Lewisite animal exposures

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. 

No human or animal studies examining the effects of lewisite following chronic exposure were located in the searched hterature. 

Human data concerning the toxicity of lewisite via the oral route of exposure are not available. However, there are limited toxicity data on lewisite ingestion from animal studies. In animals, ingestion of lewisite can produce acute inflammation of the mucous membrane of the stomach or intestine, which is characterized by hemorrhage, necrosis of the epithelium, and submucous edema. Developmental effects have been reported in pregnant rats and rabbits... 

Lewisite has the potential to cause skin lesions in any species but the risk is greatest in hairless animals such as pigs, and decreases in fur-covered species (Smith, 1997). Mice and rats appear to be almost twice as susceptible to dermal lewisite exposures than humans (LD50 equals 12,15, and 30 mg/kg, respectively) (DeRosa et al, 2002 RTECS, 2008 Sidell et al, 1997). More studies are needed to determine if rodents would be good sentinel animals. 

Lewisite damages skin, eyes, and airways by direct contact and has systemic effects after absorption. Unlike mustard, it does not produce immunosuppression. Data on human exposure are few. Lewisite was applied to human skin in a few studies however, most information on its clinical effects is based on animal studies (Rovida and Lewisite 1929 Wardell, 1940 Dailey et al., 1941 Buscher and Conway, 1944). 

Analytical Methods for Urine and Blood. Specific biomarkers of lewisite exposure are currently based on a very limited number of in vitro experiments (Jakubowski et al., 1993 Wooten et al., 2002) and animal studies (Logan et al., 1999 Fidder et al., 2000). Wooten et al. (2002) developed a solid-phase microextraction (SPME) headspace sampling method for urine samples followed by GC-MS analysis. It is the most sensitive method reported to date with a lower limit of detection of 7.4 pg/mL. Animal experiments have been limited in number and in their scope. In one study of four animals, guinea pigs were given a subcutaneous dose of lewisite (0.5 mg/kg). Urine samples were analyzed for CVAA using both GC-MS and GC coupled with an atomic emission spectrometer set for elemental arsenic (Logan et al., 1999). The excretion profile indicated a very rapid elimination of CVAA in the urine. The mean concentrations detected were 3.5 pg/mL, 250 ng/mL, and 50 ng/mL for the 0-8, 8-16, and 16-24 h samples, respectively. Trace level concentrations... 

Application to Human Exposure (Urine and Blood). To date, there have been no reports of the collection of biomedical samples from individuals with suspected lewisite exposure. Samples from such an incident will be critical for confirming the validity of assaying for the biomarkers observed in animal models. Additionally, the biomarkers that have been investigated in animal studies to date have indicated a rapid clearance in urine and less so for blood. This will obviously create severe problems for the retrospective determination of lewisite exposure beyond a few days at most when analyzing urine samples. The blood assay for both bound and free CVAA will potentially provide a longer opportunity for retrospective confirmation of exposure (based on one animal study), but also indicates a substantial decrease (90%) in concentration levels observed over a 10 day period. 

Because lewisite has not been used in warfare, descriptions are mainly derived from accidental exposures or else clinical signs in man have been inferred from observations in animals. Findings with the related phenyldichlorarsine are also relevant (see below). 

The eye lesions produced by lewisite are particularly serious blindness will follow contamination of the eye with liquid lewisite unless decontamination is very prompt. It is possible to infer from animal experiments undertaken in the USA during World War II that exposure of the eye to liquid or vapour would produce blepharospasm and irritation. Severe ocular lesions can be produced by doses as low as 0.1 mg or exposure to the saturated vapor for 8 s at 23°C. The action on the eye is to produce rapid necrosis of the anterior parts of that organ (Friedenwald and Hughes, 1948). 

Lewisite. RfDg = 1 x 10 " mg kg" d" . A NOAEL was identified in a multigeneration study conducted on rats. A total uncertainty factor of 3000 was applied to account for protection of sensitive subpopulations (10), animal-to-hu-man extrapolation (10), extrapolation from a subchronic to chronic exposure (10), and data base deficiencies (3). 

Although Lewisite has been sporadically used in the past, very little data from human exposure exist at this time. Consequently, much of what we know in the West about Lewisite s effects mostly comes from animal experimentation. Older data from the 1930s includes observing the effects of Lewisite on a human volunteer In this case. Lewisite was completely absorbed in 5 minutes with a slight burning sensation, while mustard required from 20 to 30 minutes for absorption and produced no noticeable sensation. With Lewisite, the skin commences to redden at the end of 30 minutes then the erythema increases and spreads rapidly. It occupies a surface of 12 by 15 centimeters toward the end of the third hour.22... 

The inhalation toxicity of neutralents from the RRS red process treatment of HD, HN, and lewisite was tested in rats by 14-day exposures. The neutralent contained 53 percent chloroform, 30 percent t-butyl alcohol, trace amounts of DCDMH, and less than 1 ppm HN or HD, or 37 ppm lewisite. The toxicity of the waste stream was compared with that of an aerosol containing 58.3 percent chloroform, 39.1 percent tert-butanol, and 2.6 percent water (the vehicle control). Concentrations of 24,000 ppm of the vehicle control or neutralent killed all of the test animals. Lower doses caused excessive salivation, ocular and nasal discharge, lack of coordination, listlessness, difficult breathing, and corneal opacity. The inhalation effects of the nentralent on test animals were consistent with those of the t-butanol and chloroform components of the O/SS (Morgan et al., 1997). 

Signs and symptoms of acute lewisite exposure include a rapid onset of irritation to the eyes and mucous membranes of the upper respiratory tract (lachrymation and rhinitis). In more serious cases of vapor intoxication, chest pain, nausea, vomiting, headache, weakness, convulsions, hypothermia, and hypotension occur (Sidell et al., 1997 Katos et al., 2007). Laboratory tests of the blood of persons exposed may show hemoconcentra-tion animal studies suggest elevated liver enzymes, including lactate dehydrogenase (LDH) (King et al., 1994 Sasser et al., 1999). The following sub-sections describe the effects on specific body sites. 

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