Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 3 (2003) / Chapter Skim
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2. Sulfur Mustard: Acute Exposure Guideline Levels
2. Sulfur Mustard: Acute Exposure Guideline Levels
Pages 301-383
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From page 301... ...
Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports NRC 1993, 2001~.
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An exposuredependent latency period of hours to days is documented and is relevant for all routes of exposure but may be shorter for ocular and upper respiratory tract effects than for dermal and systemic responses. Both human and animal data indicate that the eyes are the most sensitive organ/tissue; deaths resulting from sulfur mustard exposure are more often the result of respiratory tract involvement.
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, who found that an exposure concentration-time product of 12 mg min/m3 represented a threshold for conjunctival injection and minor discomfort with no functional decrement in human volunteers acutely exposed to sulfur mustard. An intraspecies uncertainty factor (UF)
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Application of any additional UFs or modifying factors was not warranted because the AEGL-3 values are equivalent to exposures in humans that are known to produce only ocular and respiratory tract irritation. The AEGL values for sulfur mustard are based on noncancer end points.
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The use of excess-cancer-risk estimates in setting AEGL values is precluded by the uncertainties involved in assessing excess cancer risk following a single acute exposure of ~ h or less, the relatively small population exposed in an
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that are known to cause moderate to severe ocular irritation and possible respiratory tract irritation in human subjects but no life-threatening health effects or death. It must be noted that all of the AEGL-l and AEGL-2 values and the 4- and 8-h AEGL-3 values are at or below the odor threshold for sulfur mustard.
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HUMAN TOXICITY DATA Either inhalation or percutaneous exposure to sulfur mustard vapor can result in lethality, although inhalation exposure is the more sensitive route. Estimates of human LCtso values for agent vapor inhalation are several times lower than the estimated human percutaneous LCtso (Robinson ~ 967; DA 1974~.
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Thousands of tons of "gas" munitions as well as tank cars and storage buildings containing sulfur mustard and other chemical warfare agents were involved. Summary reports for the years 1920-1923 by the primary-care physician at the site document "two or three" fatalities among workmen who had received concentrated sulfur mustard vapor exposures to the skin, eyes, and respiratory tract in combination.
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2.2. Nonlethal Toxicity Clinical presentation in humans following acute exposure to sulfur mustard vapor may involve dermal, ocular, and respiratory tract effects, all of which are preceded by a latency period dependent on the exposure concentration and exposure duration (Eisenmenger et al.
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These effects were somewhat less severe in the subject originally classified as more sensitive. Conjunctival injection did not resolve for over a month.
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(1941) defined "disablement" as "injury sufficient to prevent troops from taking an active part in operations for 1-2 weeks." Because the subjects wore respiratory protection, effects on the respiratory tract could not be determined and were not reported.
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(min) Subjects Results 0.1 10 6 No detectable effect 0.1 15 2 One oftwo subjects exhibited slight conjunctival injection 0.1 30 5 One of five showed marked bilat eral conjunctival injection; one of five showed slight conjunctival injection 0.5 10 5 Two of five exhibited conjunctival injection 0.5 15 3 One ofthree exhibited slight conjunctival injection 0.5 30 8 One of eight exhibited conjuncti vitis and experienced rhinitis; one of eight exhibited severe con junctivitis, marked skin burn; one of eight exhibited marked con junctivitis, slight facial burn 0.5 45 1 No effect 1.0 5 1 Marked conjunctivitis, photophobia, rhinitis, laryngitis, pulmonary congestion 1.0 10 2 One of two exhibited slight con junctivitis 1.0 15 2 No effect 1.0 20 1 Exhibited severe conjunctivitis, severe skin burns 1.0 45 1 Very severe conjunctivitis, photophobia, skin burns, mucosal exfoliation in nasopharynx 2.6 5 1 No effect 4.3 10 1 Marked conjunctivitis, no pain Note: Unprotected face assumed from study context.
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as representing the limit for ocular effects as characterized by conjunctival injection in the complete absence of irritation. Ct values of 60-75 mg min/m3 were considered a danger zone for widespread conjunctivitis frequently accompanied by chemosis, photophobia, and irritation.
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314 CQ in ¢ Cal o ¢ o in C)
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315 ~ ~ , ~ ~ ~ ~ , ~ ~ o ~ oo oo o o ~ .
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316 his s a V— ~ ~1 o o _ To ~L)
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317 ~ ~ ~ so U)
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Short-term casualty effects were the primary focus of military investigators at the time. Following a review and evaluation of all available data, an ECtso of 100 mg min/m3 for severe ocular effects (for soldiers)
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, all patients exhibited conjunctivitis and some also exhibited erosions and slight corneal opacity and reddened, blistered skin. The severity of respiratory tract involvement tended to be concentration-dependent, with only upper respiratory tract involvement at lower concentrations.
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Some of those conditions have been observed in humans following exposure to sulfur mustard, others have occurred in various test systems including bacteria, yeast, insects, and mammalian cell cultures. Retrospective studies have been conducted on Japanese workers who were employed at a chemical agent manufacturing plant from 1929 to 1945 .
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; however, the prominence of G:C to A:T transitions and the occurrence of double mutations in two of 12 cases suggested that exposures in the chemical agent manufacturing plant contributed to the development of the lung cancers. Yamakido et al.
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Beebe (1960) evaluated the occurrence of respiratory tract cancers among a group of 2,7 ~ ~ American soldiers exposed to sulfur mustard dur
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Retrospective studies of Japanese workers who were employed at a chemical warfare agent manufacturing plant from 1929 to 1945 have revealed that those individuals have an increased risk of developing respiratory tract cancers (see Yamakido et al.
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~ ~ 978) provide strong evidence for a causal link between chemical agent exposure and cancer of the respiratory tract; however, because the workers were potentially exposed to lewisite as well, it is not possible to state conclusively that the cancers were due solely to sulfur mustard.
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According to Klehr (1984) , German workers involved in the dismantling of a sulfur mustard facility developed multiple skin lesions including basal cell carcinomas, Bowen's disease, Bowen's carcinomas, and carcinoma spinocellulare.
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. At Tow exposures, sulfur-mustard-induced injury appears to be limited to the upper respiratory tract (Eisenmenger et al.
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Sulfur mustard vapor was generated using a known quantity of sulfur mustard diluted with acetone and pumped into a compressed air nebulizer. Pressure in the nebulizer was adjusted for complete evaporation of the acetone diluent.
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In this study, which examined both the toxicity and toxicokinetics of sulfur mustard, male hairless guinea pigs (eight per group) were exposed to sulfur mustard by nose-only inhalation or by percutaneous exposure to vapors.
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In addition, there was no evidence of respiratory sensitization in the sulfur-mustard-exposed dogs. Because the study did not provide acute exposure-response data and involved Tong-term, repeated exposures not consistent with the exposure scenarios for AEGL application, the data are not directly applicable to the development of AEGL values.
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An actual administered concentration of sulfur mustard was not provided, and there were no provisions in the experimental apparatus for actual measurement of the test material. The results of this study are consistent with the pattern of respiratory tract injury observed in humans following Tow-leve!
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There were no treatment-related tumors in mice exposed to sulfite mustard at 0.l mg/m3 (see Section 3.5~. Because the study did not provide acute exposure-response data and involved long-term, repeated exposures not consistent with the exposure scenarios for AEGL application, the data are not directly applicable to the development of AEGL values.
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Even at the highest exposure, no mice died during exposure, although the mice did exhibit sensory irritation resulting in pauses between inspiration and expiration and decreased ventilatory frequency. Effects of sulfur mustard exposure on blood uric acid and urinary uric acid were also examined as an index of purine catabolism.
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; marked congestion and edema in all areas of respiratory tract 31 214 mg/m3 Minor nasal and ocular irritation immediately fol (1 :30,000~; lowing exposure period that increased in severity 35 min up to sacrifice at 30 h; congestion in all areas of respiratory tract 46 130 mg/m3 Signs of irritation during exposure; dead at 60 h (1 :50,000~; postexposure (likely due to Staphylococcus infec 6 h tion) 45 130 mg/m3 Similar effects and cause of death as noted for rab (1 :50,000~; bit number 46 6h 43 130 mg/m3 Signs of ocular and nasal irritation, and lethargy 1 :50,000~; during exposure; dead at 54 h postexposure; 12 h marked respiratory tract involvement and second ary infection in larynx and trachea 44 130 mg/m3 Severe ocular effects and generalized dermal (1:50,000~; burns; congestion and necrosis in respiratory tract; 12 h congestion in other organs; secondary Staphylo coccus infection involvement; sacrificed at 92 h aValues in parentheses are the dilutions as reported by Warthin and Weller (19194.
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within 2-3 h and respiratory involvement at 2-3 h; (4) for prolonged or high-concentration exposures, pronounced respiratory effects occur somewhat later than ocular effects; (5)
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The effects of sulfur mustard inj ected intratracheally (0.3 mg/kg; equivalent to approximately 0.6 mg sulfur mustard per cubic meter teased on a body weight of 0.84 kg and ventilatory rate of 0.40 m3/~) into mate Hartley guinea pigs were studied by Calvet et al.
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Results of this toxicity study are shown in Table 2-6. Lesions considered agent-related included squamous cell carcinomas and basal cell carcinomas of the skin.
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mice, dogs, rabbits, and guinea pigs exposed to the same sulfur mustard concentration protocols as in the previously described toxicity study for varying exposure durations up to ~ y. Necropsy protocols were the same as for the rat toxicity and carcinogenic
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338 ACUTE EXPOSURE GO/DEL/NE LEVELS FOR SELECTED AIRBORNE CHEMICALS TABLE 2-7 Rat Skin Tumor Data from McNamara et al.
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Ocular and respiratory tract irritation and the fact that those are primary targets are plainly evident in studies using dogs, rats, mice, rabbits, and guinea pigs. Long-term exposure of dogs, mice, and guinea pigs to concentrations at 0.03 mg/m3 produced only minor signs of ocular and respiratory tract irritation, although similar exposures in rats were tumorigenic.
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1975 data available regarding the neurotoxic effects of inhaled sulfur mustard toxicityin animals. Limited data in rats reveaTedno increase in fetal abnormalities or fetal mortality following exposure to sulfur mustard.
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The resulting i04 excess cancer risk values are similar to the AEGL-3 values, and 10-s and lo-6 excess cancer risk values would be considerably lower than the AEGL-3s. The use of excess cancer risk estimates in setting AEGL values is precluded by the uncertainties involved in assessing excess cancer risk following a single acute exposure of 8-h or less duration, by the relatively small population exposed in an emergency release situation, and by the potential risks associated with evacuations.
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were detected in the lung at 10 min and 48 h after exposure. Abducts were detected in the nasal, nasopharynx, larynx, trachea, and carina of the respiratory tract (50-80 abducts per i07 nucleotides)
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The inhibition of glycolysis stimulates the hexose monophosphate shunt, Which causes a release of proteases that are instrumental in the skin damage associated with sulfur mustard exposure. More recently, Petrali and Oglesby-MeGee (1997)
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Necrosis was accompanied by a significant depletion of intracellular ATP. Most sulfur-mustard-induced fatalities have been due to respiratory tract involvement.
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for acute exposures to sulfur mustard. Both involve latency periods and a wide range of severity of effects depending primarily on the exposure concentration, but injury to the respiratory tract is considered more relevant regarding lethal responses.
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5.2. Summary of Animal Data Relevant to AEGL-1 The effects described in the animal studies tend to be a of greater severity than those associated with AEGL-1 (i.e., signs of severe ocular irritation, body weight loss, respiratory depression, evidence of respiratory tract histopathology, etc.~.
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The 12-mg min/m3 exposure resulted in only minor conjunctival injection and no sensation of irritation. Ocular effects appear to be the most sensitive indicator of sulfur mustard exposure and toxicity, thereby justifying ocular irritation as an appropriate endpoint for development of AEGL values.
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DATA ANALYSIS FOR AEGL-2 6.~. Summary of Human Data Relevant to AEGL-2 Quantitative data regarding the human experience and AEGL-2 level effects are limited to responses ranging from signs of mild ocular irritation to ocular irritation that impairs normal visual function.
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The 60-mg min/m3 exposure was used as the basis for developing the AEGL-2 values because it is representative of an acute exposure causing an effect severe enough to impair normal visual function and, although not irreversible, would certainly result in potential for additional injury. The ocular irritation and damage were also considered appropriate as a threshold estimate for AEGL-2 effects, because
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It was justified by the absence of Tong-term follow-up in the subjects of the Anderson (1942) study to confirm or deny development of permanent ocular or respiratory tract damage.
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7.2. Summary of Animal Data Relevant to AEGL-3 Various lethality values have been reported for laboratory species acutely exposed to sulfur mustard.
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This adjustment was considered appropriate for acute exposures to chemicals whose mechanism ofactionprimariTyinvolves surface contact irritation of ocular and/or respiratory tract tissue rather than systemic activity that involves absorption and distribution of the parent chemical or a biotransformation product to a target tissue. An interspecies UF was limited to 3 because available data do not suggest that humans are notably more sensitive than animals regarding lethality from inhalation exposure to sulfur mustard.
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and are similar to the ECt50 of 100 mg min/m3 for severe ocular effects (for soldiers) determined by Reutter and Wade (l 994)
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The exposures for theoretical excess lifetime cancer risk at lo-s and 10-6 levels would be correspondingly reduced. The use of excess cancer risk estimates in setting AEGL values is precluded by the uncertainties involved in assessing excess cancer risk following a single acute exposure of 8-h or less duration, by the relatively small population exposed in an emergency release situation, and by the potential risks associated with evacuations.
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Data providing definitive demarcation of the threshold for serious and/or irreversible effects would provide a more complete picture of responses resulting from acute inhalation exposure to sulfur mustard. That is especially relevant to assessing the potential for serious respiratory tract damage or permanent ocular pathology following acute exposure.
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356 Cat .= U
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1960. Lung cancer in World War I veterans: Possible relation of mustard gas injury and 1918 influenza epidemic.
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Lea.1955. Mustard gas poisoning, chronic bronchitis and lung cancer.
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Doll.1988. Cancers ofthe respiratory tract in mustard gas workers.
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1978. Multiple Bowen's disease observed in former workers of a poison gas fa'ctory in Japan, with special reference to mustard gas exposure.
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Skegg, and P.M Stell.1981. Cancer ofthe larynx and other occupational hazards of mustard gas workers.
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1988. Epidemiological studies of lung cancer in Japanese mustard gas workers.
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1994. P53 mutations in lung cancers from Japanese mustard gas workers.
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1963. On the late injuries following occupational inhalation of mustard gas, with special references to carcinoma of the respiratory tract.
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1988. Somatic mutation in peripheral lymphocytes offormer workers et the Okunojima poison gas factory.
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Appendixes
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for human volunteers exposed to agent HD at varying exposure regimens. The eye is generally considered to be the most sensitive organ/ tissue relative to agent HD exposure.
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Toxicity end point: A concentration-time product of 60 mg min/m3 was considered the lowest exposure causing ocular effects (well-marked, generaTized conjunctivitis, edema, photophobia, and irritation) resulting in effective performance decrement and characterized as a military casualty requiring treatment for up to 1 wk.
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Because the AEGL-l is based on human data, the interspecies OF is I A modifying factor of 3 was applied to accom modate potential onset of Tong-term ocular or respira tory effects.
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. However, there was uncertainty regarding the validity of applying linear extrapolation based on ocular effects to concentrationtime extrapolations for lethality.
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A UP for interspecies was limited to 3 because human data are available showing that exposures to the AEGL-3 values are more likely to produce only severe ocular irritation and possible minor or moderate irr~ta tion of the upper respiratory tract. Intraspecies vari ability was limited to 3 because lethality appears to be a function of extreme pulmonary damage resulting from direct contact of the agent with epithelial sur faces.
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372 ACUTE EXPOSURE GO/DEL/NE LEVELS FOR SELECTED AIRBORNE CHEMICALS 4-h AEGL-3 = (5.3 mg/m3~/~0= 0.53 mg/m3 (o.o~ ppm)
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SULFUR MUSTARD 373 APPENDIX B Determination of Temporal Scaling Factor (n) for AEGL Derivations Denvation of n for ~ x t = k; data points indicative of a 100% response for mild ocular imtation following exposure to sulfur mustard (agent HD)
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374 ACUTE EXPOSURE GO/DEL/NE LEVELS FOR SELECTED AIRBORNE CHEMICALS ~tF't~xTere~e 2 t5 1 'l Q5 O 45 ~1 -1.5 ll ~ \ \ ~ \ O Q5 1 1.5 2 25 3 35 Loom
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SULFUR MUSTARD 375 Derivation of n for ~ x t = k; data points indicative of a 75-100°/0 response for mild ocular irritation following exposure to sulfur mustard (agent HD) at venous concentrations and times (Reed 1918; Reed et al.
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376 ACUTE EXPOSURE GO/DEL/NE LEVELS FOR SELECTED AIRBORNE CHEMICALS ~~t~xT~reCuve 3' 2~ \j_ -2 -1 0 1 2 3 4 Wry
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The slope factor was a geometric mean of slope factors developed using various data sets and procedures and was considered the most tenable quantitative assessment for potential cancer risk from inhalation exposure to sulfur mustard. The corresponding Inhalation Unit Risk was 0.0041 (pg/m3~~~ or 4.1 (mg/m3~~i (USACHPPM 2000~.
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may be associated with exposures similar to the AEGL-3 values. The use of excess cancer risk estimates in setting AEGL values is precluded by the uncertainties involved in assessing excess cancer risk following a single acute exposure of 8-h or less duration, by the relatively small population exposed in an emergency release situation, and by the potential risks associated with evacuations.
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Data adequacy: The key study was conducted using human volunteers thus avoiding uncertainties associated with animal studies. Ocular irritation is considered the most sensitive end point for assessing the effects of acute exposure
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360 ACUTE EXPOSURE GO/DEL/NE LEVELS FOR SELECTED AIRBORNE CHEMICALS AEGL-1 Continued to sulfur mustard and the available data were sufficient for developing AEGL-1 values.
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Furthermore, little variability was observed in the tested subjects regarding ocular responses. Modifying factor: A modifying factor of 3 was applied to accolllillodate uncertainties regarding the onset of potential long-term ocular effects or respiratory effects Animal to human dosimetric adjustment: Not applicable Time scaling: ~ x t = k, where n = 1 based on analysis of available human exposure data for ocular effects Data adequacy: The key study was conducted using human volunteers, thus avoiding uncertainties associated with animal studies.
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Application of any additional uncertainty factors or modifying factors was not warranted because the AEGL-3 values are equivalent to exposures in humans that are known to produce only ocular and respiratory tract irritation. Intraspecies: Intraspecies variability was limited to 3 because lethality appears to be a function of extreme pulmonary damage resulting from direct contact of the agent with epithelial surfaces.
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SIFT ~~D J8J AEGL-3vsbes~= ~ou~beob~b~dus~ =~va~eoflba~donocul~ bdtation. D~aRde~acy:L~ceda~hesex~treg~d~ade~hvele~ab~d~esbold rs~gleac~ee~os~estosulh~n~st~d.
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