The Problem

The accidental or intentional releases of toxic gases or vapors¹ are the most common occurrence in hazardous material (HAZMAT) incidents that result in human injuries [1, 2]. Such atmospheric releases are typically associated with industrial accidents . (e.g., chlorine gas release after a train derailment in South Carolina [29]) and terrorism-related events. (e.g., Tokyo subway nerve agent sarin attack [3]). Historically, deliberate acts using hazardous materials and chemical agents have been sparse. Nonetheless, in the last few years, deliberate releases dispersing chlorine, mustard agent, and sarin in Iraq and Syria have occurred illustrating ongoing national and terrorist groups’ interest.

These releases of hazardous materials have significant consequences on public health and impose significant demands on HAZMAT response resources [4, 5]. During and following HAZMAT incidents, there are four main groups of people affected: (a) exposed and deceased, (b) exposed and symptomatic, (c) exposed and asymptomatic, and (d) unexposed and asymptomatic. Groups (a) and (b), usually acutely affected by inhalation exposure, are the most clearly recognized, with group (b) being able to be triaged and evacuated to hospital or treated at the scene. However, the onsite management of group (c) is problematic as it may be numerically large and potentially resource-intensive. Group (d), also known as the ‘worried well’, may self-present to first responders at the scene, or at nearby hospitals, or medical facilities, placing further demands on valuable resources and adding to the potential delay in identifying and treating those who need more urgent attention.

The established approach globally is, by default, to decontaminate the skin of all exposed persons using field portable shower systems. Jurisdictions have invested hundreds of millions of dollars establishing and extending their field deployable mass decontamination resources. Nonetheless, a significant incident will likely rapidly overwhelm the available field deployable HAZMAT mass decontamination capacity.

Is this approach consistent with the nature of the exposure incurred by the affected persons? Is it always appropriate for the skin interactions between the contaminant and the exposed persons? There is little if any published work investigating these interactions and their implication on the subsequent approaches that should be applied during a HAZMAT emergency. Most published works have focused on the mechanics of decontamination rather than whether decontamination is necessary, and what, if any, type and extent of decontamination should be applied before medical care. Decontamination modeling estimates show that if the number of persons undergoing decontamination can be reduced by 80%, then the available resource demand is reduced by 63% and the times required by 77% [6]. This has a significant impact on the efficiency of a HAZMAT response and saving the lives of those who were affected.

There is a limited evidence base describing skin absorption of toxic gases and vapors in HAZMAT exposure scenarios, which tend to be relatively brief compared with traditional test periods for skin absorption studies. In order to address this gap, there is a need for a testing strategy that encompasses the relevant kinetics and equilibria of skin deposition, absorption and penetration of gases and vapors, and the moderating effects of environmental factors. (e.g., temperature, humidity), clothing, and other factors. This is a complex multicompartment system, and any protocol should also take into account typical short-term exposures of less than 1-h duration and subsequent periods of off-gassing. Investigations within this period (sometimes termed as the “golden hour”) are of particular relevance to HAZMAT incidents [1].

From the first responder perspective, a number of key questions arise: (1) how much gas gets on, in, or through the skin in this first hour following contact, (2) what are the modifying influences of environmental factors and street clothing worn, and (3) what are the off-gassing rates from skin and clothing.

Relevant toxicological testing should aim to generate data and provide advice. These empirical data and advice relate only to the specific chemical exposures and are not intended to support recommendations regarding dissimilar HAZMAT chemicals for which alternative individual data must be gathered.

Nature of Gas Exposure

Compared with liquid or aerosol exposure scenarios, gas concentrations in gas-only scenarios are often low, i.e., typically less than 1% v/v. Following toxic gas exposure, it is often assumed that isolation from the source and removal of clothing is typically all that is needed to prevent further exposure or injury [1, 7, 8]. Levitin et al. [1] and Houston et al. [7] suggest removal and double-bagging of the victim’s clothing can eliminate 80% to 90% of the contaminant and minimize the risk of spreading the toxic agent to others. This percentage may depend on amount/type of clothing worn and the duration of exposure. Bagged clothing should be left at the scene and managed by emergency responders so as to minimize risk of exposure to hospital personnel [7, 8]. However, accident scene management and victim care varies throughout the world and is based primarily on personal judgment and dogma rather than on scientific evidence. Ill-informed decisions about the management of exposed individuals and groups during chemical releases have the potential to cause a significant drain on resources as well as a variety of undesired outcomes among those affected. In particular, decisions about mass decontamination following suspected or known chemical exposure should be risk-based and supported by suitable empirical evidence.

Following a review of toxic gas exposure literature, there appears to be limited specific advice for first responders regarding skin decontamination. As mentioned, the current generally accepted approach to mass-casualty decontamination is that all exposed individuals must “strip and shower”, regardless of the mechanism or likely form of exposure (liquid versus gas/vapor). This advice could be seen as inconsistent with ATSDR studies from 13 US states for 7 years, which determined that in 90% of cases, only six or fewer human casualties required care after chemical exposures [1, 9]. The Chemical Weapons Improved Response Program projects at least a 5:1 ratio of unaffected to affected casualties [10]. These “worried well” noninjured victims comprise the largest group in mass-casualty events (80–90% of survivors in most cases). These victims will wait for care at the scene, transport themselves to the closest medical facility for care, or leave the scene and not seek care. While evacuation from the area of chemical release will decrease their level of primary exposure, secondary exposure can potentially occur from the amount of gas/vapor remaining in their clothing. By the time showers can be set up, any trapped gas/vapor in victims’ clothing may have dispersed, making decontamination unnecessary. In this regard, Markel et al. [11] supports a “scoop and run” evacuation approach rather than onsite decontamination. Little has been done to investigate the degree and duration of trapped gas/vapor released from different types of street clothing. Furthermore, sunscreen and cosmetics may enhance, buffer or reduce dermal exposure or act as a chemical reservoir [12, 13]. In practice, emergency personnel need practical guidance about ongoing exposure potential and decontamination advice [4].

Nature of Gas/Vapor Interactions with Skin

There is a limited evidence base for the extent and kinetics of skin absorption in HAZMAT scenarios involving toxic gases and vapors [5, 14]. Much of the pre-planning has generally been based on knowledge of the basic physicochemical properties of the released chemical such as volatility/vapor pressure, water and oil solubility, molecular mass, density and other routine information. However, this information may do little to inform a dynamic or evolving risk assessment process under the variable environmental conditions that may exist during an incident.

It is well recognized that vapors, aerosols, and liquids deposit onto the skin from the atmosphere. If sufficient vapor is deposited onto the skin, condensation may occur and a liquid-like phase formed. A proportion of these absorbed molecules also evaporate. The molecules will either physically interact (absorption) or chemically interact (adsorption) with the surface. The transport of chemicals through the skin [17, 18] is either active (mediated transport requiring energy) or passive (diffusion requiring no energy). Often, the kinetics of skin absorption of gases/vapors (and their dissociation products) is slow, with competing processes of absorption and desorption more evident than that of liquid exposures.

The literature indicates that a variety of factors can play a significant role in the dermal absorption of chemicals. These include skin thickness and lipid content, occlusion, clothing, temperature and humidity, and skin damage/disease.

Clothing may serve to initially protect and buffer the skin from toxic chemicals, depending on the material, thickness, cover, and yarn twist. A tightly woven fabric using a high twist yarn gives the most protection against penetration and in conjunction with a thick fabric gives a high protection factor. However, significant skin uptake of chemical may occur if contaminated clothing is in contact with, or occludes, the skin. There do not seem to be any systematic studies of the chemical protection afforded by street clothing or personal skin products.

Personal products applied to the skin and hair, such as cosmetics and sunscreen , may enhance, buffer or reduce dermal exposure. They may also act as a chemical reservoir. The ability to enhance or reduce skin uptake depends primarily on whether the product is oil- or water-based [12], although some active ingredients can enhance penetration [13]. Indeed, it is only recently that the community usage of personal products has been studied for risk assessment purposes [15, 16].

Current Experimental Approaches to Gas Interaction Studies

The best models for understanding dermal exposures during CBR incidents would be human volunteer skin exposure studies, either whole body, or segmental, or limb exposures. These exposures may be authentic in that the chemicals may have been applied via surface sprays, droplets, spills, immersion, deposition, or from gas and vapor contact. They may be further modified under varying conditions of temperature and humidity, clothing coverage, occlusion, vehicle, and all other parameters that may be imagined or predicted for ‘real-life’ exposures . However, these methods cannot be applied for highly toxic materials, or for other materials at concentrations that may be toxic. Individuals are highly variable in their absorption, and the small number of trials that may be performed limits statistical interpretation. Also, the measures that indicate the extent of absorption may be limited to blood concentrations , urine concentrations or other such estimates that, being markers of systemic absorption, may not fully inform investigators about localized concentrations and effects. However, tape-stripping applications , in which the stratum corneum may be removed by successive applications and removal of adhesive tape, have been performed to identify the localizations of dermally applied chemicals in the stratum corneum or to demonstrate altered rates of penetration through skin in the absence of stratum corneum. Recently, confocal Raman spectroscopy has been used to examine chemical concentrations in skin strata [17]. Such approaches, however, have not been nor could easily be applied to gas or vapor exposures.

Whole animal (in vivo) models may suffer from poor extrapolation to human circumstances because of significant interspecies variation. These are also relatively expensive, especially in large, statistically justified investigations. Ex-vivo systems , including the isolated perfused pig ear, have also been used to examine the uptake of chemicals through a system whose blood circulation (through arteries, arterioles, capillaries, venules, and veins) remains intact.

In vitro models , using either animal- or human-derived tissue, remain the most common methods used for a wide range of assessments of dermal absorption of chemicals. The Organization of Economic Cooperation and Development (OECD) approach has gained widespread acceptance and adoption for in vitro testing for dermal absorption (OECD 2004) [18]. While these models suffer from the handicap of being remote from real-life situations (with consequent reduction in direct validity to human exposure scenarios), they are reliable, generally reproducible, and allow at least the rank comparison of different chemicals under similar exposure parameters. At best, they can provide quantitative comparisons, enabling some numeral risk assessments to be extrapolated.

Rat dorsum, pig ear, human cadaver skin, or viable human skin (commonly obtained from cosmetic reduction surgery) may be used in chambers with an upper application well and a lower receptor well, containing a receptor fluid to mimic cutaneous blood . This may be a simple static diffusion type (such as the Franz cell) or a dynamic, or flow-through cell. The static-type cell requires any media removed from the lower receptor chamber to be replaced at each sampling time point. The flow-through cell has a reservoir of fresh receptor fluid that is pumped through the receptor chamber and collected downstream. The tissues may be full thickness (stratum corneum, epidermis and sometimes partial dermis), split thickness (stratum corneum and epidermis only), or some defined fraction of the skin layer (sometimes dermatomed to a specified standard thickness). Each of these approaches yields different results that may not be directly comparable between methodologies. Furthermore, there are currently no test cells commercially available with a modified donor chamber to allow for gas/vapor delivery to the skin surface. This methodological challenge may in part account for the limited number of published studies on skin exposure to gases. Gaskin et al. [19]) describe a bespoke static diffusion cell with a modified donor chamber to allow for gas delivery, and appear to be one of the only research group assessing dermal exposure to toxic gases and vapors [5, 14, 19, 20].

Recent work has focused on emerging technologies to produce skin substrates that are more consistent, reliable or in other ways considered advantageous for dermal absorption experiments. These include human cell line models (growing sheets of keratinocytes of uniform or near-uniform characteristics) and partial culture (such as using viable human skin, seeded with human stem cells that form a uniform upper skin surface devoid of accessory structures and flaws).

Fresh human skin, from cosmetic reduction surgery , is the most convenient and reliable substrate available, notwithstanding the variations between donor skin characteristics. It usually provides sufficient skin for several diffusion chambers to be set up, allowing manipulation of key parameters in a controlled experiment that is internally consistent and comparable. Skin is usually from breast or abdomen, reducing the extent of site-specific variations that have been identified with skin sourced from varying anatomical sites. Skin can be used in a variety of modes (full thickness, split thickness) to satisfy the needs of the experimental approach.

Dermatomed split-thickness skin is considered by some to be superior to skin split by other methods (heat or chemical treatment), but this has been seen predominantly in studies in which maintenance of metabolic capacity of skin was desirable. For simple diffusion studies, heat-treated, split-thickness skin has been found be effective and reproducible. Integrity of skin is checked by visual inspection under a dissecting microscope prior to mounting in the diffusion cell, and by transdermal resistance (with electrical probes placed on the skin surface and in the lower receptor chamber), following mounting. This is usually sufficient to establish whether the skin sample has defects or perforations that may affect results.

Tape stripping prior to mounting or following chemical exposure can allow examination of the role of the stratum corneum as a barrier or a chemical reservoir, but is methodologically challenging. Skin washing is a common contaminant removal technique (post-exposure), and is appropriate for chemicals that have low rates of dermal absorption.

Keratinocyte culture is currently unproven and may generate a model that is more similar to the stratum corneum than to the integrated structure of the skin. Similarly, the partial culture/stem cell methods have been developed predominantly for medical applications (for treatment of skin injuries such as burns) and have not been used for dermal absorption models.

Although the use of human skin represents the most robust approach, a multispecies study has suggested that pigskin can be a very useful model for in vitro percutaneous absorption studies, provided that the skin integrity is checked prior to skin exposure, and in-house electrical resistance cut-off values are adhered to.

Systematic In Vitro Approach

The approach by Gaskin et al. represents a modification of the OECD experimental protocol for skin absorption of chemicals by specifically aligning with the context of HAZMAT incidents in which exposures occur by vapor or gas for relatively brief periods [19]. It also allows examination of the influence of fabrics and other potential barriers or reservoirs on the secondary exposure and need for decontamination. Supplementary fabric off-gassing experiments may also be conducted under variable conditions. The use of the human in vitro model allows repeatable studies to gauge variation in contributions of the various environmental conditions. Observations may then be summarized and translated into a format that guides emergency personnel in public health management at HAZMAT incidents.

The experimental approach addresses the kinetics and equilibria of skin absorption and penetration, and the moderating effects of environmental factors. (e.g., temperature, humidity), and clothing. An overview of the technique can be described in three steps: (1) Substrate (skin sample) preparation, (2) Gas challenge, and (3) Post-exposure analysis of absorption and penetration. Figure 9.1 is a block diagram of the equipment setup.

Chemicals of Interest

In Australia, using a combination of intelligence assessments , hazardous materials properties and use a list of materials was created, often referred to as the COAG (Council of Australian Governments) list of hazardous materials [28]. Similar lists have been complied by other nations [29, 30]. These lists are applied as a basis to assist communities in focusing their efforts to prevent the misuse of such materials and prepare to manage the consequence of attacks using hazardous materials. The materials are a mixture of solids, liquids and gases and range from toxic chemicals like parathion (organophosphate) to corrosive toxic gases like hydrogen chloride. They are generally toxic and/or corrosive materials.

The toxicity of the chemical is a crucial factor. Toxicity and classification criteria are described in the United Nations recommendations on the transport of dangerous goods. The toxic effect of a material is dependent on several factors, including the route of entry. Materials most toxic by inhalation find favor for deliberate use. The most effective materials to be dispersed are selected on a combination of their toxicity and physicochemical properties , such as volatility, state, and reactivity.

The prioritization of chemicals to be included in the skin decontamination studies should be based on the national lists combined with their intrinsic properties. Toxic and/or corrosive chemicals naturally found in the gaseous state are highest priority. In order to contaminate mass numbers of people, the threat material would likely be a gas or vapor.

For an initial study by the authors, ten chemicals of high priority were addressed. Based upon the way in which the chemicals interact with skin, they were divided into categories of reactive gases, biochemical degradation gases, and fumigant gases.

Detection Methodologies

Table 9.1 shows the detection techniques used for each chemical interaction assessed.

Table 9.1

Detection techniques used to assess chemical interactions with skin

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