7—
Review of Acute Human-Toxicity Estimates for HD

HD (β-β'-dichloroethyl sulfide or bis(2-chloroethyl)sulfide), also known as sulfur mustard, is a vesicant (blistering agent). The physical and chemical properties, toxicokinetics, and toxicity of sulfur mustard are discussed in detail by CDEPAT (1994), Marrs et al. (1996), and Somani (1994). Human-toxicity estimates have been derived for percutaneous vapor exposures, vapor inhalation exposures, and for percutaneous liquid exposures. Only a few toxicity end points were considered. End points of toxicity that were considered are lethality, vesication, erythema, burns on the skin, and ocular and pulmonary effects. The subcommittee's assessment of the scientific validity of CDEPAT's human-toxicity estimates for HD is discussed below.

Percutaneous Vapor Exposure

Lethal Effects (LCt50)

CDEPAT's proposed LCt50 estimate for percutaneous exposure to HD vapor is 5,000 mg-min/m3, assuming exposure durations of 30 to 50 min. The existing estimate is 10,000 mg-min/m3 (CDEPAT 1994).



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--> 7— Review of Acute Human-Toxicity Estimates for HD HD (β-β'-dichloroethyl sulfide or bis(2-chloroethyl)sulfide), also known as sulfur mustard, is a vesicant (blistering agent). The physical and chemical properties, toxicokinetics, and toxicity of sulfur mustard are discussed in detail by CDEPAT (1994), Marrs et al. (1996), and Somani (1994). Human-toxicity estimates have been derived for percutaneous vapor exposures, vapor inhalation exposures, and for percutaneous liquid exposures. Only a few toxicity end points were considered. End points of toxicity that were considered are lethality, vesication, erythema, burns on the skin, and ocular and pulmonary effects. The subcommittee's assessment of the scientific validity of CDEPAT's human-toxicity estimates for HD is discussed below. Percutaneous Vapor Exposure Lethal Effects (LCt50) CDEPAT's proposed LCt50 estimate for percutaneous exposure to HD vapor is 5,000 mg-min/m3, assuming exposure durations of 30 to 50 min. The existing estimate is 10,000 mg-min/m3 (CDEPAT 1994).

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--> The LCt50 value for humans is difficult to estimate from the available animal data, because the data indicate that animal species vary in their sensitivity to HD. The LCt50 ranged from > 6,300 to 20,000 mg-min/m3 in monkeys (NDRC 1943a, 1944), from 2,948 to 4,885 mg-min/m 3 in mice (NDRC 1943b,c), and from 4,750 to 6,430 mg-min/m3 in rabbits (NDRC 1943a, 1944). The current LCt50 estimate for HD exposure of humans is 10,000 mg-min/m3. That estimate is based on data from monkeys—one of the least-sensitive species tested for lethality. The authors of the CDEPAT report recommend lowering the estimate to 5,000 mg-min/m 3, an estimate that is more consistent with results from studies in other animal species. In the subcommittee's opinion, CDEPAT's approach is reasonable, but the estimate is not overly conservative, because data indicate that humans might be one of the most-sensitive species to HD exposure. Rats and mice are the most-sensitive animal species. Although the proposed CDEPAT estimate is more appropriate than the existing estimate, the subcommittee believes that the new estimate might still be too high. Therefore, the subcommittee recommends that the proposed estimate be lowered. The subcommittee also recommends that further research be conducted to establish the LCt50 estimate with a greater degree of confidence. ECt50 for Severe Effects CDEPAT's proposed ECt50 estimates for severe effects from exposure to HD are 500 mg-min/m3 for moderate temperatures and < 200 mg-min/m 3 for hot temperatures, assuming exposure durations of 30 to 50 min. The existing estimates for moderate and hot temperatures are 2,000 and 1,000 mg-min/m3, respectively (CDEPAT 1994). The estimates are derived from data reported in human studies conducted 50 years ago (CDEPAT 1994). The proposed estimate of < 200 mg-min/m 3 for hot-temperature exposures is supported by a study of 10 men (PCS 1946), who exercised and sweat profusely in perspiration-drenched clothing and were exposed to HD at 220 mg-min/m3 at 90°F and 85% relative humidity for 57 min. All the men had severe scrotal burns. Thus, CDEPAT's recommended estimate is based on actual human data with a reasonable number of subjects. CDEPAT's recommended estimate for exposures at moderate temperatures (70°F, 48% humidity) is 500 mg-min/m3 and is supported by a study

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--> of eight men (clothed, wearing protective gas masks, and not exercising) in which exposures of 500 mg-min/m3 for over 1 hr produced severe scrotal effects in four of the eight men (Heinen et al. 1945). The estimate is supported by the results of exposure to lower concentrations of HD in the same study. The subcommittee concludes that the proposed estimates for hot and moderate temperatures are scientifically valid. ECt50 for Threshold Effects CDEPAT's proposed ECt50 estimates for threshold (minimal) effects from percutaneous exposure to HD vapor are 50 mg-min/m3 for moderate temperatures and 25 mg-min/m3 for hot temperatures, assuming exposure durations of 30 to 50 min. There are no existing estimates for the threshold effects of HD (CDEPAT 1994). Human data used to support the proposed estimate, which apparently came from the Project Coordination Staff (PCS) report of 1946, were not given in sufficient detail in the CDEPAT report to allow for full evaluation. The PCS report concluded that the maximum safe exposure to HD for percutaneous exposure is 50 mg-min/m3. At that exposure, HD was associated with no important injury. More data on the effects of low vapor doses would have to be available to evaluate these estimates fully. The subcommittee recommends that these ECt50 estimates (for hot and moderate temperatures) serve as interim values until further research is conducted to establish the estimates with a greater degree of confidence. Inhalation Vapor Exposure Lethal Effects (LCt50) CDEPAT's proposed estimate for the LCt50 effects from inhalation exposures to HD vapor, assuming exposure durations of 2 to 10 min and minute volumes of 15 liters, was reduced from the existing value of 1,500 mg-min/m3 to the value of 900 mg-min/m3 (CDEPAT 1994). Because of the nature of the end point (lethality), the LCt50 estimates were based on animal data. CDEPAT averaged the LCt50 from all the 10-min LCt50 data in different animal species to arrive at its estimate. No animal LCt50 studies on HD are adequate for use in estimating the human

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--> LCt50. CDEPAT had no confidence in any study. Therefore, CDEPAT had no basis for determining which animal species best reflected the human response. CDEPAT performed some modeling studies, but they did not provide useful information. In the absence of better data, CDEPAT averaged the toxicity data from several studies to estimate the human LCt50. The subcommittee believes that this approach is reasonable. The subcommittee agrees with the proposed estimate but would prefer to see a range of proposed values to indicate the confidence bounds. ECt50 for Severe Effects CDEPAT's proposed ECt50 estimate for severe (ocular) effects from inhalation exposure to HD vapor, assuming exposure durations of 2 to 10 min, was lowered from the existing value of 200 mg-min/m3 to the value of 100 mg-min/m3 (CDEPAT 1994). The eye is one of the organs that is most sensitive to the effects of HD vapors. Available data indicate that temporary blindness might be produced by HD vapor exposures of 200 mg-min/m3, but other eye effects will be experienced at lower exposures. Therefore, the authors of the CDEPAT report reduced their estimates for severe nonlethal effects by 50%. From a battlefield perspective, the soldiers will first experience eye effects which will lead to the removal of soldiers from the battlefield. The subcommittee agrees with CDEPAT's proposed estimate. ECt50 for Mild Effects CDEPAT's proposed estimate for the ECt50 for mild (ocular) effects from exposure to HD is 25 mg-min/m3, assuming exposure durations of 2 to 10 min. The existing estimate is > 50 mg-min/m3 (CDEPAT 1994). As with its ECt50 estimate for severe effects, CDEPAT based its ECt 50 estimate for mild effects on the eye. Pre-1940 data indicate effects on the eye at vapor doses of 5 to 10 mg-min/m3 (Reed 1920). Later studies, which are considered more reliable because of improved techniques, indicate that the eye can withstand a higher exposure (that is, 70 mg-min/m3) (Guild et al. 1941). The subcommittee believes that CDEPAT's proposed estimate of 25 mg-min/m3 for mild effects from inhalation exposure to HD vapor is supported by human data. Therefore, the subcommittee concludes that the proposed ECt50 estimate for mild effects is scientifically valid.

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--> Percutaneous Liquid Exposure Lethal Effects (LD50) CDEPAT's LD50 estimate for percutaneous exposure to HD liquid is 1,400 mg for a 70-kg man. The existing estimate is 7,000 mg for a 70-kg man (CDEPAT 1994). As for most LD50 estimates for humans, animal data must be relied on primarily. In this case, there is even a paucity of animal data. The Army's existing estimate was based on early data that indicated an LD50 of approximately 100 mg/kg for the rabbit; extrapolation to a 70-kg man yielded an estimated LD50 of 7,000 mg for a 70-kg man. CDEPAT (1994) chose to base its LD50 estimate on the LD50 of 20 mg/kg (1,400 mg for a 70-kg man) for the dog and guinea pig rather than the LD50 for the rabbit. Based on the data of Henry (1991), that choice is reasonable. The data indicate that rabbits are 10 times less sensitive to percutaneous HD than are humans. The subcommittee agrees with the proposed estimate of 1,400 mg for a 70-kg man. ED50 for Severe Effects The proposed ED50 for severe effects from percutaneous exposure to HD was estimated by CDEPAT to be 610 mg for a 70-kg man. There is no existing estimate (CDEPAT 1994). HD has a very low vapor pressure and stays on the ground for a long time. This persistence of HD on the ground can cause toxicity to people or animals over a long time. However, decontamination procedures can be followed to remove HD from the ground. CDEPAT's proposed estimate is based on the observation of vesication of the human forearm (an area of moderate sensitivity to HD) following application of HD at a dose of 34 µg/cm2 (Landhal 1945). Landhal (1945) collected data on hundreds of human exposures at the University of Chicago Toxicology Laboratory and concluded that 34 µg/cm2 was the threshold blister dose on the volar forearm. Extrapolation of that dose to the estimated 1.8 m2 surface area of the average male yielded CDEPAT's proposed ED50 estimate of 610 mg for severe effects for a 70-kg man. Therefore, the subcommittee finds CDEPAT's proposed estimate to be scientifically valid. However, the proposed value of 610 mg should be rounded to 600 mg for a 70-kg man to avoid the appearance of precision that is not there.

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--> Conclusions and Recommendations The subcommittee's conclusions concerning the scientific validity of CDEPAT's proposed estimates for HD are summarized in Table 7-1. Of the 10 human-toxicity estimates for HD proposed by CDEPAT, the subcommittee concludes that seven of the estimates are appropriate for protecting soldiers and are scientifically valid. The subcommittee recommends that two estimates serve as interim values estimates until further research is conducted and one estimate be lowered. In general, the subcommittee agrees that most of CDEPAT's proposed estimates for HD are reasonable and based on sound scientific judgments of the available data. The subcommittee is concerned that the estimates were central values and calculated without uncertainty factors. Such an approach might not be protective of all members of the military forces. Thus, the subcommittee recommends that further research be conducted to establish the estimates with a greater degree of confidence.

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--> TABLE 7-1 Evaluation of Human-Toxicity Estimates for HD     Human-Toxicity Estimates for HD     Toxicity Type Route and Form of Exposure Existing Estimates CDEPAT's Proposed Estimates Subcommittee's Evaluation of Proposed Estimates for HD Rationale for Subcommittee's Evaluation LCt50a Percutaneous, vapor 10,000 mg-min/m3 5,000 mg-min/m3 Proposed estimate should be lowered Estimate might be too high because data from the most-sensitive species (rats and mice) not used; further research recommended   Inhalation, vapor 1,500 mg-min/m3 900 mg-min/m3 Proposed estimate is scientifically valid CDEPAT averaged LCT50 data in several animal species; in the absence of data on humans, that approach is reasonable ECt50b Threshold effects Percutaneous, vapor None 50 mg-min/m3 (moderate temperature); 25 mg-min/m3 (hot temperature) Proposed estimates should serve as interim values In the absence of details on studies on value; which estimates were based, proposed estimate should be considered interim further research recommended Severe effects Percutaneous, vapor 2000, mg-min/ m3 (moderate temperature 1000 mg-min/ m3 (hot temperature 500 mg-min/m3 (moderate temperature); <200 mg-min/m3 (hot temperature) Proposed estimated are scientifically valid Estimates based on human studies

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-->     Human-Toxicity Estimates for HD     Toxicity Type Route and Form of Exposure Existing Estimates CDEPAT's Proposed Estimates Subcommittee's Evaluation of Proposed Estimates for HD Rationale for Subcommittee's Evaluation Severe effects Inhalation vapor 200 mg-min-/ m3 (moderate temperature) 100 mg-min/m3 moderate temperature) Proposed estimate is scientifically valid Proposed estimated supported by human data Mild effects Inhalation, vapor >50 mg-min/m3 25 mg-min/m3 Proposed estimate is scientifically valid Proposed estimate supported by human data LD50c Percuataneous, liquid 7,000 mg for 70-kg man 1,400 mg for 70-kg man Proposed estimate is scientifically valid Proposed estimate supported by a study in dogs ED50d Severe effects Percutaneous, liquid None 610 mg for 70-kg man Proposed estimate is scientifically valid; however, it should be rounded to 600 mg for a 70-kg man to avoid appearance of precision that is not there Proposed estimate supported by human data a LCt50: Vapor exposure that produces lethality in 50% of the exposed animals. Ct refers to the product of concentration (c) and exposure time (t). Note that Ct is not necessarily a constant. b ECt50: Percutaneous vapor exposure or inhalation vapor exposure causing a defined effect (e.g., incapacitation, severe effects, mild effects, threshold effects). c LD50: Liquid dose causing lethality in 50% of the exposed animals. d ED50: Liquid dose causing a defined effect in 50% of the exposed animals.