* National Institute for Occupational Safety and Health, MS 4020, 1095 Willowdale Road, Morgantown, West Virginia 26505; and
Department of Surgery, West Virginia University, Morgantown, West Virginia
Received January 7, 2000; accepted March 16, 2000
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ABSTRACT |
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Key Words: latex allergy; dermal protein penetration; flow through diffusion cells; latex specific IgG1; dermal latex sensitization; immunohistochemistry; hairless guinea pig dermal penetration model.
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INTRODUCTION |
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Although large amounts of data have been generated on the elicitation of allergic reactions, less is known on how individuals become sensitized to NRL proteins. For children with spina bifida, studies in Germany have positively correlated increasing numbers of operations with the development of latex allergy (Chen et al., 1997). These studies support the possibility of mucosal or subcutaneous sensitization. For health care workers, studies have associated powdered-glove usage with increased allergic responses (Brehler et al., 1997
) suggestive of inhalation sensitization. Also, it has been demonstrated that many latex-allergic health care workers currently have or have previously had skin lesions due to irritant or contact dermatitis (Boxer, 1996
); this raises the question of skin induction. Consequently, there has been an increasing effort to prevent new NRL allergic reactions through education and intervention strategies. The Food and Drug Administration banned one product that caused 15 deaths from 1988 to 1992 due to highly antigenic latex catheter tips (Slater, 1994
), and the National Institute for Occupational Safety and Health issued an alert recommending the use of non-powdered, low-protein gloves when latex gloves are chosen (NIOSH, 1997
). These preventative directions have sought to reduce exposure to NRL proteins mainly due to inhalation and mucosal routes. As large molecular weight proteins are generally considered unable to cross the intact skin barrier, little research has focused on the role of dermal penetration in the development of latex sensitization. These studies were undertaken to evaluate the percutaneous penetration of latex proteins into and through intact and abraded skin and to demonstrate the potential for the induction of an immunological response following dermal exposure. A better understanding of the mechanisms underlying the development of latex sensitization, including the skin's role in latex-protein allergies, is needed to provide a scientific basis for future intervention strategies.
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MATERIALS AND METHODS |
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Human skin.
Human skin was obtained from two sources. First, under a protocol approved by the Institutional Review Board for the Protection of Human Subjects at West Virginia University, fresh, surgical skin samples were obtained from Ruby Memorial Hospital, Morgantown, WV. The donated skin came from females undergoing partial or full mastectomies and was received in saline immediately following surgery. Second, human skin samples were obtained from the Center for Organ Recovery and Education (CORE, Pittsburgh, PA). The fresh surgical samples were utilized in the penetration assays and for immunohistochemistry sections, and the skin received from CORE was used during immunohistochemistry procedures to adsorb cross-reacting antibodies found in the rabbit sera.
Harvesting skin for in vitro penetration studies.
For all animal studies, HGP were euthanized by carbon dioxide asphyxiation and full thickness skin removed from the dorsal thorax and lumbar areas. The excised skin was washed with a 10% (v/v) soap solution, rinsed with water, and patted dry with paper towels. For abraded specimens, the skin was tape stripped ten times with D SquameTM discs (14-mm diameter, Cuderm Co, Dallas, TX) to remove the stratum corneum. A 250-µm thickness, including the entire epidermis and extending into the upper papillary dermis, was excised with an electric dermatome (Padgett Instruments, Kansas City, MO) and 12.7 mm (0.5 in) circular punches were taken of intact and abraded skin using a steel punch (McMaster-Carr, Inc., New Brunswick, NJ). In each experiment, the entire procedure was accomplished within 2 h of the time that animals were euthanized. Processing of human surgical samples was accomplished within 2 h of receipt from the hospital and was conducted as described for animal skin, with one exception. Human skin samples were dermatomed to a thickness of 380 µm. Attempts were made to prepare thinner sections of the surgical samples, but the resulting tissue had visible holes and failed a barrier test prior to tape-stripping.
Test articles.
Both non-ammoniated latex (NAL) and ammoniated latex (AL) proteins were evaluated in these studies. The former is a more standardized test article (Hamilton and Adkinson, 1996) containing the proteins from the H. brasiliensis lactiferous cells, while the latter is the starting material often used by industry to make dipped products such as gloves and condoms and more closely represents extractable proteins from NRL products.
Protein iodination.
The latex protein solutions used for the penetration studies were radiolabeled with iodine(125) using the method described by Markwell (1982) with minor modifications. Carrier-free Na125I (NEN, Boston, MA) and Iodo-BeadsTM (Pierce, Inc., Rockford, IL) were added to 250 µl of 100 mM PBS (pH 7.0) followed by addition of the latex-protein solutions. After 25 min of incubation, the radioactive solution was dialyzed for 48 h (4°C) against 8L 50 mM KH2PO4 (pH 7) using tubing with a molecular weight cut off of 1000 Da.
In vitro penetration studies.
The in vitro penetration assay was modeled after the method of Bronaugh and Stewart (1985). Studies were conducted with In-line, Teflon diffusion cells (Permegear, Inc., Riegesville, PA) with an exposed skin surface area of 0.64 cm2 in each cell. Skin temperature was maintained at 32°C by aluminum cell warmers. An environmental chamber covered the diffusion cells to control the ambient temperature and humidity at 26.7°C and 60%, respectively. A HEPES-balanced Hank's salt solution (Gibco) was pumped through the cells at a flow rate of 1.8 ml/h and the effluent was collected every 6 h. The entire epidermal surface area of the dermatomed skin samples was covered with 100 µl of the radiolabeled latex mixtures (100 µg protein). Two skin samples (one intact and one abraded) in each study were exposed with the same concentration of non-radioactive latex proteins, under identical conditions, and were used for the immunohistochemistry experiments. Following 24 h of exposure, the skin samples were washed for contribution to mass balance, and the radioactive skin samples and 500 µl of receptor effluent for each time point were quantified. The non-radioactive skin samples were fixed in 10% buffered formalin overnight, processed, and embedded in paraffin for immunohistochemistry.
Barrier test.
The barrier integrity of all skin samples receiving radioactive test compounds was verified using a 20-min 3H2O penetration assay (Bronaugh and Collier, 1991). Briefly, 200 µl of 3H2O was applied to the skin sample, covering the entire exposed surface area. The solution was left on for 20 min and then blotted dry with cotton-tipped applicators (Fisher Scientific). After washing once with 300 µl distilled H20, and drying the surface of residual water, the effluent was collected for an additional 60 min. Finally, 10 ml of Scintisafe PlusTM 50% scintillation cocktail (Fisher Scientific) was added to each tube and the radioactivity quantified via a Packard Tri-Carb 2500TR beta liquid scintillation counter. A 200-µl sample of the dosing solution was counted in duplicate and averaged. The percent 3H2O penetration for each cell was calculated by the following formula:
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Only skin samples that passed the test (<0.35% 3H2O penetration, (Bronaugh and Collier, 1991) were used for intact skin analysis and only cells failing the test were used as abraded samples.
Characterization of effluent.
Receptor effluents pools were generated for both intact and abraded samples. The solutions were freeze-dried, resuspended in 10% formic acid, and dialyzed against 4 L dH2O (48 h, 4°C) to remove the salts and formic acid. The dialyzed solution was lyophilized again and resuspended in sample buffer for running on gels. A sample of this solution for both the intact and abraded skin samples was resolved on 16.5% tris-tricine ready gels (BioRad), dried, and subjected to phosphoimaging.
Immunohistochemistry.
Paraffin-embedded skin samples were cut at 5 µm and placed on microscope slides. To block endogenous peroxidase, the slides were placed in a 1:1 solution of 3% H2O2 and methanol for 20 min and then incubated with 0.1% avidin and 0.01% biotin for 30 min (DAKO Co.) to block endogenous biotin in the skin. The slides were next coated with a 10% BSA block buffer for 1 h, followed by incubation with a rabbit polyclonal anti-latex antibody overnight at 4°C (NAL, 1:200;
AL, 1:1000). The slides were then incubated with a biotinylated swine, anti-rabbit F(ab`)2 fragment (1:300, DAKO) absorbed with human skin, for 30 min at RT, followed by incubation with streptavidin-HRP (1:100). The slides were developed with liquid 3-amino-9-ethylcarbazole, washed with dH2O, and counter stained with Mayer's hematoxylin (5 min).
In vivo exposure.
Twenty-five hairless guinea pigs were weighed and assigned to homogeneous weight groups (n = 5). Due to the limited availability of HGP, it was necessary to use both males (15) and females (10), and they were assigned randomly into each group. Animals were divided into 5 exposure groups: vehicle tape-stripped, NAL intact, NAL tape-stripped, AL intact, and AL tape-stripped. Only one vehicle group was designated because of the limited availability of HGP. Prior to the first latex exposure, animals were pre-bled to establish a baseline latex specific IgG1 level. To ensure that compound application and tape-stripping occurred at the same area throughout the exposure period, a circle was outlined with a Sharpie pen on each animal's dorsal thorax area. To accomplish the tape-stripping, animals were manually restrained and a 22-mm D-SquameTM disc was applied to the skin inside the marked circle and swiftly peeled away. This was repeated 10 times for each animal in the tape-stripped groups. For the first 6 weeks of exposure, the tape-stripping occurred once every 2 weeks, during the remainder of the study, this procedure was increased to once per week. The animals designated as intact received no skin modifications during the study. NAL and AL proteins were diluted in vehicle (3 parts 50 mM KH2PO4 and 1 part acetone solution (pH 78)) to 1 mg/ml to administer the same volume (100 µl) and protein amount (100 µg) as was used in the in vitro penetration studies. The addition of 1 part acetone to the vehicle was necessary to break the surface tension of the vehicle when applied to the skin and to prevent the solution from rolling off. Initial attempts to apply the protein in vehicle without the addition of acetone, using Finn chambers, failed because the hairless guinea pigs would not tolerate the bandage materials used to secure the chambers, and excoriated their skin. The solutions were diluted fresh each day and applied topically with a pipette tip inside the marked circle, 5 days per week for 3 months. Post-exposure blood samples were obtained at the termination of the study. Prior to blood collection for both pre- and post-exposure samples, the animals were lightly anesthetized with ketamine (intramuscular injection, 25 mg/kg). Peripheral blood was taken and allowed to clot for 1 h at room temperature. The clotted blood was centrifuged at approximately 1500 x g for 20 min and the sera fractions were stored at 20°C until use.
IgG1 ELISA.
Immulon-II microtiter plates (Dynatech Labs) were coated overnight (4°C) with 100 µl of either NAL or AL proteins (5 µg/ml) in carbonate buffer, followed by a block with 5% nonfat dry milk in block buffer (PBS-Tween, Sigma Chemical Co.). The sera (1:5 initial dilution) were serially diluted (1:2) down the plate in block buffer and incubated for 2 h at 37°C followed by incubation with a horseradish peroxidase-conjugated goat anti-guinea pig IgG1 (1:2000, Bethyl Laboratories, Inc.) for 1 h at 37°C. Between each step, the plates were washed 6 times with phosphate-buffered saline containing 0.5% Tween-20. The plates were developed with substrate (p-nitrophenyl phosphate, Sigma Chemical Co.) and the optical density (OD) read at 405 nm after 1 h.
Statistical analysis.
All data analysis was accomplished using Prism 2.0 software for the PC. For the in vitro penetration experiments, unpaired t-tests were performed to compare intact and abraded skin results. Correlations between the barrier tests and percutaneous penetration into the receptor fluid were assessed with either non-linear or linear regression analysis.
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RESULTS |
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Immunohistochemical staining was used to localize latex proteins to distinct regions of the skin. Representative sections of human and guinea pig skin exposed to AL proteins and incubated with rabbit anti-latex sera are shown in Figures 3 and 4, respectively. In the intact skin, latex proteins were seen in the stratum corneum non-viable layers as well as in the viable epidermal layers, which are rich in antigen presenting Langerhans cells. Removal of the barrier layers resulted in more intense staining in the epidermis with visualization of latex proteins in the vascularized dermal layers, which gives rise to the possibility of systemic absorption following skin exposure. Similar patterns of staining were observed in human and guinea pig skin exposed to NAL (data not shown). Positive antibody staining of latex proteins in the skin helps confirm that the radioactive counts recovered in the penetration assays were due to latex proteins and not unincorporated radiolabel. Also, the radioactive counting of the skin samples following extensive washes and immunohistochemistry demonstrate that the skin is able to retain latex proteins after a 24-h exposure period.
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DISCUSSION |
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Many latex-sensitive individuals suffer from hand dermatitis either brought on idiopathically or by various factors including hand washing (Larson et al., 1986), glove use (Turjanmaa, 1994
), and/or atopy (Lammintausta and Kalimo, 1981
) and therefore an abraded skin model may more closely represent the skin condition of individuals at risk for latex allergy. Taylor and Praditsuwan (1996) correlated a clinical diagnosis of latex protein allergy with atopy (77%) and pre-existing hand eczema (82%). In these studies, when skin samples were abraded prior to exposure to latex proteins, penetration was significantly enhanced, with the skin retaining approximately 3% of the applied dose and a mean of 23% recovered from the receptor fluid from human skin exposed to NAL. The percent penetration positively correlated with the degree of abrasion, which may explain the lower mean percent penetration seen in the HGP skin exposed to AL (7.67%) as compared to NAL (19.14%). In the 3H2O penetration test, which evaluates the degree of barrier disruption, 10 of 20 skin samples exposed to NAL permitted greater than 10% 3H2O penetration as compared to only 3 of 19 samples from the AL study. Similarly, in evaluating the penetration of vasopressin (1000 Da), using skin from haired rats in 1-chambered (static) cells, Banerjee and Ritschel (1989) demonstrated approximately 2% penetration when the hair was clipped from the animals' skin as compared to approximately 50% penetration when the skin was shaved.
In vivo studies were conducted using the development of an immunoglobulin response as a biomarker of exposure to further demonstrate that latex proteins are able to penetrate intact and abraded skin. Due to the limited number of hairless guinea pigs available, optimization studies were not conducted in this strain. Instead, the study design was based on the results of dose-response and time-course studies conducted in BALB/c mice (Woolhiser et al., 2000). Only 35% of the hairless guinea pigs exposed dermally to latex proteins developed a latex-specific IgG1 response over the 3-month period. This may reflect a different time course of development of IgG1 in the guinea pig as compared to IgE in the mouse, or it may reflect an altered immune status in the hairless guinea pig. The immune status of this species has not been well defined. It is known that in some other species, the mutations leading to the hairless phenotype also result in altered immune function (Harris et al., 1993
). Based on expectations due to the penetration data (i.e., a higher degree of penetration through abraded versus non-abraded skin), there may appear to be a contradiction in the number of animals that developed latex-specific immunoglobulin following exposure to abraded (2 of 10 animals) versus intact (5 of 10 animals) skin. However, Woolhiser et al. (2000) demonstrated that although IgE levels were elevated earlier in animals exposed to latex proteins through abraded skin, by day 53 post-initial exposure, levels were comparable in animals exposed through intact and abraded skin. Sera samples were evaluated from guinea pigs at 3 months following initial exposure.
In reviewing the relevance of skin exposure in the workplace, Fiserova-Bergerova (1993) concluded that concerns for skin exposure will increase as respiratory exposures are diminished. This may prove to be the case for latex allergy. Latex proteins have been shown to bind to glove donning powder and be aerosolized (Beezhold and Beck, 1992; Tomazic et al., 1994
) with latex protein levels in highly powdered glove use areas of hospitals reaching 121 ng/m3 (Swanson et al., 1992
). Given that the most common serious adverse effects of latex allergy are related to asthmatic responses, much attention has been focused on reducing aerosolized levels of protein and thereby reducing the elicitation of respiratory symptoms. Less attention has been given to investigating the role of the route of exposure in the development of latex sensitization. These studies demonstrated that latex proteins are able to penetrate excised human and guinea pig skin, and that exposure to 100 µg of latex proteins 5 days per week for 3 months induced an IgG1 response in 35% of exposed animals. Woolhiser et al. (2000) demonstrated that BALB/c mice exposed to 50 µg of latex protein through abraded skin developed elevated levels of IgE in as little as 23 days. In terms of human exposure, latex examination gloves have been shown to contain from 0.2 to 4000 µg proteins per glove (Zehr and Beezhold, 1995
) and latex proteins have been demonstrated to transfer onto the skin by donning gloves (Beezhold et al., 1994
). The implication for these data is that the skin is not only a plausible route for NRL sensitization, but can be a major exposure route when the integument has been compromised. The data further support the recommendations that only reduced-protein latex gloves should be used to avoid skin exposure and potential sensitization to NRL proteins.
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ACKNOWLEDGMENTS |
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NOTES |
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