Part III Dermal Exposure © 2007 by Taylor & Francis Group, LLC 255 11 Dermal Exposure, Uptake, and Dose Alesia C. Ferguson University of Arkansas for Medical Sciences Robert A. Canales Harvard University James O. Leckie Stanford University CONTENTS 11.1 Synopsis 256 11.2 Introduction 256 11.3 Importance of Dermal Exposure and Dose 256 11.4 Defining Dermal Exposure and Dose 257 11.5 The Human Skin 259 11.5.1 General Skin Structure 259 11.5.2 General Skin Function 260 11.5.3 The Function and Structure of the Stratum Corneum (SC) 260 11.5.4 Shedding and Hydration in the Stratum Corneum 261 11.6 Factors Affecting Dermal Dose 262 11.7 Mechanisms and Pathways for Dermal Exposure 263 11.8 Direct Methods for Measuring Dermal Exposure 265 11.8.1 Surrogate Skin Techniques 265 11.8.2 Removal Techniques 266 11.8.3 Fluorescent Tracer Techniques 266 11.8.4 Surface Sampling Techniques 267 11.9 Dermal Exposure Examples 269 11.10 Direct Techniques for Measuring Absorption 270 11.10.1 In Vitro Methods 271 11.10.2 In Vivo Methods 272 11.11 Highlighted Dermal Dose Examples 273 11.12 Conclusion 274 11.13 Questions for Review 275 Glossary of Terms 276 References 278 © 2007 by Taylor & Francis Group, LLC 256 Exposure Analysis 11.1 SYNOPSIS The dermal route of exposure and dose to toxic agents has gained recognition over the last decade as being important for certain population groups and certain classes of chemicals. This chapter introduces the field of dermal exposure and dose, and all its related components, such as the human skin, the factors affecting percutaneous absorption, the mechanisms of exposure, techniques used in the field for directly measuring dermal exposure, and the in vitro and in vivo techniques used for measuring percutaneous absorption. Some studies that demonstrate the amounts of chemical agents that contact the skin surface and types of chemicals that are absorbed through the skin are also presented in this chapter. Lastly, this chapter discusses the relative benefits of the direct and indirect techniques for determining dermal exposure and dose. Some effort has been made to describe the chemical and physical structure of the human skin. This type of knowledge can potentially provide insights for predicting the complex interactions between the skin and a toxic agent. Ultimately we wish to accurately predict the amount of a toxic agent that contacts the skin surface, and the mass that is able to cross the skin barrier into the dermal vasculature (i.e., blood vessels of the skin). By understanding the dermal route and developing reliable tools to quantify exposure and dose, the relative importance of the dermal route in a total health risk assessment can be established. Words that may be unfamiliar to the reader, especially biological terms related to the human skin, are in italics where first encountered, and found in the glossary at the end of the chapter. Happy reading!! 11.2 INTRODUCTION Human exposure and intake dose to environmental toxins has long been recognized as occurring via the inhalation and ingestion routes. More recently, the dermal route of exposure and dose has gained recognition as being an important route to study for certain classes of chemicals (e.g., metals, polychlorinated biphenyls [PCB], polycyclic aromatic hydrocarbons [PAH], and pesticides) and for certain high-risk, susceptible groups of individuals (e.g., children and pesticide handlers). However, much remains to be understood about the scenarios under which chemicals contact and adhere to the skin surface, the types of chemicals that are able to penetrate a mostly impermeable barrier (i.e., the skin), and how the process of dermal penetration occurs. In general, we are interested in dermal exposure and dose for the following reasons: (1) the local effect of chemicals (e.g., corticosteroids) applied to the skin for dermatology; (2) the transport of chemicals through the skin for systemic effects (e.g., nicotine patches); (3) the surface effects of chemicals (e.g., sunscreens); (4) the effect of chemicals applied to target deeper tissues (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs) for muscle inflammation); and (5) the unwanted exposure to and absorption of harsh agents (e.g., environmental exposures to industrial solvents, pesticides, allergens) (Roberts and Walters 1998). In most of these cases, we want to enhance the absorption rate of chemicals by altering the barrier function of the skin via chemical enhancement, iontophoresis, or phono- phoresis, for example (Rosado and Rodriques 2003). However, in the case of unwanted environ- mental exposures, we want to understand the extent of chemical loading on the skin and the absorption process so we can consequently develop methods of reducing that exposure and dose. 11.3 IMPORTANCE OF DERMAL EXPOSURE AND DOSE The five components of the complete human health risk model have been introduced in Chapter 1. As mentioned, the two components that have not been developed extensively are total human exposure analysis and dosage estimation (Zartarian and Leckie 1998). Risk estimation can therefore be improved with more robustness in aggregate or multiroute exposure and dose estimations. The Food Quality Protection Act (FQPA) of 1996 requires the U.S. Environmental Protection Agency (USEPA) to quantify aggregate exposure for chemical health risks — in particular, the health risk © 2007 by Taylor & Francis Group, LLC Dermal Exposure, Uptake, and Dose 257 posed by pesticides (U.S. Congress 1996). This importance for aggregate exposure assessment has motivated researchers to explore new and refined methodologies for measuring and modeling dermal exposure and dose (Fenske 2000), especially given that the dermal route has been understudied relative to the ingestion and inhalation routes. For the dermal route, quantifying exposure and dose has been challenging because loading onto, removal from, and uptake into the skin varies in space and time (Zartarian et al. 2000). Special interest has also been given to population groups that might receive enhanced exposure through the dermal route because of their unique activity patterns, environmental conditions, or increased biological susceptibility. These groups may include children, pregnant women and their fetuses, pesticide applicators, industrial workers, hairdressers, metal workers, furniture workers, and food handlers. A common exposure scenario where the dermal route is of special interest is the exposure of children to pesticides in and around the residential environment, including schools and daycare environments (Schmidt 1999; Wilson, Chuang, and Lyu 2001; Wilson et al. 2003, 2004). Up to 90% of households use products containing pesticides (see Chapter 15) providing ample opportunity for exposure through regular use, as well as through misuse and accidents. Homeowners used an estimated 74 million lbs of conventional pesticides in 1995; at the time, 939 million lbs were used for agriculture (Aspelin 1997). Home and garden consumption of pesticides was even higher in 1997 at 137 million lbs (62 million kg), while 946 million lbs (429 million kg) was consumed for agriculture (see Chapter 15). Pesticide use poses a variety of health issues for the general public. Illnesses like brain cancer, childhood leukemia, immune system disorders, and learning disabilities have been linked to long-term exposure to pesticides (Sinclair 1995). Short-term acute health issues include skin rashes, headaches, dizziness, and even death. In 1993, for example, there were 140,000 acute pesticide exposures reported nationwide, and 93% of those exposures took place in the home. Children under age 6 accounted for over half of all reported exposures (Grossman 1995). When it comes to exposure to pesticides through the dermal exposure route, young children are possibly at greater risk when compared to adults because of their unique activity patterns (e.g., crawling on floors, carpets, and in sandboxes in and around the home where pesticides may be present), their larger surface area to body weight ratio, and their developing organs. Children in agricultural communities are a special susceptible group with possible increased exposure to multiple pesticides due to their proximity to agricultural fields and contaminants tracked from farms to the home by their parents (Simcox et al. 1995; Fenske et al. 2000). There is also concern for children’s health due to their possibly increased dermal exposure to heavy metals, such as lead, found in house dust (Roels et al. 1980), and arsenic found in a chrominated copper arsenate (CCR) material used to coat decks and play structures (Hemond and Solo-Gabriele 2004). A number of initiatives stemming from the 1996 FQPA and the National Research Council’s report Pesticides in the Diets of Infants and Children (NRC 1993) have been implemented to protect children, including but not limited to: (1) the Federal Executive Order of 21st April 1997, “Protection of Children from Environmental Risks and Safety Risks”; (2) the creation of the Centers for Children’s Environmental Heath and Disease Prevention Research established by the USEPA, Centers for Disease Control and Prevention (CDC), and the National Institute of Environmental Health Sciences (NIEHS) (O’Fallon, Collman, and Dearry 2000); (3) the development of the Children’s Health Act; (4) the Strategy for Research on Environmental Risks to Children; (5) the creation of the Child-Specific Exposure Factors Handbook; (6) and the Guidance for Assessing Cancer Susceptibility from Early-Life Exposure (Williams, Holicky, and Paustenbach 2003). 11.4 DEFINING DERMAL EXPOSURE AND DOSE Figure 11.1 illustrates the relationship between dermal exposure and dermal dose and the contact boundary, the skin. Dermal exposure and dose are intimately related, with both processes occurring simultaneously. Dermal exposure occurs at the surface and dermal dose through the skin. Dermal exposure occurs when the human skin (i.e., exposure boundary) contacts a chemical (e.g., pesticide), © 2007 by Taylor & Francis Group, LLC 258 Exposure Analysis physical (e.g., building), or biological (e.g., bacteria) agent present in an environmental carrier medium, such as air, liquid, or soil (Zartarian 1996). Chemical exposure is specifically defined as the contact of an exposure boundary (i.e., skin, mouth, nasal passage) of a human target with a pollutant concentration (Duan, Dobbs, and Ott 1990; Zartarian, Ott, and Duan 1997; see Chapter 2). An environmental carrier medium is often called the vehicle of transport, and a chemical agent is always associated with one or more vehicles (e.g., water, air, soil, chemical formulation). A dermal exposure analysis attempts to determine how much of an agent comes into contact with the skin via a carrier medium and how much of the agent remains on the skin surface. The magnitude of an individual’s dermal exposure is dictated by: (1) the duration and frequency of contact with surfaces and objects in the environment (i.e. personal activity patterns), (2) the concentrations of chemicals on the surfaces and objects contacted, and (3) the transfer rates of chemicals from surfaces and objects to the skin during the contact events. A dermal dose analysis attempts to determine the mass of a chemical agent that has penetrated the target via the exposure/contact boundary, the skin (see Chapter 2). Percutaneous absorption is another commonly used term for dermal dose, especially in the medical field. Technically, when the pollutant mass of the agent enters the skin, but has not yet entered the bloodstream beneath the epidermis, it is called the potential dose; it becomes an actual dose (or absorbed dose) after entering the bloodstream. There is reason to believe that most of the chemical that enters or is retained in the skin will eventually be systemically absorbed with time, unless there is permanent binding or metabolism of the chemical in the upper layers of the skin. From a dermal exposure estimate of the mass of an agent on the skin surface, calculations can be made of the mass of the agent that enters the skin over time. The dermal intake dose estimate is equal to or less than exposure mass at the skin surface, and is affected by skin, chemical, and environmental factors. The delivered portion of the absorbed dose (i.e., dose to a target tissue or organ as determined by the processes of distribution, metabolism, and elimination) can ultimately result in a health effect. FIGURE 11.1 Relationship between dermal exposure and dermal dose. For dermal exposure, a mass of agent comes into contact with the surface of the skin. If conditions allow, the agent begins to diffuse through the skin barrier towards the bloodstream for dermal dose. Any mass of agent that enters the skin is called potential dose, while any mass that enters the bloodstream is called actual dose. Once in the bloodstream, the agent is distributed throughout the rest of the body. Dermal Exposure: mass of agent contacting skin surface Contact Boundary Human Skin Bloodstream Dermal Dose: mass of agent diffusing through the skin Mass of agent contacting and diffusing through skin Relationship between Dermal Exposure and Dermal Dose © 2007 by Taylor & Francis Group, LLC Dermal Exposure, Uptake, and Dose 259 11.5 THE HUMAN SKIN 11.5.1 G ENERAL S KIN S TRUCTURE The dermal exposure boundary, the skin, is a complex, multilayer, multipathway, biological mem- brane that requires special consideration in order to understand the process of dermal absorption. Being the largest organ of the body, the skin surface area of a male adult is close to 20,000 cm 2 , while the mass of the skin accounts for over 10% of our total body mass at around 7 kg for a 65- kg adult (Roberts and Walters 1998). With a thickness between 0.5 to over 4 mm, depending on the area of the body, the skin consists of an outer epidermis, an inner dermis layer, and an underlying subcutaneous layer (Figure 11.2). The epidermis is a stratified, squamous, keratinized, thin, avas- cular layer that consists of four to five cell layers (stratum germinativum, stratum spinosum, stratum granulosum, stratum lucidum, stratum corneum), depending on the body site. The last four layers of the epidermis are commonly lumped together and called the viable epidermis (VE), while the outermost layer, the stratum corneum (SC) or horny layer, is considered separately as the most impermeable barrier to absorption of chemicals due to its dried and hardened structure. The dermis, on the other hand, consists mainly of dense irregular connective tissue surrounded by collagen, elastic, and reticular fibers embedded in an amorphous ground substance. The dermis consists of two layers, the papillary layer and the reticular layer (Figure 11.2). In the papillary layer, the collagen and elastin fibers are folded in ridges or papillae, which extend into the epidermis (most noticeable in the palms of hands and soles of the feet; Figure 11.2). These undulating papillae increase the surface contact between the epidermis and dermis, facilitating the diffusion of nutrients, growth factors, and xenobiotics for the avascular epidermis. FIGURE 11.2 Complex structure of the skin. The human skin is the largest organ of the body, exhibiting a complex heterogeneous structure. The three main layers of the human skin are the epidermis, dermis, and subcutaneous layers. These layers possess varied structural and physiochemical features that allow the skin to metabolize compounds, detect pain and touch, regulate temperature, protect itself from ultraviolet radiation, give mechanical support, and regulate sweat and sebum secretion. Epidermis 50–100 μm Undulating papillae Collagen and elastin fibers Erector pili muscle Hair follicle Papillary layer Stratum corneum Stratum lucidum Stratum granulosum Stratum spinosum Stratum germinativum Reticular layer Dermis 1–2 mm Subcutaneous layer 1–2 mm Sweat duct Sweat gland Hair Nerve Artery Vein Sebaceous gland © 2007 by Taylor & Francis Group, LLC 260 Exposure Analysis The subcutaneous layer contains adipose tissue, nerve fibers, and blood vessels supplying the skin capillaries and lymphatics. There is an increase in thickness of the layers of the skin from the surface of the skin toward the bloodstream. Additionally, the skin’s thickness varies throughout the body as a function of body site, age, and sex and is an important factor when considering dermal absorption (Whitton and Everall 1973). Appendages on the skin surface are no more than 0.1% of total body surface area, and include sweat ducts (400 glands per cm 2 ), hair follicles (300–500 per cm 2 ), and nail (Roberts and Walters 1998), through which chemicals can be absorbed. Sebaceous glands are found along the shaft of hair follicles, and there are one to two glands per hair follicle, which vary in size from 200 to 2,000 µm in diameter. 11.5.2 G ENERAL S KIN F UNCTION Acting like a protective waterproof layer, the skin has many functions, including regulation of body temperature, metabolism, drug biotransformation, and use of sensory nerve endings to detect changes in environmental conditions (Monteiro-Reviere 1996; Chuong et al. 2002). The epidermis allows the exchange of warmth, air, and fluids, is resistant to damage, provides mechanical support, prevents bacterial invasion and evaporation, and contains melanin for skin color and ultraviolet protection. The dermis gives the skin its strength and elastic properties. Sweat and sebaceous glands that originate in the dermis also provide the acid mantle (pH of 5.5), which is a natural film of sebum and sweat that protects the skin from outside attack and may have some effect on the adherence of chemicals to the surface of the skin. The dermis also contains countless tiny blood vessels. These blood vessels: (1) feed the outermost epidermal layer above the dermis; (2) absorb substances applied to skin; and (3) contain important enzymes to break down or inactivate toxic substances (e.g., esterase enzymes). Feeding, excretion, heat exchange, metabolism, and insulation are found in the subcutaneous layer. The subcutaneous layer also anchors the dermis to the underlying muscle or bone. 11.5.3 T HE F UNCTION AND S TRUCTURE OF THE S TRATUM C ORNEUM (SC) Because the SC has unique structural characteristics and is believed to be the main barrier to absorption (USEPA 1992), additional discussion of this layer is warranted. Originally considered a disorganized, nonfunctional layer before the 1950s, the SC is now recognized as being a meta- bolically active, compartmentalized layer (Kligman 1964). In general, the functions of the SC are to retain body fluids, to prevent the disruption of living cells by water or harsh environmental chemicals, and to protect tissues from fatal drying and osmotic damage from bathing. While performing these functions, the SC must still remain thin enough to be flexible and plastic (Kligman 1964). The SC provides a stable environment; it contains insoluble cell membranes, matrix- embedded fibers, specialized desmosome junctions between cells, and intercellular cement. The desmosome junctions between cells are keratin, cytoskeletal structures that attach cells creating a tissue very resistant to shearing forces (Roberts and Walters 1998). The SC’s importance in the prevention of chemical absorption can be illustrated by considering the oral mucosa, which lacks a SC. The oral mucosa is highly penetrable; drugs are often administered by this route for quick absorption (Kligman 1964). The physical appearance of the SC has often been called a brick and mortar structure, with the brick being the protein corneocytes, and the mortar being the lipid intercellular regions between the corneocytes (Figure 11.3). The SC cells are non-nucleated, fused, flattened, squamous cells filled with keratin fibers. The protein corneocyte cells comprise 99% of the SC and are stacked almost vertically in 15 to 25 layers, making the SC layer 10 to 20 µm thick (Roberts and Walters 1998). The SC cells are thicker in areas of the body that are subjected to frequent direct interaction with the physical environment (e.g., the palms of hands and soles of feet). A typical SC corneocyte cell is 0.8–1.0 µm thick and 25–45 µm in diameter (30 times as wide as thick; Mershon 1975). © 2007 by Taylor & Francis Group, LLC Dermal Exposure, Uptake, and Dose 261 Each SC cell is made of about 70% insoluble bundled keratins and about 20% lipid encased in a cell envelope (Roberts and Walters 1998). Macromolecular protein fibers dominate in the envelope as well as in the contents (Kligman 1964). The lipid corneocyte envelope resists the passage of water and other small polar molecules in and out of the corneocyte, while playing a role in SC cohesion (Moghimi, Barry, and Williams 1999) The intercellular region is about 150 ° A wide in most tissues but may reach 400 ° A between keratinized cells (Mershon 1975), and is many times greater than the internal or external surface of the epidermis. The intercellular lipids are arranged in lamellar sheets, which are paired bilayers formed from fused lamellar granule disks (magnified in Figure 11.3). In essence, the polar regions of lipids are attracted to each other and dissolved in an aqueous layer while the hydrocarbon, lipid, non-polar regions mirror each other on the other side of the bilayer (Moghimi, Barry, and Williams 1999). No single component provides the barrier properties in the SC intercellular domain, but experiments establish that the order and physical state of the lamellar structure as described above is essential. Apart from the continuous lipid bilayers of the SC intercellular domain that provide a diffusional barrier, a geometrical barrier also exists due to the tortuous pathway around corneocyte cells that chemicals are believed to mostly travel to get across the SC layer. 11.5.4 S HEDDING AND H YDRATION IN THE S TRATUM C ORNEUM The entire epidermis is said to possess a cohesion gradient; as the cells move upward to the surface of the skin they acquire a tough envelope, and the cytoplasm in the cells becomes progressively packed with more and more consolidated fibrous keratin. The maximum cohesion gradient is reached in the lower SC; the cohesion gradient is reversed in the upper SC, and cell units are able FIGURE 11.3 Brick and mortar structure of the SC and bilayer structure of the intercellular lipids. The stratum corneum is the topmost layer of the viable epidermis and is comprised mostly of protein-rich corneocyte cells that are surrounded by a lipid-rich intercellular region. The corneocytes tend to be stacked vertically, and slowly make their way to the surface of the skin in a shedding process called desquamation. The SC content is 70% protein, 15% water, and another 15% is lipids and other materials. Skin surface Hard proteineceous corneocyte cells Lipid-rich intercellular region Polar heads Nonpolar lipid tails © 2007 by Taylor & Francis Group, LLC 262 Exposure Analysis to be destroyed as forces holding them together become weak as desquamation takes place (Kligman 1964). Corneocyte cells take 1–6 weeks to reach the surface, resulting in complete renewal of the SC in 15 days. Adults may shed 3.5 g/m 2 -day from the palm and about 0.2 g/m 2 -day from the upper arm (Kligman 1964). Chemicals may be lost from the skin surface in the process of shedding. The density of the SC is about 1.4 g/cm 3 in the dry state; hydration is only about 15–20%, compared with the rest of body at 70% hydration. Water may be lost by sweating or by diffusion, where this loss is dependent on conditions of airflow, temperature, humidity, surface characteristics (e.g., occlusion and immersion) and thickness of the SC. The average adult has a total transepidermal water loss of 85–170 mL/day under normal conditions. Due to sweating, water loss can increase to 300–500 mL/day (Idson 1978). The general belief is that increased hydration causes an increase in skin absorption. 11.6 FACTORS AFFECTING DERMAL DOSE Once a chemical agent contacts the skin surface, there is potential for the chemical agent to be absorbed through the skin. Although the SC is said to be the rate-limiting barrier to absorption of chemicals applied to the skin (Monteiro-Riviere 1996; Wertz 1996) permeation can occur, mainly through the intercellular lipid domain of the SC (Malkinson 1964), and mostly for nonpolar compounds. In addition, hair follicles and sebaceous and sweat glands provide possible channels through the skin, especially for ions and large polar molecules; some chemicals therefore bypass the rate-limiting SC barrier (Moghimi, Barry, and Williams 1999). Polar compounds (e.g., organic ions) are also hypothesized to travel by special polar pathways such as keratinized protein cell remnants and polar head regions of the lipid domain (Sznitowska and Berner 1995). In general, three major variables may account for the chemical rate and amount of penetration through the skin: (1) the concentration of chemical applied, (2) the partition coefficient of the chemical between SC and vehicle, and (3) the diffusivity of the chemical within the vehicle and within the skin. These three variables are in turn controlled by other chemical factors, skin factors, and environmental factors (Figure 11.4). The chemical-related factors affecting absorption through the skin include a chemical’s lipid and water solubility, molecular size, volatility, and chemical configuration (Malkinson 1964). The skin-related factors include the physiology of the skin (e.g., metabolism, natural psychological changes in blood flow), the anatomy of the skin (e.g., variation in number of cell layers and thickness of layers due to anatomy location or aging skin), and the condition of the skin (e.g., disease, damage, physical injury, skin exposure) (Jackson 1990). The mechanical properties of the skin (e.g., elasticity) are also important in the skin’s protective function (Marks 1983). Some environmental factors affecting absorption include exposure conditions (e.g., fluctuation in chemical mass loadings, occlusion and residence time on skin surface), temperature, humidity, and vehicle properties. Occlusion, humidity, perspiration, and high external temperatures can lead to an increase in chemical absorption by causing an increase in skin hydration (Chang and Riviere 1991; Jewell et al. 2000; Poet et al. 2000; Zhai and Maibach 2001; Pendlington et al. 2001). Increased perspiration, heart rate, body temperature and circulation, on occasion caused by vigorous exercise, can also increase dermal absorption (Williams, Aston, and Krieger 2004). Reactive vehicles added to pesticide formulations such as organic, aprotic solvents (e.g., dimethyl sulfoxide, DMSO), and surfactants (e.g., sodium dodecyl sulfate) can affect solute per- meability by damaging the skin lipids or increasing the chemical agent’s ability to spread over the skin (Scheuplein and Blank 1971; Schaefer, Zesch, and Stuttgen 1982; Menzel 1995). Studies reflect that the permeability coefficient of a chemical for absorption through the skin correlates with its percentage saturation in the vehicle, its partitioning from the vehicle to the epidermis, and its likely new diffusion rate along the epidermal pathway caused by vehicle changes to the epidermis (Hilton et al. 1994; Roy, Manoukian, and Combs 1995; Sartorelli et al. 1997; Selim et al. 1999; Jepson and McDougal 1999; Riviere et al. 2001; Rosado et al. 2003). © 2007 by Taylor & Francis Group, LLC Dermal Exposure, Uptake, and Dose 263 Significant skin dynamics affecting the absorption of chemicals include skin surface properties and metabolism. Skin surface properties may affect the adherence of chemical agents and vehicles and consequently the mass transfer or diffusion of the agent through the skin. For example, moisture on the skin may increase the adherence of a soil particle that has a pesticide concentration. Skin surface properties may vary from person to person (e.g., by age, sex, or race), from one anatomical site to the next (e.g., torso, palm of hand, scrotum) or because of differences in environmental conditions. A few researchers in the cosmetic industry have attempted to define various surface properties of the skin such as roughness, scaliness, skin surface pH, and hydration (Moghimi, Barry, and Williams 1999; Randeau et al. 2001; Eberlein-Konig, Spiegel, and Przybilla 1996; Eberlein- Konig et al. 2000; and Manuskiatti, Schwindt, and Maibach 1998). Metabolism is the process where chemicals are converted to other chemicals by the reaction and interaction with enzymes. Viable skin contains most of the metabolizing enzymes; xenobiotics- metabolizing enzymes, for example, are thought to be mostly in the basal layer of the epidermis (Jewell et al. 2000). Acetylation, hydrolysis, alcohol oxidation, and reduction are some of the metabolic processes that have been demonstrated in the skin (Bronaugh et al. 1999). Bashir and Maibach (1999) claim that metabolic enzymes in the skin primarily act on lipophilic chemicals and convert them to hydrophilic chemicals that are less active and can be excreted via the kidneys. In analyzing the absorption rate and reservoir tendencies of chemicals, consideration must be given to the metabolic rates and metabolic by-products of the chemicals in the skin. 11.7 MECHANISMS AND PATHWAYS FOR DERMAL EXPOSURE Exposure is a complex phenomenon involving a number of potential chemical agents (e.g., chlor- pyrifos, lead) and the vehicles or medium (e.g., water, air, soil, xylene), in which they are immersed, FIGURE 11.4 Compound, skin, and environmental factors, in addition to the complex reactions between all three, affect the percutaneous absorption of the chemical. Insufficient data exist today to clarify the exact relationship between each factor and percutaneous absorption. In general, relatively small lipophilic, nonvol- atile chemicals are able to penetrate the skin more readily, absorption is increased through skin that is thin or damaged, and increased temperature and humidity and harsh vehicles increase the rate of absorption. Chemical ree Main Factors Affecting Percutaneous Absorption Skin Environment configuration molecular weight volatility solubility anatomy condition physiology exposure amount exposure time humidity temperature vehicle type PERCUTANEOUS ABSORPTION © 2007 by Taylor & Francis Group, LLC [...]... hand exposure during contact with equipment and in harvesting or spraying of crops (Whitmore et al 1994) Whole-body samplers have been used to assess occupational and residential pesticide exposure (Krieger and Dinoff 1996; Krieger et al © 2007 by Taylor & Francis Group, LLC 266 Exposure Analysis 2000), worker exposure to antifungal products during wood treatment (Fenske 1993a; Ross et al 1990), exposure. .. is developed (Fenske 1993a,b) Postexposure (i.e., after the exposure event to the source of interest) the skin is then held under a longwave ultraviolet light, and images capture the exposed body parts An indication of relative exposure can be obtained by comparing pre- and post -exposure images A quantitative estimate of exposure can then be obtained by comparing post -exposure images to the developed... goal of any exposure and dose estimate 11. 13 QUESTIONS FOR REVIEW 1 Under what exposure scenario might the dermal route of exposure be more important relative to the ingestion and inhalation pathway? 2 What types of human activities affect the magnitude of dermal exposure and dose? Are these activities different than the activities that would affect the magnitude of inhalation and ingestion exposure? ... Study of Preschool Children’s Aggregate Exposures to Persistent Organic Pollutants in Their Everyday Environments, Journal of Exposure Analysis and Environmental Epidemiology, 14: 260–274 Wilson, N.K., Chuang, J.C., and Lyu, C (2001) Levels of Persistent Organic Pollutants in Several Child Day Care Centers, Journal of Exposure Analysis and Environmental Epidemiology, 11: 449–458 Wilson, N.K., Chuang, J.C.,... application for in vivo and in vitro analysis, include the isolated perfused porcine skin flap (IPPSF) (Chang, Dauterman, and Riviere 1994), microdialysis (McDonald and Lunte 2003) and various spectroscopy and fluorescence microscopy techniques (Yu et al 2003; Notinger and Imhof 2004) © 2007 by Taylor & Francis Group, LLC Dermal Exposure, Uptake, and Dose 273 11. 11 HIGHLIGHTED DERMAL DOSE EXAMPLES There... 2.26 0.79 0.32 1.94 0.39 1.69 274 Exposure Analysis TABLE 11. 2 The Absorption Dynamics for Four Pesticides in the IPPSF Compounds Carbaryl Lindane Malathion Parathion Molecular Weight (g/mol) Vapor Pressure (mPa) Water Solubility (ppm @2000C) Henry’s Law (Pa-m3/mol @2500C) Log Octonol–Water Partition Coefficient (log Kow) 201.23 0.181 100 0.00028 2.29–3.46 290.85 5.6 6.6 11 0.183 3.6–3.72 330.4 0.45 145... surface contact, vaporization, absorption through the skin, and mouthing 11. 8 DIRECT METHODS FOR MEASURING DERMAL EXPOSURE Direct measurements of dermal exposure (to mostly non- and semi-volatile contaminants) are typically considered as skin exposure sampling techniques or personal sampling techniques (Cohen Hubal et al 2000) Exposure sampling techniques primarily fall into three categories: (1) use... Community on the U.S./Mexico Border: Preliminary Results, Journal of Exposure Analysis and Environmental Epidemiology, 13: 42–50 Simcox, N.J., Fenske, R.A., Wolz, S.A., Lee, I., and Kalman, D.A (1995) Pesticides in Household Dust and Soil: Exposure Pathways for Children of Agricultural Families, Environmental Health Perspectives, 103(12): 112 6 113 3 Sinclair, W (1995) Pesticide Health Effects Studies, in Allergy,... the study group (e.g., intentional exposure to toxic chemicals may not be practical for children) For all skin exposure sampling techniques not only is consistency in the application method important for interpreting the dermal exposure measurements, but the analytical procedures for extraction and analysis of the contaminant mass are also crucial for data quality 11. 8.1 SURROGATE SKIN TECHNIQUES Surrogate... for Understanding Dermal Exposure to Chemicals, Ph.D diss., Department of Civil Engineering, Stanford University, Stanford, CA Zartarian, V.G and Leckie, J.O (1998) Dermal Exposure: The Missing Link, Environmental Science and Technology, 3(3): 134A–137A Zartarian, V.G., Ott, W.R., and Duan, N (1997) A Quantitative Definition of Exposure and Related Concepts, Journal of Exposure Analysis and Environmental . University CONTENTS 11. 1 Synopsis 256 11. 2 Introduction 256 11. 3 Importance of Dermal Exposure and Dose 256 11. 4 Defining Dermal Exposure and Dose 257 11. 5 The Human Skin 259 11. 5.1 General Skin Structure 259 11. 5.2. 267 11. 9 Dermal Exposure Examples 269 11. 10 Direct Techniques for Measuring Absorption 270 11. 10.1 In Vitro Methods 271 11. 10.2 In Vivo Methods 272 11. 11 Highlighted Dermal Dose Examples 273 11. 12. for Dermal Exposure 263 11. 8 Direct Methods for Measuring Dermal Exposure 265 11. 8.1 Surrogate Skin Techniques 265 11. 8.2 Removal Techniques 266 11. 8.3 Fluorescent Tracer Techniques 266 11. 8.4 Surface