Applied Dermatotoxicology: Clinical Aspects

By Howard I. Maibach and Golara Honari

Applied Dermatotoxicology: Clinical Aspects provides concise, systematic, and state-of-the-art information on the toxicological effects of substances on skin, and recent advances in dermal toxicity testing.

This book specifically addresses the clinical presentations borne out of exposure to a variety of chemicals. It begins with an overview of skin biology to provide toxicologists with a basic understanding of its anatomy and physiology. Next it presents a variety of dermatotoxicological effects, as well at the toxic agents that cause them, with color photographs to illustrate these effects.

Applied Dermatotoxicology: Clinical Aspects is an essential reference for toxicologists in industry, and for those medical professionals who encounter cases of dermal exposure to toxic agents.

• A concise, yet inclusive review of effects of chemical exposure
• Includes background on basic skin biology
• Provides vital clinical reference for toxicologists in non-clinical settings

• Language: English
• Publisher: Academic Press
• Release date: Jun 24, 2014
• ISBN: 9780124201996

Howard I. Maibach

Howard Maibach is a Professor at the Department of Dermatology at UCSF, USA. He is an expert in contact and occupational dermatitis and sees patients at the Environmental Dermatosis Clinic, which is part of the Dermatology Clinic. His specialty is dermatotoxicology, or skin exposure toxicity; allergies and skin disorders; and dermatopharmacology or the study of medications for skin disorders. Maibach has been on the editorial board of more than 30 scientific journals and is a member of 19 professional societies including the American Academy of Dermatology, San Francisco Dermatological Society, and the Internal Commission on Occupation Health. His current research programs include defining the chemical-biologic faces of irritant dermatitis and the study of percutaneous penetration. When Dr Maibach is not in the lab conducting research or in the classroom teaching, he is seeing patients at the Environmental Dermatoses Clinic (of the Dermatology Clinic), mostly providing second opinions on allergic contact dermatitis.

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Preface

Golara Honari and Howard I. Maibach

This book offers an introduction to disciplines in dermatotoxicology; the science that studies the effect of environmental physical or chemical elements affecting skin along with their clinical consequences. For detailed information, we refer the readers to the textbook of Dermatotoxicology, 8th edition.

We provide concise information on clinical presentations and morphologic characteristics of distinct clinical entities, caused by environmental exposures, as well as latest toxicologic methods. We have tried to present the science of dermatotoxicology in a practical and easy to follow format, aiming to discuss clinical consequences of exposure to offending agents along with the main predictive methods for the assessment of these agents.

We thank all authors and our publisher with special thanks to Ms. Shannon Stanton and Ms. Priya Kumaraguruparan from Elsevier for their immense dedication.

We hope you find this book a useful introduction and appreciate your comments and suggestions.

Chapter 1

Skin Structure and Function

Golara Honari and Howard Maibach

Skin as the main interface between body and environment is a functional barrier with unique anatomic and physiologic features. This chapter provides an overview of the key elements of skin structure including skin layers, appendages, and immunologic components. Protective properties of skin, absorption pathways, as well as methods for objective measurement of these features are presented.

Keywords

Epidermis; stratum corneum; functional barrier; skin penetration; skin absorption; skin pH; desquamation; transepidermal water loss (TEWL)

Introduction

Skin as one of the largest organs in body has multiple key features required to interact dynamically with the environment. Primary functions include a barrier function against environmental hazards such as ultraviolet (UV) radiation, chemical and physical insults, and microorganisms. Skin also prevents dehydration, regulates temperature, and has self-healing properties. Dynamic and complex arrangement of variety of cells, element of the extracellular matrix, vascular, appendageal, and nervous structures each play a role. Knowledge of skin penetration pathways is essential in assessment of chemical safety, drug delivery systems, and formulation of cosmetic products.

These chapter overviews essential structural elements of skin, their key functions relevant to dermatotoxicology, skin absorption pathways, and key devices and methods to measure skin properties.

Structure and Function

Normal skin consists of three main layers: epidermis, dermis, and hypodermis.

• Epidermis: Barrier function, innate immunity, UV protection.

• Dermis: The largest component of skin, dermis is an integrated system of fibrous cellular and acellular matrix. Many cell types reside in dermis including fibroblasts, macrophages, mast cells. Vascular, lymphatic, and nervous networks are present in dermis.

• Hypodermis (subcutis): Provides mechanical and physiologic support and contains larger source of vessels and nerves.

There are regional variations in the skin thickness and presence of different appendages such as hair, sebaceous, and sweat glands, which can affect the functional properties. For example, hair baring skin is typically thinner and more permeable than nonhair baring skin of palms and soles.

Epidermis

Epidermis is the outermost layer and is about 0.05–1 mm in thickness depending on body part. Three main populations of cells reside in the epidermis: keratinocytes, melanocytes, and Langerhans cells. Keratinocytes are the predominant cells in the epidermis, which are constantly generated in the basal lamina and go through maturation, differentiation, and migration to the surface. As keratinocytes differentiate, they form three layers above the basal layer known as stratum spinosum (SP), stratum granulosum (SG), and stratum corneum (SC) (Figure 1.1). Keratinocyte transit time from basal layer up to SC is about 14 days¹ and turn over time within SC is also around 14 days,² certain inflammatory conditions can affect these turn over times.

Figure 1.1 Schematic of epidermis—basal cell layer is the deepest layer of epidermis differentiating to spinous cells then to granular cells and eventually terminally differentiate to SC.

SC is the outer layer of the epidermis and serves as the main functional barrier. A theoretical model is brick and mortar like structure where bricks represent terminally differentiated nonviable keratinocytes, also known as corneocytes embedded in intercellular lipid membranes.³ As corneodesmosomes (protein bridges between corneocytes) degrade, lacunar spaces are created within the SC referred to as aqueous pore pathway. These spaces can extend and form continues networks, creating a pathway for penetration across the SC.⁴

Major components of the SC lipid membranes are free fatty acids, ceramides, and esterols.⁵ Melanocytes are neural crest-derived, pigment synthesizing dendritic cells that reside primarily in the basal layer. Merkel cells are mechanosensory receptors also present in basal layer. Langerhans cells are dendritic antigen-processing and antigen-presenting cells in the epidermis.⁶ They form 2–8% of the total epidermal cell population, mostly found in a suprabasal position. The dermal–epidermal junction (DEJ) is a basement membrane zone that forms the interface between the epidermis and dermis. The major functions of the DEJ are to attach the epidermis and dermis to each other and to provide resistance against external shearing forces.

Dermis

The dermis is an integrated system of fibrous cellular and acellular matrix that accommodates nervous and vascular structures as well as epidermally derived appendages. Many cell types reside in the dermis including fibroblasts, macrophages, mast cells, and circulating immune cells. Dermis is responsible for skin elasticity, pliability, and tensile strength and provides protection against mechanical injury, retins water, and aids in thermal regulation. Dermis also contains and supports receptors of sensory stimuli and a key element in wound healing.⁷

Hypodermis

Hypodermis is primarily composed of adipose tissue, which insulates the body, serves as a reserve energy supply. It cushions and protects skin and supports nerves, vessels, and lymphatics located within the septa, supplying the overlying region.

Skin Appendages

Skin appendages include nails, hair, sebaceous glands, eccrine (sweat) glands, and apocrine glands. They have two distinct components: superficial and deeper components in the dermis, which are down growths of epidermis. Dermal component regulates differentiation of the appendage. During embryonic development, dermal–epidermal interactions are critical for the induction and differentiation of these structures.

Skin a Route of Entry

The SC is 3–20 µm in thickness, composed of 15–25 layers of corneocytes. It provides an effective barrier against transcutaneous water loss and entry of exogenous materials.

Extracellular lipids contribute to barrier function and the route taken through the SC by all molecules. Arrangement of extracellular lipids, their hydrophobicity, composition, and distribution of key components (ceramides, cholesterol, and free fatty acids) provide more barrier function.⁸ Skin absorption varies between different body parts, and between individuals, these regional intra- and inter-individual variations are partly related to variations in lipid composition and SC thickness.⁸ A range of biological factors can influence the rate and extent of percutaneous penetration including anatomical site, age, appendageal density, SC morphology, and composition. Routs through which chemicals can cross the SC (Figure 1.2) include⁹:

• Intercellular (or extracellular), in which chemicals pass exclusively through the lipid matrix

• Intracellular or transcellular, in which chemicals pass through both the lipid matrix and the corneocytes themselves.

• Through skin appendages

• Mechanical methods to remove SC such as stripping, ablation, micro needles, etc.

Figure 1.2 Schematic pathways of penetration into the skin with arrangement of corneocytes in a brick and mortar model.⁹

In vivo measurements skin absorption to quantify and rate the extent of absorption is of fundamental importance in the risk assessment of compounds that are active via the dermal route of entry, though the details are beyond the scope of this chapter.

Measuring Skin

Measuring physical characteristics of skin using biophysical instruments provides key information about various skin parameters. Many noninvasive techniques and equipment are available with increasing applications within dermatotoxicology, allowing study of skin in real time and providing objective, quantitative data.

Parameters measured with these techniques provide information about a particular aspect of skin. Using multiple parameters measured simultaneously, along with clinical assessment provides more comprehensive analysis. Histologic studies may be used to complement these analyses. Few parameters and techniques are briefly introduced in this chapter; additional texts are available for comprehensive study.¹⁰,¹¹

Skin Surface pH

Skin pH is normally acidic, ranging in pH values of 4–6, while the PH in body’s internal environment is near-neutral, ranging from 7 to 9.¹² The term acid mantle refers to inherent acidic nature of the SC. Skin pH affects barrier function and SC cohesion. Elevation of pH in normal skin creates a disturbed barrier.¹³ Measurement of skin surface pH is used to assess the acidity of the skin’s surface which skin surface pH can vary according to the time of day, skin site, and between individuals. There are several instruments available for measurement of skin pH; basically any standard, portable pH meter with a planar electrode should