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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Appendix E Health Risk Assessment for Sulfur Mustard (HD)
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents This page in the original is blank.
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents HEALTH RISK ASSESSMENT FOR SULFUR MUSTARD (HD) DRAFT REPORT September 1996 (editorial corrections made April 1997) Prepared for U.S. Department of the Army Army Environmental Center under Interagency Agreement No. 1769-1769-A1 Prepared by Life Sciences Division OAK RIDGE NATIONAL LABORATORY* Oak Ridge, Tennessee 37831 Submitted to Material/Chemical Risk Assessment Working Group Advisory and Coordinating Committee Environmental Risk Assessment Program * Managed by Lockheed Martin Energy Research Corp. for the U.S. Department of Energy under Contract No. DE-AC05-96OR22464
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents DISCLAIMER This document is an internal review draft for review purposes only and does not constitute U.S. Government policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents PREFACE This report assesses the potential non-cancer and cancer effects of sulfur mustard (HD) (CAS No. 505-60-2). This document supports the activities of the Material/Chemical Risk Assessment Working Group of the Environmental Risk Assessment Program, a cooperative endeavor of the Department of Defense, Department of Energy, and Environmental Protection Agency. This working group is developing toxicity values for selected chemicals of concern at federal facilities. Toxicity values will be submitted for consideration by the EPA's IRIS Consensus Process for inclusion on IRIS (EPA's Integrated Risk Information System). The Material/Chemical Risk Assessment Working Group consists of Drs. Jim Cogliano (chair) and Harlal Choudhury (U.S. EPA), Dr. Bruce Briggs (Geo-Centers); Lt. Cmdr. Warren Jederberg and Dr. Robert L. Carpenter (U.S. Naval Medical Research Institute); Dr. Elizabeth Maull and Mr. John Hinz (U.S. Air Force Occupational and Environmental Health Directorate); Drs. Glenn Leach and Winnie Palmer (U.S. Army Center for Health Promotion and Preventive Medicine); Drs. Robert Young and Po-Yung Lu (Oak Ridge National Laboratory). This document was written by Drs. Dennis M. Opresko and Rosmarie Faust, Life Sciences Division, Oak Ridge National Laboratory (ORNL), Oak Ridge, TN. Internal peer review was provided by Dr. Robert Young, Dr. Annetta Watson, and Mr. Robert Ross. External review of the toxicity data was provided by Dr. Thomas J. Bucci, Integrated Services, White Hall, AR and Dr. I.K Ho of the U. of Mississippi Medical Center, Jackson MS. External review of the derivation of the RfDs was provided by Drs. Michael Dourson and Susan Velazquez of Toxicology Excellence for Risk Assessment, Cincinnati, OH, and Dr. William Hartley of Tulane Medical Center, New Orleans LA. Additional reviews were provided by Mr. Joe King, Dr. Jack Heller, Ms. Veronique Hauschild, Ms. Bonnie Gaborek, Mr. Maurice Weeks, Maj. Robert Gum, and Mr Kenneth Williams of the U.S Army.
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents TABLE OF CONTENTS 1. Introduction 1 1.1 Physical/Chemical Properties 1 1.2 Environmental Fate 1 2. Mechanism of Action 2 3. Toxicology 3 3.1 Introduction 3 3.2 Acute Toxicity 3 3.3 Subchronic Toxicity 4 3.4 Chronic Toxicity 5 3.5 Delayed Toxicity 8 3.6 Developmental and Reproductive Effects 8 3.7 Carcinogenicity 10 3.7.1 Human Data 11 3.7.2 Animal Studies 13 3.8 Genotoxicity 16 4. Oral Reference Dose 17 4.1 Selection of the Principal Study 17 4.2 Derivation of the Oral RfD 18 4.3 Confidence in the Oral RfD 20 5. Carcinogenicity Assessment 20 5.1 Inhalation Unit Risk 20 5.1.1 Inhalation Unit Risk Derived from Experimental Animal Data 20 5.1.2 Inhalation Unit Risk Derived from Relative Potency 22 5.2 Oral Slope factor 23 5.2.1 Oral Slope Factor Derived from Inhalation Unit Risk 23 5.2.2 Oral Slope Factor Derived from Relative Potency 24 5.3 Confidence in the Quantitative Carcinogenicity Estimates 25 5.3.1 Inhalation Unit Risk 25 5.3.2 Oral Slope Factor 25 6. References Cited 27
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents LIST OF TABLES Table 1. Ocular effects of sulfur mustard in dogs 6 Table 2. Toxicity of sulfur mustard to dogs 7 Table 3. Lowest doses of sulfur mustard causing maternal and fetal effects in rats and rabbits 9 Table 4. Incidences of skin tumors in McNamara et al. (1975) toxicity study 14 Table 5. Incidences of skin tumors in McNamara et al. (1975) cancer study 15 Table 6. Summary of toxicity data for sulfur mustard 18 Table 7. Skin tumor data (toxicity study) used in EPA quantitative assessment 21 Table 8. Skin tumor data (carcinogenicity study) used in EPA quantitative assessment 22
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 1. INTRODUCTION Sulfur mustard (HD) is a chemical vesicant capable of causing severe skin and eye damage at very low concentrations. The chemical name, synonyms, identification codes, molecular formula and structural formula for this agent are as follows: Sulfur mustard bis(2-chloroethyl)sulfide 1,1'-thiobis(2-chlorethane) 1-chloro-2-(2-chloroethylthio)ethane Distilled mustard Agent HD CAS No. 505-60-2 C4H8Cl2S 1.1. PHYSICAL/CHEMICAL PROPERTIES Pure sulfur mustard (HD) is a colorless, odorless, oily liquid with a molecular weight of 159.08 (MacNaughton and Brewer, 1994). Commercial products, however, have a yellow-brown color and sweet odor due to contaminants (MacNaughton and Brewer, 1994). Sulfur mustard has a vapor density of 5.5 (air = 1), a liquid density of 1.27 g/mL at 25°C, a vapor pressure of 0.11 mm Hg at 25°C, and a water solubility of 0.092 g per 100 g at 22°C (DA, 1974). 1.2. ENVIRONMENTAL FATE 1.2.1 Air The vapor pressure of sulfur mustard is 0.11 mm Hg at 25°C, indicating moderate volatility. A vapor concentration of 920 mg/m3 has been reported for a temperature of 25°C (DA, 1974) (although not adequately described in the reference, this presumably is the saturation concentration above a pure liquid). Information on the half-life of HD in air under various environmental conditions was not found in the available literature.
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 1.2.2 Water The water solubility of sulfur mustard has been reported as 0.092 g per 100 g water at 22°C (DA, 1974), and 5 × 10-3 M at room temperature (MacNaughton and Brewer, 1994). In dilute aqueous solutions sulfur mustard hydrolyzes almost completely to thiodiglycol and hydrochloric acid (Papirmeister et al., 1991). For dissolved HD, the hydrolysis half-life ranges from about 4 to 15 min for temperatures of 20–25°C; however, bulk HD may persist in water for up to several years (Small, 1984). Small (1984) reported that it would take 15 days for the mass of a 1 cm droplet of HD in quiescent water to decrease by one half. The Henry's Law Constant for HD has been estimated to be 2.1 × 10-5 atm m3/mol (MacNaughton and Brewer, 1994), indicating a moderate potential for evaporation from water. 1.2.3 Soil Sulfur mustard can be very persistent in soil (Rosenblatt et al., 1995). Persistence depends on the soil type, pH, moisture content, and whether the agent is at the soil surface or buried. Small (1984) reported that when HD was applied to the soil surface, volatilization would be the main route of HD loss (half-life about 30 min), but if the soil was wet, hydrolysis would be the main loss pathway. When sprayed onto soil, a vesicant action was still apparent after about 2 weeks; when the agent leaked into the soil, however, a vesicant action was still present after 3 years (DA, 1974). Rosenblatt et al. (1995) state that the persistence of sulfur mustard in soil is due to the formation of oligomeric degradation products that coat the surface of the mustard agent and that are resistant to hydrolysis. Sulfur mustard has a log Kow of 1.37 and a Koc of 133, indicating that binding to soil organics would limit transport through soil to groundwater (MacNaughton and Brewer, 1994). MacNaughton and Brewer (1994) calculated a leaching index of 7.2 for HD, (i.e., the number of leachings required to reduce the HD soil concentration to one-tenth of the original amount, assuming that for each leaching one kilogram of soil is in equilibrium with one liter of water). 2 MECHANISM OF ACTION The acute toxic effects of mustard vesicants are usually attributed to the consequences of alkylation reactions with organic compounds including nucleoproteins such as DNA. Alkylation reactions can result in physiological and metabolic disturbances as well as genotoxic effects. Several hypotheses have been advanced concerning the primary cause of cell death following acute exposures. As reviewed by Papirmeister et al. (1991), the three major hypotheses are: Poly(ADP-ribose) polymerase (PADPRP) hypothesis. - In this theory DNA is the initial target of the mustard agent. Alkylated DNA purines undergo spontaneous and enzymatic depurination, leading to the production of apurinic sites which are cleaved by apurinic endonucleases to yield DNA breaks. Accumulation of DNA breaks leads to activation of the chromosomal enzyme PADPRP, which utilizes nicotinamide adenine dinucleotide (NAD+) as a substrate to ADP-ribosylate and a variety of nuclear
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents proteins, causing severe lowering of cellular NAD+. Depletion of NAD+ results in the inhibition of glycolysis, and stimulation of the nicotinamide adenine dinucleotide phosphate (NADP+)-dependent hexose monophosphate shunt (HMS) pathway follows as a result of the accumulation of glucose-6-phosphate, a common precursor for both glycolysis and the HMS. Induction and secretion of proteases is stimulated as a result of enhanced HMS activity, and this leads to pathological changes in the cell. Thiol-Ca+2 peroxidation hypothesis. The first step in this process is thought to be the alkylation of glutathione (GSH) by the mustard agent. Depletion of GSH subjects protein sulfhydryl groups to damage from the agent or from reactive cellular oxidants. Proteins most susceptible to damage include Ca2+ translocases (Ca2+-stimulated, Mg2+-dependent ATPase) which are dependent on thiol groups to maintain cellular Ca2+ homeostasis, and microfilamentous proteins, where loss of sulfhydryl groups could result in disruptions of the cytoskeletal and structural integrity of the plasma membrane. Lipid peroxidation hypothesis. According to this hypothesis the mustard agent causes depletion of GSH which, in turn leads to the buildup of highly toxic oxidants, usually through H2O2-dependent reaction sequences. The oxidizing agents react with membrane phospholipids to form lipid peroxides, initiating a chain reaction of lipid peroxidation which can lead to alterations in membrane fluidity, loss of membrane protein function, and loss of membrane integrity. 3. TOXICOLOGY 3.1 Introduction Sulfur mustard vesicants are acutely toxic by direct contact. Edema, ulceration, and necrosis of the skin and respiratory tract epithelium can occur, as well as conjunctivitis and blindness. General symptoms of systemic toxicity include nausea, vomiting, fever, and malaise (ITII, 1975). Delayed effects which may occur following acute exposures include: eye lesions, chronic bronchitis, and cancers of the respiratory tract and skin. However, information on adverse effects following long-term exposures to less-than acutely toxic concentrations is very limited. Health effects of sulfur mustard agents have recently been reviewed by ATSDR (1992), Somani (1992), Sidell and Hurst (1992), Watson and Griffin (1992), and the Institute of Medicine (1993). The following is a brief summary of the most important toxicological data for sulfur mustard. 3.2 Acute Toxicity Acute exposures to sulfur mustard can result in skin and eye damage, gastrointestinal irritation, and depressed myelopoiesis (resulting in leukopenia and anemia) (Vogt et al., 1984). Damage to the respiratory tract, which is the principal cause of mortality in the first few days to weeks after exposure to sulfur mustard, involves acute edema, inflammation, and destruction of the airway epithelial lining (Institute of Medicine, 1993). Infection of the respiratory tract resulting in bronchopneumonia is a common complication of exposure to sulfur mustard.
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents The skin and eyes are especially sensitive to the toxic effects of sulfur mustard. When applied to human skin, about 80% of the dose evaporates and 20% is absorbed (Vogt et al., 1984). About 12% of the amount absorbed remains at the site and the remainder is distributed systemically (Renshaw, 1946). Doses up to 50 µg/cm2 cause erythema, edema, and sometimes small vesicles. Doses of 50-150 µg/cm2 cause bullous-type vesicles, and larger doses cause necrosis and ulceration with peripheral vesication. Droplets of liquid sulfur mustard containing as little as 0.0025 mg may cause erythema (Ward et al., 1966). Eczematous sensitization reactions were reported in several early studies and may occur at concentrations below those causing direct primary irritation (Rosenblatt et al., 1975). In humans, the LCt50 (estimated concentration x exposure period lethal to 50% of exposed individuals) for skin exposures is 10,000 mg-min/m3 (DA, 1974) (for masked personnel; however, the amount of body surface area exposed was not reported). The ICt 50 (estimated concentration x exposure period incapacitating to 50% of exposed individuals) for skin exposures is 2000 mg-min/m3 at 70–80°F in a humid environment and 1000 mg-min/m3 at 90°F in a dry environment (DA, 1974, 1992). The ICt50 for contact with the eyes is 200 mg-min/m 3 (DA, 1974, 1992). The LDLo for skin exposure is 64 mg/kg and the LD50 is estimated to be about 100 mg/kg (DA, 1974, 1992). Repeated exposure to 1.4 mg-min/m3 produced no eye irritation or injury to laboratory animals (Rosenblatt et al., 1975). In humans, a Ct of ≤12 mg-min/m3 is considered a no-effect dose for eye irritation (McNamara et al., 1975) at ambient temperatures. At higher temperatures (≥32°C), threshold and other biological effects occur at lower concentrations. Cts of 12–70 mg-min/m3 cause mild reddening of the eyes (McNamara et al., 1975); Cts of 40–90 can cause eye irritation and conjunctivitis after a latency period of 2 to 48 hr; and Cts of 90–100 mg-min/m3 produce moderately severe burns, ulcers, opacity, and perforation after a latency period of 2 to 10 hr (Doull et al., 1980). In some cases there may be a recurrent vascularization and ulceration many years after the initial exposure. The LCt50 for inhalation exposures in humans has been estimated to be 1500 mg-min/m3 (DA, 1992). In animals, median lethal Ct values for sulfur mustard range from 600 to 1900 mg-min/m3 for 10-min exposures (see Rosenblatt et al., 1975 for review). An LCLo (lowest lethal concentration) of 189 mg/m3/10 min has been reported for mice (Lewis and Sweet, 1984), and a 5-min LCLo of 77 ppm has been reported for dogs (ITII, 1975). Information on the acute oral toxicity of sulfur mustard is quite limited. The oral LDLo for humans has been estimated to be 0.7 mg/kg (DA, 1992). The oral LD50 for rats is 17 mg/kg (DA, 1974). Rats treated with 2.5 mg/kg/day for 14 days developed inflammation, petechial hemorrhage, thickening, and sloughing of the gastric mucosa (Hackett et al., 1987). 3.3 Subchronic Toxicity In a subchronic study conducted by Sasser et al. (1989a), Sprague-Dawley rats (12/sex/group) were dosed by gavage with 0, 0.003, 0.01, 0.03, 0.1 or 0.3 mg sulfur mustard (in sesame oil)/kg body weight/day, 5 days/week, for 13 weeks. No mustard-related mortality occurred at any dose level. Body weights were significantly decreased in animals in the high-dose group. Epithelial hyperplasia of the forestomach occurred in 5/12 males and 5/12 females of the high-dose group and in 1/12 males receiving 0.1 mg/kg/day, but not in any other treatment group. Forestomach lesions were not seen in any of the control animals. No other treatment-related pathological lesions, clinical chemistry changes, or hematological abnormalities were reported.
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents considered to be the same as that for MC, it was estimated that the unit risk for sulfur mustard would be 10–13 times the inhalation cancer unit risk for BaP. The latter was derived from the oral slope factor of 11.5 (mg/kg/day)-1 using the standard defaults of 20 m3/day for ventilation rate and 70 kg for body weight. The resulting inhalation unit risk estimate for sulfur mustard, based on the relative potency method, was 0.033–0.043 (µg/m3)-1 (U.S. EPA, 1991). 5.2 Oral Slope Factor Long-term oral carcinogenicity studies have not been conducted on sulfur mustard. In oral subchronic studies in which the agent was administered by gavage to rats (see section 3..3), epithelial hyperplasia of the forestomach occurred in 5/12 males and 5/12 females dosed with 0.3 mg HD/kg/day (in sesame oil), 5 days/week for 13 weeks. In light of the known carcinogenicity of sulfur mustard, the epithelial hyperplasia is suggestive of a pre-neoplastic condition. To derive an oral slope factor in the absence of long-term experimental data, two non-standard approaches can be considered. One involves the direct conversion of the inhalation unit risk to an oral slope factor, and the other involves the use of relative potency methods. Both approaches are summarized in the following sections. 5.2.1 Oral Slope Factor Derived from Inhalation Unit Risk The U.S. EPA (1991) identified an "inhalation" unit risk of 8.5 × 10-2 per µg/m3, derived from the Weibull time-to-tumor model, as the most appropriate estimate of the carcinogenic potency of sulfur mustard. This unit risk can be converted to a slope factor by normalizing the value for a 70 kg man inhaling 20 m3 of air per day. The resulting slope factor is 0.3 (µg/kg/day)-1. Although it can be argued that conversion of an inhalation unit risk to an oral slope factor might be acceptable under certain conditions, including cases where 1) the cancer target organ is the same regardless of the route of exposure, 2) where differences in g.i. and pulmonary absorption can be taken into account, and 3) where metabolic activation is not critical or, if it is, the differences in first-pass metabolism in the liver and lung are accounted for. In the case of sulfur mustard, the inhalation unit risk is based on the occurrence of skin tumors in rats following exposure to sulfur mustard vapors. There is no evidence that the tumors occurred following systemic absorption and distribution to the skin. Considering the vesicant action of the agent, it is likely that the skin tumors resulted from the direct contact of the vapors or condensation droplets on the skin of the test animals. As mentioned above, for oral exposures the only evidence available suggests that if tumors did occur, they would be localized in the epithelial tissue of the g.i. tract. Therefore, it is unlikely that the target organs would be the same, although it could be argued that in both cases an epithelial surface is the target. Because a dose per unit surface area of skin can not be determined from the McNamara et al. (1975) study, quantitative extrapolation from a skin response to a g.i. tract response is not possible. Furthermore, because sulfur mustard is subject to rapid hydrolysis, the amount ingested that actually reaches the epithelial surface of the g.i. tract may be considerably limited, and, in fact, a significant dose may only be possible through gavage administration in an organic solvent vehicle, as was done in the animal toxicity studies. As noted in section 3.7.1, there is only limited evidence that sulfur mustard causes digestive tract tumors in humans. Yamada (1974, as reported by Inada et al., 1978) found 17 cases of digestive tract cancers among 94 autopsy cases and 8 surgical cases of former workers at a chemical warfare
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents manufacturing facility. No comparisons were made with control groups; therefore, the significance of this finding cannot be determined. It is known that many of these workers were exposed to sulfur mustard concentrations thought to be sufficiently high (est. 50–70 mg/m3) to produce signs of acute toxicity (i.e., acute conjunctivitis, acute rhinitis, acute bronchitis, and acute dermatitis with blister formation) (Nakamura, 1956). 5.2.2 Oral Slope Factor Derived from Relative Potency Estimates As described in section 5.1.2, U.S. EPA (1991) derived an inhalation unit risk for sulfur mustard using the relative potency method in which sulfur mustard was considered to be 10–13 times more potent than BaP. The oral slope factor for BaP, as currently listed on IRIS, is 7.3 (mg/kg/day)-1 (U.S. EPA, 1996). Multiplying this slope factor by the relative potency range of 10–13, results in an oral slope factor of 0.073–0.095 (µg/kg/day)-1 for sulfur mustard. Watson et al. (1989) estimated the carcinogenic potency of HD by the "rapid screening of hazard" (RASH) method developed by Jones et al. (1988). This approach compares exposures that produce documented toxic effects of a chemical of interest to exposures of a reference chemical producing a similar effect. The RASH procedure was applied to Heston's intravenous (1950) and subcutaneous injection studies (1953). Comparing the carcinogenicity of HD and the well characterized industrial carcinogen benzo[a]pyrene (BaP), Watson et al. (1989) showed that the two compounds are of approximate equivalent carcinogenic potency in experimental animals with a best estimate relative potency of 1.3 for sulfur mustard relative to BaP and an interquartile range (middle 50% of distribution) of 0.6-2.9. Consistent results were obtained when the potency of sulfur mustard was compared to that of bis-chloromethyl ether (BCME, CAS No. 542-88-1) another alkylating agent that is a powerful lung and eye irritant, as well as an IARC Class 1 carcinogen (Watson et al., 1989; IARC, 1987) The estimated comparative carcinogenic potency can be used to derive a slope factor (SF) or q1* for sulfur mustard. The slope factor converts the estimated daily intake averaged over a lifetime exposure to incremental risk of an individual developing cancer. Because the slope factor is an upper 95th percentile confidence limit on the probability of response based on experimental animal data, the carcinogenic risk will generally be an upper-bound estimate. Applying the Watson et al. (1989) estimated relative potency of 1.3 and using the currently accepted oral slope factor of 7.3 per (mg/kg)/day for BaP, a SF for HD can be calculated as follows:
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 5.3 Confidence in the Quantitative Estimates of Carcinogenic Potency 5.3.1 Inhalation Unit Risk U.S. EPA (1991) notes that the dose-response estimates derived from the McNamara et al. (1975) study are highly uncertain due to the fact that the study was not of a standard design and too few animals were exposed and followed for a lifetime to give adequate sensitivity for detecting long-term effects. In addition, the uncertainty concerning the experimental conditions was too great to allow confidence about the absolute carcinogenic potency value. In view of the fact that in the McNamara et al. (1975) study, malignant tumors appeared only at the highest mustard concentration and only late in life, U.S. EPA (1991) observed: "perhaps it may exert its carcinogenic activity secondarily through lifelong exposure to its cytotoxic or irritating effects. Under such circumstances, human exposures at low concentrations for limited times may entail much less risk than implied by the unit risk factor estimated from lifetime effects at higher doses. On the other hand, the lack of low-dose responses and early-appearing tumors in the McNamara data may be due simply to the inherent difficulty of detecting low-risk levels in experiments of reasonable size". Because sulfur mustard is known to be a strong and direct DNA alkylating agent, the likelihood is very high that it functions as a non-threshold carcinogen. Consequently, the risks associated with exposures to low concentrations require evaluation, and the McNamara et al. (1975) study provides the only data set that allows for a quantification of carcinogenic potency following exposure to sulfur mustard vapors. 5.3.2 Oral Slope Factor Although human and animal data are lacking, there is indirect evidence suggesting that sulfur mustard may be carcinogenic by the oral exposure route. The mechanism of action of sulfur mustard as a direct DNA alkylating agent, its known genotoxicity in exposed humans and in various animal bioassays, its induction of respiratory tract and skin tumors following inhalation exposures, and its induction of forestomach hyperplasia in rats following subchronic gavage dosing (see Section 3.3), all support the conclusion that this compound functions as a point of contact carcinogen on epithelial tissues. Furthermore, the mechanism of action of sulfur mustard would be expected to be similar to that of other known or suspected mustard carcinogens such as nitrogen mustard (sulfur mustard tumorigenicity was determined to be comparable to that of the nitrogen mustard agents HN2 and HN2-HCl and the therapeutic nitrogen mustard compounds melphalan and BCME; see Institute of Medicine, 1993, Appendix I), as well as bis-(chloro) ethyl ether (BCEE). In the absence of human or animal oral dose-response data, the relative potency approaches developed by Watson et al. (1989) and U.S. EPA (1991) are considered to be appropriate methods for estimating the tumorigenic potency of sulfur mustard by the oral route of exposure. The oral slope factor derived by Watson et al. is approximately one order of magnitude less than the one derived from the relative potency estimated by U.S. EPA (1991). In the emerging area of relative potency analysis, a factor of 10 difference represents a good fit. There is no significant difference between the estimates of sulfur mustard carcinogenic potency relative to B(a)P published by Watson et al. (1989) and U.S. EPA (1991).
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Although there are dose-response data from an animal inhalation exposure study (McNamara et al., 1975, see Section 5.1.1), route-to-route extrapolation (from inhalation to oral, as calculated in Section 5.2.1) is not considered appropriate because the exposure protocol of McNamara et al. (1975) resulted in rat skin tumors which might have occurred, not a result of systemic uptake, but as a result of dermal contact with sulfur mustard vapor (perhaps trapped by the rat pelt). Therefore, there is no method for estimating the dermal dose of sulfur mustard, or for converting this to an oral dose.
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 6.REFERENCES CITED ATSDR (Agency for Toxic Substances and Disease Registry). 1992. Toxicological Profile for Mustard Gas. ATSDR, Atlanta, GA, TP-91/22. Auerbach, C and J.M. Robson. 1946. Chemical production of mutagens. Nature (Lond.) 157:302. Azizi, F., A. Keshavarz, F. Roshanzamir, et al. 1995. Reproductive function in men following exposure to chemical warfare with sulfur mustard. Med. War 11:34–44. Beebe, G.W. 1960. Lung cancer in World War I veterans: possible relation to mustard gas injury and 1918 influénza epidemic. J. Natl. Cancer Inst. 25:1231–1252. Capizzi, R.L., W.J. Smith, R. Field and B. Papirmeister. 1973. A host-mediated assay for chemical mutagens using L5178Y/Asn murine leukemia. Mutat. Res. 21:6. Case, R.A.M. and A.J. Lea. 1955. Mustard gas poisoning, chronic bronchitis and lung cancer. An investigation into the possibility that poisoning by mustard gas in the 1914–1918 war might be a factor in the production of neoplasia. Brit. J. Prev. Med. 9:62–72. (as cited by IARC, 1975; Beebe, 1960) Crathorn, A.R. and J.J. Roberts. 1965. Reactions of cultured mammalian cells of varying radiosensitivity with the radiomimetic alkylating agent mustard gas.. Prog. Biochem. Pharmacol. 1:320–326. Crathorn, A.R. and J.J. Roberts. 1966. Mechanism of the cytotoxic action of alkylating agents in mammalian cells and evidence for the removal of alkylated groups from deoxyribonucleic acid. Nature (Lond) 211:150–153. DA (U.S. Department of the Army). 1974. Chemical Agent Data Sheets, vol. 1. Edgewood Arsenal Special Report, EO-SR 74001. Defense Tech, Inform. Center, Alexandria, VA. DA (U.S. Department of the Army). 1992. Material Safety Data Sheets: HD and THD. Edgewood Research, Development and Engineering Center, Aberdeen Proving Ground, MD. Dahl, H., B. Glund, P. Vangstad and M. Norn. 1985. Eye lesions induced by mustard gas. Acta Ophthalmol. 63(suppl. 173):30–31. (as cited in Watson and Griffin, 1992) Doull, J., C.D. Klaassen and M.O. Amdur (eds.). 1980. Casarett and Doull's Toxicology. The Basic Science of Poisons. 2nd ed., MacMillan, New York, NY. Easton, D.F., J. Peto and R. Doll. 1988. Cancers of the respiratory tract in mustard gas workers. Br. J. Ind. Med. 45(10):652–659. Fox, M. and D. Scott. 1980. The genetic toxicology of nitrogen and sulfur mustard. Mutat. Res. 75:131–168.
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 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. AD A 187495. Pacific Northwest Laboratory, Richland, WA. for the U.S. Army Medical Research and Development Command, Fort Detrick, MD. Heston, W.E. 1950. Carcinogenic action of 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. Heston, W.E. and W.D. Levillain. 1953. Pulmonary tumors in strain A mice exposed to mustard gas. Proc. Soc. Exp. Biol. 82:457–460. IARC (International Agency for Research on Cancer). 1975. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man: Some Aziridines, N, S, & O-mustards and Selenium, vol. 9, pp. 181–207. International Agency for Research on Cancer, Lyons, France. IARC (International Agency for Research on Cancer). 1987. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man: Overall Evaluation of Carcinogenicity: An Updating of IARC Monographs Volumes 1–42, Suppl. 7, p. 67. International Agency for Research on Cancer, Lyons, France. Inada, S., K. Hiragun, K. Seo and T. Yamura. 1978. Multiple Bowen's disease observed in former workers of a poison gas factory in Japan, with special reference to mustard gas exposure. J. Dermatol. 5:49–60. Institute of Medicine, Committee to Survey the Health Effects of Mustard Gas and Lewisite, Division of Health Promotion and Disease Prevention. 1993. Veterans at Risk; The Health Effects of Mustard Gas and Lewisite, C.M. Pechura and D.P. Rall, eds. National Academy Press, Washington, DC. ITII (International Technical Information Institute). 1975. Toxic and Hazardous Industrial Chemicals Safety Manual. p. 351. International Technical Information Institute, Tokyo, Japan. Jones, TD, P.J Walsh, A.P. Watson, et al. 1988. Chemical scoring by a Rapid Screening Hazard (RASH) method. Risk Anal. 8:99–118. Jostes, R.F., L.B. Sasser and R.J. Rausch. 1989. Toxicology Studies on Lewisite and Sulfur Mustard Agents: Genetic Toxicity of Sulfur Mustard (HD) in the Chinese Hamster Ovary Cells. Final Report from Pacific Northwest Laboratories (PNL-6916) to U.S. Army Medical Research and Development Command, Fort Detrick, MD. Kircher, M. and M. Brendel. 1983. DNA alkylation by mustard gas in yeast Saccharomyces cerevisiae strains of different repair capacity. Chem.-Biol. Interact. 44:27–39. Klehr, N. 1984. Cutaneous late manifestation in former mustard gas workers. Z. Hautkrankh. 59:1161–1170. (In German with English abstract)
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Representative terms from entire chapter: