Introduction to Histological Aspects of DermatotoxicologyDermatotoxicology is the discipline that deals with

the toxic effects of compounds penetrating through theskin. Skin is often considered to be the primary barrierbetween the external environment and the well-regulated milieu interieur. Recently, there has beenincreasing interest with the routes of potential humanexposure to environmental and occupational toxins.Additionally, advanced transdermal drug delivery sys-tems and dermatologic therapeutics have been ap-proved for human use. Skin is a complex yet integratedand dynamic organ that has several functions that gofar beyond its role as a barrier to the environment. Fortransdermal drug delivery, dermal therapeutic, andabsorption assessment studies, a detailed knowledge ofthe microscopic anatomy is crucial for understandingboth how a compound traverses the stratum corneumand the earliest manifestations of cytotoxicity.Cutaneous toxicology has been focused on dermal

penetration, acute toxicity, and skin irritation. In mostinstances, these studies have been performed usinglaboratory animals or cell cultures with the ultimategoal that data generated could be extrapolated forhuman risk assessment. Over the past few years stan-dardized tests have been developed to assure consis-tency between testing in different systems and laborato-ries. However, all of these systems are different andhave strengths and limitations that may restrict theiruse for specific purposes (absorption vs. toxicity). Thesenuances may only be understood by detailed anatomi-cal, physiological, and biochemical studies. This topicalissue, ‘‘Histological Aspects of Dermatotoxicology,’’ willfocus on articles pertaining to this subject.The need to select the proper model systems to study

cutaneous toxicity becomes increasingly important. Thefirst contribution by Monteiro-Riviere, Inman, Snider,Blank, and Hobson morphologically and biochemicallycompares a recently developed commercial human skinequivalent organ culture system with normal humanskin to assess its feasibility for use in dermatologicalresearch. This paper compares parameters that areimportant if such systems are to be routinely integratedinto dermatotoxicity studies.When a compound or formulation traverses through

the outermost layer of skin, the stratum corneum, itmust go through its intercellular lipid moiety consist-ing of cholesterol, fatty acids, and ceramides. Theselipids have been shown to comprise the permeabilitybarrier and are reviewed by Menon and Ghadially.They explain the origin and fate of the stratum cor-neum bilayers and discuss abnormalities. A diet defi-cient in linoleic acid can lead to essential fatty aciddeficiency and therefore barrier dysfunction. In addi-tion, topical application of several agents that causeinhibition of either cholesterol synthesis, glycolipid

synthesis, or epidermal fatty acid synthesis can affectthe barrier function. These authors also describe theeffect of application of emollients and other agents aswell as various diseases on the lipid bilayers and theirfunction. One of the most beneficial sections of theircontribution deals with the techniques and pitfalls usedto evaluate and visualize the stratum corneum lipidalterations.Studies by Fartasch further enlighten us on the

importance of the epidermal lipid layers. The results ofthis study show ultrastructural alterations in the lipidlayers after topical treatments with the irritants so-dium dodecyl sulfate and acetone. She demonstrateshow different irritants can induce distinct morphologi-cal alterations and affect the water permeability bar-rier in human skin.The article by Cranne-van Hinsberg, Verhoef, Spies,

Boustra, Gooris, Junginger, and Bodde discuss theperturbing effects of electrical current on the intercellu-lar lipids of the human stratum corneum. These studiesbeg the question that direct toxicity to this barrier mayalter a toxicant’s own absorption. The next contributionby McDougal, Grabau, Dong, Mattie, and Jepson inves-tigates this hypothesis; they report on the dermatotox-icity of 1,2-dichlorobenzene and chloropentafluoroben-zene in rats and guinea pigs, two chemicals whoseabsorption profiles these authors have previously stud-ied. They conclude that dermatotoxicity is an importantparameter that must be addressed when assessingcompound absorption.The next two and final contributions focus onmorpho-

logical aspects of chemical vesication induced by sulfurmustard. Petrali andOglesby-Megee describe the ultra-structural changes seen after vapor exposure in variouslaboratory animals and in vitro model systems. Theyreport on the ultrastructural changes induced in thestratum basale cells of the epidermis and the formationof microvesicles at the epidermal-dermal junction.Mon-teiro-Riviere and Inman describe these changes furtherusing the isolated perfused porcine skin flap system.The advantage of this model system is that ultrastruc-tural changes can be correlated to biochemical andphysiological events in the same preparation.In conclusion, these contributions give one an appre-

ciation of certain facets of dermatotoxicology that areimportant to consider when assessing the nature of acompound’s interaction with the skin. I hope that theyserve as a stimulus for further investigation in thisexciting field.

NANCYA. MONTEIRO-RIVIERE, Ph.D.Professor of Investigative Dermatology and Toxicology

North Carolina State UniversityRaleigh, North Carolina

MICROSCOPY RESEARCH AND TECHNIQUE 37:171 (1997)

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