Sulfur mustards inhalation exposure

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

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. 

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... 

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 (1975) study contained a number of deficiencies, such as outdated testing protocols, brief exposures, and small numbers of animals, which made quantitative analysis difficult.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). 

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). 

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. 

Pant, S.C., Vijayaraghavan, R. (1999). Histomorphological and histochemical alterations following short-term inhalation exposure to sulfur mustard on visceral organs of mice. Biomed. Environ. Sci. 12 201-13. 

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-... 

In general, a battlefield chemical casualty has also responded intensely to other stresses, such as sleep and food deprivation, dehydration, thermal extremes, and the summation of exposure to multiple blasts, concussions, and inhalation of smoke and combustion products. Reports of wartime sulfur mustard casualties show considerable variation in the occurrence of such findings as prostration, circulatory collapse, impaired cognition, severe headache, nausea and vomiting, lethargy, and depression (Vedder, 1925 Warthin et al., 1918 Willems, 1989). The extent of this variation suggests that factors other than sulfur mustard exposure may contribute to these problems. 

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