD for sulfur mustard. Although
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents not a chronic exposure study, the Sasser et al. (1989a) study involved exposure to sulfur mustard for 21 weeks and involved oral exposure, the route of interest for deriving an RfD; the study included a range of doses and an adequate number of animals per group. APPROPRIATENESS OF CRITICAL END POINT The LOAELadj (0.022 mg/kg per day) used by ORNL for derivation of the RfD for sulfur mustard was based on the dose that caused mild epithelial acanthosis in the forestomach of rats (Sasser et al. 1989a). The subcommittee believes that those lesions were probably a result of administering doses of sulfur mustard directly to the forestomach, which is typically more toxic than delivering doses at a slower rate throughout the day. If rats were administered sulfur mustard at a slower rate, in feed, for example, the daily dose required to induce the same mild lesions would likely be higher. Although humans do not have forestomachs, the subcommittee believes that the primary mechanism of toxicity of sulfur mustard is epithelial tissue damage from direct contact and agrees with ORNL that epithelial acanthosis of the forestomach in rats can be used as the critical noncancer toxicity end point for deriving the RfD. However, that end point resulting from direct administration to the forestomach is likely to overestimate the toxicity of sulfur mustard, resulting in an RfD that might be overprotective for noncancer health effects. APPROPRIATENESS OF UNCERTAINTY FACTORS For sulfur mustard, ORNL assigned values greater than 1 to four out of five uncertainty factors and a value of 1 to the modifying factor. The product of those factors was 3,000. The subcommittee evaluated each of the uncertainty factors and the modifying factor below. Extrapolation from Animal to Human Because sulfur mustard is a highly corrosive agent, the subcommittee believes that epithelial lesions at the point of entry into the stomach are
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents likely to occur across species. For that reason, the subcommittee considers the typical default value of 10 for the uncertainty factor for extrapolation of data from animals to humans (UFA) to be too high and recommends a lower value of 3. The value of 3 is meant to indicate some similarity in action across species, while not excluding the possibility of some greater overall human susceptibility. Protecting Susceptible Subpopulations The subcommittee agrees with ORNL that a factor of 10 is appropriate for the uncertainty factor to protect susceptible subpopulations (UFH). Extrapolation from LOAEL to NOAEL ORNL assigned a factor of 3 to the uncertainty factor for extrapolation from a LOAEL to a NOAEL (UFL) to account for the corrosive action of sulfur mustard. The subcommittee believes, however, that action is best accounted for in the uncertainty factor for animal-to-human extrapolation (see UFA above) and that a factor of 10 should be assigned to UFL. Extrapolation from Subchronic to Chronic Exposures The subcommittee agrees with ORNL that a factor of 10 is appropriate for the uncertainty factor for extrapolation from subchronic to chronic exposures (UFs) because the LOAEL was estimated from a subchronic exposure study. The subcommittee believes that a UFs of 10 is conservative, because the subchronic exposure was for 21 weeks, which is one-fifth of the time of a chronic exposure. Data-Base Adequacy The subcommittee agrees with ORNL that a factor of 1 for the uncertainty factor for data-base adequacy (UFD) is appropriate. Although no chronic oral exposure studies are available on sulfur mustard, several subchronic oral exposure studies are available, including two developmental toxicity studies in different species (Hackett et al. 1987), a two-
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents generation reproductive study (Sasser et al. 1989a), and a standard subchronic exposure study in one species (Sasser et al. 1989b). In addition, chronic inhalation exposure studies in five species (McNamara et al. 1975) are available as supporting information. The critical study (Sasser et al. 1989a) used by ORNL identifies a toxic effect (epithelial acanthosis of the forestomach) that is consistent with the vesicant properties of sulfur mustard. Exposure was exaggerated by the route of administration (gastric intubation). Because there is no evidence that any other experimental species might be more sensitive to sulfur mustard than rats, the subcommittee believes that additional oral toxicity studies in other species are not necessary. Modifying Factor for Additional Uncertainty The subcommittee considers the uncertainties of the data on sulfur mustard to be represented adequately by the values assigned to the uncertainty factors above and agrees with ORNL that a modifying factor (MF) of 1 is appropriate. Summary Table 7-1 presents the values assigned to the uncertainty factors by ORNL and those recommended by the subcommittee. The product of the factors for deriving the RfD for sulfur mustard is 3,000 for both sets of values. Thus, the subcommittee recommends the same RfD as ORNL for sulfur mustard (7 × 10-6 mg/kg per day) but notes that slightly different uncertainty factors were used in the calculation. WEIGHT AND STRENGTH OF EVIDENCE The subcommittee believes that the data on sulfur mustard support the interim RfD of 7 × 10-6 mg/kg per day. The strength of evidence for that RfD is moderately good but might lead to overestimation of the oral toxicity of sulfur mustard, because toxicity might have resulted from administration of sulfur mustard directly to the forestomach. Administration in feed, for example, over much greater time would be unlikely to have the same result.
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents TABLE 7-1 Uncertainty Factors Used by ORNL and the NRC to Calculate the RfD for Sulfur Mustard Uncertainty Factor Description ORNL NRC UFA For animal- to-human extrapolation 10 3 UFH To protect susceptible subpopulations 10 10 UFL For LOAEL-to-NOAEL extrapolation 3 10 UFS For subchronic-to-chronic extrapolation 10 10 UFD For data-base adequacy 1 1 MF Modifying factor for additional uncertainty 1 1 TOTAL UF 3,000 3,000 Abbreviations: LOAEL, lowest-observed-adverse-effect level; MF, modifying factor; NOAEL, no-observed-adverse-effect level; NRC, National Research Council; ORNL, Oak Ridge National Laboratory; RfD, reference dose; UF, uncertainty factor. EVALUATION OF THE ARMY'S INTERIM CANCER SLOPE FACTOR DERIVATION OF THE ARMY'S INTERIM CANCER SLOPE FACTOR The carcinogenic potential of sulfur mustard administered orally has not been studied in either epidemiological or animals studies. In the absence of oral exposure studies, ORNL used the relative carcinogenic potency calculated by Watson et al. (1989) to estimate a slope factor (SF) for sulfur mustard. Watson et al. (1989) estimated the potency of sulfur mustard by an indirect method called the rapid screening of hazard (RASH) (Jones et al. 1988), which involved comparing the carcinogenicity of sulfur mustard (based upon intravenous (Heston 1950) and subcutaneous studies (Heston 1953) with that of the well-characterized carcinogen benzo[a]pyrene (B[a]P). They showed that the relative carcinogenic potency of sulfur mustard was approximately equivalent to that of B[a]P, having a best-estimate relative potency of 1.3. ORNL (1996) multiplied that value by the currently accepted SF for B[a]P of 7.3 per mg/kg per day (EPA 1992) to yield an SF for sulfur mustard of 9.5 per mg/kg per day.
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents APPROPRIATENESS OF METHOD USED As described above, ORNL used the carcinogenic potency of sulfur mustard estimated by Watson et al. (1989) relative to B[a]P to calculate the interim SF for sulfur mustard. The subcommittee noted that Watson et al. (1989) also compared the potency of sulfur mustard with that of the direct-acting carcinogen bis-(chloromethyl)ether (BCME). Both compounds are alkylating agents, are powerful lung and eye irritants, cause necrotic skin lesions, and exhibit comparable modes of action in biological systems. The median relative potency of sulfur mustard compared with BCME for a variety of biological effects was 0.6 (Watson et al. 1989), which is within an order of magnitude of the potency derived for sulfur mustard when compared with B[a]P. Because the SF for BCME is 220 per mg/kg per day (EPA 1992), the SF for sulfur mustard calculated on the basis of its potency factor relative to that of BCME is 132 per mg/kg per day (220 per mg/kg per day × 0.6), compared with 9.5 per mg/kg per day derived in relation to B[a]P. ORNL also considered calculating an SF on the basis of the U.S. Environmental Protection Agency's (EPA 1991) estimated inhalation unit risk (8.5 × 10-2 per µg/m3) of sulfur mustard. Normalizing the inhalation unit risk for a 70-kg person inhaling 20 m3 of air per day would yield an SF of 0.3 per µg/kg per day. ORNL decided not to use this method because the inhalation study (McNamara et al. 1975) used to estimate the inhalation unit risk resulted in rat skin tumors that appeared to be caused by dermal exposure rather than by systemic absorption and distribution to the skin, and inhalation-to-oral extrapolation was not considered appropriate. Furthermore, the McNamara et al. (1975) study contained a number of deficiencies, such as outdated testing protocols, brief exposures, and small numbers of animals, which made quantitative analysis difficult. The subcommittee agrees with ORNL that calculating an SF for sulfur mustard using the relative potency approach was more appropriate than using estimates from inhalation unit risk. The subcommittee notes, however, that a recent study by Culp et al. (1998) reported a lower carcinogenic potency value for B[a]P. That chronic exposure study of B[a]P in feed was conducted under Good Laboratory Practice conditions in B6C3F1 female mice (Culp et al. 1998). The incidence of forestomach tumors was found to be 1 of 48, 3 of 47, and 36 of 46 at concentrations
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents of 0, 5, and 25 ppm, respectively. The carcinogenic potency of B[a ]P was estimated to be less than 1.2 per mg/kg per day, assuming equal potency between animals and humans for dose adjusted by body weight to the ¾ power. That is one-sixth of the current EPA potency value for B[a]. On the basis of that new potency, if sulfur mustard is 1.3 times more potent than B[a]P (Watson et al. 1989), the upper limit for carcinogenic potency for sulfur mustard is estimated to be less than 1.6 per mg/kg per day (1.2 mg/kg per day × 1.3). The subcommittee also used another approach to estimate the upper limit for carcinogenic potency of sulfur mustard. This approach involved evaluating the carcinogenic potency of sulfur mustard relative to its maximum tolerated dose (MTD). In a study of 139 animal carcinogens tested in the National Toxicology Program, Gaylor and Gold (1995) found that carcinogenic potency can be estimated by dividing 0.74 by the MTD (expressed in terms of milligrams per kilogram per day). The subcommittee applied the MTD approach to BCME, as well as to sulfur mustard, to determine whether the approach is predictable for direct-alkylating agents. The MTD for BCME is estimated to be 0.0078 mg/kg per day on the basis of a 6-month inhalation study in male rats (Leong et al. 1988). That dose averaged over a 2-year lifetime is about 0.002 mg/kg per day. Assuming equivalent potency of BCME by oral and inhalation exposure, the MTD approach yields a carcinogenic potency of 370 per mg/kg per day (0.74 ÷ 0.002 mg/kg per day) for BCME, which is close to the slope factor of 220 per mg/kg per day reported by EPA (1992). For sulfur mustard, the MTD was estimated to be 0.2 mg/kg per day on the basis of a study by Sasser et al. (1989a), who reported significant body-weight depression in rats administered sulfur mustard at 0.3 mg/kg per day for 90 days but no toxic effects at 0.1 mg/kg per day. With an MTD of 0.2 mg/kg per day for 5 days per week, the average daily dose would be 0.14 mg/kg per day (0.2 mg/kg per day × (5/7)). Using the method of Gaylor and Gold (1995), an estimate of the carcinogenic potency of sulfur mustard is less than 5.3 per mg/kg per day (0.74 ÷ 0.14 mg/kg per day). In the absence of a chronic bioassay for sulfur mustard, the two approaches described above for estimating an upper limit on the carcinogenic potency give remarkably similar results—1.6 and 5.3 per mg/kg per day for lifetime exposure. Those potency values are less than an order of magnitude lower than the 9.5 per mg/kg per day derived by ORNL (see Table 7-2). That would indicate that the potency estimate of 132 per mg/kg per day relative to BCME (described earlier) is too high
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents TABLE 7-2 Estimates of the Upper Limit for Carcinogenic Potency of Sulfur Mustard Method of Estimation Estimate (per mg/kg/d) Reference Potency relative to B[a]P potency from EPA's IRIS database 9.5 Watson et al. 1989 Potency relative to B[a]P potency from GLP study 1.6 Culp et al. 1998 Potency relative to the MTD 5.3 Gaylor and Gold 1995 Potency relative to BCME potency from EPA's IRIS database 132 Watson et al. 1989 Abbreviations: B[a]P, benzo[a]pyrene; BCME, bis-(chloromethyl)ether; GLP, good laboratory practice; IRIS, Integrated Risk Information System; MTD, maximum tolerated dose. and that the potency estimate relative to B[a]P should be used. The subcommittee believes that the updated potency of B[a]P reported by Culp et al. (1998) should be used as the basis for calculating the SF for sulfur mustard and recommends an SF of 1.6 per mg/kg per day. Cancer risk is estimated by multiplying the carcinogenic potency with the average lifetime daily dose. Thus, if the potential carcinogenic risk from ingestion of sulfur mustard is restricted to less than 1 × 10-5 (1 in 100,000 persons) for those individuals exposed for a lifetime, daily oral doses should be limited to 6 × 10-6 mg/kg per day (10-5 ÷ 1.6 per mg/kg per day). That value is similar to the RfD of 7 × 10-6 mg/kg per day for noncancer effects. The level of carcinogenic risk might even be lower, because exposure duration is likely to be less than 70 years. According to an analysis by Israeli and Nelson (1992), only about 5% of all households are expected to stay at the same residence for over 23 years in a 70-year lifetime. Additionally, past regulations concerning acceptable risk levels generally correspond to implied estimates of excess lifetime cancer risk of less than 10-4 (Rodricks et al. 1987). Those facts strongly suggest that the RfD recommended by the subcommittee should be adequately protective of health with respect to possible carcinogenic effects. WEIGHT AND STRENGTH OF EVIDENCE The strength of evidence for the SF of sulfur mustard is poor because no epidemiological or animal carcinogenicity studies have been conducted
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents on long-term oral exposure to sulfur mustard. Therefore, only indirect approaches can be used to calculate the SF. Two indirect approaches, one using relative potency calculations and the other estimating the carcinogenic potency of orally administered sulfur mustard, resulted in estimated potency values that were within a factor of 3 of each other, lending some credibility to the indirect comparative approach used by ORNL. However, the subcommittee used an updated estimate for B[a]P potency in its relative potency calculations. CONCLUSIONS The approach used by ORNL to calculate the interim RfD for sulfur mustard is consistent with the guidelines of the EPA. On the basis of available toxicity and related data on sulfur mustard, the subcommittee concludes that the Army's RfD for sulfur mustard of 7 × 10-6 mg/kg per day is scientifically valid, although the subcommittee believes that slightly different uncertainty factors should be used. The approach selected by ORNL to calculate the SF for sulfur mustard was scientifically valid given the absence of epidemiological or animal carcinogenicity studies of sulfur mustard. Another approach using the MTD for estimating the potency of sulfur mustard yielded a similar result. Using an updated estimate for B[a]P potency, the subcommittee believes that the Army's interim SF of 9.5 per mg/kg per day should be lowered to 1.6 per mg/kg per day. DATA GAPS AND RESEARCH RECOMMENDATIONS The major gap in the available information on sulfur mustard is the lack of long-term oral toxicity and carcinogenicity studies from which to derive the RfD and SF directly. Because of that deficiency, the RfD for sulfur mustard can only be estimated by extrapolating from subchronic exposure studies of adverse effects in animals in to humans, and the SF can only be established by applying comparative carcinogenic potency methods. The absence of long-term data can be addressed by conducting a long-term oral exposure study in which such routes as diet are used to deliver sulfur mustard to animals at a slow rate.
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents REFERENCES Culp, S.J., D.W. Gaylor, W.G. Sheldon, L.S. Goldstein, and F.A. Beland. 1998. A comparison of the tumors induced by coal tar and benzo[a]pyrene in a 2-year bioassay. Carcinogenesis 19:117–124. EPA (U.S. Environmental Protection Agency). 1991. Upper-bound Quantitative Cancer Risk Estimate for Populations Adjacent to Sulfur Mustard Incineration Facilities. EPA/600/8-91/053. U.S. Environmental Protection Agency, Office of Research and Development, Washington, D.C. EPA (U.S. Environmental Protection Agency). 1992. Integrated Risk Information Service. Online file. http://www.epa.gov/ngispgm3/iris/ (Accessed May 15, 1998). Gaylor, D.W., and L.S. Gold. 1995. Quick estimate of the regulatory virtually safe dose based on the maximum tolerated dose for rodent bioassays. Regul. Toxicol. Pharmacol. 22:57–63. Hackett, P.L., R.L. Rommereim, F.G. Burton, R.L. Buschbom, and L.B. Sasser. 1987. Teratology Studies on Lewisite and Sulfur Mustard Agents: Effects of Sulfur Mustard in Rats and Rabbits. Final Report. DTIC AD-A187495. Prepared by Pacific Northwest Laboratory, Richland, Wash., for the U.S. Army Medical Research and Development Command, Fort Detrick, Frederick, Md. Heston, W.E. 1950. Carcinogenic action of the mustards. J. Natl. Cancer Inst. 11:415–423. Heston, W.E. 1953. Occurrence of tumors in mice injected subcutaneously with sulfur mustard and nitrogen mustard. J. Natl. Cancer Inst. 14:131-140. IOM (Institute of Medicine). 1993. Veterans at Risk: The Health Effects of Mustard Gas and Lewisite. Washington, D.C.: National Academy Press. Israeli, M., and C.B. Nelson. 1992. Distribution and expected time of residence for U.S. households. Risk Anal. 12: 65–72. Jones, T.D., P.J. Walsh, A.P. Watson, B.A. Owen, L.W. Barnthouse, and D.A. Sanders. 1988. Chemical scoring by a rapid screening hazard (RASH) method. Risk Anal. 8:99–118. Leong, B.K., R.J. Kociba, and G.C. Jersey. 1981. A lifetime study of rats and mice exposed to vapors of bis (chloromethyl)ether. Toxicol. Appl. Pharmacol. 58(2):269–281. McNamara, B.P., E.J. Owens, M.K. Christensen, F.J. Vocci, D.F. Ford, and H. Rozimarek. 1975. Toxicological Basis for Controlling Levels of Mustard in the Environment. EASP EB-SP-74030. Biomedical Laboratory, Department of the Army, Headquarters, Edgewood Arsenal, Aberdeen Proving Ground, Md. ORNL (Oak Ridge National Laboratory). 1996. Health Risk Assessment for Sulfur Mustard (HD). Draft Report. Interagency Agreement No. 1769-1769-A1. Prepared by Oak Ridge National Laboratory, Life Sciences Division, Oak
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Ridge, Tenn., for the U.S. Department of the Army, Army Environmental Center, Aberdeen Proving Ground, Edgewood, Md. Rodricks, J.V., S.M. Brett, and G.C. Wrenn. 1987. Significant risk decisions in federal regulatory agencies. Regul. Toxicol. Pharmacol. 7:307–320. Sasser, L.B., R.A. Miller, D.R. Kalkwarf, R.L. Buschbom, and J.A. Cushing. 1989a. Toxicology Studies on Lewisite and Sulfur Mustard Agents: Two-Generation Reproduction Study of Sulfur Mustard (HD) in Rats. Final Report. PNL-6944. DTIC AD-A216423. Prepared by Pacific Northwest Laboratory, Richland, Wash., for the U.S. Army Medical Research and Development Command, Fort Detrick, Frederick, Md. Sasser, L.B., R.A. Miller, D.R. Kalkwarf, P.W. Mellick, and R.L. Buschbom. 1989b. Toxicology Studies on Lewisite and Sulfur Mustard Agents: Subchronic Toxicity of Sulfur Mustard (HD) in Rats. Final Report. PNL-6860. DTIC AD-A217886. Prepared by Pacific Northwest Laboratory, Richland, Wash., for the U.S. Army Medical Research and Development Command, Fort Detrick, Frederick, Md. Watson, A.P., T.D. Jones, and G.D. Griffin. 1989. Sulfur mustard as a carcinogen: Application of relative potency analysis to the chemical warfare agents H, HD, and HT. Regul. Toxicol. Pharmacol. 10:1–25.
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