Immediate dry decontamination using efficient absorbent materials is beneficial following skin exposure to low-volatile toxic chemicals.

In a chemical mass casualty incident requiring skin decontamination, dry removal using absorbent materials may be beneficial to enable immediate decontamination. The efficacy of absorbent materials has therefore been evaluated, alone or procedures including both dry and wet decontamination, following skin exposure to two low volatile toxic chemicals using an in vitro human skin penetration model. Additionally, removal using active carbon wipes was evaluated with or without the Dahlgren Decon solution. All dry decontamination procedures resulted in a significantly decreased skin penetration rate of the industrial chemical 2-butoxyethanol compared to the control without decontamination. Wet decontamination following dry absorption significantly improved the efficacy compared to dry removal alone. Dry decontamination post-exposure to the chemical warfare nerve agent VX showed no decontamination efficacy. However, dry and wet decontamination resulted in a decreased agent skin penetration rate during the last hour of the experiment. At -15°C, significantly reduced VX skin penetration rates were demonstrated for both dry decontamination alone and the dry and wet decontamination procedure. The Dahlgren Decon solution significantly reduced the amount of VX penetrating the skin, but the active carbon wipe alone did not impact the skin penetration rate. In conclusion, absorbent materials are beneficial for the removal of low-volatile chemicals from the skin, but the degree of efficacy varies between chemicals. Despite the variability, immediate dry decontamination using available absorbent materials prior to wet decontamination is recommended as a general procedure for skin decontamination. The procedure should also be prioritized in cold-weather conditions to prevent patient hypothermia.

Comparison of skin decontamination strategies in the initial operational response following chemical exposures.

In mass casualty incidents including hazardous chemical skin exposure, decontamination is the primary intervention to avoid systemic uptake of the toxic compound. The protocol needs to be both simple and efficient to enable a rapid response and avoid delay of patient management. In the present study, decontamination strategies included in the initial operational response were evaluated following human skin exposure in vitro to four different contaminants. Results demonstrated that the efficacy of selected decontamination procedures was highly dependent on the chemical contaminant used. Dry removal of the sulfur mustard simulant methyl salicylate prior to wet decontamination was found beneficial compared to wet decontamination alone. Rapidly initiated wet decontamination was more efficient compared to dry and wet removal of the industrial chemical 2-butoxyethanol and the nerve agent tabun. Following VX-exposure, all wet decontamination procedures resulted in increased agent penetration compared to the control. In conclusion, challenges in establishing simple and efficient decontamination procedures for a broad-spectrum of chemicals have been demonstrated. The impact of including a dry removal step during decontamination was evidently agent specific. Despite the variation in efficacy, immediately initiated dry removal may facilitate patient management until wet decontamination resources are available and to reduce the risk of secondary contamination.

Supplemental treatment to atropine improves the efficacy to reverse nerve agent induced bronchoconstriction.

Exposure to highly toxic organophosphorus compounds causes inhibition of the enzyme acetylcholinesterase resulting in a cholinergic toxidrome and innervation of receptors in the neuromuscular junction may cause life-threatening respiratory effects. The involvement of several receptor systems was therefore examined for their impact on bronchoconstriction using an ex vivo rat precision-cut lung slice (PCLS) model. The ability to recover airways with therapeutics following nerve agent exposure was determined by quantitative analyses of muscle contraction. PCLS exposed to nicotine resulted in a dose-dependent bronchoconstriction. The neuromuscular nicotinic antagonist tubocurarine counteracted the nicotine-induced bronchoconstriction but not the ganglion blocker mecamylamine or the common muscarinic antagonist atropine. Correspondingly, atropine demonstrated a significant airway relaxation following ACh-exposure while tubocurarine did not. Atropine, the M3 muscarinic receptor antagonist 4-DAMP, tubocurarine, the ß2-adrenergic receptor agonist formoterol, the Na+-channel blocker tetrodotoxin and the K+ATP-channel opener cromakalim all significantly decreased airway contractions induced by electric field stimulation. Following VX-exposure, treatment with atropine and the Ca2+-channel blocker magnesium sulfate resulted in significant airway relaxation. Formoterol, cromakalim and magnesium sulfate administered in combinations with atropine demonstrated an additive effect. In conclusion, the present study demonstrated improved airway function following nerve agent exposure by adjunct treatment to the standard therapy of atropine.

Do cold weather temperatures affect the efficacy of skin decontamination?

Skin decontamination in cold weather temperatures might be challenging due to the aggravating circumstances. However, no information is available on the efficacy of commonly used procedures in winter conditions. Therefore, the efficacy of the reactive skin decontamination lotion (RSDL) and soapy water decontamination following skin exposure to the nerve agent VX was evaluated at three ambient air temperatures (-5°C, -15°C and room temperature). Experiments were performed in vitro using human dermatomed skin. The ability of RSDL to degrade VX at the three different air temperatures was separately evaluated. The ambient air temperature in experiments without decontamination did not influence the penetration rate of VX through skin. RSDL decontamination was highly efficient in removing VX from skin when performed in all three ambient temperatures, despite the slower agent degradation rate of VX at the lower temperatures. Decontamination with soapy water at RT resulted in an increased skin penetration of VX compared with the control without decontamination; however, in colder temperatures the VX skin penetration was similar to the corresponding control without decontamination. At RT, dry removal prior to washing with soapy water did not improve decontamination of VX compared with washing solely with soapy water. This study demonstrated high efficacy of RSDL decontamination following skin exposure to VX also at cold temperatures. The previously reported 'wash-in' effect of soapy water on VX skin penetration was reduced at cold temperatures. Altogether, this study found a scientific basis to establish guidelines for skin decontamination of chemical casualties at cold weather temperatures.

Efficient agent degradation within skin is important for decontamination of percutaneously exposed VX.

AIM OF THE STUDY: Following percutaneous exposure to the nerve agent VX, the remaining intact agent within the skin after decontamination is of great concern. Consequently, this leads to prolonged agent release to the blood circulation resulting in sustained intoxication, which may complicate the medical management. The decontamination procedure used should therefore possess the ability for agent removal both on and within the skin. The efficacy of three decontamination procedures was evaluated by measuring VX and the primary degradation product ethyl methyl phosphonic acid (EMPA) penetrated through human skin and the amount remaining within the skin. MATERIALS AND METHODS: Decontamination was initiated 5 min post-exposure to VX on human dermatomed skin. Experiments were conducted using an in vitro skin penetration model and the amount remaining within the skin was determined by combining the tape-stripping technique and acetylcholinesterase activity measurements. RESULTS: In control experiments without decontamination, higher amounts of VX were recovered in the deeper layers of skin compared to EMPA, which was primarily located in the stratum corneum. Both Reactive Skin Decontamination Lotion (RSDL) and the RSDL training kit (TRSDL) significantly reduced the amount of VX within the skin and decreased the penetration through the skin. However, the degradation ability of RSDL was demonstrated to be beneficial by the reduction of intact agents remaining in the skin compared to TRSDL without agent degradation capability. Soapy water decontamination caused a "wash-in" effect of VX with decreased agent amounts within stratum corneum but increased the amount VX penetrated through the skin. CONCLUSION: Efficient skin decontamination of VX requires skin decontaminants reaching deeper layers of the skin, and that both absorption and degradation properties are important. In addition, the "wash-in" effect by using soapy water may enhance VX release to the blood circulation.

In vitro human skin decontamination efficacy of MOF-808 in decontamination lotion following exposure to the nerve agent VX.

Metal-organic frameworks (MOFs) have shown promising properties for removal of chemical warfare agents, in particular for material decontamination and functionalized fabrics. The MOF-properties could also be beneficial for skin decontamination, especially when exposed to highly toxic and low volatile nerve agents. In such exposures, efficient decontamination is crucial for adequate medical management. In the present study, seven zirconium-based MOFs were evaluated for their ability to degrade VX and subsequently tested in vitro for decontamination of VX on human dermatomed skin. Of the MOFs evaluated, MOF-808 showed the greatest ability to degrade VX in an alkaline buffer with complete degradation of VX within 5 min. PCN-777, Zr-NDC and NU-1000 displayed degradation half-lives of approximately 10 min. When including MOF-808 in a skin friendly carrier with slightly acidic pH, a decreased agent degradation rate was observed, requiring over 24 h to reach complete degradation. In skin decontamination experiments, MOF-808 enhanced the efficacy compared to the carrier alone, essentially by improved agent absorption. Adding MOF-808 to Reactive Skin Decontamination Lotion (RSDL) did not improve the high effectiveness of RSDL alone. The present study showed that including MOF in skin decontamination lotions could be beneficial. Further studies should include optimizing the particulates and formulations.

Skin penetration and decontamination efficacy following human skin exposure to fentanyl.

Unintentional exposure to potent synthetic opioids during law enforcement seizures and rescue operations can potentially result in incapacitating effects or life-threatening respiratory depression. The hazard comes mainly from inhalation exposure, however, the skin contact risk should be considered. In the present study, the skin penetration of fentanyl and the efficacy of different decontamination protocols were evaluated by applying two forms of fentanyl on dermatomed human skin mounted in a diffusion cell. Studies were performed on dry skin or skin moistened by water, sweat or hand sanitizer. The free base of fentanyl displayed greater skin penetration ability than the hydrochloride salt and a higher steady state penetration rate of fentanyl in solution compared to powder on dry skin. Sweaty skin increased the penetration rate, both when applied in solution and as powder. The hand sanitizer increased skin penetration of the free base fentanyl but not the hydrochloride salt. Of the evaluated decontamination procedures, only soapy water demonstrated a general efficacy. In conclusion, the skin contact hazard of fentanyl is highly dependent on the exposure conditions and contamination density. The risk for physiological effects of fentanyl is assessed to occur only at very high exposures on sweaty skin. In such events, skin decontamination using soap and water is estimated to be a sufficient decontamination procedure.

Decontamination efficacy of soapy water and water washing following exposure of toxic chemicals on human skin.

Aim of the study: Following exposure to toxic chemicals, skin uptake is a potential route of intoxication. Therefore, efficient methods for rapid skin decontamination to mitigate systemic effects are of utmost importance. In operational guidelines, skin decontamination is recommended to be performed by dry absorption and washing with water or soapy water. In the present study, evaluation of decontamination efficacy using water or soapy water was performed for five chemicals, three toxic industrial chemicals and two simulants for chemical warfare agents.Materials and methods: Decontamination was initiated at time points 5, 15, 45 and 120 min after exposure in order to evaluate the time window for efficient decontamination. Experiments were conducted utilizing an in vitro skin penetration model to allow exposure of toxic chemicals on human skin. Results: For all test substances, it was clearly demonstrated that decontamination had greater efficacy when initiated at the earliest time-point while decontamination after 120 min was less efficient. Adding soap to the water showed no significant improvement for any of the tested substances.Conclusion: These results are of reledvance for the development of efficient operational decontamination procedures.

Tumour epithelial expression levels of endocannabinoid markers modulate the value of endoglin-positive vascular density as a prognostic marker in prostate cancer.

Fatty acid amide hydrolase (FAAH) is responsible for the hydrolysis of the endogenous cannabinoid (CB) receptor ligand anandamide. Here we have investigated whether the expression levels of FAAH and CB1 receptors influence the prognostic value of markers of angiogenesis in prostate cancer. Data from a cohort of 419 patients who were diagnosed with prostate cancer at transurethral resection for lower urinary tract symptoms, of whom approximately 2/3 had been followed by expectancy, were used. Scores for the angiogenesis markers endoglin and von Willebrand factor (vWf), the endocannabinoid markers fatty acid amide hydrolase (FAAH) and cannabinoid CB1 receptors and the cell proliferation marker Ki-67 were available in the database. For the cases followed by expectancy, the prognostic value of endoglin was dependent upon the tumour epithelial FAAH immunoreactivity (FAAH-IR) and CB1IR scores, and the non-malignant epithelial FAAH-IR scores, but not the non-malignant CB1IR scores or the tumour blood vessel FAAH-IR scores. This dependency upon the tumour epithelial FAAH-IR or CB1IR scores was less apparent for vWf, and was not seen for Ki-67. Using an endoglin cut-off value of 10 positively stained vessels per core and a median split of tumour FAAH-IR, four groups could be generated, with 15year of disease-specific survival (%) of 68±7 (low endoglin, low FAAH), 45±11 (high endoglin, low FAAH), 77±6 (low endoglin, high FAAH) and 21±10 (high endoglin, high FAAH). Thus, the cases with high endoglin and high FAAH scores have the poorest rate of disease-specific survival. At diagnosis, the number of cases with tumour stages 1a-1b relative to stages 2-4 was sensitive to the endoglin score in a manner dependent upon the tumour FAAH-IR. It is concluded that the prognostic value of endoglin as a marker of neovascularisation in prostate cancer can be influenced by the expression level of markers of the endocannabinoid system. This article is part of a Special Issue entitled Lipid Metabolism in Cancer.

Fatty acid amide hydrolase in prostate cancer: association with disease severity and outcome, CB1 receptor expression and regulation by IL-4.

BACKGROUND: Recent data have indicated that there may be a dysregulation of endocannabinoid metabolism in cancer. Here we have investigated the expression of the endocannabinoid metabolising enzyme fatty acid amide hydrolase (FAAH) in a well characterised tissue microarray from patients diagnosed with prostate cancer at transurethral resection for voiding problems. METHODOLOGY/PRINCIPAL FINDINGS: FAAH immunoreactivity (FAAH-IR) was assessed in formalin-fixed paraffin-embedded non-malignant and tumour cores from 412 patients with prostate cancer. CB(1) receptor immunoreactivity (CB(1)IR) scores were available for this dataset. FAAH-IR was seen in epithelial cells and blood vessel walls but not in the stroma. Tumour epithelial FAAH-IR was positively correlated with the disease severity at diagnosis (Gleason score, tumour stage, % of the specimen that contained tumour) for cases with mid-range CB(1)IR scores, but not for those with high CB(1)IR scores. For the 281 cases who only received palliative therapy at the end stages of the disease, a high tumour epithelial FAAH-IR was associated with a poor disease-specific survival. Multivariate Cox proportional-hazards regression analyses indicated that FAAH-IR gave additional prognostic information to that provided by CB(1)IR when a midrange, but not a high CB(1)IR cutoff value was used. Interleukin-4 (IL-4) receptor IR was found on tumour epithelial cells and incubation of prostate cancer PC-3 and R3327 AT1 cells with IL-4 increased their FAAH activity. CONCLUSIONS/SIGNIFICANCE: Tumour epithelial FAAH-IR is associated with prostate cancer severity and outcome at mid-range, but not high, CB(1)IR scores. The correlation with CB(1)IR in the tumour tissue may be related to a common local dysregulation by a component of the tumour microenvironment.

Effect of nitric oxide donors on membrane tritium accumulation of endocannabinoids and related endogenous lipids.

The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are metabolised by cells by hydrolysis to arachidonic acid followed by esterification into phospholipids. Here, we report that nitric oxide (NO) donors significantly increase the amount of tritium accumulated in the cell membranes of RBL2H3 rat basophilic cells, 3T3-L1 mouse fibroblast cells and b.End5 mouse brain endothelioma cells following incubation of the intact cells with AEA labelled in the arachidonate part of the molecule. Similar results were seen with 2-AG and with arachidonic acid, whilst the NO donors reduced the accumulation of tritium after incubation of RBL2H3 cells with AEA labelled in the ethanolamine part of the molecule. Pretreatment of intact cells with NO donors did not increase the activity of the enzyme mainly responsible for metabolism of AEA, fatty acid amide hydrolase (FAAH). Furthermore, inhibition of FAAH completely blocked the effect produced by NO donors in cells with a large FAAH component, suggesting that for AEA, the effects were downstream of the enzyme. These data raise the possibility that the cellular processing of endocannabinoids following its uptake can be regulated by nitric oxide.