Sulfur mustard inhalation

Ghanei, M., Shohrati, M., Harandi, A.A., Eshraghi, M., Aslani, J., Alaeddini, F., Manzoori, H. (2007). Inhaled corticosteroids and long-acting beta 2-agonists in treatment of patients with chronic bronchiolitis following exposure to sulfur mustard. Inhal. Toxicol. 19 889-94. 

Pant, S.C., Vijayaraghavan, R. (2002). Histochemical and histomorphological alterations in the lungs of mice following acute sulfur mustard inhalation. J. Bums 1 6-15. 

Anderson DR, Yourick JJ, Moeller RB, Petrali JP, Young GD, Byers SL. 1996. Pathologic changes in rat lungs following acute sulfur mustard inhalation. Inhal Toxicol 8 285-297. 

Kumar, O., Vijayaraghavan, R., 1998. Effect of sulfur mustard inhalation exposure on some urinary variables in mice. J. Appl. Toxicol. 18, 257-259. 

Anderson, D.R., Yourick, J.J., Moeller, R.B., et al., 1996. Pathologic changes in rat lungs following acute sulfur mustard inhalation. Inhal. Toxicol. 8, 285-297. Anzueto, A., Delemos, R.A., Seidenfeld, J., et al., 1990. Acute inhalation toxicity of soman and sarin in baboons. Fund. Appl. Toxicol. 14, 676-687. 

Emad A, Rezaian GR The diversity of the effects of sulfur mustard gas inhalation on respiratory system 10 years after a single, heavy exposure. Analysis of 197 cases. Chest 112(3) 734-738, 1997... 

Rozmiarek, H., Capizzi, R.L., Papirmeister, 8., Fuhrman, W.H., and Smith, W.J. Mutagenic activity in somatic and germ cells following chronic inhalation of sulfur mustard. Mutat. Res. 21 13-14, 1973. (abstract)... 

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 (lOM 1993) evaluation of the health effects of mustard gas and found no other relevant studies with respect to derivation of the RfD. 

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 x 10 per pg/m ) of sulfur mustard. Normalizing the inhalation unit risk for a 70-kg person inhaling 20 m of air per day would yield an SF of 0.3 per pg/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 B6C3Fi 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... 

The LCtso for inhalation exposures in humans has been estimated to be 1500 mg-min/m (DA, 1992). In animals, median lethal Ct values for sulfur mustard range from 600 to 1900 mg-min/m for 10-min exposures (see Rosenblatt et al., 1975 for review). An LClo (lowest lethal concentration) of 189 mg/m /10 min has been reported for mice (Lewis and Sweet, 1984), and a 5-min LClo of 77 ppm has been reported for dogs (fTll, 1975). 

The data base for sulfur mustard contains two developmental toxicity studies in different species, a reproductive bioassay and a standard subchronic toxicity study in one species. In addition, chronic inhalation studies have been conducted on sulfur mustard using rats, mice, guinea pigs and dogs. The principal study identifies a toxic effect that is consistent with the vesicant properties of sulfur mustard. There is no evidence that any other experimental species would be more sensitive to ingested sulfur mustard therefore, additional oral toxicity studies in other species are not considered critical. 

Inhalation unit risks have been derived for sulfur mustard directly from experimental animal data as weU as from an analysis of the relative carcinogenic potency of sulfur mustard in comparison with that of known carcinogens for which there are both long-and short-term data. Epidemiological and long-term animal data are not available to directly derive an oral slope factor for sulfur mustard. Estimates of the oral slope factor are made from the inhalation unit risk and from the relative potency method. 

U.S. EPA (1991) derived a cancer inhalation unit risk for sulfur mustard based on the results of inhalation animal studies conducted by McNamara et al. (1975, see Section 3.7.2) however, it was emphasized in the EPA report that the studies of McNamara et al. (1975) contained deficiencies which made a quantitative analysis difficult. Conducted in 1970, the studies do not conform to the modem norms of acceptable experimental protocol, and it is likely that there was bias in the assignment of the animals to the test categories (U.S. EPA, 1991). In addition, many of the exposures were very brief, included only a few animals, and many of the animals were sacrificed (and some were replaced) before their capacity to develop late-appearing tumors was fully developed (U.S. EPA, 1991). Despite these shortcomings, it was noted by EPA that the McNamara et al. data are the best available for estimating the carcinogenic potency of sulfur mustard. The authors of the EPA report analyzed two sets of McNamara s data one from a toxicity study and one from a carcinogenicity study (see Section 3.7.2). 

The inhalation carcinogenicity of sulfur mustard has also been evaluated using relative potency methods. Using the results of studies by Heston (1950, see Section 3.7.2) and Shimkin and McClelland (1949), U.S. EPA (1991) determined that the potency of sulfur mustard to induce pulmonary tumors in strain A mice was equivalent to that of 20-methylcholanthrene (MC). EPA then used the results of studies conducted by Stoner et al. (1984) to determine that MC was 10-13 times more potent than benzo(a)pyrene (BaP) in inducing lung tumors in this same strain of mice. Since the potency of sulfur mustard was... 

The U.S. EPA (1991) identified an "inhalation" unit risk of 8.5 x 10 per fig/w , 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 inhahng 20 m of air per day. The resulting slope factor is 0.3 (ug/kg/day). ... 

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) (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 (ug/kg/day)" for sulfur mustard. 

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. 

War I. More recent use occurred in Middle East conflicts. Its oily nature makes it persistent on surfaces it contacts. Because sulfur mustard exerts toxic effects following dermal, ocular, and inhalation exposure, its use necessitated fiill body protection which, in tmn, required the development of protective clothing and significant changes in warfare operations. 

TABLE 8.7. Acute lethality of sulfur mustard in laboratory species following inhalation exposure... 

The genotoxicity of sulfur mustard is well documented. It is known to produce DNA cross-hnks, mutations following replication or repair errors, chromosomal breaks, and chromosomal aberrations. Occupational exposures have been associated with increased frequencies of somatic cell mutations, sister chromatid exchanges, and chromosome abnormalities. Studies with rats indicate that subchronic inhalation or oral exposures can produce dominant lethal effects. 

FIGURE 50.5. Concentration over time, following i.v. and respiratory exposure to sulfur mustard in the guinea pig model. A Decline of sulfur mustard exposure after intravenous injection. B Concentration over time after respiratory exposure initial increase in the inhalation phase, followed hy a decline and a secondary increase, concentration of approximately 2 ng/ml is sustained for 4h. 

Illig, L., Paul, E., Eyer, P., Weger, N., Bom, W. (1979). Treatment of psoriasis vulgaris with external sulfur mustard gas with particular reference to its potential carcinogenic risk. III. Clinical and experimental studies on the extent of percutaneous and inhalational uptake of sulfur mustard gas. Z Hautkr. 54 941-51. 

Van Helden, H.P., Kuijpers, W.C., Diemel, R.V. (2004). Asthma like symptoms following intratracheal exposure of guinea pigs to sulfur mustard aerosol therapeutic efficacy of exogenous lung surfactant curosurf and salhutamol. Inhal. Toxicol. 16 537 8. 

Ghanei, M., Harandi, A.A. (2007). Long term consequences from exposure to sulfur mustard a review. Inhal. Toxicol. 19 451-6. 

Ocular, percutaneous, inhalation, ingestion, and injection are all possible routes of exposure. Effects may be local, systemic, or both. All of the nitrogen mustards are oily liquids that are colorless to pale yellow and evaporate slowly. They are more dangerous than sulfur mustard but, like sulfur mustard, they are derivatives of ammonia. The most toxic and most volatile of the three nitrogen mustards is HN-2, but HN-3 is used more because it is stable. 

Although incapacitating airway injury occurs at vapor exposures significantly lower than those that cause severe skin blistering, inhaled sulfur mustard injures respiratory epithelium from the nasopharynx to the bronchioles. Since WWI, the majority of deaths occurring in sulfur mustard casualties have resulted from respiratory complications (Vedder, 1925 Warthin et al., 1918 Willems, 1989). Mild cases are treated to allow maximum comfort, whereas severe cases must attain ade-... 

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