Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents (1999) / Chapter Skim
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E: Health Risk Assessment for Sulfur Musturd (HD)
E: Health Risk Assessment for Sulfur Musturd (HD)
Pages 235-274
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Appendix E Health Risk Assessment for Sulfur Mustarcl (HD)
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. Delayed effects which may occur following acute exposures include: eye lesions, chronic bronchitis, and cancers of the respiratory tract and skin.
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1769-1769-A1 Prepared by Life Sciences Division OAK RIDGE NATIONAL LABORATORY* Oak Ridge, Tennessee 37831 Submitted to Material/Chemical Risk Assessment Working Group Advisory and Coordinating Committee Environmental Risk Assessment Program *
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Age Mao Day ~ ~-~ Sad DISCLAIMER h document ~ ~ Entomb mvlew dam far review purposes only and does not con~1e U.S. Government policy.
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(CAS No. This document supports the activities of the MateriaUChemical Risk Assessment Working Group of the Environmental Risk Assessment Program, a cooperative endeavor of the Department of Defense, Department of Energy, and Environmental Protection Agency.
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Oral Slope factor . 5.2.1 Oral Slope Factor Derived from Inhalation Unit Risk ...............
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Skin tumor data (toxicity study) used in EPA quantitative assessment Table 8.
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is a chemical vesicant capable of causing severe skin and eye damage at veto low concentrations. The chemical name, synonyms, identification codes, molecular formula and structural formula for this agent are as follows: Sulfur mustard his(2-chloroethyl)
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Alkylation reactions can result in physiological and metabolic disturbances as well as genotoxic effects. Several hypotheses have been advanced concerning the primary cause of cell death following acute exposures.
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. Delayed effects which may occur following acute exposures include: eye lesions, chronic bronchitis, and cancers of the respiratory tract and skin.
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No mustard-related mortality occurred at any dose level. Body weights were significantly decreased in animals in the high-dose group.
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Pneumonitis occurred in several of the dogs exposed to 0.1 mg HD/m3, but this condition was also seen in the control animals, and because no other respiratory tract lesions were found, McNamara et al.
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. Corneal opacity pannus, chronic keratitis, granulation NE NE Corneal opacity, pannus, chronic keratitis, granulation Vascularization and pigmentation Corneal opacity, pannus, chronic keratitis, granulation Corneal opacity SOURCE: McNamara et al., 1975, Table A-18, p.
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It is possible that the HD condensed on the fur of the animals and was subsequently ingested as a result of grooming behavior. Gastroenteritis could then have resulted from direct contact of the vesicant with the gastrointestinal epithelium.
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evaluated the occurrence of respiratory tract disease among a group of World War I soldiers. Soldiers who had been exposed to mustard gas exhibited greater mortality from tuberculosis and pneumonia than either of two reference groups.
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In the range-finding study a significant depression in fetal body weights occurred at a dose level c) f 2 n m~/ko/rl~v hn~v~v~r in the Costly no.
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Both studies had a number of short-comings; in particular, the authors stated that the fetuses were examined, but they did not indicate whether there were fetal abnormalities. 3.7 Carcinogenicity Several studies on workers occupationally exposed to sulfur mustard have revealed elevated risks of respiratory tract and skin tumors after long-term exposure.
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concluded that there was no evidence in this limited data set that mustard exposure and cigarette smoking had a synergistic effect on lung cancer mortality. Retrospective studies of Japanese workers who had been employed at a chemical agent manufacturing plant from 1929 to 1945 have revealed that these individuals have an increased risk of developing respiratory tract cancers.
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For individuals 30-39 years old the SMRs for respiratory tract cancer were not significantly elevated; however, the SMRs for the 40-49,50-59,60-69, and 70-79 yr aids were 10.3,3.9,4.4, and 2.5, respectively; all statistically significant at p |
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, 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. The incidence rate for all tumors (including skin tumors)
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The rats were tested in two separate studies; a "toxicity study" in which the animals were exposed for up to 52 weeks and then followed for 6 months at which time they were sacrificed, and a "carcinogenicity study" in which the animals were exposed for varying times and then observed for varying periods of time before being sacrificed. In both studies skin tumors occurred in animals exposed to the highest concentration, but not in those exposed to the lower concentration.
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At 0.1 mg/m3, one type h tumor co-occurred in one animal with a squamous cell carcinoma.
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Because sulfur mustard is a strong DNA alkylating agent, genotoxic effects occur through cross-link formation, inhibition of DNA synthesis and repair, point mutations, and chromosome and chromatic aberrations (ATSDR, 1992)
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The experimental study considered most suitable for the derivation of an oral RfD for sulfur mustard is the rat two-generation reproductive toxicity study conducted by Sasser et al.
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There was a significantly (p <0.05) decreased body weight gain in the F 1 rats of both sexes born to parents who had received the highest dose of sulfur mustard.
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is of questionable relevance to humans, because sulfur mustard is a direct alkylating agent, tissue damage would be expected to occur at the point of contact, even if it were another part of the gastrointestinal tract. 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.
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Epidemiological and longterm 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.
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EPA (1991) selected the unit risk of 8.5 x 10-2 per ,ug/m3, derived from the Weibull time-to-tumor model, as the recommended upper bound estimate of the carcinogenic potency of sulfur mustard for a lifetime exposure to HO vapors.
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5.1.2 Inhalation Unit Risk Derived from Relative Potency 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)
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To derive an oral slope factor in the absence of long-term experimental data, two non-standard approaches can be considered. One involves the direct conversion of the inhalation unit risk to an oral slope factor, and the other involves the use of relative potency methods.
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. 5.2.2 Oral Slope Factor Derived from Relative Potency Estimates As described in section 5.1.2, U.S.
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5.3.2 Oral Slope Factor Although human and animal data are lacking, there is indirect evidence suggesting that sulfur mustard may be carcinogenic by the oral exposure route. The mechanism of action of sulfur mustard as a direct DNA alkylating agent, its known genotoxicity in exposed humans and in various animal bioassays, its induction of respiratory tract and skin tumors following inhalation exposures, and its induction of forestomach hyperplasia in rats following subchronic Savage dosing (see Section 3.3)
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(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)
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1988. Cancers of the respiratory tract in mustard gas workers.
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1978. Multiple Bowen's disease obersved in former workers of a poison gas factory in Japan, with special reference to mustard gas exposure.
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1988. Epidemiologicl studies of lung cancer in Japanese mustard gas workers.
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Technical Report 8304, AD A149515, US Army Medical Bioengineering Research and Development Laboratory, Fort Detrick, Frederick, MD. Somani, S.M.
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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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DRAFT _WISITE Table 1. Lewisite Degradation Products Product Hydrolysis Product: 1 Formula I CAS No.
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