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• W2045478818 abstract "We conducted a randomized trial designed to calculate human in vivo immune protection factors of two sunscreen preparations in a model of ultraviolet-induced local suppression of the induction of contact hypersensitivity to 2,4-dinitrochlorobenzene. Seventy-five male subjects were exposed in a multistage study to multiples of their individual minimal erythema dose of solar-simulated ultraviolet radiation with or without protection by an ultraviolet B sunscreen (sun protection factor 5.2) or a broad-spectrum ultraviolet A+B sun-screen (sun protection factor 6.2). After 24 h subjects were sensitized with 50 μL of 0.0625% 2,4-dinitrochlorobenzene on a nonirradiated or ultraviolet-irradiated field on the buttock that was unprotected or protected by sunscreen. Three weeks after sensitization the subjects were challenged with varying concentrations of 2,4-dinitrochlorobenzene on their upper inner arm, and the contact hypersensitivity response was determined at 48 and 72 h based on a semiquantitative clinical score, contact hypersensitivity lesion diameters, and dermal skin edema measurement by 20 MHz ultrasound. The 50% immunosuppressive dose ranged from 0.63 to 0.79 minimal erythema dose, depending on the endpoint parameter. Both sunscreens offered significant immunoprotection (p=0.014 – 0.002) and their immune protection factor ranged from 4.5 to 5.8 (ultraviolet B sunscreen) and from 7.7 to 11 (ultraviolet A+B sun-screen). The immune protection factor of the ultraviolet B sunscreen was similar to the sun protection factor (5.2), whereas the sunscreen with broad-spectrum ultraviolet A+B protection exhibited better immunoprotective capacity than predicted from the sun protection factor. We conducted a randomized trial designed to calculate human in vivo immune protection factors of two sunscreen preparations in a model of ultraviolet-induced local suppression of the induction of contact hypersensitivity to 2,4-dinitrochlorobenzene. Seventy-five male subjects were exposed in a multistage study to multiples of their individual minimal erythema dose of solar-simulated ultraviolet radiation with or without protection by an ultraviolet B sunscreen (sun protection factor 5.2) or a broad-spectrum ultraviolet A+B sun-screen (sun protection factor 6.2). After 24 h subjects were sensitized with 50 μL of 0.0625% 2,4-dinitrochlorobenzene on a nonirradiated or ultraviolet-irradiated field on the buttock that was unprotected or protected by sunscreen. Three weeks after sensitization the subjects were challenged with varying concentrations of 2,4-dinitrochlorobenzene on their upper inner arm, and the contact hypersensitivity response was determined at 48 and 72 h based on a semiquantitative clinical score, contact hypersensitivity lesion diameters, and dermal skin edema measurement by 20 MHz ultrasound. The 50% immunosuppressive dose ranged from 0.63 to 0.79 minimal erythema dose, depending on the endpoint parameter. Both sunscreens offered significant immunoprotection (p=0.014 – 0.002) and their immune protection factor ranged from 4.5 to 5.8 (ultraviolet B sunscreen) and from 7.7 to 11 (ultraviolet A+B sun-screen). The immune protection factor of the ultraviolet B sunscreen was similar to the sun protection factor (5.2), whereas the sunscreen with broad-spectrum ultraviolet A+B protection exhibited better immunoprotective capacity than predicted from the sun protection factor. contact hypersensitivity dinitrochlorobenzene 50% immunosuppressive dose immune protection factor minimal erythema dose sun protection factor Exposure of the skin to ultraviolet (UV) radiation induces various biologic alterations, including local and systemic immune suppression (Krutmann and Elmets, 1995Krutmann J. Elmets C.A. Photoimmunology. Blackwell Science Ltd, London1995Google Scholar;Duthie et al., 1999Duthie M.S. Kimber I. Norval M. The effects of ultraviolet radiation on the human immune system.Br J Dermatol. 1999; 140: 995-1009https://doi.org/10.1046/j.1365-2133.1999.02898.xCrossref PubMed Scopus (190) Google Scholar). There is evidence that UV-induced immune suppression is a significant factor in skin cancer formation, not only in experimental animals (Kripke and Fisher, 1976Kripke M.L. Fisher M.S. Immunologic parameters of ultraviolet carcinogenesis.J Natl Cancer Inst. 1976; 57: 211-215Crossref PubMed Scopus (265) Google Scholar;Streilein et al., 1994Streilein J.W. Taylor J.R. Vincek V. et al.Relationship between ultraviolet radiation-induced immunosuppression and carcinogenesis.J Invest Dermatol. 1994; 103: 107-111https://doi.org/10.1111/1523-1747.ep12399400Abstract Full Text PDF PubMed Scopus (88) Google Scholar) but also in human subjects (Yoshikawa et al., 1990Yoshikawa T. Rae V. Bruins-Slot W. Van den Berg J.W. Taylor J.R. Streilein J.W. Susceptibility to effects of UVB radiation on induction of contact hypersensitivity as a risk factor for skin cancer in humans.J Invest Dermatol. 1990; 95: 530-536https://doi.org/10.1111/1523-1747.ep12504877Crossref PubMed Scopus (371) Google Scholar). For instance, patients with a history of nonmelanoma skin cancer such as basal cell and/or squamous cell carcinoma have been shown to be much more susceptible than normal, healthy control subjects to UV-induced immunosuppression as measured in the model of UV-induced local suppression of the induction of contact hypersensitivity (CHS) to a contact allergen (Yoshikawa et al., 1990Yoshikawa T. Rae V. Bruins-Slot W. Van den Berg J.W. Taylor J.R. Streilein J.W. Susceptibility to effects of UVB radiation on induction of contact hypersensitivity as a risk factor for skin cancer in humans.J Invest Dermatol. 1990; 95: 530-536https://doi.org/10.1111/1523-1747.ep12504877Crossref PubMed Scopus (371) Google Scholar). The significance of an intact immune system is particularly highlighted by the well-known observation that therapeutically immunosuppressed organ transplant recipients have an increased risk of squamous cell carcinoma at sun-exposed body sites (Boyle et al., 1984Boyle J. MacKie R.M. Briggs J.D. Junor B.J. Aitchison T.C. Cancer, warts, and sunshine in renal transplant patients: A case-control study.Lancet. 1984; I: 702-705Abstract Scopus (234) Google Scholar). Moreover, there is evidence that UV-induced immunologic alterations may be involved in the formation of cutaneous melanoma (Donawho and Wolf, 1996Donawho C. Wolf P. Sunburn, sunscreen, and melanoma.Curr Opin Oncol. 1996; 8: 159-166Crossref PubMed Scopus (34) Google Scholar). Skin cancer has become a major health problem; for example, the American Cancer Society has estimated that in the USA alone there might have been approximately 1.3 million cases of skin cancer (including nonmelanoma skin cancer and melanoma) in the year 2000, placing the incidence of skin cancer ahead of that of all other malignancies (Moodycliffe et al., 2000Moodycliffe A.M. Nghiem D. Clydesdale G. Ullrich S.E. Immune suppression and skin cancer development: Regulation by NKT cells.Nature Immunol. 2000; 1: 521-525https://doi.org/10.1038/82782Crossref PubMed Scopus (276) Google Scholar). Because exposure to UV radiation from sunlight seems to be the major reason for the enormous incidence of skin cancer (Urbach, 1997Urbach F. Ultraviolet radiation and skin cancer of humans.Photochem Photobiol. 1997; 40: 3-7https://doi.org/10.1016/S1011-1344(97)00029-8Crossref Scopus (113) Google Scholar), cancer prevention strategies have focused on the reduction of environmental UV exposure by a broad range of different measures, including the administration of sunscreens. The designated efficacy of sunscreens is indicated by the sun protection factor (SPF), which is solely based on ability to prevent erythema. Significant improvements in the development of sunscreens have led to preparations with SPF ratings of 30 and higher. Sunscreens are highly protective against sunburn but the efficacy in protecting against nonerythema endpoints is not well understood (Donawho and Wolf, 1996Donawho C. Wolf P. Sunburn, sunscreen, and melanoma.Curr Opin Oncol. 1996; 8: 159-166Crossref PubMed Scopus (34) Google Scholar). In animal studies, sunscreens protected against chronic UV-induced skin aging, tumor initiation, and tumor promotion (for review seeDonawho and Wolf, 1996Donawho C. Wolf P. Sunburn, sunscreen, and melanoma.Curr Opin Oncol. 1996; 8: 159-166Crossref PubMed Scopus (34) Google Scholar). There is some evidence that sunscreens protect human subjects from the formation of squamous cell (but not basal cell) carcinoma (Green et al., 1999Green A. Williams G. Neale R. et al.Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: A randomised controlled trial.Lancet. 1999; 345: 723-729https://doi.org/10.1016/S0140-6736(98)12168-2Abstract Full Text Full Text PDF Scopus (762) Google Scholar) and from the formation of actinic keratoses, lesions that may be precursors to squamous cell carcinoma (Thompson et al., 1993Thompson S.C. Jolley D. Marks R. Reduction of solar keratoses by regular sunscreen use.N Engl J Med. 1993; 329: 1147-1151https://doi.org/10.1056/NEJM199310143291602Crossref PubMed Scopus (630) Google Scholar;Naylor et al., 1995Naylor M.F. Boyd A. Smith D.W. Cameron G.S. Hubbard D. Neldner K.H. High sun protection factor sunscreens in the suppression of actinic neoplasia.Arch Dermatol. 1995; 131: 170-175https://doi.org/10.1001/archderm.131.2.170Crossref PubMed Google Scholar). There is inconclusive evidence concerning the benefit of sunscreens in the prevention of cutaneous melanoma, the most dangerous and potentially lethal form of skin cancer. The results of several retrospective epidemiologic studies have suggested that the use of sunscreens may even be associated with an increased melanoma risk, after statistical adjustment of phenotypic and sun exposure-related factors (for review seeDonawho and Wolf, 1996Donawho C. Wolf P. Sunburn, sunscreen, and melanoma.Curr Opin Oncol. 1996; 8: 159-166Crossref PubMed Scopus (34) Google Scholar;Weinstock, 1999Weinstock M.A. Do sunscreens increase or decrease melanoma risk: An epidemiologic evaluation.J Invest Dermatol Symp Proc. 1999; 4: 97-100Crossref PubMed Scopus (60) Google Scholar). A possible explanation for these results is that sun-screens may provide insufficient immunoprotection to be effective in skin cancer prevention. Indeed, the ability of sunscreens to protect laboratory animals and humans against the immunosuppressive effects of UV radiation has been the subject of great controversy (for review seeGranstein, 1995Granstein R.D. Evidence that sunscreens prevent UV radiation-induced immunosuppression in humans.Arch Dermatol. 1995; 131: 1201-1204https://doi.org/10.1001/archderm.131.10.1201Crossref PubMed Google Scholar;Wolf and Kripke, 1997Wolf P. Kripke M.L. Immune aspects of sunscreens.in: Gasparro F. Sunscreen Photobiology: Molecular, Cellular and Physiological Aspects. Springer-Verlag, Berlin1997: 99-126Crossref Google Scholar;Ullrich et al., 1999Ullrich S.E. Kim T.H. Ananthaswamy H.N. Kripke M.L. Sunscreen effects on UV-induced immune suppression.J Invest Dermatol Symp Proc. 1999; 4: 65-69Abstract Full Text PDF PubMed Scopus (27) Google Scholar). It has been suggested that insufficient sunscreen protection from immunosuppression may increase the skin cancer risk of consumers, particularly when high SPF sunscreens are used to prolong sun exposure extensively (Wolf et al., 1994Wolf P. Donawho C.K. Kripke M.L. Effect of sunscreens on UV radiation-induced enhancement of melanoma growth in mice.J Natl Cancer Inst. 1994; 86: 99-105Crossref PubMed Scopus (106) Google Scholar). The labeled SPF on a sunscreen product approved for market is determined in UV dose–response studies in humans, according to defined regulations (COLIPA, 1994COLIPA Sun protection factor test method published by the European Cosmetic Toiletry and Perfumery Association (COLIPA). 1994Google Scholar;Food and Drug Administration (FDA), 1999Food and Drug Administration (FDA) Sunscreen products for over-the-counter human use. Final Monograph FR.Fed Regist. 1999; 64: 27666-27693PubMed Google Scholar). There is no similar requirement for assessing the immunoprotective capacity of sunscreens; a very high number of subjects would be necessary for such studies. In this study, we used a CHS model to investigate the immunoprotective capacity of a sunscreen preparation containing a chemical UVB filter and of a broad-spectrum sunscreen preparation containing the same UVB filter and an additional chemical UVA filter. The purpose of the study was to assess the sunscreens in terms of their immune protection factors (IPF) and to compare IPF with conventional SPF. Sunscreen preparations were assessed in terms of IPF for a specific form of immunosuppression, determined in the commonly used human model of UV-induced local suppression of the induction of CHS to the contact allergen dinitrochlorobenzene (DNCB) (Kelly et al., 2000Kelly D.A. Young A.R. McGregor J.M. Seed P.T. Potten C.S. Walker S.L. Sensitivity to sunburn is associated with susceptibility to ultraviolet radiation-induced suppression of cutaneous cell-mediated immunity.J Exp Med. 2000; 191: 561-566https://doi.org/10.1084/jem.191.3.561Crossref PubMed Scopus (144) Google Scholar). We used a three-stage study design in which data were analyzed after each stage and used to determine appropriate UV light doses in the next stage. The results of the study are particularly significant because the susceptibility to this specific form of UV-induced immunosuppression has been previously linked to skin cancer history (Yoshikawa et al., 1990Yoshikawa T. Rae V. Bruins-Slot W. Van den Berg J.W. Taylor J.R. Streilein J.W. Susceptibility to effects of UVB radiation on induction of contact hypersensitivity as a risk factor for skin cancer in humans.J Invest Dermatol. 1990; 95: 530-536https://doi.org/10.1111/1523-1747.ep12504877Crossref PubMed Scopus (371) Google Scholar). The studies consisted of a small study in healthy volunteers to determine the SPF of sunscreen preparations and a larger, randomized, 4 wk study in healthy volunteers, designed to evaluate IPF of the sunscreen preparations, both conducted between November 1998 and April 2000 at the Photodermatology Department of the Department of Dermatology, University of Graz, Austria. The studies were conducted during periods of the year with low environmental sunlight radiation (November to April) to minimize interference with the artificial UV exposure given in the study. Inclusion criteria were as follows: age between 18 and 60 y, general good health status, skin phototype II to IV, and absence of skin cancer at study entry. Exclusion criteria were pregnancy, lactation, childbearing potential in the absence of a reliable contraceptive method, psychiatric disease, seizure disorders and/or compromised central nervous system function, congenital or acquired immunodeficiency syndrome, genetic disease with DNA repair deficiency (e.g., xeroderma pigmentosum), porphyria, serious infection within the previous 28 d, Karnofsky index less than 80, administration of an investigational new drug or immunosuppressive medication within the last 6 mo before study entry (IPF study only), taking an anti-inflammatory or photosensitizing medication, previous contact with DNCB (IPF study only), skin disease or other disease that might interfere with sensitization and/or CHS to DNCB (IPF study only), and high amounts of total body exposure or direct exposure of the test sites on the buttocks and upper arm to environmental and/or artificial UV radiation during the last 4 wk prior to study entry. The study protocols were approved by the local ethics committee, and all subjects provided informed consent before participation. Different groups of volunteers were enrolled in the SPF study and the IPF study. The SPF study included sunscreen application and exposure to a series of UV doses on day 1 and reading of the UV erythema response on day 2 (as described below for determination of the sunscreen SPF). The IPF study included a screening visit and study visits on days 1, 2, 4, 22, 24, and 25. At the screening, the individual minimal erythema dose (MED) of solar-simulated radiation was determined for each subject (as described below for determination of the sunscreen SPF). Patients were enrolled in three sequential study stages, with enrollment in each stage delayed until data analysis from the previous stage was complete. There were three different treatment groups: group A (no sunscreen), group B (UVB sunscreen no. 321), and group C (UVA+B sunscreen no. 322) for the different study stages. All subjects in stage I were in group A and were randomly assigned to a UV irradiation treatment cohort for the CHS assay. Subjects in stages II and III were randomly assigned both to treatment group (group A, group B, or group C) and to UV irradiation treatment cohort for the CHS assay, using a randomization procedure. UV irradiation treatment cohorts for the CHS assay received no irradiation (control group) or one of four UV dose levels. UV doses in stage I were chosen on a regular UV dosage grid. In stages II and III the grid was decreased in order to place the UV doses within the confidence interval (CI) of the location parameter of the logistic function, as described below. If used, a sunscreen was applied 20 min before UV exposure at a concentration of 2 mg per cm2. Subjects received a single exposure to solar-simulated UV radiation in a previously unexposed, 5 × 5 cm field on the left buttock (with or without prior sunscreen treatment) on day 1. In stage I subjects (all in group A) were exposed to UV irradiation on the designated 5 × 5 cm area of the buttocks at single doses equivalent to 0, 0.5, 1, 2, or 3 × the individual MED; in stage II, at single doses equivalent to 0, 0.5, 0.75, 1, or 1.5 × the individual MED; and in stage III, at single doses equivalent to 0, 0.75, 1, 1.25, or 1.5 × the individual MED. In stages II and III sunscreen-treated subjects in groups B and C received the same relative range of UV doses but the UV doses were multiplied by the specific SPF of the sunscreen (5.2 and 6.2 for subjects in groups B and C, respectively; see Results below). Twenty-four hours after UV irradiation (day 2), volunteers were sensitized on unirradiated or UV-irradiated, sunscreen-protected or unprotected buttock skin with DNCB, as previously described (Kelly et al., 2000Kelly D.A. Young A.R. McGregor J.M. Seed P.T. Potten C.S. Walker S.L. Sensitivity to sunburn is associated with susceptibility to ultraviolet radiation-induced suppression of cutaneous cell-mediated immunity.J Exp Med. 2000; 191: 561-566https://doi.org/10.1084/jem.191.3.561Crossref PubMed Scopus (144) Google Scholar). Twenty-one days after sensitization (day 22), the subjects were challenged with DNCB for determination in a CHS assay, described below. UV-simulated radiation was provided by an Oriel 1000 W solar simulator (Oriel Corp., Darmstadt, Germany) equipped with a dichroic mirror, an atmospheric attenuation filter (WG320/1 mm), and a UG5/1 mm visible infrared light bandpass blocking filter. Irradiance was routinely measured and monitored by a wide-band thermopile radiometer (Dexter Research 2M model with quartz window) (Medical Physics, Dryburn Hospital, Durham, UK), calibrated by the Regional Medical Physics Department, Royal Victoria Infirmary Unit (Newcastle upon Tyne, UK), using a reference thermopile (Hilgar-Swartz FT17). The total irradiance at 20 cm from the outermost filter of the system was 12.0 mW per cm2, as measured by the wide-band Dexter Research thermopile radiometer. During the study, this UV irradiance of the Oriel solar simulator was kept constant by use of an integrated automated photo feedback system. The spectrum of the light source conformed to FDA and COLIPA (Comité de Liaison des Associations Euro-péenes de l'Industrie de la Parfumerie, des Produits Cosmetiques et de Toilette) regulations for sunscreen testing, as determined by an International Light spectroradiometer system (International Light Inc., Newburyport, Massachusetts). Proprietary sunscreen preparations were provided for this study by Beiersdorf AG (Hamburg, Germany). A preparation designated as UVB sunscreen no. 321 contained 4% of the chemical UVB filter methylbenzylidine camphor, and a preparation designated as broad-spectrum UVA+B sunscreen no. 322 contained 4% methylbenzylidine camphor and 1.5% butyl methoxy dibenzoylmethane, a chemical UVA filter. The same oil-in-water emulsion (containing stearic acid, glyceryl stearate, octyldodecanol, dicaprylyl ether, cetearyl alcohol, phenoxyethanol, methylparaben, ethylparaben, propylparaben, butylparaben, sodium hydroxide, glycerin, trisodium ethylenediamine tetraacetic acid, caprylic/capric triglyceride, and carbomer) was used as vehicle for formulation of both sunscreens. The absorbance spectrum of the sunscreen preparations is shown in Figure 1. The critical wavelength of the UVB sunscreen no. 321 was 332 nm and that of the UVA+B sunscreen no. 322 was 375 nm, according to the Diffey definition (Diffey et al., 2000Diffey B.L. Tanner P.R. Matts P.J. Nash J.F. In vitro assessment of the broad-spectrum ultraviolet protection of sunscreen products.J Am Acad Dermatol. 2000; 43: 1024-1035https://doi.org/10.1067/mjd.2000.109291Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar). Before starting the CHS studies, the mean SPF of each sunscreen was determined, according to FDA and COLIPA guidelines. Briefly, healthy volunteers were UV irradiated with the Oriel 1000 W solar simulator in series of six 1 × 1 cm areas on unprotected or sunscreen (2 mg per cm2)-protected buttocks with graded solar-simulated UV doses at 25% increments. Erythema was scored visually 24 h after UV exposure and the MED was defined as the lowest dose required to produce perceptible erythema with a sharp border. The individual SPF of a sunscreen was determined in each subject by calculating the ratio of MED with a sunscreen versus MED without a sunscreen. Then, a mean SPF value and 95% CI were calculated for each sunscreen. For sensitization, DNCB (Sigma-Aldrich, St Louis, Missouri) was applied using a 12 mm paper filter disk, soaked with 50 μL of 0.0625% DNCB in ethanol (31.25 μg per 50 μL). The filter paper was mounted inside a 12 mm aluminum Finn chamber (Epitest Ltd, Tuusula, Finland) that was taped with hypoallergenic Scanpore (Epitest Ltd) tape to an unirradiated site or to the 5 × 5 cm UV-irradiated site on the buttocks for 48 h until removal on day 3. The DNCB concentration used for epicutaneous application was previously found to be sufficient to sensitize human subjects (Friedmann, 1994Friedmann P.S. Clinical aspects of allergic contact dermatitis.in: Dean J.H. Luster M.I. Munson A.E. Kimber I. Immunotoxicology and Immunopharmacology. Raven Press, New York1994: 589-616Google Scholar;Kelly et al., 1998Kelly D.A. Walker S.L. McGregor J.M. Young A.R. A single dose of solar-simulated radiation suppresses contact hypersensitivity responses both locally and systemically in humans: Quantitative studies with high-frequency ultrasound.J Photochem Photobiol B Biol. 1998; 44: 130-142https://doi.org/10.1016/S1011-1344(98)00136-5Crossref PubMed Scopus (61) Google Scholar,Kelly et al., 2000Kelly D.A. Young A.R. McGregor J.M. Seed P.T. Potten C.S. Walker S.L. Sensitivity to sunburn is associated with susceptibility to ultraviolet radiation-induced suppression of cutaneous cell-mediated immunity.J Exp Med. 2000; 191: 561-566https://doi.org/10.1084/jem.191.3.561Crossref PubMed Scopus (144) Google Scholar). An average prechallenge skin thickness was calculated for each study participant; prestudy testing had revealed significant interindividual differences but no significant intraindividual differences in the skin thickness of the upper inner arm in different subjects (data not shown). On day 22, the average prechallenge dermal skin thickness of the challenge area on the arm was determined by ultrasound measurements made at three randomly selected sites in the challenge area, immediately before application of the patch apparatus (see below). Subjects were then challenged on the upper inner arm by the application of a patch with a series of 5 8 mm Finn chambers, each containing an 8 mm paper filter disk (Epitest) that was moistened with a 20 μL solution of DNCB in ethanol. The five Finn chambers were arranged to have increasing amounts of DNCB, from 0, 3.125, 6.25, 12.5, to 25.0 μg DNCB. Before taping the patch apparatus in place, CHS elicitation sites were marked by putting slight pressure on the patch apparatus positioned at the exact application site, in order to recognize the imprints of the Finn chambers, and then marking the site of each chamber of the patch apparatus with a surgical marker pen. The patch was taped and left in place on the arm for 48 h. At 49 h after challenge (1 h after removal of the patch) and at 72 h after challenge, CHS responses at the five challenge sites were quantified by means of: (1) a clinical score (0, no reaction; 0.5, macular erythema; 1, erythema and edema; 2, papules and small blisters; 3, bulla or erosion or spreading reaction); (2) measurement of the lesion diameter in millimeters; and (3) measurement of skin swelling using 20 MHz ultrasound (Dermascan C, Cortex Technology, Hadsund, Denmark). The ultrasound measurements were performed using ultrasonic coupling gel, and a scanning image of each elicitation site was recorded. The mean dermal skin thickness of a challenge site was obtained from measurements at three randomly selected locations along the horizontal length of a ultrasound scanning image. The increase of dermal skin thickness after challenge (i.e., dermal skin swelling) was calculated for each elicitation site by subtracting the average dermal skin thickness before CHS challenge (obtained by measurements at the three randomly selected prechallenge locations) from the mean dermal skin thickness after challenge. The CHS responses (endpoints) were dermal skin thickness, clinical score, and the CHS lesion diameter. For statistical analysis, the data of the 49 and 72 h postchallenge readings from the five different DNCB challenge sites of each of the endpoints (i.e., dermal skin thickness, clinical score, and the CHS lesion diameter) were pooled for each subject and a mean response value was calculated for each endpoint for each subject (Matthews et al., 1990Matthews J.N. Altman D.G. Campbell M.J. Royston P. Analysis of serial measurements in medical research.Br Med J. 1990; 300: 230-235Crossref PubMed Scopus (2635) Google Scholar). The relationship between UV radiation dose and mean CHS response was modeled by a four-parameter logistic model for the logarithm of dose. The model formula is as follows: μ(D)=(c-d)⋅invlogit(log(D)-ab)+d where μ is prediction of immune reaction, D is the UV dose, invlogit(x) is ex/(ex+1), a is 50% immunosuppressive UV dose (ID50), b is slope, c is maximal immune suppression, and d is minimal immune reaction. The predicted values range from minimum response (d) to maximum response (c). The slope of the logistic curve at the point of steepest descent is inversely proportional to the slope parameter (b). The middle of the range of predicted response values is obtained if the dose is equal to the ID50 (a). The standard deviation of the CHS response (σ) was modeled as dose dependent, as follows: σ(μ)=σ0(1+0μ) where σ represents standard deviation of response, μ represents prediction of immune reaction, σ0 and θ represent parameters of the standard deviation function of the immune reaction. Each of the three experimental groups had a separate ID50 parameter (a), whereas the remaining parameters were common to all groups. The model parameters were calculated by the weighted least squares method (Carroll and Ruppert, 1988Carroll R.J. Ruppert D. Transformation and Weighting in Regression. Chapmann and Hall, London1988Crossref Google Scholar). IPF was calculated by dividing the ID50 of a sunscreen-treated group by the ID50 of the sunscreen-untreated group. Ninety-five percent CI and p-values were calculated by nonparametric bootstrap and randomization tests (Efron and Tibshirani, 1993Efron B. Tibshirani R.J. An Introduction to the Bootstrap. Chapman and Hall, London1993Crossref Google Scholar). A thousand replications were performed in the simulations. Two-sided p-values less than 0.016 were considered significant after Bonferroni adjustment of the significant p-value level for multiple endpoint testing. Eighteen Caucasian volunteers (nine men and nine women; median age, 29 y; age range, 19–46 y; all of skin phototype III) were enrolled for SPF sunscreen testing, according to FDA and COLIPA guidelines. The SPF were determined to be 5.2 (95% CI, 4.6–5.7) for the UVB sunscreen no. 321 and 6.2 (95% CI, 5.3–7.1) for the broad-spectrum UVA+B sunscreen no. 322, respectively (p=0.002; Student's paired t test). Seventy-five healthy, Caucasian men (median age, 26 y; range, 19–57 y; Fitzpatrick skin phototype II, seven; III, 66; and IV, two) and 15 Caucasian women (median age, 29 y; range, 18–47 y; skin phototype II, one; and III, 14) were enrolled in the sunscreen CHS immunoprotection studies (Table I). Two men dropped out in stage I of the study due to personal reasons, and three men had to be withdrawn from the study in stage III due to a technical defect of the photo feedback system of the UV light source. No data from those five male subjects were included in the statistical analysis.Table IStudy disposition of subjectsaSubject numbers are based on intent-to-treat data. Two men in Stage I dropped-out due to personal reasons, and 3 men in Stage III had to be withdrawn due to a technical defect of the light source.Number and sex of su" @default.
• W2045478818 created "2016-06-24" @default.
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• W2045478818 date "2003-11-01" @default.
• W2045478818 modified "2023-10-16" @default.
• W2045478818 title "Immune Protection Factors of Chemical Sunscreens Measured in the Local Contact Hypersensitivity Model in Humans" @default.
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