Sulfur mustards exposure routes

The distribution and rate of elimination of sulfur mustard is partially dependent on the route of exposure and the dose received. Studies with radiolabeled (35S) agent showed that typically 50-80% of an absorbed dose is eliminated in urine, mostly within the first 3 days (2,3). Hambrook et al. (2) showed that >70% was excreted in urine following intravenous (i.v.) or intraperitoneal (i.p.) injection in rats, somewhat less (50-70 %) following cutaneous exposure to vapor. The lower percentage following cutaneous exposure resulted from retention in the... 

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 tnmorigenic 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 pnblished by Watson et al. (1989) and U.S. EPA (1991). 

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. 

Outside of military conflicts, exposure to sulfur mustard has occurred or may occur in work environments associated with chemical weapon materiel (e.g. storage depots, demilitarization facilities, research laboratories), during emergency response operations or remediation and decontamination activities, or during treaty verification activities in support of the Chemical Weapons Convention. Chemical weapons such as the vesicants are stiU considered potential military threats and terrorist targets. The most likely route of exposure to sulfur mustard is via aerosol/vapor exposure of the skin, eyes, and respiratory tract. 

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. 

Adver.se health effects cau.sed by sulfur mustard depend on the amount people are exposed to. the route of exposure, and the length of time that people are exposed. 

Agent HD (Sulfur Mustard). RfDe = 7 x 10 mg kg d. A LOiAEL was identified in a two-generation reproductive toxicity study conducted in rats. A total uncertainty factor of 3000 was applied to account for protection of sensitive subpopulations (10), animal-to-human extrapolation (10), LOAEL-to-NOAEL extrapolation (3), and extrapolation from a subchronic to chronic exposure (10). A LOAEL-to-NOAEL UF of 3, instead of the default value of 10, was used because the critical effect (stomach lesions) was considered to be mild in severity and may have been enhanced by the vehicle used (sesame oil in which sulfur mustard is fully soluble) and the route of administration (gavage), which is more likely to result in localized irritant effects. The key study did identify a toxic effect that is consistent with the vesicant properties of sulfur mustard. In none of the other available studies was there any indication of a different effect occurring at a lower exposure level. 

As mentioned previously, Benson et al. (2011) confirmed that 90% of percutaneously absorbed sulfur mustard was deposited in skin, whereas more than 70% absorbed sulfur mustard was distributed to the carcass and pelt after respiratory exposure. The distribution of sulfur mustard is highly dependent on the original route of exposure. It was confirmed that a considerable amoimt of sulfur mustard was still present in deep lipophilic compartments even after the end of exposure. 

Zhang and Wu (1987) chose the small pig (male and female, black, 4.2-13.0 kg) because of the aforementioned resemblance of its skin to that of humans. They chose this model to study the percutaneous toxicokinetics of occluded liquid sulfur mustard, and studied the iv route in this species as the reference route, as well as the toxicokinetics after subcutaneous (sc) exposure. 

In a sulfur mustard vapor environment, unprotected military personnel will be exposed simultaneously via the respiratory and percutaneous routes. Such a combined exposure has not yet been studied, but it would be interesting to see which route would be predominant. Obviously, the environmental conditions will have a profound influence on the relative importance of the two exposure routes. 

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