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Environmental reactions to chemical, physical, and biologic agents Writers: James S. Taylor, M.D., John A. Parrish, M.D., and Irvin H. Blank, Ph.D. Cleveland, OH, and Boston, MA Ad hoc committee: Robert M. Adams, M.D., William A. Akers, M.D., David R. Bickers, M.D., Donald J. Birmingham, M.D., Irvin H. Blank, Ph.D., Edward A. Emmett, M.B., B.S., John Epstein, M.D., James R. Fours, Ph.D., Kimie Fukuyama, M.D., Ph.D., Richard W. Gange, M.D., Gerald A. Gellin, M.D., Barbara A. Gilchrest, M.D., Marcus M. Key, M.D., Albert M. Kligman, M.D., Ph.D., Kenneth H. Kraemer, M.D., Gerald S. Lazarus, M.D., Howard I. Maibach, M.D., Warwick L. Morison, M.D., Alan N. Moshell, M.D., John A. Parrish, M.D., Madhukar A. Pathak, M.B., Ph.D., Robert B, Pittetkow, M.D., Alan Poland, M.D., S. Madli Puhvel, Ph.D., Robert L. Rietschel, M.D., Edward Shmunes, M.D., Frances J. Storrs, M.D., Raymond R. Suskind, M.D., and James S. Taylor, M.D. The skin is a major interface between humans and their physical, chemical, and biologic environment. It is a foremost portal of entry of potentially hazardous agents and is a vulnerable target for damage by environmental agents. It is a uniquely accessible model system to detect hazards and to study mechanisms of a wide variety of biologic functions, including adaptive processes and adverse reactions. Important advances have been made in defining the cause and in realizing prevention of environmental skin disease in both basic and clinical research areas. However, much work remains if we are to reduce the prevalence of these diseases that bring about an enormous loss of productivity each year and are a major cause of disability. This report details progress over the past 5 years and identifies areas in which new technology shows promise of generating new solutions.

RECENT PROGRESS Prevalence, severity, and importance Recognition by federal government. In December 1978, the Occupational Safety and Health Administration (OSHA) issued the comprehensive

report Cutaneous Hazards, 2 a landmark document. It is an important compendium on the prevalence, identification, classification, and methods of prevention and control of occupational skin disease. It cited specific information on ten industries that contribute to the frequency of occupational dermatoses, and it identified important research gaps. In 1980, the National Institute for Occupational Safety and Health (NIOSH) issued research applications stating that widespread, debilitating, work-related skin disorders were the most pervasive current occupational problem in the U.S? More persons suffer from occupational skin disorders than from any other single category of occupational disease in the U.S. Skin disease, the vast majority of which is attributable to effects of toxic chemicals, still accounts for greater than 40% of all reported occupational diseases. Inadequate reporting masks the true incidence, suspected to be ten to fifty times greater than the reported incidence. It is generally accepted that these disorders impose a serious personal and economic burden in lost production and wages, increased medical costs, family disruption, personal discomfort, and ill health?

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In addition to environmental exposures in the handling of chemicals, there is exposure to potentially hazardous materials that touch the skin during daily life: clothing, cosmetics, cleansing agents, contaminated surfaces, incompletely cured plastics and resins, plants, food, jewelry, and a vast array of consumer products. Renewed clinical interest. There has also been a renewed clinical interest in occupational skin disease. A course has been reinstituted at the annual meeting of the American Academy of Dermatology, and NIOSH has sponsored two meetings with workshops since 1979. A number of new textbooks have recently been publishedY ~ Contact dermatitis Contact dermatitis is still by far the most frequent occupational skin disease and has forced many persons to lose seniority positions and change careers. Data from California reported in 1982 indicated that, in 1977, 92.5% of the cases of occupational skin disease were contact dermatitis, either irritant or allergic, t t,12Although irritant dermatitis accounts for most contact dermatitis, it is the least understood. Marginal irritants that are cumulative are especially baffling. Allergic contact dermatitis deserves notice because of the specificity of the response and the relatively minute amounts of allergen that elicit an inflammatory reaction. Basic research. There has been significant progress in deciphering the mechanism of contact allergy: in particular, the involvement and function of Langerhans cells, manipulation of the immune system to induce tolerance, and the timing and route of exposures to allergens. 13 Ultraviolet light (UVA and UVB) also has been found to influence the development of contact dermatitis. 14 The Langerhans cells may be operative in the pathogenesis of mycosis fungoides, a malignancy that might be partially related to exposure to environmental chemicals and antecedent allergies, j5"16 New information has developed on modulation of mitogenie response to human T ceils in prostaglandin (PG) and leukotriene research, which could open new pathways to the prevention of allergic contact dermatitis. ~7 Clinical research. Advances have been made in the prevention and treatment of certain types of

Journal of the American Academy of Dermatology contact dermatitis. Poison oak/ivy dermatitis, a major occupational hazard, is a T cell-mediated immune reaction against urushiol, a hapten contained in the oil of the plants. There are recent reports of the induction of i m m u n e tolerance with subsequent hyposensitization to urushiol in children and of the induction of antigen-specific hyposensitization to urushiol in sensitized adults. 18-zo Contact dermatitis of the hands, a major occupational disorder, zI,22has been successfully treated with psoralens-UVA (PUVA). Advances in chemistry have been of significance. The clarification of the structure-activity relationship of chemicals producing allergic contact dermatitis is of direct relevance in identifying cross-sensitizing substances and in preventing allergic contact dermatitis. The chemical composition of some contact allergens has been reported (e.g., plants in the family Compositae, a significant environmental health problem). ~ Epidemiologic studies o f contact dermatitis among normal populations in the U.S. and in Denmark indicate that the prevalence of contact dermatitis to certain allergens (e. g., nickel, ethylenediamine) may approach that seen in patients with eczema in patch test clinics. 4,5 Contact urticaria has been reported with increasing frequency, and delayed onset type (4 to 6 hours) has recently been described. 23New contact allergens of occupational and environmental significance have been reported (glycerylmonothioglycolate, a significant problem among hairdressers24; polyfunctional acrylates in UV light-cured links; fragrances such as musk ambrette and 6-methylcoumarin; epoxy resin; and components of metal working fluids). 4~ Standardization of patch test antigens has improved and the true significance of false positive tests (excited skin or angry back syndrome) has been appreciated. 48 Recognition of the magnitude of reactions from systemic exposure to contact allergens has increased (e.g., nickel and hand eczema and reactions to implanted devices and to medicaments). 25 A c c o m m o d a t i o n . A small percentage of huraans (approximately 10%) have accornmodated to irritants over a time course of 4 to 6 weeks of continued exposure. Although accommodation can be maintained, it does not protect against in-

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duction of new contact allergy or the recall of a previously established allergy. Humans with chronically inflamed skin from external irritants who maintain their exposure but do not harden well do not become sensitized to new chemicals as much as would be expected. The inflammatory process might inhibit the acquisition of new allergy in some but not all persons. Those with chronically inflamed skin who were least likely to become sensitized to new allergens can be characterized by little or no reactivity to PGE2 .2~

Percutaneous absorption 2~37 Advances in percutaneous absorption have been reported: identification of the nature of the permeability of the stratum corneum barrier to water, key elements in that barrier, abnormalities related to disease, results of exposure to various occupational and environmental agents, and protection strategies. Pharmacokinetics of topically applied drugs. Investigators have only recently begun to look at the pharmacokinetics of and the response of the target organ to drugs that are topically applied to the skin (e.g., nitroglycerin, scopalamine). These studies are directly relevant to environmental chemicals. Systemic toxicity from exposure to chemicals. Additional quantitative studies have emphasized the skin as a prime route of absorption for certain occupational and environmental chemicals (e.g., dimethylformamide and neurotoxic compounds). Nature of stratum corneum and mechanism of molecular transport across the skin. It has been proposed that the stratum comeum functions as a two-compartment system. The lipophilic compartments, primarily the intercellular cement, are composed mostly of lipids and are the pathway through which nonpolar molecules diffuse. The intracellular material, primarily proteins, is the laydrophilic compartment through which water and polar molecules diffuse. The flux of water through the stratum comeum is a function of its water content. The higher its water content, the more easily molecules can move through the stratum corneum. Even with this information, the effect of increasing relative humidity on transepidermal water loss (TEWL) cannot

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be predicted because the increase caused by hydration of the tissue is balanced by a decrease caused by a lower concentration gradient. TEWL and water concentration profile change very little between 0% and 80% relative humidity. Endogeneous hydration of the stratum corneum that occurs with occlusion makes most molecules, polar and nonpolar, move through this tissue more easily. Increasing attention is being paid to the lipid compartment as the part of the stratum corneum that nonpolar molecules such as the steroids dissolve, thereby allowing this tissue to serve as a reservoir. For strongly lipid-soluble molecules that enter the stratum corneum easily and probably move through it with ease (high diffusion constant), it is beginning to appear that the rate-limiting barrier is not the stratmn corneum but the lipid/aqueous fluid interface at the base of the stratum corneum. Lipid-soluble materials tend to stay in the stratum corneum rather than move into the aqueous tissue fluids of the viable epidermis. Effect of age on skin permeability. There is little solid evidence that skin permeability varies as a function of age. It is difficult to study this factor because there is so much variability within each age group. However, it has been shown that the infant's skin is more permeable to some molecules. Vehicles. Vehicles influence skin penetration by altering the partition coefficient. In addition, a vehicle can enter the stratum corneum and alter its barrier characteristics. It is probably this mechanism by which dimethylsulfoxide increases penetration. Azone may function similarly, although its mechanism is not yet definitely known.

Skin reactions with water Dry skin. Studies on the causes and treatment of dry skin continue to focus on the water content of the stratum corneum. It is now believed that any significant deficiency in water is limited to the upper two or three cell layers of this tissue. Such water deficiencies can be corrected simply by water itself or by an occlusive covering such as petrolatum. Causes of water deficiency are not always known, except possibly when low environmental relative humidity is involved. A lack of natural moisturizing factors has been postulated but not

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proved. Roughness, somewhat independent of water content, is a characteristic of dry skin and can be corrected by a simple emollient. Physical characteristics of the stratum corneum contribute to the sensation of dryness. Viscoelasticity can now be measured in vivo 38 and is probably a meaningful parameter of dry skin. Efforts at measuring the water content of the stratum corneum in vivo have been disappointing. Possibly a recently developed focused microwave probe 39 will be helpful. It will not yet determine the water concentration profile of the stratum comeum. Studies on the effect of hydration on the diffusion of water through stratum corneum of different levels of hydration have yielded data that make possible the calculation of theoretical profiles and of the TEWL at different environmental relative humidities. 4~ Methods of measuring TEWL in vivo at different relative humidities are not entirely satisfactory. A new instrument, the evaporimeter, 42is simple to use. Data from it need critical evaluation. Premature infants ( < 3 0 weeks gestational age) have a high TEWL. The barrier to water loss causes normal values approximately 2 weeks after birth. 43 Measurements of the penetration of various molecules through normal and hydrated stratum corneum have shown that penetration is more rapid through hydrated skin. The stratum corneum may be hydrated exogenously or endogenously, i.e., occlusion. This reversible alteration of the barrier characteristic of the stratum comeum can be used effectively in topical therapy. Water-damaged skin, There continues to be very limited investigation of water-damaged skin, which is of considerable importance to the military (immersion feet, etc.) and to the civilian population (e.g., dishwashers, bartenders, homemakers, machinists).

significant implications for dermatologic and cancer research. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related chlorinated aromatic dibenzo-p-dioxins induce microsomal mon0oxygenase activity in a dose-related manner. The structure-activity relationship for enzyme induction correlates with toxicity, including chloracne. A specific soluble protein that reversibly binds TCDD with a high affinity and has the in vitro properties predicted for the receptor or recognition site for the induction of arylhydrocarbon hydroxylase activity has been characterized. Most important, the structure-activity relationship for receptor affinity corresponds to that of potency for enzyme induction and for toxic potency. This relationship holds for chlorinated dibenzo-o-dioxins, dibenzofurans, azo(xy)benzenes, and chlorinated and brominated biphenyls. Several specific tissue toxicities produced by TCDD in mice segregate with a genetic locus (Ah locus): teratogenesis, thymic involution, epidermal hyperplasia, and hyperkeratosis. In mice, the gene for hairlessness is linked to the gene for the toxic cutaneous effects of TCDD. The implication of and working hypothesis from recent studies on toxicity and carcinogenicity is that TCDD and congeners act on a soluble cellular receptor protein to elicit two distinct pleiotropic responses: (1) the induction of the drug-metabolizing enzymes and (2) morphologic changes that often involve epithelial tissue proliferation and differentiation. The same receptor m a y have served two separate functions in the course of evolution. Toxicity and tumor promotion appear to be related to the second of these pleiotropic responses. Passi et al. 48 analyzed comedonal lipids in children from the Seveso accident. They demonstrated that comedonal lipids in chloracne reflect epidermal, not sebaceous, lipid patterns.

Toxicity of dioxin and related halogenated aromatic compounds 44-49

Cutaneous carcinogenesis 7,s~

In humans, the skin is one of the most sensitive indicators of exposure to highly toxic halogenated aromatic chemicals of specific chemical structure, as expressed by chloracne. Recent studies on the mechanism of action of these compounds have

Research in the field of malignant transformation of skin ceils remains in its infancy. However, there is now cleat- evidence that enzyme-mediated transformation of chemicals and carcinogens (e. g., benzo[aJpyrene) into reactive metabolites such as bay region diol epoxides can mediate toxic effects

Volume 11 Number 5, Part 2 November, 1984

by binding to macromolecules, thereby initiating the formation of cancer. The role these enzymes play in toxic responses in human skin remains speculative. One of the major advances in this field has been the availability of systems for culturing mammalian keratinocytes. These culture systems provide a straightforward approach to the monitoring of effects of environmental chemicals on a variety of biologic and biochemical systems. Whereas cultured keratinocytes have been exploited for a large number of studies of the factors that regulate proliferation and for studies related to chemical carcinogenesis, they have not been sufficiently well utilized to assess the toxic effects of envir0nmental chemicals. Recent studies have shown that tumor promoters such as the phorbol esters can influence the activity of enzymes such as ornithine decarboxylase, which can participate in the regulation of proliferation. In addition, it is now clear that these compounds can influence cell membrane receptors; for example, the receptor for epidermal growth factor, as well as various proteases, cells of which may be important in mediating their effects. Studies of mechanisms of tumor promotion, particularly, indicate that several semi-independent steps, affected differentially by various environmental chemicals, can be involved. DepigmentationS9 -6~ The pathomechanisms of chemically induced depigmentation have been studied by using p-ter: tiary butyl catechol (TBC) as the prototype depigmenting compound. Anatomic alterations in melanosomes and melanin biosynthesis have been clarified. In vitro and in vivo methods have been employed on mouse and guinea pig skin and human melanoma cell lines. Light and electron microscopy and assay of enzymes involved in melanin formation have been employed. Major findings have included conversion from eumelanin to pheomelanosome synthesis, enzymatic changes (in the melanocyte) such as increased activity of glutathione reductase and gamma-glutamyl transpeptidase, increased sulfur content of TBC-treated cells, and lightening of the melanocytes. Mice and

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guinea pig models have been recommended for predictive screening for depigmentation produced by topically applied chemicals. gccrine sweat glands ~2,6~ A recent significant contribution was a study on rusters, persons whose sweat corrodes metal. The corrosive activity was caused by the volume of sweat (hyperhidrosis), not the pH or the concentration of sodium chloride per unit volume of sweat. Topical applications of aluminum chloride hexahydrate in a 25% solution in absolute ethanol to the palms proved effective against both the hyperhidrosis and the corrosive tendency. Sweat may be a pathway for excretion of certain trace metals. Surveillance and epidemiology of environmental skin disorders Surveillance and epidemiology of environmental skin disorders are hampered by inaccurate prevalence and severity data, tack of standardized reporting systems, under reporting, and latency reporting in malignancies related to chemical and physical agents. Studies of workers exposed to TCDD have not yet shown an excess mortality from malignant neoplasms. However, questions have been raised about the relationship of TCDD to soft-tissue sarcomas. 49 A recent study of work-related skin disease in South Carolina was based on workers' compensation records.~ 4 A high percentage of all claimants said they were affected by their skin problem. This type of research is helpful in detecting trends and calling attention to new problem areas. In-depth studies of outbreaks of dermatitis in factories are valuable in identifying unrecognized hazards. Since the report of allergic contact dermatitis from UV light-cured inks in 1977, several reports of similar outbreaks have been made. Chloracne is another example. Control technology A recent study established methods to determine relative bertefits of various types of protective equipment such as gloves and clothing to Protect

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skin against external contactants. 65 Another study deals with protective clothing in a quantitative manner (e.g., dimethylforamide). ~6 Standardized technics have improved measurement of the effectiveness of protective material such as gloves and clothing against carcinogens and polychlorinated biphenyls (PCBs).2 The skin as an organ of accumulation/ storage of chemicals 56.67

The skin as an organ of accumulation of environmental chemicals is a relatively new concept. Animal studies show that the skin is a major tissue storage site for PCB and polybrominated biphenyls. Skin as a metabolic organ 45,sl-5~,68

The skin is an organ that actively metabolizes chemicals, drugs, and other highly reactive toxic materials (see preceding sections concerning cutaneous carcinogenesis and toxicity of TCDD and related halogenated aromatic compounds). Recent studies utilizing freshly isolated skin cells or skin cells in culture have generally mirrored results seen with histologic and histochemical assays. Xenobiotic agents studied have included UV light, PCBs, TCDD, chlordane and metabolites, glucocorticoids, and polycyclic aromatic hydrocarbons. Changes in cutaneous metabolism can occur as a result of enzyme induction and might be influenced in certain disease (e.g., psoriasis) and by heredity. Cell toxicity, D N A d a m a g e , and repair 69

Human genetic diseases have been identified with clinical and cellular hypersensitivity to physical or chemical agents. Xeroderma pigmentosum, an autosomal recessive disease, causes clinical sun sensitivity, UV light-induced cutaneous neoplasia, and defective DNA repair. Cultured cells from patients with xeroderma pigmentosum are also hypersensitive to DNA-damaging chemicals such as benzopyrene derivatives, PUVA, aflatoxin, and nitroquinoline oxide. Ataxia-telangiectasia, another autosomal recessive disorder, has clinical x-ray hypersensitivity. Patients with ataxia-telangiectasia have developed

Journal of the American Academyof Dermatology acute and chronic radiation dermatitis from standard therapeutic doses of x-rays. Cellular hypersensitivity to x-rays is parallel to hypersensitivity to certain x-ray-mimetic chemicals such as bleomycin. The underlying molecular defect is still elusive; it may involve defective DNA synthesis or defective DNA repair. Fanconi's anemia, an autosomal recessive disorder, has in vitro cellular hypersensitivity to DNA cross-linking agents, such as PUVA or mitomycin C. Chromosomal hypersensitivity to diepoxybutane has been used in prenatal diagnosis. Patients with Cockayne's syndrome have sun sensitivity and cellular UV hypersensitivity without neoplasia, with no as yet identified DNA repair abnormality. Patients with basal cell nevus syndrome have clinical x-ray hypersensitivity. Several patients have developed many basal cell carcinomas in portions of the skin in radiation therapy fieIds (usually for treatment of medulloblastoma). No consistent cellular abnormality has been demonstrated. In dysplastic nevus syndrome (familial malignant melanoma), cultured cells from some patients were hypersensitive to killing and hypermutable to UV light and to the chemical carcinogen nitroquinoline oxide. The mechanism of this hypersensitivity is yet to be determined. Skin reactions to light and U V radiation Sunburn. New and more effective sunscreens are now available. When used regularly, they delay tanning, the natural protective mechanism. One sunscreen chemical, octyl p-aminobenzoic acid, appears to retain its protective ability because of its lower water solubility, not because of its entrance into or combination with the stratum corneum. 70 When sunscreens are not used or when sun exposure has been excessive, sunburn cannot be avoided. Topically applied steroids and cyclooxygenase inhibitors, especially indomethacin, diminish erythema if applied early in the course of the sunburn reaction but have not yet proved clinically useful and do not prevent cellular damage by histologic criteria. Oral corticosteroids, long used to treat severe sunburn, have not been shown to alter erythema under any of several administra-

Volume 11 Number 5, Part 2 November, 1984

tion schedules in controlled trials.Tt Antihistamines and antioxidants may diminish UV erythema, but data are very limited. PGs and other derivatives of arachidonic acid are probably mediators of sunburn. These oxygenated fatty acid derivatives of low molecular weight are released from cell membranes, are active in minute (nanogram) amounts, and are rapidly metabolized locally. Inflammation is evoked by intraderal injection of PG, and increased levels of PG have "been observed in human tissues in several widely different types of inflammation. UVR increases the biosynthesis of PG from arachidonic acid by a skin microsomal fraction preparation in vitro. More recent work has established the fact that the release of PGs in skin closely paralleled the time course of erythema, at least during the first 48 hours, for each of the three spectral bands (UVC, n UVB, 73 and UVA74),and strongly suggests a causative role in sunburn erythema. The effectiveness of cyclooxygenase inhibitors in diminishing ,UV erythema is taken as additional evidence that PGs are mediators of the inflammation, 75although indomethacin and aspirin have many other pharmacologic actions, and these data must therefore be interpreted with caution. Mast cell degranulation and histamine release have recently been demonstrated early in the course of UVB and UVA erythema and might contribute causally to the reaction. Animal experiments have indicated a role for leukocyte mediators in the later phases. 76 Lysosomal hydrolases might also contribute, because they are released in the epidermis after UV irradiation. Carcinogenesis. Skin cancer and actinic degeneration are long-term hazards from environmental UV radiation. A considerable effort has been made to establish the mechanisms of UVinduced carcinogenesis on the basis of the effects of UV light on DNA and its repair. 77 In the long term, reason indicates that this approach might prove vital to our understanding of the process and to its ultimate control. Progress has been made in quantifying many of the experimental UV radiation exposures that cause cancer in animals (frequency, split dose, time-irradiance reciprocity, dose effects, number of sunburns, e.g.). To date, however, the knowledge derived from these on-

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deavors has been transferred slowly to clinical application or has little relevance to the current state of clinical dermatology. The simplest way to diminish skin cancer is to avoid sun, but the long latent period (years to decades) makes it difficult to do this in the face of competing outdoor activities and the social pressure for tan. Another approach to the problem is to identify environmental factors that might interact with UV, particularly UVA, that are conducive to cutaneous carcinogenesis, with t h e ultimate hope of eliminating these offending agents from the environment. The costs as well as the restraints imposed on our technologic society by regulatory statute seem to make this approach impractical. This is not to say that constant monitoring for detrimental agents is unwarranted. A third and more effective recourse would be to strengthen natural host defense mechanisms to minimize UV-induced carcinogenesis, for which a requisite is an understanding of early physiologic and biochemical responses to UV insult (aside from those involving DNA), naturat pigmentation, immunologic processes, and, specifically, carcinogenic modifiers. Carcinogenic modifiers can be antioxidants, diet, therapeutic agents, age of host when placed at risk, or exposure dose, for example. They can be employed in inhibition analysis to dissect and study various stages of the carcinogenic continuum in much the same manner as specific metabolic inhibitors have been used to map metabolic pathways. This approach would seek to reverse the current increase in skin cancer. Actinic degeneration. The other major longterm effect of sun exposure is actinic degeneration. It has become apparent that photoaging and natural chronologic aging are different entities. 78Sun damage is not an acceleration of age-dependent changes. For example, elastosis, a hallmark of excessive actinic exposure, never occurs in healthy protected skin of even very old persons. Chronologic aging involves only a moderate increase in elastic fibers and some mild ultrastructural deterioration. The glycosaminoglyc~ms (GAGS) of the ground substance are greatly increased in actinically damaged skin, whereas in unexposed aged skin, if changed at all, GAGS are only slightly decreased. Photoaged skin contains less collagen,

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which is largely replaced by elastic fibers and GAGS. In normal aging, collagen bundles become larger and more stable. Studies on the effects of UV irradiation on the connective tissue of hairless mice have confirmed many of the findings in humans. Elastosis can be produced with amounts of UVB that are terrestrially realistic. Mature collagen, when damaged, can be partly replaced with material that stains as reticulin, whereas GAGS are greatly increased. Recent animal studies also suggest that a portion of these changes are reversible if UVR exposure is discontinued or sunscreen is applied. 79 Photoimmunology. Dermatologists are responsible for the development of photoimmunology as a legitimate field of scientific research, the most impressive aspects of which are the sheer volume of information and the fact that systemic alterations occur from local exposure, g~ UV radiation has specific local and systemic effects on immune function. In mice, UV radiation facilitates the development of UV-induced tumors by a mechanism that involves the generation of suppressor cells which inhibit normal immunologic rejection of the tumors. UV radiation also effects the development of delayed and contact hypersensitivity, photoallergy, and cutaneous graft versus host disease. The mechanism of these effects has attracted much research interest and appears to involve altered mediator production in the skin, including epidermal thymocyte-activating factor from keratinocytes, changes in the function of Langerhans cells, which are macrophage-monocyte cells in the skin, and a systemic alteration of antigen presenting cell function. Many of the initial observations were made with sunlamp radiation on laboratory animals. There is now preliminary evidence that the immune system of humans is also affected by UV radiation and that environmental sources o f radiation can have similar effects. The relevance of these observations to the understanding of human disease is also being explored. For example, the mechanism of contact photoallergy has similarities to ordinary contact allergy and is a photoimmunologic response, 8~ Furthermore, UV radiation might have potential for therapeutic manipulation via its immunologic effects, as suggested by UV-induced prevention of graft versus host disease. Additional

Journal of the American Academy of Dermatology understanding of both the mechanism and scope of the effects of nonionizing radiation on i m m u n e function will lead to the realization of the value of photoimmunology to human health and disease. Laser medicine, When dermatologists use lasers in studies of skin biology, they are contributing information that will alter laser application in many medical and surgical specialties. In dermatology, the use of laser-induced thermal effects is still largely at the mechanistic level of classic cautery. However, laser technology has rapidly advanced, so that monochromatic output from inflared, visible, UV, and tunable-wavelength lasers has been controlled, extremely brief pulsed exposures have been focused to beam diameters of 1 ~m or less, and the laser output has been transmitted through fiberoptic endoscopes, impressively exact confinement of damage in tissues previously inaccessible to light may therefore be possible. These developments, combined with a better understanding of the optical and thermal properties of skin, make it possible to obtain selective effects. One such effect is the possibility of confining in vivo thermally induced damage to microscopic pigmented structures, cells, or organelles in the skin without requiring precise aiming of the laser.~2 The fact that thermal effects, previously thought to be always nonspecific, can be spatially confined in vivo to targets as small as organelles and as large as whole organs will offer therapeutic applications in the future. Miscellaneous. Increased epidemiologic data suggest relationships between melanoma and sun exposureS3; photochemical studies reveal molecular mechanisms of chemical photosensitization84; activity of photoreactivating enzyme has been shown in human skin85; isolation and purification of uroporphyrinogen decarboxylase clarifies its role in porphyria cutanea tarda; the in vivo photochemistry of vitamin D has been shownS6; and the effects of long-wave UV radiation on the skin alone and in combination with other wavebands or chemicals have been more clearly defined) ~ AREAS IN WHICH NEW TECHNOLOGY SHOWS PROMISE OF GENERATING NEW SOLUTIONS Advances in chemistry. Significant improvements in analytical chemistry technics (e.g., gas-

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chromatography/mass spectroscopy high-pressure liquid chromatography) enable investigators to identify, measure, and separate increasingly smaller amounts of environmental chemicals (TCDD, furans, porphyrins, and contact allergens). Isotopes. The use of stable isotopes to study absorption, distribution, and metabolism of labeled compounds such as metals is applicable to occupational and environmental dermatology. Isotopic labeling of cells with ~lindium-oxime might offer a quantitative method by which to study various cell types in cutaneous injury from environmental agents. 87 Computers. The practical everyday use of computers can be applied in dermatology to develop central information retrieval systems and national allergen banks and in laboratory research. Monoclonal antibodies. Application of monoclonal antibodies in studies of pathogenesis and prevention of allergic contact dermatitis is a possibility. 9

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NEED FOR ADDITIONAL RESEARCH Surveillance and data systems research. Projects to identify the potential extent and societal impact of occupational skin disease demand a unified data-collecting system that will properly identify high-risk industries, processes, and agents. National and regional agencies, newly formed to determine the type and frequency of skin disease, duration and extent of disability, and economic impact would be an adjunct to other federal health agencies (NIOSH, NIEHS, OSHA, FDA, EPA), state government, industry, and academic medicine9 Epidemiologic research. Clinical epidemiologic studies that quantitate exposure and effects should be designed (e.g., continuing studies of long-term cutaneous effects of TCDD and related compounds; study of ten "high dermatitis" industries identified by OSHA). Percutaneous absorption. Continuing effort should be expended to develop new models to study systemic uptake and manifestations of toxic substances absorbed through the skin. These models should focus on the biochemical and physiologic aspects of penetration, metabolism, and distribution of chemicals within the skin. Skin reactions with water. The current focused

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microwave probe measures the water content of the outside 3 ~m of the stratum comeum only. It must be developed to permit the determination of the concentration profile. If this technic is developed, it will be possible to study the effect on the water concentration profile of the stratum corneum caused by such factors as environmental relative humidity, occlusive ointment bases, soap and detergent solutions, and contact with organic solvents. We need more quantitative data on how hydration of the stratum comeum affects the penetration of various drugs and toxins from different vehicles. In future years, the study of "dry skin" will likely focus more on physical characteristics of the cutaneous surface than on the stratum corneum water content. It may involve research on the viscoelasticity, contour, and friction of the stratum corneum. How various Iipids modify dry skin also needs attention. The effect of topical therapeutic agents such as petrolatum, glycerine, and propylene glycol on the water content of the stratum corneum needs further study. A completely reliable method for quantifying the TEWL at different relative humidities should be developed. Cutaneous effects of material components. There is a need for further study of the mechanisms and amounts of chemicals absorbed by the skin from materials that directly contact the skin (e.g., absorption and dosage of TCDD from soil; chemicals from robber gloves and clothing). Mechanism of irritant dermatitis. Single versus multiple pathogenesis, rates of penetration, the nature of preclinical changes at a cellular and biochemical level, cumulative irritancy, accommodation, and structure-function relationships need continuing study. The cellular, biochemical, and metabolic factors that "turn off" the inflammatory response should be identified. Allergic contact dermatitis. The role of PGs and leukotrienes in allergic contact dermatitis should be studied. Additional research is needed on induction of tolerance, hyposensitization, and the relationship between allergic contact dermatitis and malignancy, especially chronic T cell lymphoma. New findings on mechanisms of allergic

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contact dermatitis must be applied to clinical, occupational, and environmental exposures, preventions, and treatment. To standardize further patch test antigens and to understand false positive and negative reactions are continuing needs. An organized endeavor to locate antigens in the environment (e. g., exposure lists) should be undertaken. Most of the effort to find a useful in vitro assay for allergic contact dermatitis has ceased. It should be renewed, TCDD and related compounds. The biologic mechanism involved in the pathogenesis of adverse skin effects of acnegenic substances such as TCDD, PCBs and furans should be determined. Attention should be given to the action of such agents and metabolites on sebaceous ceils, keratinocytes, lipid metabolites, cutaneous flora that produce lipolytic enzymes, endocrine activity (including direct or indirect androgenic effects), and on pigmentation and its relation to porphyrin metabolism and UV radiation reactivity. Is chloracne caused by the chemical per se or a metabolite? Is enzyme induction involved? How does the effect on drug-metabolizing systems relate to the lipid metabolism derangements? Are only sebaceous cell metabolism and functions affected? Light a n d UV radiation. The following are needed in this field: 1. Further studies in the field of photoimmunology, especially those examining the molecular and cellular mechanisms. 2. Studies of the molecular mechanisms of laser interaction with tissue. 3. Studies to define the chromophores in human skin that result in biologic responses such as erythema and tanning. 4. Studies to define better the pathogenesis of all photosensitivity diseases. 5. Study of the mechanisms of natural and induced photoprotection. 6. Improvement of phototherapy and photochemotherapy by expansion of the available photosensitizing chemicals that can be used for photochemotherapy; clearer definition of the longterm risks of phototherapy and photochemotherapy; and careful planning for the development of diagnostic and treatment facilities for ambulatory outpatients.

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7. Public education about the hazards of unprotected sun exposure, a major need in preventing the acute and chronic effects on human skin. Cutaneous carcinogenesis. To discem more about the nature of carcinogenesis in general and the pathogenesis of skin tumors in particular from exposures to environmental chemicals is essential. Systems should be devised for the study of the effects of environmental chemicals in cutaneous tissue that will promote correlation of an in vitro phenomenon with in vivo events. Test methodology. Projects to improve and validate test methodologies will facilitate early identification of cutaneous hazards. Continuing study is needed of methods to predict cutaneous hazards and to assess adverse effects such as contact dermatitis, photosensitivity, marginal irritancy, acne, granulomas, and pigment alteration. Research methodologies, including nonbiologic screening technics, should be developed to determine the potential cutaneous hazards of all existing and new commercial substances, processes, and agents. Control technology. The need is increasing for more information and study on the effectiveness of protective clothing that may prevent serious harm from environment chemicals. The use of tracers (e.g., fluorescent compounds) offers some possibility for identifying trace contaminants of potentially toxic chemicals on the skin. It is essential to develop barrier agents and methods to prevent skin penetration by specific types of compounds, to monitor and control cutaneous hazards in the workplace, to use innovative approaches such as alternative materials, engineering controls, and process modification, to prevent occupational skin disease problems already identified, and to solve emerging problems. Health, education, and research. Projects to increase awareness of the magnitude of occupational and environmental skin diseases and to develop education and training programs for health professionals, workers, and management wii1 increase their sensitivity to occupational and environmental skin disorders. More centers where expertise in occupational and environmental dermatology and dermatologic allergy, toxicology, and chemistry should be readily available.

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REFERENCES 1, Suskind RR: Environment and the skin. Environ Health Perspect 20:27-37, 1977. 2. Unpublished report of the Advisory Committee on Cutaneous Hazards, prepared for the Assistant Secretary of Labor, OSHA. U.S, Department of Labor, OSHA, 1978, 84 pages. 3. Occupational cutaneous hazards and diseases. USDHEW, NIOSH Dermatology Program Announcement, Jan. 3, 1980, 7 pages. 4. Adams RM: Occupational skin disease. New York, 1983, Grune & Stratton, Inc. 5. Cronin E: Contact dermatitis. Edinburgh, 1980, Churchill Livingstone. 6. Mitchell J, Rook A: Botanical dermatology, Vancouver, 1979, Greenglass, Ltd. 7. Marzulli FM, Maibach HI: Dermatotoxieology, ed. 2. Washington DC, 1983, Hemisphere Publishing Corp. 8. Dupuis G, Benezra C: Allergic contact dermatitis to simple chemicals, a molecular approach. New York, 1982, Marcel Dekker, Inc. 9. Maibach HI, Gellin GA, editors: Occupational and industrial dermatology. Chieago, 1982, Yearbook Medical Publishers, Inc. 10. Nater JP, DeGroot AC: Unwanted effects of cosmetics and drugs used in dermatology. Amsterdam, 1983, Excerpta Medico Foundation. 11. Baginsky E: Occupational disease in California, 1978. San Francisco, 1982, Division of Labor Statistics and Research, California Department of Industrial Relations. 12. Baginsky E: Occupational skin disease in California. San Francisco, 1982, Division of Labor Statistics and Research, California Department of Industrial Relations. 13. Baer RL, Berman B: Role of Langerhans cells in cutaneous immunological reactions, in Safai B, Good RA, editors: lmmunodermatology. New York, 1981, Plenum Press. 14. Morison WL, Parrish JA, Woehler ME, et al: The influence of ultraviolet radiation on allergic contact dermatitis in the guinea pig. I. UVB radiation. Br J Dermatol 104:161-164, 1981. 15. Fischmann AB, Bunn PA Jr, Cuccion JG, et al: Exposure to chemicals, physical agents, and biological agents in mycosis fungoides and the S~eezary syndrome. Cancer Treat Rep 63:59!-596, 1979. 16. Rowden G, Phillips TM, Lewis MG, et ah Target role of Langerhans cells in mycosis fungoides: Transmission and immunoelectron microscopic studies. J Cutan Pathol 6:364-382, 1979. 17. Stobo JD, Kennedy MS, Goldyne ME: Prostaglandin E modulation of the mytogenic response of human T cells. J Clin Invest 64:1188-1195, 1979. 18. Watson ES, Murphy JC, Worth PW, et al: Immunologic studies of poisonous Anacardiaeeae. I. Production of tolerance and desensitization to poison ivy and oak urushiols using a sterified urushiol derivative in guinea pigs. J Invest Dermatol 76:164-170, 1981.

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19. Epstein WL, Byers VS, Frankart W: Induction of antigen specific hyposensitization to poison oak in sensitized adults. Arch Dermatol 118:630-633, 1982. 20. Epstein WL, Byers, VS,BaerHA: Induction ofpersistent tolerance to urushiol in man. J Allergy Clin Immunol 68:20-25, 1981, 21. Noonan FP, DeFabo EC, Kripke ML: Suppression of contact hypersensitivity by ultraviolet radiation: An experimental model. Semin Immunopathol 4:293-304, 198I. 22. Bmynzeel DP, Boonk WJ, van Ketal WG: Oral psoralen photoehemotherapy of allergic contact dermatitis of the hands. Derm Beruf Umwelt 30:16-20, 1982. 23. Calnan C: The contact urticaria syndrome, in Dermatotoxicology, ed. 2. Washington DC, 1983, Hemisphere Publishing Corp., p, 301. 24. Warshawshki L, Mitchell JC, Storrs FJ: Allergic contact dermatitis from glyceryl monothioglycolate in hairdressers. Contact Dermatitis 7:351-352, 1981. 25. Menne 2", Hjorth N: Reactions from systemic exposure to contact allergens. Semin Dermatol 1:15-24, 1982. 26. Rietschel RL, Klemm J, Thompson M: The influenee of accommodation (hardening) on the response to irritants, allergens, and mediators of inflammation in humans. Clin Res 30:605A, 1982. 27. Rietsehel RL, Klemm J, Jones HE: Chronic irritant dermatitis interferes with induction of dinitrochlombenzene (DNCB) sensitization. Clin Res 30:915A, 1982. 28. Guy RH, Hadgraft J, Maibach HI: A pharmacokinetic model for percutaneous absorption. Int J Pharmacol 11:119-120, 1982. 29. Elias PE: Percutaneous transport in relation to stratum corneum structure and lipid composition. J Invest Dermatol 76:297-30l, 1981. 30. Blank 1, Moloney J, EmsIie AG, et al: The diffusion of water across the stratum corneum as a function of its water content. J Invest Dermatol 82:188-194, 1984. 31. Holland M: Viability as a determinant of epidermal penetration. Presented at International Symposium on Skin Penetration, Washington DC, 1983. 32. Fisher L: Permeability of infant skin. Presented at International Symposium on Skin Penetration, Washington DC, 1983. 33. De la TorTe JC, editor: Biological actions and medical applications of dimethylsulfoxide. Ann NY Acad Sci 411:1-404, 1983. 34. Stoughton R: Animal models for studying azone--a penetration enhancer. Presented at International Symposium on Skin Penetration, Washington DC, 1983. 35. Smith WP, Young D, Nacht S: Stratum corneum isolation: effect on physical properties. J Invest Dermatol 78:341, 1982. 36. Pegum JS: Penetration of protective gloves by epoxy resin. Contact Dermatitis S:281-283, 1979. 37. Bronaugh RL, Stewart RF, Congdon ER, et al: Methods for in vitro pereutaneous absorption studies. I. Comparison with in vivo results. Toxicol Appl Pharmacol 62:474-480, 1982.

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38. Hargens CW: The gas bearing electrodynamometer applied to measuring mechanical changes in skin and other tissues, in Marks R, Pyne PA, editors: Bioengineering and the skin. Hingham, MA, 1981, Kluwer Boston Inc., pp. 113-122. 39. Jacques SL: A linear measurement of the water content of the stratum comeum of human skin using a microwave probe, in IEEE 1979 frontiers of engineering in health care. New York, 1979, Publishing Services IEEE, pp. 180-182. 40. Blank IH, et al: The diffusion of water across the stratum comeum as a function of its water content. J Invest Dermatol. (In pressl) 41. Wu M-S: Water diffusivity and water concentration profile in human stratum comeum from transepidermal water loss measurements. J Soc Cosmet Chem 34:191-196, 1983. 42. Nilsson GE: Measurement of water exchange through the skin. Med BiolEng Comput 15:209, 1977. 43. Harpin VA, Rutter N: Barrier properties of the newborn infant's skin. J Pediatr 102:419-425, 1983. 44. Poland A, Knutson J, Glover E, et al: Tumor promotion in the skin of hairless mice by halogenated aromatic hydrocarbons, in Weinstein IB, Vogel H, editors: Genes and proteins in oncogenesisl New York, 1983, Academic Press, Inc., pp, 143-161. 45. Poland A, Knutson J: 2,3,7,8-Tetrachlorodibenzo-pdioxin and related halogenated aromatic hydrocarbons: Examination of the mechariism of toxicity. Annu Rev Pharmacol Toxicel 22:517-584, 1982. 46. Taylor JS, Lloyd KM: Chloracne from 3,3'4,4'-tetracl~loroazoxybenzene and 3,3'4,4'-tetrachlorazobenzene--update and review, in Hutzinger O, et al, editors: Chlorinated dioxins and related compounds--impact on the environment. Oxford, 1982, Pergamon Press, pp. 535-544. 47. Nicholson WJ, Moore JA: Health effects of halogenated aromatic hydrocarbon.s. Ann NY Acad Sci 320:1-730, 1979. 48. Passi S, Nazzaro-Porro M, Boniforti L, et al: Analysis of lipids and dioxin in chloracne due to tetrachloro2,3,7,8-p-dibenzodioxin. Br J Dermatol 105:137-143, 1981. 49. Honchar PA, Halperin WE: 2,4,5-'I", trichlorophenol, and soft tissue sarcoma. Lancet 1:268-269, 1981. (Letter to editor.) 50. Slaga TJ, Fisher SM, Nelson K, et al: Studies on the mechanism of skin tumor promotion: Evidence for several stages in promotion. Proc Natl Acad Sci USA 77:3659-3663, 1980. 51. Bickers DR, Kappas A: Human skin aryl hydrocarbon hydrolase. Induction by coal tar. J Clin Invest 62:10611068, 1978. 52. Parkinson EK, Newbold RF: Benzo(a)pyrene metabolism and DNA adduct formation in serially cultivated strains of human epidermal keratinocytes. Int J Cancer 26:289299, 1980.

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53. Fouts JR: The metabolism of xenobiotics by isolated puImonary and skin cells. Trends Pharmacol Sci 3:164-166, 1982. 54. Coomes MW, Norlina AH, Pohl RJ, et al: Foreign compound metabolism by skin cell s from the hairless mouse. J Pharmcol Exp Thor 225:770-777, 1983. 55. DiGiovanni J, Sina JF, Ashurst SW, et al: Benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene metabolism and DNA adduct formation in primary cultures of hamster epidermal cells. Cancer Res 43:163-170, 1983~ 56. Richter E, Lay JP, Klein W, et al: Paraffin-stimulated excretion of 2,4,6,2',4'-pentachlorobi[~4C]phenyl by rats. Toxicol Appl Pharmacol 50:17-23, 1979. 57. Becket FF: Recent concepts of initiation and promotion in carcinogenesis. Am J Pathol 105:3-9, 1981. 58. Yuspa SH: Chemical carcinogenesis related to the skin. Parts I and II, in Progress in Dermatology. Vol. 15, No. 4, 1981, and Vol. 16, No. 1, Evanston, IL, 1982, Dermatology Foundation. 59. Fukuyama K, Gellin GA, Nishimura M, et al: Occupational leukoderma" Morphological and biological studies of 4-tertlarybutyl catechol depigmentation, in Kligman AM, Leyden JJ, editors: Safety and efficacy of topical drugs and cosmetics. New York, 1982, Grune &Stratton, Inc.,pp. 135-155. 60. Yonemoto K, Gellin GA, Epstein WL, et al: Glutathione reductase activity in skin exposed to 4-tertiary butyl catechol. Int Arch Occup Environ Health 51:341-345, ! 983. 61. Yonemoto K, Gellin GA, Epstein WL, et al: Reduction in eurnelanin by the activation of glutathione reductase and gama-na glutamyl transpeptidase after exposure to a depigmenting chemical. Biochem Pharmacol 32:13791382, 1983. 62. Cohn JR, Emmett EA: The excretion of trace metals in human sweat. Ann Clin Lab Sci 8:270-275, 1978. 63. Jensen O: Rusters. The corrosive action of palmar sweat. I. Sodium chloride in sweat. II. Physical and chemical factors in palmar hyperhidrosis. Acta Derm Venereol 59:135-143, 1979. 64. Keil JE, Shmunes E: The epidemiology of work-related disease in South Carolina. Arch Dermatol 119:650-654, 1983. 65. Brooks SM, Anderson L, Emmett E, et al: The effects of protective equipment on styrene exposure in workers in the reinforced plastics industry. Arch Environ Health 35:287-294, 1980. 66. Lauwerys R, Kivits A, Lhoir M, etal: Biological surveillance of workers exposed to dimethylformamide and the influence of skin protection on its percutaneous absorption. Intl Arch Occup Environ Health 45:189-203, 1980. 67. Mathews HB, Kate S, Morales NM, etal: Distribution and excretion of 2,4,5,2'4'5' hexabromo biphenyl, the major component of Firemaster BP-6. J Toxical Environ Health 3:599-605, 1977. 68. Pannatier A, Jenner P, Testa B, et al: The skin as a dragmetabolizing organ. Drug Metab Rev 8:319-343, 1978.

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69, Kraemer KH: Heritable diseases with increased sensitivity to cellular injury, in Update: Dermatology in general medicine. New York, 1983, McGraw-Hill Book Co., pp. 113-139. 70. Blank Ill, Cohen JH, Anderson BS, et al: Observations on the mechanism of the protective action of sunscreens. J Invest Dermatol 78:381-385, 1982. 71. Greenwald JS, Parrish JA, Jaenicke KF, et al: Failure of systemically administered corticosteroids to suppress UVB-induced erythema. J AMACADDERMATOL51197202, 1981. 72. Camp RD, @eaves MW, Heasby CN, et al: Irradiation of human skin by short-wavelength ultraviolet radiation (100-290 nm, UVC): Increased concentration of arachidonic acid and prostaglandins E2 and F2, Br J Clin Pharmacol 6:145-148, 1978. 73. Gilchrest BA, Soter NA, Stoff JS, et al: The human sunburn reaction: Histologic and biochemical studies. J AM ACADDERMATOL5:411-422, 1981. 74. Hawk JL, Black AK, Jaenicke KF, et al: Increased concentrations of archidonic acid, prostaglandins E2, D2, 6OXO-FI and histamine in human skin following ultraviolet-A irradiation. J Invest Dermatol 80:496-498, 1983. 75. Snyder DS, Eaglestein WM: lntradermal antiprostaglandin agents and sunburn. J Invest Dermatol 62:47-50~ 1974. 76, Eaglestein WH, Sakai M, Mizuno N: Ultraviolet radiation-induced inflammation and leukocytes. J Invest Dermatol 72:59-63, 1979. 77, Forbes PD, Davies RE: Factors that influence photocarcinogenesis, in Parrish JA, Morison WL, Kripke M, ed-

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itors: Photoimmunology.New York, 1983, Plenum Press, pp, 131-156. 78. Braverman IM, Fonferho E: Studies in cutaneous aging. I. The elastic fiber network. J Invest Dermatol 78:434443, 1982. 79. K!igman L; Akin F, Kligman A: Sunscreen promoted repair of ultraviolet radiation-induced dermal damage. J Invest Dermatol 81:98-102, 1983. 80. Parrish JA, Morison WL, Kripke M, editors: Photoimmunology. New York, 1983, Plenum Press. 81. Morison WL, Kochevar IE. Photoailergy, in Parrish JA, Morison WL, Kripke M, editors: Photoimmunology. New York, 1983, Plenum Press, pp. 227-271. 82. Anderson RR, Parrish JA: Selective photothermolysis: Precise microsurgery by selective absorption of pulsed radiation. Science 220:524-527, 1983. 83. Beral V, Robinson N: The relationship of malignant melanoma, basal and squamous cell cancers to indoor and outdoor work. Br J Cancer 44:856, 1981. 84. Kochevar IEt Phototoxicity mechanisms: Chlorpromazine photosensitization damage and DNA and cell membranes. J Invest Dermatol 77:59-64, 1981. 85. D'Ambrosio S, Whetstone WJ, Slazinski L, et al: Photorepair of pyrimidine dimers in human skin in vivo. Photochem Photobiol 34:461-464, 198i. 86. Holick M: The cutaneous photosynthesis of vitamin D~, A unique photoendocrine system. S Invest Dermatol 77:51-58, 1981. 87. Wahba AV, Barnes B, Lazaras GS: Labelling of peripheral blood polymorphonuclear leukocytes with Indium"': A new method for the quantitation of in vivo aceumula6on in rabbit skin. J Invest Dermato182:126-131,1984.

AD HOC COMMITTEE MEMBERS Robert M. Adams, M.D. Clinical Professor Department of Dermatology Stanford University School of Medicine Stanford, CA

Donald J. Birmingham, M.D. Professor Emeritus Department of Dermatology and Syphilology Wayne State University School of Medicine Detroit, MI

William A. Akers, M.D. Head, Department of Dermatology Syntex Research Palo Alto, CA

Irvin H. Blank, Ph.D. Associate Biochemist Massachusetts General Hospital Boston, MA

David R. Bickers, M.D. Professor and Chairperson Department of Dermatology School of Medicine Case Western Reserve University Cleveland, OH

Edward A. Emmett, M.B., B.S. Professor of Environmental HeaIth Sciences and Director of Division of Occupational Medicine School of Hygiene and Public Health Johns Hopkins University Baltimore, MD

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AD H O C C O M M I T T E E M E M B E R S - - C o n t ' d . John Epstein, M,D. Clinical Professor of Dermatology School of Medicine University of California, San Francisco San Francisco, CA James R. Fouts, Ph.D. Laboratory Pharmacology National Institute of Environmental Health Sciences Research Triangle Park, NC Kimie Fukuyarna, M.D., Ph.D. Professor in Resident Director of Research Department of Dermatology School of Medicine University of California--San Francisco San Francisco, CA Richard W. Gange, M.D. Assistant Professor of Dermatology Harvard Medical School Boston, MA Gerald A. Gellin, M.D. Clinical Professor of Dermatology School of Medicine University of California--San Francisco San Francisco, CA Barbara A. Gilchrest, M.D. Associate Professor of Dermatology Tufts University School of Medicine Boston, MA Marcus M. Key, M.D. Professor of Occupational Medicine School of Public Health University of Texas Houston, TX Albert M. Kligman, M.D., Ph.D. Professor of Dermatology University of Pennsylvania School of Medicine Philadelphia, PA Kenneth H. Kraemer, M.D. Clinical Professor of Dermatology School of Medicine Research Scientist Laboratory of Molecular Carcinogenesis National Cancer Institute National Institutes of Health Bethesda, MD

Gerald S. Lazarus, M.D. Professor and Chairperson Department of Dermatology School of Medicine University of Pennsylvania Philadelphia, PA Howard I. Maibach, M.D. Professor of Dermatology School of Medicine University of California--San Francisco San Francisco, CA Warwick L. Morison, M.D. Senior Research Scientist National Cancer Institute Frederick Cancer Research Facility Frederick, MD Alan N. Moshell, M.D. Skin Diseases Program Director National Institute of Arthritis, Diabetes, and Digestive and Kidney Disease National Institutes of Health Bethesda, MD John A, Parrish, M.D. Associate Professor Department of Dermatology Harvard Medical School Boston, MA Madhukar A. Pathak, M.B., Ph.D. Senior Associate in Dermatology Harvard Medical School Boston, MA Robert B. Pittelkow, M.D. Associate Clinical Professor Departments of Preventive Medicine and Dermatology Medical College of Wisconsin Milwaukee, WI Alan Poland, M.D. Associate Professor of Oncology McArdlc Memorial Laboratory for Cancer Research Medical School University of Wisconsin Madison, WI S. Madli Puhvel, Ph.D. Adjunct Professor of Medicine/Dermatology Division of Dermatology School of Medicine University of California--Los Angeles Los Angeles, CA

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AD H O C COMMITTEE M E M B E R S - - C o n t ' d . Robert L. Rietschel, M.D. Associate Professor of Dermatology School of Medicine Emory University Atlanta, GA Edward Shmunes, M.D. Associate Professor Department of Environmental Health Sciences School of Health University of South Carolina Columbia, SC Frances J. Storrs, M.D. Professor of Dermatology Department of Dermatology Oregon Health Sciences University Portland, OR

Raymond R. Suskind, M.D. Professor and Director Institute of Environmental Health College of Medicine University of Cincinnati Cincinnati, OH James S. Taylor, M.D. Head, Section of Industrial Dermatology Cleveland Clinic Foundation Cleveland, OH

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