Lewisite exposure

E.M. Jakubowski Haas, J.R. Smith, T.P. Logan, N.D. Wiltshire, C.L. Woodard, R.A. Evans and T.W. Dolzine, Verification of Lewisite exposure quantification of chlorovinyl arsonous acid in biological samples, Proceedings of the 1993 Medical Defense Bioscience Review, 10-13 May,... 

Human data regarding reproductive/developmental effects due to lewisite exposure are inconclusive because of confounding factors such as concurrent exposure to other agents such as sulfur mustards and incomplete exposure data. Yamakido et al. (1985) studied workers from the Okuno-jima (Japan) factory where mustard and lewisite were manufactured in the World War II era, and noted no evidence of agent-induced mutations. 

Similar to the mustard agents, exposure prevention is the first line of defense against lewisite. Rapid decontamination is especially relevant to lewisite exposure due to the rapid development of pain (1-2 min) associated with lewisite exposure. Unlike other vesicants, an effective antidote for lewisite toxicity exists in the form of British anti-lewisite (BAL 2,3-dimercaptopropanol) which binds with arsenicals, thereby countering the lewisite-induced damage. Such chelation therapy is associated with notable side effects (e.g. renal effects) and requires carefiil medical management. More effective analogs of BAL have been developed with less significant side effects. 

Immediate eye pain and blepharospasm result from lewisite exposure, followed by conjunctival and lid edema. Severe exposures can produce necrotic injuries of the iris with depigmentation, hypopion, and synechia development. In contrast, very low levels may only involve the conjunctivae (McManus and Huebner, 2005). The eye lesions produced by lewisite are particularly serious blindness will follow contamination of the eye with liquid lewisite unless decontamination is prompt. 

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. 

Once incorporated, unbound lewisite is quickly hydrolyzed. Its predominant metabolite is 2-chlorovinylarsonous acid, CVAA (Figure 50.8). Analytical methods to confinn lewisite exposure have, at least in the past, focused on the detection and quantification of CVAA. However, Noort et al. (2002) also pointed out that due to the high affinity of arsenic towards sulfhydryl groups, adducts of lewisite/ CVAA and cysteine residues of proteins are formed. In an in vitro study, incubating " C-labeled lewisite with human blood samples, 90% of lewisite was found in erythrocytes, whereas 25 to 50% of arsenic was bound to globin. From these protein adducts, CVAA can be released to form an adduct with the antidote British Anti-Lewisite (BAL) (Fidder et al, 2000). The authors were also able to identify a specific protein adduct of lewisite formed with the cysteine residues 93 and 112 of P-globin. See Detection of DNA and protein adducts of vesicants, below, for analytical... 

Snider et al. (1990) determined the elimination of lewisite from rabbits after p.c. injection. Half-life was determined, ranging from 55 to 75 h. A clearance of 120ml/h/kg was found. However, these findings only describe the overall elimination of arsenic from the organism, following a lewisite exposure. 

In vivo, unbound CVAA is quickly excreted via the renal pathway and cannot be detected in urine samples taken later than 12 h post-exposure. However, the biological half-life of protein adducts is much longer in blood samples taken 10 days post-exposure and treated with BAL, Fidder et al. (2000) were still able to release 10% of the CVAA-BAL concentration found on day 1. Thus, protein adducts of CVAA have an important role in the verification of potential lewisite exposure. 

Incubation of lewisite-protein adducts with BAL is capable of transferring its metabolite 2-chlorovinylarsonous acid (CVAA) into a BAL-CVAA derivative. This derivative can be quantified using GC-MS. The method is able to detect a 1 nM lewisite exposure of human blood in vitro (Fidder et al, 2000). 

Jakuhowski, E.M., Smith, J.R., Logan, T.P., Wiltshire, N., Woodward, C.L. (1993). Verification of lewisite exposure quantification of chlorovinylarsonous acid in biological samples. Proceedings 1993 Medical Defense Bioscience Review, United States Army Medical Research and Material Command, pp. 361-8. 

The long-term effects of lewisite exposure do not include extensive skin burning as is seen with the mustard agents, but chronic respiratory disease may... 

Management of Lewisite or Mustard-Lewisite exposure is similar to that of nitrogen and sulfur mustard exposures with two exceptions. First, patients exposed to Lewisite or the mixture will have an abrupt onset of symptoms and will likely present to emergency rooms immediately after exposure. On the other hand, because of the delayed effects, most patients with severe exposures to nitrogen or sulfur mustards will go home or elsewhere after their exposure and may only present later at emergency rooms or physicians offices when they begin developing symptoms. 

The second exception is that while an antidote is available for systemic effects of Lewisite exposure, there are no antidotes for nitrogen mustard or sulfur mustard toxicity, with one minor caveat if given within minutes after exposure, intravenous sodium thiosulfate may prevent death due to sulfur mustard exposure (25). Otherwise, the medical management for skin, ocular, and respiratory exposure is only supportive. One guideline physicians can follow is to keep skin, eye, and airway lesions free from infection. 

Lewisite-exposed patients arriving at the hospital within 30-60min of exposure will likely have pain or irritation. Patients without symptoms most likely did not snfifer Lewisite exposure, and they can go home, with instructions to return immediately if they develop symptoms. After decontamination. Lewisite-exposed patients with respiratory symptoms require placement in a critical care unit. Patients withont symptoms, including those sent home, require observation for 18-24h. The sooner after exposure symptoms develop, the more likely they are to progress (24). 

Arsines are known to cause hemolytic anemia, but there is little mention of this in reports on Lewisite exposure. A true or hemolytic anemia was noted with Lewisite shock (Goldman and Dacre, 1989). 

Lewisite exposure can be distinguished from mustard exposure by the history of pain on contact with the agent. Phosgene oxime also causes pain on contact, but phosgene oxime does not produce a... 

There are no data on human exposure from which to predict the long-term effects from Lewisite. There is no substantial evidence to suggest that Lewisite is carcinogenic, teratogenic, or mutagenic (Goldman and Dacre, 1989). The committee appointed by the National Academy of Science reported a causal relationship between Lewisite exposure and chronic respiratory diseases, and also that acute, severe injuries to the eye from Lewisite will persist (Pechura and RaU, 1993). 

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. 

Jakubowski EM, Smith JR, Logan TP, et al. Verification of lewisite exposure quantification of chloroviny-larsonous acid in biological samples. In Proceedings ofthe 1993 Medical Defense Bioscience Review, Aberdeen Proving Ground, MD US Army Medical Research Institute of Chemical Defense, 1993 361-368, AD A275667. 

Logan TP, Smith JR, Jakubowski EM, Nielson RE. Verification of lewisite exposure by the analysis of 2-chlorovinyl arsonous acid in urine. Toxicol Methods, 1999 9 275-284. 

Lewisite is a vesicant and toxic lung-irritant that is absorbed into tissues. If inhaled in high concentrations, it can be fatal in as little as 10 minutes the body is unable to detoxify itself from lewisite exposure. Routes of entry into the body include the eyes, skin absorption, and inhalation. Eye contact results in pain, inflammation, and blepharospasm (spasms of the muscles of the eyelid), which leads to closure of the eyelids, comeal scarring, and iritis (inflammation of the iris). If decontamination of the eyes occurs quickly after exposure, damage may be reversible however, permanent injury or blindness can occur within one minute of exposure. 

An antidote is available for lewisite exposure. BAL (British-Anti-Lewisite dimercaprol) was developed by the British during World War II. The antidote is produced in oil diluent for intramuscular administration to counter the systemic effects of lewisite. There is no effect, however, on the skin lesions (eyes, skin, and respiratory system) from the antidote. Mustard agents (H), (HD), (HS), and (HT), like nerve agents, would be classihed as Class 6.1 poisons by the DOT and would have NFPA 704 designations of health 4, flammability 1, reactivity 1, and special... 

The 1993 Institute of Medicine study24 of the effects of mustard and Lewisite exposure on the health of veterans concluded that acute, severe injury of the eye with mustard might result in recurrent corneal ulcerative disease for the remainder of the patient s life, with a maximum incidence occurring 15 to 20 years after the injury. Based on extensive data, the study concluded that a causal relationship between severe exposure to mustard and the development of delayed recurrent keratitis exists.109 The study also found a causal relationship between exposure to mustard and the development of prolonged, intractable conjunctivitis. 

Signs and symptoms occur immediately following a lewisite exposure. Lewisite can have the following effects on specific parts of the body ... 

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