Subchronic toxicity, lewisite

Sasser, L.B., R.A. Miller, D.R. Kalkwarf, P.W. Mellick, and R.L. Buschbom. 1989b. Toxicology Smdies on Lewisite and Sulfur Mustard Agents Subchronic Toxicity of Sulfur Mustard (HD) in Rats. Final Report. PNL-6860. DTIC AD-A217886. Prepared by Pacific Northwest Laboratory, Richland, Wash., for the U.S. Army Medical Research and Development Command, Fort Detrick, Frederick, Md. 

The subcommittee believes the uncertainty factor for data-base adequacy (UFd) should be assigned a value of 10 because no long-term exposure studies involving lewisite are available, only a few studies that address the acute or subchronic toxicity of lewisite are available, and httle or no information about the metabolism of lewisite or its degradation products is available. 

Sasser, L.B., J.A. Cushing, P.W. Mellick, D.R. Kalkwarf, and J.C. Dacre. 1996. Subchronic toxicity evaluation of lewisite in rats. J. Toxicol. Environ. Health 47 321-334. 

Another phase of the Hackett et al. (1987) study investigated the potential teratogenicity of lewisite in rats. In this phase of the study, no maternal toxicity or teratogenic effects were observed, thereby identifying 1.5 mg/kg as a NOAEL. However, it must be noted that in a dose range-finding study in rats (Hackett et al. 1987) (see Section XIII.A.2, Subchronic Toxicity), doses of 2.0 mg/kg and 2.5 mg/kg resulted in 10% and 20% maternal mortality, respectively. 

Sasser LB, Miller RA, Kalkwarf DR, Buschbom RL, Cushing JA (1989a) Toxicology studies on lewisite and sulfur mustard agents subchronic toxicity of sulfur mustard (HD) in rats. PNL-6870 (DTIC AD A2144555). Pacific Northwest Laboratories. Prepared for the U.S. Department of the Army, Medical Research and Development Command, Fort Detrick, MD. 

Sasser LB, Cushing JA, Mellick PW, Kalkwarf DR, Dacre JC (1996b) Subchronic toxicity of lewisite in rats. J Toxicol Environ Health 47 321-334. 

Sasser, L.B., Cushing, J.A., Kalkwarf, D.R., et al., 1989a. Toxicology studies on Lewisite and sulfur mustard agents subchronic toxicity study of Lewisite in rats. Final Report, Pacific Northwest Laboratory Report, PNL-6860, Richland, WA. 

The major gaps in the available information on lewisite are the lack of information on the implications of administering lewisite directly to the stomach over a short time and the absence of chronic oral toxicity data from which to derive an RfD. Because of those deficiencies, the RfD for lewisite was estimated by extrapolating from a less-than-ideal animal study to humans. Confidence in the RfD can be increased if subchronic oral toxicity studies in rabbits and rats are conducted to compare the effects of chronic oral exposure to low concentrations of lewisite with the effects of short-term intragastric administration of small volumes of lewisite. Such studies will provide not only the data needed to better understand the implications of dosing techniques but also more pertinent information on whether the rabbit is more appropriate than the rat for deriving an RfD for lewisite. 

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