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Nerve agents are a class of organophosphorus chemicals that inhibit certain cholinesterase enzymes (ChE). If untreated, percutaneous exposure to nerve agents, such as VX (O-ethyl-S-[2(diisopropylamino)ethyl] methylphosphonothioate) can cause paralysis, apnoea and death. Much of the information concerning the percutaneous absorption and subsequent toxicity of nerve agents has been obtained using various rodent models. However, the most relevant 'skin model' is arguably the pig. Therefore, the purpose of this study was to examine the clinical manifestations of VX intoxication in the domestic white pig following a 2 LD[sub 50] (120 μg/kg) percutaneous challenge. There was a consistent onset of signs (where present) in each animal: mastication was followed by miosis, salivation, fasciculations and apnoea. Whilst ChE activity did not correlate with the onset of signs, there was a qualitative relationship in that mastication preceded substantial ChE inhibition, miosis lagged behind the linear decrease in acetylcholinesterase (AChE) activity and fasciculations and apnoea occurred after maximum ChE inhibition had been attained (5-10% of normal). These observations may be of use for the triage of patients exposed to VX. In comparison with similar studies with GD, VX did not affect glucose utilization. However, VX was similar to GD in that it caused a mild hyperkalaemia and hyperphosphataemia, although the significance of this observation was not clear. There was substantial lateral diffusion of the initial droplet of VX over the application site, indicating that, when decontaminating exposed skin, attention should also be directed to areas peripheral to the original site of exposure. [ABSTRACT FROM AUTHOR]

The purpose of this review is to summarize essential biological, pharmaceutical, and clinical aspects in the field of topically applied medicines that may help scientists when trying to develop new topical medicines. After a brief history of topical drug delivery, a review of the structure and function of the skin and routes of drug absorption and their limitations is provided. The most prevalent diseases and current topical treatment approaches are then detailed, the organization of which reflects the key disease categories of autoimmune and inflammatory diseases, microbial infections, skin cancers, and genetic skin diseases. The complexity of topical product development through to large-scale manufacturing along with recommended risk mitigation approaches are then highlighted. As such topical treatments are applied externally, patient preferences along with the challenges they invoke are then described, and finally the future of this field of drug delivery is discussed, with an emphasis on areas that are more likely to yield significant improvements over the topical medicines in current use or would expand the range of medicines and diseases treatable by this route of administration. SIGNIFICANCE STATEMENT: This review of the key aspects of the skin and its associated diseases and current treatments along with the intricacies of topical formulation development should be helpful in making judicious decisions about the development of new or improved topical medicines. These aspects include the choices of the active ingredients, formulations, the target patient population's preferences, limitations, and the future with regard to new skin diseases and topical medicine approaches., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

The incidence of "acid attacks" (vitreolage) is a global concern, with those affected often receiving lifelong medical care due to physical and psychological damage. The purpose of this study was to evaluate the effectiveness of several emergency skin decontamination approaches against concentrated (>99 %) sulphuric acid and to identify the effective window of opportunity for decontamination. The effects of four decontamination methods (dry, wet, combined dry & wet and cotton cloth) were assessed using an in vitro diffusion cell system containing dermatomed porcine skin. Sulphuric acid (H 2 SO 4 ) was applied to the skin with decontamination protocols performed at 10 s, 30 s, 8 min, and 30 min post exposure. Skin damage was quantified by tritiated water ( 3 H 2 O) penetration, receptor fluid pH and photometric stereo imaging (PSI), with quantification of residual sulphur (by SEM-EDS) to determine overall decontamination efficiency. Skin translucency (quantified by PSI) demonstrated a time-dependent loss of dermal tissue integrity from 10 s. Quantification of dermal sulphur content confirmed the rapid (exponential) decrease in decontamination efficiency with time. The pH of the water effluent indicated complete neutralisation of acid from the skin surface after 90 s of irrigation. Wet decontamination (either alone or immediately following dry decontamination) was the most effective intervention evaluated, although no decontamination technique was statistically effective after 30 s exposure to the acid. These data demonstrate the time-critical consequences of dermal exposure to concentrated sulphuric acid: we find no practical window of opportunity for acid decontamination, as physical damage is virtually instantaneous., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Increasing indications, reports and studies demonstrate that threats from the deliberate use of chemical weapons remain high and are evolving. One of the deadliest classes of chemical weapons are the organophosphorus nerve agents. It is now clear that both state and non-state actors have the ability to deploy and use these types of weapons against individuals and the wider civilian population posing a real and significant threat. The objective of this article is to provide an overview of the issues impacting on a timely critical response to the accidental or deliberate release of Organophosphorus Nerve Agents in order to enhance the understanding of their effects and provide guidance on how first responders might better treat themselves or victims of exposure through a discussion of available evidence and best practices for rapid skin decontamination. The article also examines use of the current nomenclature of 'wet' and 'dry' to describe different forms of decontamination. One of the key conclusions of this article is that adequate preparedness is essential to ensuring that responders are trained to understand the threat posed by Organophosphorus Nerve Agents as well as how to approach a contaminated environment. A key aspect to achieving this will be to ensure that generic medical countermeasures are forward-deployed and available, preferably within minutes of a contamination and that first responders know how to use them., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Aims: The COVID-19 pandemic triggered a demand for vaccines, cures, and the need of related documentation for travel, work and other purposes. Our project aimed to identify the illicit availability of such products across the Dark Web Markets (DWMs)., Methods: A retrospective search for COVID-19 related products was carried out across 118 DWMs since the start of the pandemic (March 2020-October 2021). Data on vendors as well as advertised goods such as asking price, marketplace, listed date were collected and further validated through additional searches on the open web to verify the information relating to specific marketplaces. Both quantitative and qualitative methods were used for data analysis., Results: Forty-two listings of unlicenced COVID-19 cures and vaccination certificates were identified across 8 marketplaces sold by 25 vendors with significant variation in prices. The listings were found to be geographically specific and followed the progression of the pandemic in terms of availability. Correlations between vendor portfolios of COVID-19 products and variety of goods of other illicit nature such as illegal weaponry, medication/drugs of abuse also emerged from our analysis., Conclusion: This study is one of the first attempts to identify the availability of unlicenced COVID-19 products on DWMs. The easy accessibility to vaccines, fake test certificates and hypothetical/illegal cures poses serious health risks to (potential) buyers due to the uncontrolled nature of such products. It also exposes buyers to an unwanted contact with vendors selling a variety of other dangerous illicit goods. Further monitoring and regulatory responses should be implemented to protect the health and safety of citizens especially at times of global crisis., Competing Interests: The authors have declared that no competing interests exist, (Copyright: © 2023 Catalani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Barium is an alkaline earth metal whose toxicity is dictated by its compounded salt form: barium sulfate is insoluble and safe to ingest, but other barium salts (chloride, carbonate, sulfide, oxide and acetate) are bioavailable and therefore toxic when ingested. There have been 49 previous reports of fatal intoxications following barium consumption: 38 deemed accidental in nature, 8 suicidal, 1 homicidal and 2 of undetermined intent. In this report, we detail the first intentional fatal self-poisoning with barium chloride to be reported in the UK, along with a review of the surrounding literature. This is the first case to report quantified levels of barium in blood and vitreous humor, and by providing details of sample collection, storage and processing, this case will aid in future interpretations., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In a time of unprecedented global change, the COVID-19 pandemic has led to a surge in demand of COVID-19 vaccines and related certifications. Mainly due to supply shortages, counterfeit vaccines, fake documentation, and alleged cures to illegal portfolios, have been offered on darkweb marketplaces (DWMs) with important public health consequences. We aimed to profile key DWMs and vendors by presenting some in-depth case studies., Methods: A non-systematic search for COVID-19 products was performed across 118 DWMs. Levels of activity, credibility, content, COVID-19 product listings, privacy protocols were among the features retrieved. Open web fora and other open web sources were also considered for further analysis of both functional and non functional DWMs. Collected data refers to the period between January 2020 and October 2021., Results: A total of 42 relevant listings sold by 24 vendors across eight DWMs were identified. Four of these markets were active and well-established at the time of the study with good levels of credibility. COVID-19 products were listed alongside other marketplace content. Vendors had a trusted profile, communicated in English language and accepted payments in cryptocurrencies (Monero or Bitcoin). Their geographical location included the USA, Asia and Europe. While COVID-19 related goods were mostly available for regional supply, other listings were also shipped worldwide., Interpretation: Findings emerging from this study rise important questions about the health safety of certain DWMs activities and encourage the development of targeted interventions to overcome such new and rapidly expanding public health threats., Funding: CovSaf, National Research centre on Privacy, Harm Reduction and Adversarial Influence Online (REPHRAIN), Commonwealth Fund., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Introduction and Objective: United Kingdom Health Security Agency (UKHSA) guidance related to mask use for health care workers in a non-aerosol generating procedure (AGP) setting has remained as Level 2 water repellent paper mask (surgical mask) only. Energetic respiratory events, such as coughing, can generate vast numbers of droplets and aerosols. Coughing, considered to be a non-AGP event, frequently occurs in the relatively small, confined space of an ambulance (∼25 m 3 ). The report seeks to explore whether existing research can provide an indication of the risk to ambulance staff, via aerosol transmission, of an acute respiratory infection (ARI) during a coughing event within the clinical setting of an ambulance., Methods: International bibliographic databases were searched (CINAHL Plus, SCOPUS, PubMed, and CENTRAL) using appropriate search strings and a combination of relevant medical subject headings with appropriate truncation. Methodological filters were not applied. Papers without an English language abstract were excluded from the review. Grey literature was sought by searching specialist databases OpenGrey and GreyNet, as well as key organizations' websites. The initial search identified 2,405 articles. Following screening, along with forward and backward citation of key papers identified within the literature search, 36 papers were deemed eligible for the scoping review., Discussion: Attempts to replicate a clinical environment to investigate the risk of transmission of airborne viruses to health care workers during a coughing event provided evidence for the generation of respirable aerosol particles and thus potential transmission of pathogens. In cases of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), potential to infect versus true airborne transmission is a debate that continues, but there is general consensus that a large variation of cough characteristics and aerosol generation amongst individuals exists. Studies widely endorsed face masks as a source control device, but there were conflicting views about the impact of mask leakage., Conclusion: Further research is required to provide clarity of the risk to health care workers when caring for a coughing patient in the confined clinical ambulance setting and to provide an evidence base to assist in the determination of appropriate respiratory protective equipment (RPE).

Introduction The objectives were to characterise the particle size distribution of aerosols generated by standard dental aerosol generating procedures (AGPs) and to assess the impact of aerosol-management interventions on 'fallow time'. Interventions included combinations of high-volume intraoral suction (HVS[IO]), high-volume extraoral suction (HVS[EO]) and an air cleaning system (ACS).Method A sequence of six AGPs were performed on a phantom head. Real-time aerosol measurements (particle size range 0.0062-9.6 μm) were acquired from six locations within a typical dental treatment room (35 m 3 ).Results The majority (>99%) of AGP particles were <0.3 μm diameter and remained at elevated levels around the dental team during the AGPs. With no active aerosol-management interventions, AGP particles were estimated to remain above the baseline range for up to 30 minutes from the end of the sequence of procedures.Conclusions The results emphasise the importance of personal protection equipment, particularly respiratory protection. Use of HVS(IO), either alone or in combination with the ACS, reduced particle concentrations to baseline levels on completion of AGPs. These data indicate potential to eliminate fallow time. The study was performed using a phantom head so confirmatory studies with patients are required.

Background: Established procedures for mass casualty decontamination involve the deployment of equipment for showering with water (such as the ladder pipe system [LPS] and technical decontamination [TD]). This necessarily introduces a short, but critical delay. The incorporation of dry decontamination to the incident response process offers the potential to establish a more rapid and timely intervention. Objectives: To investigate the effectiveness of various dry (DD) and wet decontamination strategies for removing a chemical warfare simulant (methyl salicylate; MS) from the hair and skin of human volunteers. Methods: The simulant was applied to volunteers via whole body exposure to an aerosol. Three decontamination protocols (dry, LPS and technical decontamination) were applied, singly and in various combinations. The efficacy of the protocols was evaluated by fluorescent photography and analysis of residual MS from skin/hair swabs, decontamination materials and air samples. Results: Dry decontamination was effective, with the greatest reduction in skin and hair contamination arising from the "Triple Protocol" (DD+LPS+TD). Secondary hazards associated with contaminated individuals and equipment decreased as the number of decontamination procedures increased. In particular, dry decontamination reduced the potential contact and inhalation hazard arising from used washcloths, towels and vapor within the TD units. Discussion: The introduction of dry decontamination prior to wet forms of decontamination offers a simple strategy to initiate treatment at a much earlier opportunity, with a corresponding improvement in clinical outcomes and substantial reduction of secondary hazards associated with operational processes.

This in vitro study evaluated the "triple protocol" of dry decontamination, the ladder pipe system (a method for gross decontamination), and technical decontamination for the decontamination of hair following chemical contamination. First, we assessed the efficacy of the 3 protocols, alone or in combination, on excised porcine skin and human hair contaminated with either methyl salicylate (MS), phorate (PHR), sodium fluoroacetate (SFA), or potassium cyanide (KCN). A second experiment investigated the residual hair contamination following decontamination with the triple protocol at different intervals postexposure. In a third experiment, hair decontaminated after exposure to MS or PHR was evaluated for off-gassing. Though skin decontamination was highly effective, a substantial proportion (20%-40%) of the lipophilic compounds (MS and PHR) remained within the hair. The more water-soluble contaminants (SFA and KCN) tended to form much smaller reservoirs within the hair. Interestingly, substantial off-gassing of MS, a medium volatility chemical, was detectable from triple-decontaminated hair up to 5 days postexposure. Overall, the decontamination strategies investigated were effective for the decontamination of skin, but less so for hair. These findings highlight the importance of contaminated hair serving as a source of potential secondary contamination by contact or inhalation. Therefore, consideration should be given to the removal of contaminated hair following exposure to toxic chemicals., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology.)

Study Objective: The aim of this study was to evaluate the clinical and operational effectiveness of US federal government guidance (Primary Response Incident Scene Management [PRISM]) for the initial response phase to chemical incidents., Methods: The study was performed as a large-scale exercise (Operation DOWNPOUR). Volunteers were dosed with a chemical warfare agent simulant to quantify the efficacy of different iterations of dry, ladder pipe system, or technical decontamination., Results: The most effective process was a triple combination of dry, ladder pipe system, and technical decontamination, which attained an average decontamination efficiency of approximately 100% on exposed hair and skin sites. Both wet decontamination processes (ladder pipe system and technical decontamination, alone or in combination with dry decontamination) were also effective (decontamination efficiency >96%). In compliant individuals, dry decontamination was effective (decontamination efficiency approximately 99%), but noncompliance (tentatively attributed to suboptimal communication) resulted in significantly reduced efficacy (decontamination efficiency approximately 70%). At-risk volunteers (because of chronic illness, disability, or language barrier) were 3 to 8 times slower than ambulatory casualties in undergoing dry and ladder pipe system decontamination, a consequence of which may be a reduction in the overall rate at which casualties can be processed., Conclusion: The PRISM incident response protocols are fit for purpose for ambulatory casualties. However, a more effective communication strategy is required for first responders (particularly when guiding dry decontamination). There is a clear need to develop more appropriate decontamination procedures for at-risk casualties., (Copyright © 2018 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

The UK is currently in the process of implementing a modified response to chemical, biological, radiological and nuclear and hazardous material incidents that combines an initial operational response with a revision of the existing specialist operational response for ambulant casualties. The process is based on scientific evidence and focuses on the needs of casualties rather than the availability of specialist resources such as personal protective equipment, detection and monitoring instruments and bespoke showering (mass casualty decontamination) facilities. Two main features of the revised process are: (1) the introduction of an emergency disrobe and dry decontamination step prior to the arrival of specialist resources and (2) a revised protocol for mass casualty (wet) decontamination that has the potential to double the throughput of casualties and improve the removal of contaminants from the skin surface. Optimised methods for performing dry and wet decontamination are presented that may be of relevance to hospitals, as well as first responders at the scene of a chemical incident., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aims: Following an incident involving toxic chemicals, deployment of countermeasures before the arrival of specialised services at the scene may provide a "therapeutic" window in which to mitigate skin absorption., Methods: Five potential candidates (itaconic acid, N,N'-methylenebisacrylamide, 2-trifluoromethylacrylic acid, fuller's earth and Fast-Act®) previously found effective against a simulant (methyl salicylate) were evaluated against a 10 μL droplet of 14 C-sulphur mustard (HD), soman (GD) or VX applied to the surface of porcine skin mounted on static skin diffusion cells., Results: All the decontaminants applied to the skin 5 min post exposure achieved a marked reduction in the amount of 14 C contaminant remaining within the skin at 24 h. Itaconic acid significantly (p < .05) reduced the amount of 14 C-HD, GD and VX remaining in the skin at 24 h. Additionally, 2-trifluoromethylacrylic acid significantly reduced the amount of 14 C-HD, whilst fuller's earth significantly reduced the amounts of 14 C-HD and VX recovered within the skin at 24 h., Conclusion: All of the products evaluated in this study performed well in reducing the dermal absorption of all the chemical warfare agents tested., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective : The UK's Initial Operational Response (IOR) is a new process for improving the survival of multiple casualties following a chemical, biological, radiological or nuclear incident. Whilst the introduction of IOR represents a patient-focused response for ambulant casualties, there is currently no provision for disrobe and dry decontamination of nonambulant casualties. Moreover, the current specialist operational response (SOR) protocol for nonambulant casualty decontamination (also referred to as "clinical decontamination") has not been subject to rigorous evaluation or development. Therefore, the aim of this study was to confirm the effectiveness of putatively optimized dry (IOR) and wet (SOR) protocols for nonambulant decontamination in human volunteers. Methods : Dry and wet decontamination protocols were objectively evaluated using human volunteers. Decontamination effectiveness was quantified by liquid chromatography-mass spectrometry analysis of the recovery of a chemical warfare agent simulant (methylsalicylate) from skin and hair of volunteers, with whole-body fluorescence imaging to quantify the skin distribution of residual simulant. Results : Both the dry and wet decontamination processes were rapid (3 and 4 min, respectively) and were effective in removing simulant from the hair and skin of volunteers, with no observable adverse effects related to skin surface spreading of contaminant. Conclusions : Further studies are required to assess the combined effectiveness of dry and wet decontamination under more realistic conditions and to develop appropriate operational procedures that ensure the safety of first responders.

Most casualty or personnel decontamination studies have focused on removing contaminants from the skin. However, scalp hair and underlying skin are the most likely areas of contamination following airborne exposure to chemicals. The aim of this study was to investigate the interactions of contaminants with scalp hair and underlying skin using a hybrid in vitro diffusion cell model. The in vitro hybrid test system comprised "curtains" of human hair mounted onto sections of excised porcine skin within a modified diffusion cell. The results demonstrated that hair substantially reduced underlying scalp skin contamination and that hair may provide a limited decontamination effect by removing contaminants from the skin surface. This hybrid test system may have application in the development of improved chemical incident response processes through the evaluation of various hair and skin decontamination strategies.

Background: "Residual skin surface components" (RSSC) is the collective term used for the superficial layer of sebum, residue of sweat, small quantities of intercellular lipids and components of natural moisturising factor present on the skin surface. Potential applications of RSSC include use as a sampling matrix for identifying biomarkers of disease, environmental exposure monitoring, and forensics (retrospective identification of exposure to toxic chemicals). However, it is essential to first define the composition of "normal" RSSC. Therefore, the aim of the current study was to characterise RSSC to determine commonalities and differences in RSSC composition in relation to sex and ethnicity., Methods: Samples of RSSC were acquired from volunteers using a previously validated method and analysed by high-pressure liquid chromatography-atmospheric pressure chemical ionisation-mass spectrometry (HPLC-APCI-MS). The resulting data underwent sebomic analysis., Results: The composition and abundance of RSSC components varied according to sex and ethnicity. The normalised abundance of free fatty acids, wax esters, diglycerides and triglycerides was significantly higher in males than females. Ethnicity-specific differences were observed in free fatty acids and a diglyceride., Conclusions: The HPLC-APCI-MS method developed in this study was successfully used to analyse the normal composition of RSSC. Compositional differences in the RSSC can be attributed to sex and ethnicity and may reflect underlying factors such as diet, hormonal levels and enzyme expression.

Purpose: The aim of this study was to evaluate a candidate haemostat (WoundStat™), down-selected from previous in vitro studies, for efficacy as a potential skin decontaminant against the chemical warfare agent pinacoyl methylfluorophosphonate (Soman, GD) using an in vivo pig model., Materials and Methods: An area of approximately 3 cm 2 was dermatomed from the dorsal ear skin to a nominal depth of 100 µm. A discrete droplet of 14 C-GD (300 µg kg -1 ) was applied directly onto the surface of the damaged skin at the centre of the dosing site. Animals assigned to the treatment group were given a 2 g application of WoundStat™ 30 s after GD challenge. The decontamination efficacy of WoundStat™ against GD was measured by the direct quantification of the distribution of 14 C-GD, as well as routine determination of whole blood cholinesterase and physiological measurements., Results: WoundStat™ sequestered approximately 70% of the applied 14 C-GD. Internal radiolabel recovery from treated animals was approximately 1% of the initially applied dose. Whole blood cholinesterase levels decreased to less than 10% of the original value by 15 min post WoundStat™ treatment and gradually decreased until the onset of apnoea or until euthanasia. All treated animals showed signs of GD intoxication that could be grouped into early (mastication, fasciculations and tremor), intermediate (miosis, salivation and nasal secretions) and late onset (lacrimation, body spasm and apnoea) effects. Two of the six WoundStat™ treated animals survived the study duration., Conclusions: The current study has shown that the use of WoundStat™ as a decontaminant on damaged pig ear skin was unable to fully protect against GD toxicity. Importantly, the findings indicate that the use of WoundStat™ in GD contaminated wounds would not exacerbate GD toxicity. These data suggest that absorbent haemostatic products may offer some limited functionality as wound decontaminants.

The pupillary light reflex (PLR) describes the constriction and subsequent dilation of the pupil in response to light as a result of the antagonistic actions of the iris sphincter and dilator muscles. Since these muscles are innervated by the parasympathetic and sympathetic nervous systems, respectively, different parameters of the PLR can be used as indicators for either sympathetic or parasympathetic modulation. Thus, the PLR provides an important metric of autonomic nervous system function that has been exploited for a wide range of clinical applications. Measurement of the PLR using dynamic pupillometry is now an established quantitative, non-invasive tool in assessment of traumatic head injuries. This review examines the more recent application of dynamic pupillometry as a diagnostic tool for a wide range of clinical conditions, varying from neurodegenerative disease to exposure to toxic chemicals, as well as its potential in the non-invasive diagnosis of infectious disease., Competing Interests: The authors declare no conflict of interest.

This study used a damaged skin, porcine model to evaluate the in vivo efficacy of WoundStat™ for the decontamination of superficial, nerve agent-contaminated wounds. Anaesthetized animals were randomly assigned to either control (n = 7), no decontamination (n = 12) or WoundStat™ (n = 12) treatment groups. Pigs were exposed to a 5× LD 50 dose of neat, radiolabelled S-[2-(diisopropylamino)ethyl]-O-ethyl methyl-phosphonothioate (VX; or equivalent volume of sterile saline for the control group) via an area of superficially damaged skin on the ear. WoundStat™ was applied at 30 seconds post-exposure to assigned animals. The VX contaminant (or saline) and decontaminant remained in place for the duration of the study (up to 6 hours). Physiological parameters and signs of intoxication were recorded during the exposure period. Skin and organ samples were taken post mortem for 14 C-VX distribution analyses. Blood samples were taken periodically for toxicokinetic and whole-blood acetylcholinesterase (AChE) activity analyses. VX exposure was accompanied by a rapid decrease in AChE activity in all animals, regardless of decontamination. However, decontamination significantly improved survival rate and time and reduced the severity of signs of intoxication. In addition, the distribution of 14 C-VX in key internal organs and post mortem blood samples was significantly lower in the WoundStat™ treatment group. This study demonstrates that WoundStat™ may be a suitable medical countermeasure for increasing both survival rate and time following VX exposure. The results also suggest that AChE activity is not a useful prognostic indicator., (Copyright © 2017 John Wiley & Sons, Ltd.)

Context Incontinence-associated dermatitis (IAD) is a type of moisture-associated dermatitis caused by repeated skin exposure to urine or stool. A product that could mitigate such symptoms would have a significant impact on cost of care and patients' quality of life. Objective This study compared the clinical efficacy of RD1433 and a comparator product (Vaseline®) in preventing and treating experimental IAD skin lesions. Materials and methods For the "prevention" part of the study, skin sites in eight human volunteers were treated daily for 5 d with either RD1433 or Vaseline® immediately prior to synthetic urine exposure. In the "treatment" part, exposure to synthetic urine was substituted for Vaseline® or RD1433 application on the first 2 d to promote the development of skin lesions prior to the application of the products from day three. Product efficacy was quantified by visual scoring and an array of biophysical instruments. Results Both RD1433 and Vaseline® significantly reduced lesion progression when applied as a prophylactic. When applied as a treatment (following establishment of skin lesions), RD1433 demonstrated a statistically significant improvement in several measures of skin function whereas there was no statistically significant improvement following treatment with Vaseline®. Conclusions The findings of this study suggest that RD1433 may be superior to Vaseline® in the prevention and treatment of experimental IAD lesions. Clearly, further work is required to establish the efficacy of RD1433 with patients in a clinical environment.

This study used a damaged skin, porcine model to evaluate the in vivo efficacy of WoundStat™ for decontamination of superficial (non-haemorrhaging), sulphur mustard-contaminated wounds. The dorsal skin of 12 female pigs was subjected to controlled physical damage and exposed to 10 μL 14 C-radiolabelled sulphur mustard ( 14 C-SM). Animals were randomly assigned to either a control or a treatment group. In the latter, WoundStat™ was applied 30 s post exposure and left in situ for 1 h. Skin lesion progression and decontaminant efficacy were quantified over 6 h using a range of biophysical measurements. Skin, blood and organ samples were taken post mortem for histopathological assessment, 14 C-SM distribution and toxicokinetic analyses. Application of SM to damaged skin without decontamination was rapidly followed by advanced signs of toxicity, including ulceration and decreased blood flow at the exposure site in all animals. WoundStat™ prevented ulceration and improved blood flow at the exposure site in all decontaminated animals (n = 6). Furthermore, significantly smaller quantities of 14 C-SM were detected in the blood (45% reduction), and recovered from skin (70% reduction) and skin surface swabs (99% reduction) at 6 h post-challenge. Overall, the distribution of 14 C-SM in the internal organs was similar for both groups, with the greatest concentration in the kidneys, followed by the liver and small intestine. WoundStat™ significantly reduced the amount of 14 C-SM recovered from the liver, a key organ for SM metabolism and detoxification. This study demonstrates that WoundStat™ is a suitable product for reducing the ingress and toxicity of a chemical warfare agent. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Metabolic imbalance in chronic diseases such as type-1 diabetes may lead to detectable perturbations in the molecular composition of residual skin surface components (RSSC). This study compared the accumulation rate and the composition of RSSC in type-1 diabetic patients with those in matched controls in order to identify potential biomarkers of the disease. Samples of RSSC were collected from the foreheads of type-1 diabetic (n = 55) and non-diabetic (n = 58) volunteers. Samples were subsequently analysed to identify individual components (sebomic analysis). There was no significant difference in the rate of accumulation of RSSC between type-1 diabetics and controls. In terms of molecular composition, 171 RSSC components were common to both groups, 27 were more common in non-diabetics and 18 were more common in type-1 diabetic patients. Statistically significant (P < 0.05) differences between diabetic and non-diabetic volunteers were observed in the recovered amounts of one diacylglyceride (m/z 594), six triacylglycerides (m/z 726-860) and six free fatty acids (m/z 271-345). These findings indicate that sebomic analysis can identify differences in the molecular composition of RSSC components between type-1 diabetic and non-diabetic individuals. Further work is required to determine the practical utility and identity of these potential biomarkers.

Previous studies have demonstrated that haemostatic products with an absorptive mechanism of action retain their clotting efficiency in the presence of toxic materials and are effective in decontaminating chemical warfare (CW) agents when applied to normal, intact skin. The purpose of this in vitro study was to assess three candidate haemostatic products for effectiveness in the decontamination of superficially damaged porcine skin exposed to the radiolabelled CW agents, soman (GD), VX and sulphur mustard (HD). Controlled physical damage (removal of the upper 100 μm skin layer) resulted in a significant enhancement of the dermal absorption of all three CW agents. Of the haemostatic products assessed, WoundStat™ was consistently the most effective, being equivalent in performance to a standard military decontaminant (fuller's earth). These data suggest that judicious application of haemostatic products to wounds contaminated with CW agents may be a viable option for the clinical management of casualties presenting with contaminated, haemorrhaging injuries. Further studies using a relevant animal model are required to confirm the potential clinical efficacy of WoundStat™ for treating wounds contaminated with CW agents. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Previous studies have demonstrated that rapid evacuation, disrobing and emergency decontamination can enhance the ability of emergency services and acute hospitals to effectively manage chemically-contaminated casualties. The purpose of this human volunteer study was to further optimise such an "Initial Operational Response" by (1) identifying an appropriate method for performing improvised skin decontamination and (2) providing guidance for use by first responders and casualties. The study was performed using two readily available, absorbent materials (paper towels and incontinence pads). The decontamination effectiveness of the test materials was measured by quantifying the amount of a chemical warfare agent simulant (methyl salicylate) removed from each volunteer's forearm skin. Results from the first study demonstrated that simulant recovery was lower in all of the dry decontamination conditions when compared to matched controls, suggesting that dry decontamination serves to reduce chemical exposure. Blotting in combination with rubbing was the most effective form of decontamination. There was no difference in effectiveness between the two absorbent materials. In the following study, volunteers performed improvised dry decontamination, either with or without draft guidelines. Volunteers who received the guidance were able to carry out improvised dry decontamination more effectively, using more of the absorbent product (blue roll) to ensure that all areas of the body were decontaminated and avoiding cross-contamination of other body areas by working systematically from the head downwards. Collectively, these two studies suggest that absorbent products that are available on ambulances and in acute healthcare settings may have generic applicability for improvised dry decontamination. Wherever possible, emergency responders and healthcare workers should guide casualties through decontamination steps; in the absence of explicit guidance and instructions, improvised dry decontamination may not be performed correctly or safely.

The UK's Initial Operational Response (IOR) is a revised process for the medical management of mass casualties potentially contaminated with hazardous materials. A critical element of the IOR is the introduction of immediate, on-scene disrobing and decontamination of casualties to limit the adverse health effects of exposure. Ad hoc cleansing of the skin with dry absorbent materials has previously been identified as a potential means of facilitating emergency decontamination. The purpose of this study was to evaluate the in vitro oil and water absorbency of a range of materials commonly found in the domestic and clinical environments and to determine the effectiveness of a small, but representative selection of such materials in skin decontamination, using an established ex vivo model. Five contaminants were used in the study: methyl salicylate, parathion, diethyl malonate, phorate and potassium cyanide. In vitro measurements of water and oil absorbency did not correlate with ex vivo measurements of skin decontamination. When measured ex vivo, dry decontamination was consistently more effective than a standard wet decontamination method ("rinse-wipe-rinse") for removing liquid contaminants. However, dry decontamination was ineffective against particulate contamination. Collectively, these data confirm that absorbent materials such as wound dressings and tissue paper provide an effective, generic capability for emergency removal of liquid contaminants from the skin surface, but that wet decontamination should be used for non-liquid contaminants., Competing Interests: The authors have declared that no competing interests exist.

Mass casualty decontamination is a public health intervention that would be employed by emergency responders following a chemical, biological, or radiological incident. The decontamination of large numbers of casualties is currently most often performed with water to remove contaminants from the skin surface. An online survey was conducted to explore US fire departments' decontamination practices and their preparedness for responding to incidents involving mass casualty decontamination. Survey respondents were asked to provide details of various aspects of their decontamination procedures, including expected response times to reach casualties, disrobing procedures, approaches to decontamination, characteristics of the decontamination showering process, provision for special populations, and any actions taken following decontamination. The aim of the survey was to identify any differences in the way in which decontamination guidance is implemented across US states. Results revealed that, in line with current guidance, many US fire departments routinely use the "ladder-pipe system" for conducting rapid, gross decontamination of casualties. The survey revealed significant variability in ladder-pipe construction, such as the position and number of fire hoses used. There was also variability in decontamination characteristics, such as water temperature and water pressure, detergent use, and shower duration. The results presented here provide important insights into the ways in which implementation of decontamination guidance can vary between US states. These inconsistencies are thought to reflect established perceived best practices and local adaptation of response plans to address practical and logistical constraints. These outcomes highlight the need for evidence-based national guidelines for conducting mass casualty decontamination.

Rapid decontamination is vital to alleviate adverse health effects following dermal exposure to hazardous materials. There is an abundance of materials and products which can be utilised to remove hazardous materials from the skin. In this study, a total of 15 products were evaluated, 10 of which were commercial or military products and five were novel (molecular imprinted) polymers. The efficacies of these products were evaluated against a 10 µl droplet of (14)C-methyl salicylate applied to the surface of porcine skin mounted on static diffusion cells. The current UK military decontaminant (Fuller's earth) performed well, retaining 83% of the dose over 24 h and served as a benchmark to compare with the other test products. The five most effective test products were Fuller's earth (the current UK military decontaminant), Fast-Act® and three novel polymers [based on itaconic acid, 2-trifluoromethylacrylic acid and N,N-methylenebis(acrylamide)]. Five products (medical moist-free wipes, 5% FloraFree™ solution, normal baby wipes, baby wipes for sensitive skin and Diphotérine™) enhanced the dermal absorption of (14)C-methyl salicylate. Further work is required to establish the performance of the most effective products identified in this study against chemical warfare agents.

The treatment of penetrating, haemorrhaging injuries sustained within a hazardous environment may be complicated by contamination with toxic chemicals. There are currently no specific medical countermeasures for such injuries. Haemostats with an absorbent mechanism of action have the potential to simultaneously stop bleeding and decontaminate wounds. However, a primary requirement of a 'haemostatic decontaminant' is the retention of clotting function in the presence of chemical contaminants. Thus, the aim of this study was to investigate the haemostatic efficacy of seven commercially available haemostats in the presence of toxic chemicals (soman, VX, sulphur mustard, petrol, aviation fuel and motor oil). Clot viscosity was assessed ex vivo using thrombelastography following treatment of pig blood with: (i) toxic chemical; (ii) haemostat; or (iii) haemostat in combination with toxic chemical. Several contaminants (VX, petrol and GD) were found to be pro-haemostatic and none had an adverse effect on the rate with which the test products attained haemostasis. However, the total clot strength for blood treated with certain haemostats in the presence of sulphur mustard, soman and petrol was significantly decreased. Three test products failed to demonstrate haemostatic function in this ex vivo (thrombelastography) model; this was tentatively ascribed to the products achieving haemostasis through a tamponade mechanism of action, which can only be replicated using in vivo models. Overall, this study has identified a number of commercial products that may have potential as haemostatic decontaminants and warrant further investigation to establish their decontaminant efficacy., (Copyright © 2014 John Wiley & Sons, Ltd.)

The risk of penetrating, traumatic injury occurring in a chemically contaminated environment cannot be discounted. Should a traumatic injury be contaminated with a chemical warfare (CW) agent, it is likely that standard haemostatic treatment options would be complicated by the need to decontaminate the wound milieu. Thus, there is a need to develop haemostatic products that can simultaneously arrest haemorrhage and decontaminate CW agents. The purpose of this study was to evaluate a number of candidate haemostats for efficacy as skin decontaminants against three CW agents (soman, VX and sulphur mustard) using an in vitro diffusion cell containing undamaged pig skin. One haemostatic product (WoundStat™) was shown to be as effective as the standard military decontaminants Fuller's earth and M291 for the decontamination of all three CW agents. The most effective haemostatic agents were powder-based and use fluid absorption as a mechanism of action to sequester CW agent (akin to the decontaminant Fuller's earth). The envisaged use of haemostatic decontaminants would be to decontaminate from within wounds and from damaged skin. Therefore, WoundStat™ should be subject to further evaluation using an in vitro model of damaged skin., (Copyright © 2014 Crown copyright. Journal of Applied Toxicology © 2014 John Wiley & Sons, Ltd.)

Incontinence-associated dermatitis (IAD) is a painful yet preventable form of cumulative skin irritation prevalent amongst those with limited movement. Consequently, it has a significant impact on the quality of life for those affected as well as substantial cost implications. Prevention and intervention is typically through good skin hygiene regimes and regular use of barrier products. In this paper, we describe the development of an in vivo model of IAD in healthy volunteers by occluded application of alkaline synthetic urine to the volar aspect of volunteer's forearms for 6 h per day over a five-day period to reproduce the moist and irritant conditions causative of IAD. Irritation was assessed and quantified on a daily basis by a series of non-invasive biophysical measurements and compared to a contralateral saline-treated (control) site. Dermal irritation was assessed by subjective (visual) and objective measurements (laser Doppler and polarisation spectroscopic imaging, infrared thermography, skin reflectance spectroscopy, transepidermal water loss and skin surface pH). The provocation of reproducible, cumulative skin irritation was successfully demonstrated and quantified. This five-day model of irritation is considered appropriate for the initial clinical assessment of topical products to prevent or treat IAD.

Context: Topical skin protectants (barrier creams) have the potential to reduce or enhance the severity of dermal lesions following exposure to allergens or irritants. Therefore, it is essential that such products are subject to appropriate clinical evaluation prior to marketing. Consequently, it is important to accurately define a dosing regime in order to assess test products under appropriate conditions., Objective: In this study, we extended the use of a standard rubefacient (methyl nicotinate; MN) assay to establish the optimum thickness and duration of action of a novel barrier cream (RD1433). White petroleum jelly (Vaseline(®)) was used as a comparator product., Methods: The dermal response to MN was measured on the volar forearm skin of volunteers (n = 12; average age 47.5 years) using an array of biophysical instruments and visual scoring. When applied at a nominal thickness of 0.1 mm, RD1433 retained effectiveness against MN for up to six hours. In contrast, Vaseline(®) was relatively ineffective. Moreover, RD1433 provoked no measurable signs of irritation and so can be considered acceptable for further clinical evaluation., Conclusion: Future clinical studies using RD1433 should be based on topical application of a 0.1 mm thickness layer every six hours.

Careful planning and regular exercising of capabilities is the key to implementing an effective response following the release of hazardous materials, although ad hoc changes may be inevitable. Critical actions which require immediate implementation at an incident are evacuation, followed by disrobing (removal of clothes) and decontamination. The latter can be achieved through bespoke response facilities or various interim methods which may utilise water or readily available (dry, absorbent) materials. Following transfer to a safe holding area, each casualty's personal details should be recorded to facilitate a health surveillance programme, should it become apparent that the original contaminant has chronic health effects., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The efficient removal of contaminants from the outer surfaces of the body can provide an effective means of reducing adverse health effects associated with incidents involving the accidental or deliberate release of hazardous materials. Showering with water is frequently used by first responders as a rapid method of mass casualty decontamination (MCD). However, there is a paucity of data on the generic effectiveness and safety of aqueous decontamination systems. To address these issues, we have developed a new in vitro skin diffusion cell system to model the conditions of a common MCD procedure ("ladder pipe system"). The new diffusion cell design incorporates a showering nozzle, an air sampling port for measurement of vapour loss and/aerosolisation, adjustable (horizontal to vertical) skin orientation and a circulating manifold system (to maintain a specified flow rate, temperature and pressure of shower water). The dermal absorption characteristics of several simulants (Invisible Red S, curcumin and methyl salicylate) measured with the new in vitro model were in good agreement with previous in vitro and in vivo studies. Moreover, these initial studies have indicated that whilst flow rate and water temperature are important factors for MCD, the presence of clothing during showering may (under certain circumstances) cause transfer and spreading of contaminants to the skin surface., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background/purpose: The superficial layer on the skin surface, known as the acid mantle, comprises a mixture of sebum, sweat, corneocyte debris and constituents of natural moisturizing factor. Thus, the phrase 'residual skin surface components' (RSSC) is an appropriate term for the mixture of substances recovered from the skin surface. There is no general agreement about the effects of ethnicity, gender and age on RSSC. The aim of this human volunteer study was to evaluate RSSC in relation to ethnicity, gender and age. A suitable acquisition medium for RSSC collection was identified and samples of RSSC were subsequently analysed using gas chromatography-mass spectrometry (GC-MS) and gravimetry., Methods: A total of 315 volunteers participated in the study from a range of self-declared ethnic backgrounds. Six acquisition media were compared to determine the most suitable media for RSSC collection. The effect of age, gender and ethnicity on RSSC collection was evaluated by gravimetric analysis while GC-MS was used to determine the composition of RSSC., Results: Of the six candidate materials assessed, cigarette paper provided the most practical and reproducible sample acquisition medium. There was no significant difference in the amount of RSSC collected when based on gender and ethnicity and no significant correlation between RSSC recovery and age. Up to 49 compounds were detected from human RSSC when analysed by GC-MS., Conclusions: The results of the present study suggest that RSSC can be effectively collected using cigarette paper and analysed by GC-MS. Ethnicity, gender and age had no significant impact on the quantity of RSSC recovered from the skin surface., (© 2013 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

The purpose of this in vivo study was to assess a new, putatively optimised method for mass casualty decontamination ("ORCHIDS protocol") for effectiveness in removing the chemical warfare agent VX from the skin of anaesthetised, domestic white pigs. ORCHIDS protocol consists of a 1.5-minute shower with a mild detergent (Argos™) supplemented by physical removal. A standard method of wet decontamination was used for comparison. Experimental animals were divided into four groups (A-D). Two groups were exposed to a supra-lethal percutaneous dose (5 × LD(50); 300 μg kg(-1)) of VX for 1 h prior to decontamination with either the ORCHIDS (C) or standard protocol (D). A third (B, positive control) group was exposed but not subject to decontamination. Blank controls (A) received anaesthesia and the corresponding dose of normal saline instead of VX. Observations of the clinical signs of intoxication were supplemented by measurements of whole blood cholinesterase (ChE) performed on samples of arterial blood acquired at 30-minute intervals for the duration of the study (up to 6 h). Untreated (B) animals displayed typical cholinergic signs consistent with VX intoxication (local fasciculation, mastication, salivation, pilo-erection and motor convulsions) and died 165-240 min post exposure. All animals in both decontamination treatment groups (C, D) survived the duration of the study and exhibited less severe signs of cholinergic poisoning. Thus, both the standard and ORCHIDS protocol were demonstrably effective against exposure to the potent nerve agent VX, even after a delay of 1 h. A critical advantage of the ORCHIDS protocol is the relatively short shower duration (1½ min compared to 3 min). In practice, this could substantially improve the rate at which individuals could be decontaminated by emergency responders following exposure to toxic materials such as chemical warfare agents.

The handling of elemental gallium is not thought to be harmful, but this assumption does not consider metal coordination which readily occurs in physiological fluids. The aim of this work was to determine Ga(III) coordination behaviour in simple solutions and assess the effects of complex formation upon skin permeation in vitro. Ga(III) coordination was modelled using metal-ligand stability constants in silico and the permeation of the metal through human and porcine skin determined using four test conditions. Ga(III) was presented to the skin as: (1) Ga³+ ions; (2) a -ve citrate complex (Ga(neg)); (3) a mixture of +ve and -ve complexes (Ga(mix)) and (4) a mixture of +ve hydroxide complexes (Ga(pos)). The permeability coefficient (Kp) of Ga(III) through human skin increased by almost 2 orders of magnitude when applied as free Ga³+ ions or a Ga(neg) complex (the two most water soluble complexes), compared to Ga(mix) or Ga(pos). This trend was not well modelled by porcine skin which proved to be less of a barrier to Ga(III) permeation compared to human skin (Kp=2 x 10⁻³ ± 2 x 10⁻⁴ cm h⁻¹). Given the significant transdermal bioavailablity of Ga(III) demonstrated by this study, it would appear prudent to re-evaluate the dermal toxicity of this metal., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

A well-established provision for mass-casualty decontamination that incorporates the use of mobile showering units has been developed in the UK. The effectiveness of such decontamination procedures will be critical in minimizing or preventing the contamination of emergency responders and hospital infrastructure. The purpose of this study was to evaluate three empirical strategies designed to optimize existing decontamination procedures: (1) instructions in the form of a pictorial aid prior to decontamination; (2) provision of a washcloth within the showering facility; and (3) an extended showering period. The study was a three-factor, between-participants (or "independent") design with 90 volunteers. The three factors each had two levels: use of washcloths (washcloth/no washcloth), washing instructions (instructions/no instructions), and shower cycle duration (three minutes/six minutes). The effectiveness of these strategies was quantified by whole-body fluorescence imaging following application of a red fluorophore to multiple, discrete areas of the skin. All five showering procedures were relatively effective in removing the fluorophore "contaminant", but the use of a cloth (in the absence of instructions) led to a significant ( appox. 20%) improvement in the effectiveness of decontamination over the standard protocol (p <0.05). Current mass-casualty decontamination effectiveness, especially in children, can be optimized by the provision of a washcloth. This simple but effective approach indicates the value of performing controlled volunteer trials for optimizing existing decontamination procedures.

Studies of the percutaneous reservoir of sulphur mustard (HD) formed during absorption carried out during WWI and WWII are inconclusive. More recent studies have indicated that a significant amount of unreacted HD remains in human epidermal membranes during percutaneous penetration studies in vitro. The present study investigated the nature and persistence of the HD reservoir formed during in vitro penetration studies using dermatomed slices of human and pig skin (0.5mm thick). Amounts of (14)C-HD that (a) penetrated, (b) remained on the surface, (c) were extractable from and (d) remained in the skin after extraction were estimated by liquid scintillation counting (confirmed using GC-MS analysis). The results demonstrated that there is a reservoir of HD in human and pig skin for up to 24 h after contamination of the skin surface in vitro with liquid agent. At least some of this reservoir could be extracted with acetonitrile, and the amounts of extracted and unextracted HD exceed the amount required to produce injury in vivo by at least 20 fold. The study demonstrated the presence of a reservoir whether the skin was covered (occluded) or left open to the air (unoccluded). The study concluded that the extractable reservoir was significant in terms of the amount of HD required to induce a vesicant response in human skin. The extractable reservoir was at least 20 times the amount required per cm(2) estimated to cause a response in all of the human population, as defined by studies carried out in human volunteers during the 1940s.

Previous studies in our laboratory have demonstrated that barrier creams, comprising perfluorinated polymers, are effective against the chemical warfare agent sulphur mustard (SM) when evaluated using human skin in vitro. The purpose of this follow-up study was to further evaluate three candidate (perfluorinated) barrier creams against SM (vapour) using the domestic white pig. The severity and progression of the resulting skin lesions were quantified daily for three weeks post-exposure using biophysical measurements of transepidermal water loss (TEWL) and skin reflectance spectroscopy (SRS). Skin biopsies obtained post-mortem were evaluated by light microscopy and additional skin samples were obtained from adjacent (unexposed) skin sites for a comparative in vitro skin absorption study. Samples of SM vapour within the dosing chambers were measured ex vivo to ascertain the exposure dose (Ct). The three creams were highly effective against SM in vivo (Ct approximately 5000 mg.min.m(-3)): After 3 weeks, barrier cream pre-treated sites were not significantly different from control (unexposed) skin when evaluated by TEWL, SRS or histology. In contrast, skin exposed to SM without pre-treatment showed evidence of persistent damage that was consistent with the slow healing time observed in humans. The amount of SM absorbed in vitro in untreated pig skin was similar to that required to cause comparable lesions in human skin (8-20 and 4-10 microg.cm(-2), respectively), further validating the use of pigs as a toxicologically-relevant dermal model for SM exposure.

The physico-chemical properties of VX make the skin the most likely route of absorption into the human body. The development of effective medical countermeasures against such percutaneous threat agents relies on the use of appropriate animal models, as the inherent toxicity of nerve agents precludes the use of human volunteers. Previous studies have characterised the mechanism of nerve agent toxicity in rodent models, however, it is generally accepted that one of the most appropriate animal models for human skin absorption is the domestic pig. The purpose of the present study was to measure and compare the skin absorption kinetics of VX in vitro using pig, human and guinea pig skin to highlight any potential species differences in skin permeability. When undiluted VX was applied directly to the skin, the permeability of guinea pig skin was approximately 7-fold greater than human skin. There was no significant difference in the permeability of pig and human skin. When VX diluted with isopropyl alcohol was applied to the skin, the permeability of guinea pig skin was approximately 4-fold greater than human skin. There was no significant difference in the permeability of pig and human skin. From this data it may be inferred that dermatomed, abdominal pig skin is an appropriate model for the human skin absorption of VX.

Percutaneous vapor dosing studies have generally used saturated vapor concentration (SVC) measurements to estimate the exposure dose (Ct) of vapor produced from a volatile liquid within a closed system. The purpose of this study was to clarify whether the assumption was valid when translated to a biological system (pig skin) using sulfur mustard (SM) as a model skin penetrant. Three systems were evaluated, two containing skin and a control system (without skin). At set time points, samples from the headspace of each dosing system were extracted using a gas-tight syringe and analyzed by gas chromatography in conjunction with a flame-ionization detector. This demonstrated the rapid achievement of a constant vapor concentration within the biological and control systems and enabled a comparison with previously determined SVCs attained under ideal conditions. All three systems attained a constant vapor concentration within 2 min of exposure to SM. The control system reached an equilibrium vapor concentration of 1179 +/- 164 mg/m3, a value not significantly different from that derived from the SVC (1363 mg/m3). Because of absorption in the skin systems, SM vapor concentrations were significantly lower than that derived from the SVC and were dependent on the skin surface area within the dosing chamber (592 +/- 246 mg/m3 for a surface area of 10.15 cm2 and 740 +/- 224 mg/m3 for a surface area of 2.54 cm2). The assumption that SVC gives an acceptable measure of the Ct was shown to be valid by comparison with sulfur mustard recovered from the skin.

The purpose of this study was to evaluate the efficacy of a novel barrier cream formulation at reducing the percutaneous toxicity of a 2xLD(50) liquid challenge of nerve agent (VX). The study was conducted in vitro and in vivo using the domestic pig. Pretreatment of the (inner ear skin) exposure site with barrier cream eliminated mortality, reduced cholinesterase inhibition and prevented any physiological or biochemical signs of intoxication. In contrast, untreated animals exposed to VX exhibited severe signs of intoxication, near total AChE inhibition and generally died within the (3 hr) exposure period (5/6 animals). Application of the barrier cream caused a significant decrease in the area of skin contaminated by VX. It was tentatively concluded that spreading was predominantly a surface phenomena (possibly mediated by capillary movement of the agent through the microrelief or between hair follicles) with little or no contribution from lateral diffusion within the stratum corneum. There was a disparity between the in vitro and in vivo skin absorption measurements that was ascribed to the absence of systemic clearance in vitro. However, both models indicated a substantial reservoir of VX within the skin, providing a potential strategy for future investigations into "catch-up therapies". In summary, the novel barrier cream formulation was effective against a 2xLD(50) (liquid, percutaneous) dose of VX applied for 3 hr. Further work should be conducted to investigate more pragmatic issues such as optimal reapplication frequency and environmental effects such as temperature and humidity.

The purpose of this study was to characterize the skin absorption and distribution of VX (O-ethyl-S-[2 (diisopropylamino)ethyl] methylphosphonothioate) in the domestic pig in order to evaluate the animal as a potential model for assessing pretreatments against toxic anti-cholinesterase compounds. A liquid droplet (equivalent to a 2 x LD50 dose) of radiolabelled VX was applied to the inner ear-skin of each anaesthetized animal. Blood and tissue samples (liver, lung, kidney, heart and skin exposure sites) were obtained post-mortem. The amount of radioactivity in each sample was measured by liquid scintillation counting, from which the skin absorption rate and dose distribution of VX were calculated. A substantial proportion (22 +/- 3%) of the applied dose remained within the skin at the site of application. It is conceivable that strategies to minimize or remove this reservoir may be of benefit in the early treatment of VX-exposed casualties. Image analysis of autoradiographs of exposed skin sites indicated that each milligram of radioactive VX covered an area of 1.2 +/- 0.5 cm2. The average skin absorption rate of 14C-VX was 661 +/- 126 microg/cm2 per hour. Comparison of these data with previous studies suggests that human skin is less permeable to VX than pig skin, but VX spreads over a greater surface area when applied to human skin. Thus, paradoxically, while pig-ear skin is more permeable than human skin, the difference in skin surface spreading may lead to the absorption of an equivalent systemic dose.

In vitro measurements of skin absorption are an increasingly important aspect of regulatory studies, product support claims, and formulation screening. However, such measurements are significantly affected by skin variability. The purpose of this study was to determine inter- and intralaboratory variation in diffusion cell measurements caused by factors other than skin. This was attained through the use of an artificial (silicone rubber) rate-limiting membrane and the provision of materials including a standard penetrant, methyl paraben (MP), and a minimally prescriptive protocol to each of the 18 participating laboratories. "Standardized" calculations of MP flux were determined from the data submitted by each laboratory by applying a predefined mathematical model. This was deemed necessary to eliminate any interlaboratory variation caused by different methods of flux calculations. Average fluxes of MP calculated and reported by each laboratory (60 +/- 27 microg cm(-2) h(-1), n = 25, range 27-101) were in agreement with the standardized calculations of MP flux (60 +/- 21 microg cm(-2) h(-1), range 19-120). The coefficient of variation between laboratories was approximately 35% and was manifest as a fourfold difference between the lowest and highest average flux values and a sixfold difference between the lowest and highest individual flux values. Intralaboratory variation was lower, averaging 10% for five individuals using the same equipment within a single laboratory. Further studies should be performed to clarify the exact components responsible for nonskin-related variability in diffusion cell measurements. It is clear that further developments of in vitro methodologies for measuring skin absorption are required., (Copyright 2005 Wiley-Liss, Inc. and the American Pharmacists Association.)

Sulfur mustard is an alkylating chemical warfare agent that primarily affects the eyes, skin, and airways. Sulfur mustard injuries can take several months to heal, necessitate lengthy hospitalizations, and result in significant cosmetic and/or functional deficits. Historically, blister aspiration and/or deroofing (epidermal removal), physical debridement, irrigation, topical antibiotics, and sterile dressings have been the main courses of action in the medical management of cutaneous sulfur mustard injuries. Current treatment strategy consists of symptomatic management and is designed to relieve symptoms, prevent infections, and promote healing. There are currently no standardized or optimized methods of casualty management that prevent or minimize deficits and provide for speedy wound healing. Several laboratories are actively searching for improved therapies for cutaneous vesicant injury, with the aim of returning damaged skin to optimal appearance and normal function in the shortest time. Improved treatment will result in a better cosmetic and functional outcome for the patient, and will enable the casualty to return to normal activities sooner. This editorial gives brief overviews of sulfur mustard use, its toxicity, concepts for medical countermeasures, current treatments, and strategies for the development of improved therapies.