Allergy to natural rubber latex

Allergy to natural rubber latex

Allerw to natural rubber latex _ --- - - urn -- By Dori R. Germolec, Michael R. Woolhiser, and B. Jean bade N atural rubber is used in the man...

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Allerw to natural rubber latex _






By Dori R. Germolec, Michael R. Woolhiser, and B. Jean bade


atural rubber is used in the manufacture of over 40,000 products. The versatility, elasticity, tactile properties, and barrier capabilities of natural rubber latex (NRL) have been nearly impossible to reproduce using synthetic rubbers and elastomers. The rubber tree, Hevea brasiliensis, is primarily grown and cultivated in Southeast Asia; some trees are also harvested in South America and West Africa. The biology and manufacture of NRL is described in numerous other publications.l” Within collected latex serum are the rubber particles (cis-1,4-polyisoprene units) as well as significant amounts of carbohydrates, lipids, and proteins. When the latex is collected, chemicals such as ammonia, formaldehyde, or zinc oxide are added to prevent coagulation, deterioration, and bacterial growth. Raw latex is centrifuged to separate the rubber particle fraction from the aqueous serum layer. Antioxidants are added to stabilize the highly reactive, unsaturated isoprene bonds and prevent deterioration of the final product. To produce dipped latex products such as gloves or condoms, molds (e.g., porcelain or glass)

Don' R. Germolec is with the National Institutes of Environmental Health Sciences, Environmental Immunology Laboratory, Research Triangle Park, NC; and Michael R. Woolhiser and B. Jean Meade are with the National Institute for Occupational Safety and Health, Health Effects Laboratory Division, Morgantown, WV. 44

Published by Elsevier Science Inc.






are immersed into tanks of compounded rubber. This is followed by vulcanization to improve the strength and elasticity of the product. Chemical accelerators are added during compounding, before dipping, to control the rate and degree of disulfide cross-linking during vulcanization. After drying, the NRL product may be repeatedly washed to remove excess debris; however, some of the constituent Hevea proteins may remain on the product following this process. Despite its extensive use for decades, recognition of allergy to NRL has become widespread only over the past 12 years in industrialized countries. One of the first reports of an immunoglobulin-E (IgE)-mediated, urticarial response to a NRL product (denture plate) was reported in 1927.4 In 1979, the first IgE-mediated reaction to latex gloves was described5 and by the late 1980s there was a dramatic increase in the number of reports describing allergic reactions to NRL. Between 1989 and 1992 the Food and Drug Administration (FDA) received more than 1100 reports of allergic responses and 15 cases of anaphylactic deaths resulting from NRL exposure.6 Through 1997 there were an additional 1300 allergic reactions reported and an additional 13 deaths.7 Adverse reactions to NRL products include irritant dermatitis, allergic contact dermatitis (due to delayed-type hypersensitivity [DTH]) and immediate type hypersensitivity (IgE-mediated). Irritant dermatitis is the most frequent adverse reaction and is considered to be due to chemical additives/friction caused by contact with latex products (e.g., gloves). Allergic contact dermatitis to NRL products has been estimated to account for more than 80% of all occupationally acquired latex allergies.’ DTH has been shown to be





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largely directed toward chemical additives used in NRL product manufacturing,8~galthough a small percentage of contact dermatitis may be due to latex itself. lo Although there are a number of isolated case studies describing contact dermatitis to dozens of chemicals used in the manufacture of NRL (e.g., cetyl pyridinium chloride or butylhydroxyanisole),11*12 most of the reported DTH reactions to latex products occurs toward thiurams, carbamates, or mercapto compounds (all three are chemical accelerators) or phenylenediamines (antioxidant). Conde-Salazar et al.’ reported that 686 out of 4680 dermatology patients (14.7%) had positive patch tests to at least one chemical rubber additive. Greater than 80% of the 686 patients reacted to a thiuram-mix, whereas 22% reacted to a carba-mix. When individual rubber chemicals were tested, three different thiuram compounds elicited contact dermatitis in at least 50% of the 686 patients; two phenylenediamines were the next most recognized chemicals (14%) followed by mercaptobenzothiazole (12%) and a carbamate (11%). Unlike IgE-mediated allergy to latex proteins in which the primary occupational patient population is health care workers (HCWs), the primary occupation of persons sensitized to chemical additives was construction work. Positive patch tests to chemical additives were reported for only a few HCWs and no patients with spina bifida (SB), the other population commonly associated with latex allergy. Similar chemicals are used in dozens if not hundreds of production processes, so sensitization to these chemicals is probably not unique to NRL exposure. Immediate IgE-mediated hypersen1074-9098/99/$20.00 PII SlO74-9098 (99) 00011-8

sitivity occurs rarely but has the most severe consequences. IgE-mediated reactions to latex include urticaria, asthma, and life threatening anaphylaxis, and can occur in sensitized individuals from minutes to hours following latex allergen exposure. Numerous investigators have identified Hevea brasiliensis proteins as the cause of IgE-mediated latex allergy. 13-17The potential for cross reactivity to plant and food allergens is an additional concern for persons who are allergic to latex. The number of foods that have demonstrated cross-reactive allergenicity has become quite extensive and includes bananas, kiwis, chestnuts, avocados, potatoes, sweet peppers, and melons.‘8-22 Several proteins are suspected to be common among these foods and plants and may explain the high degree of cross reactivity.23-27 In individuals demonstrating cross reactivity, it remains unknown whether sensitization initially occurs toward latex proteins or toward food allergens. A great deal of research has focused on characterization of latex protein allergens. Two recent publications have reviewed the major protein allergens as well as the other latex proteins that appear to play some lesser role in latex allergy.‘3’28 Eight such proteins found in Hevea brasiliensis (Table 1) have been identified and classified as major NRL allergens by the International Union of Immunological Societies (IUIS). Hev b 1 and hev b 3 are rubber particle-associated proteins that have a higher degree of binding to IgE from patients with SB than the IgE of HCWs2’ Conversely, hev b 2 and hev b 6 are aqueous latex proteins and are considered major allergens for HCWs. Hev b 6 (hevein) has been shown to have a high degree of cross reactivity and sequence homology with a 30- to 33-kD chitinase, which is found in bananas and avocados.24,30-32 The most recently named latex allergen is hev b 8 (profilin). Hevea brasiliensis profilin can be purified from latex in small amounts and has IgE-binding capabilities33; its role in latex allergy remains uncertain at this time. In addition to these major NRL allergens, numerous other latex proteins

Table 1. Major Natural Rubber Latex Allergies

Nomenclature Hev b 1 Hev b 2 Hev b 3 Hev Hev Hev Hev Hev Hev Hev

b b b b b b b

4 5 6.01 6.02 6.03 7 8

Protein ID Rubber elongation factor /3-1,3-glucanase Rubber particle protein Microhelix protein Acidic protein Prohevein Hevein Prohevein Patatin-like protein Profilin

may have allergenic potential but have not been officially classified by the IUIS. Hevamine is a 29.5-kD defenserelated plant protein that also has a high degree of homology to plant chitinases. Its role in latex allergy may be limited; in one study, IgE from only 1 out of 29 patients identified purified hevamine on an immunoblot.34 Hevea brasiliensis also has 30-to 33-kD plant chitinases similar to those foods such as banana and avocado. It seems reasonable that these proteins could possess a common epitope(s) for latex and fruit allergies. In one study, Akasawa et a135demonstrated that 64% of sera from latex allergic patients reacted with a 30-kD chitinase isolated from avocado. As mentioned previously, there also appears to be homology and a cross reactivity between chitinases and hev b 6. A number of other proteins have been purified and/ or are recognized by sera from persons allergic to latex13128; their roles in latex allergy appear to be minimal at this time. Latex gloves are coated with lubricating powders such as corn starch and it has been well documented that these powders bind latex proteins, thus allowing protein aerosolization.36JQ In addition, starch powders could theoretically act as adjuvants; several investigators have described immune responses involving starch powder.40-42 More recently, the role of endotoxin associated with latex products has been investigated as another potential mechanism of immune potentiation.43*44 Higher levels of endotoxin have been observed in powdered than nonpowdered gloves, presumably due to bacterial growth in

Chemical Health & Safety, July/August 1999

Approximate Size (kD) 14.5

References 76-78

35 22-27

34,79 80-83

100 16 20 4.7 14 4346 14

79 23,84 29,31,34,85-88 26.89-91 28133

corn starch slurries during the manufacturing process. Not only does endotoxin provide an early stimulatory signal in many immune responses, it is potent in vitro as a murine, B-cell mitogen and has been shown to possess some in vivo adjuvant activity.45-47 As mentioned previously, there are two well-recognized populations that demonstrate an increased prevalence of IgE-mediated, latex allergy: HCWs and patients with SB. Physicians and dentists to hospital house keeping personnel have been identified to have an increased risk for latex allergy. It is estimated that between 8% and 17% of HCWs have developed hypersensitivity to NRL products.48-52 An even higher prevalence of latex allergy (18% to 72%) has been discovered in patient with SB.53-5g Although the prevalence of NRL allergy in the general population is suspected to be less than 2%,56, 60-62it has been suggested that latex specific IgE may be present in the sera of as much as 6% of the general population when evaluating blood donors63 and persons in nonhealthcare occupations.64 Although the details of sensitization to latex remains unclear (e.g., protein exposure levels, exposure route, number of exposures), sensitization is suspected to occur among HCWs when proteins are inhaled or pass through compromised sites in the skin. Dermal penetration of many agents is known to be enhanced by the humid, moist environment beneath the glove surface. An additional factor in the development of latex allergy in patients with SB appears to be direct tissue contact with latex during the multiple number 45

of surgeries performed early in life.55,56,58,65,66 A number of events associated with NRL exposure correlates with the recent increase in latex allergy preva‘lence. The reported increase in prevalence closely followed the 1987 release of Recommendations for Prevention of HIV Transmission in Health-care Settings, the 1988 release of Update: Universal Precautions for Prevention of Transmission of Human Immunodeficiency Virus, Hepatitis B Virus, and Other Blood Borne Pathogens in Health-care Settings and the 1989 release of Guidelines for Prevention of Transmission of Human Immunodeficiency Virus and Hepatitis B Virus to Health-care and Public-safety Workers by the

Centers for Disease Control and Prevention in response to the increase of these infectious diseases.67-6g Implementation of universal precautions resulted in an increase of latex glove imports that rose from less than 1 billion gloves per year to about 11 billion gloves by 1992,’ and up to 20 billion gloves by 1996. ‘O In addition, latex glove usage increased in a wide variety of nonhealth care occupations, such as food handling, public safety, and child day care. The rapid increase in usage led to new, less experienced manufacturers of latex gloves. The demand most likely resulted in decreased protein/allergen degradation due to decreased shelf time, increased rubber harvesting, and/or changes in manufacturing processes to speed up production. As a result, HCWs were not only exposed to NRL products more frequently, they were probably exposed to NRL products that carried higher levels of latex proteins than in previous years. In addition, as the number of reported cases of latex allergy continued to grow, heightened awareness by physicians may have contributed to a larger number of latex allergy diagnoses. The contributions of these and possibly other factors to the rather sudden increase in latex allergy remains uncertain. The increase in latex allergy prevalence in occupationally exposed groups prompted the National Institute for Occupational Safety and Health (NIOSH) to publish a Safety 49

Alert, Preventing Allergic Reactions to Natural Rubber Latex in the Workplace,71 to heighten awareness

regarding latex allergy, to provide recommendations to help prevent further sensitization, and to reduce exposure to allergic individuals. These recommendations include using nonlatex gloves for activities that are not likely to involve contact with infectious materials as well as using powder-free latex gloves (which reduces protein exposure) when latex gloves are chosen in situations where additional barrier protection is needed. There is recent evidence to suggest that elimination of powdered gloves will reduce aeroallergen levels in the workplace and alleviate symptoms in sensitized individuals.72,73 The FDA has established a task force to address the potential adverse health effects of medical glove powder. This task force has proposed a number of recommendations to reduce potential adverse health effects and ensure adequate protective properties in medical gloves. Some of these recommendations are as follows: (1) establish maximum allowable powder levels on medical gloves; (2) standardize methodologies for the measurement of glove powder content; (3) reduce the amount of water-soluble protein on finished medical gloves; (4) define the effects of processing, handling, and occupational setting on barrier characteristics; and (5) require specific labeling information as to protein and powder content on all medical gloves. Subsequent to these recommendations, the FDA is currently working on a regulation to limit the amount of powder and the amount of extractable protein in latex gloves. Over the years, the American Society for Testing and Materials (ASTM) has developed guidelines to strengthen the quality of manufactured NRL products; a number of standards directly, and indirectly address products such as latex gloves.74 These ASTM Standards provide guidelines to test NRL at many stages of manufacturing. Standard D1076-97 outlines techniques to determine characteristics such as rubber content, alkalinity, viscosity, and density of NRL batches before product

manufacturing. In the case of latex gloves, standards were developed to monitor barrier quality (i.e., detection of holes), to test deterioration rates, and to verity sterility (Standards D3578-95, D3577-91, and D515193). The ASTM has also set guidelines to test latex gloves for total extractable protein content using a modified Lowry assay (Standard D57 12-95), for residual powder levels (Standard D6124), and for the potential to elicit allergic reactions via Human Repeat Insult Patch Tests (Standard PS7797). Scientists from NIOSH and the National Toxicology Program are involved in research projects to better understand the mechanisms underlying latex sensitization and the elicitation of allergic symptoms, as well as evaluating intervention strategies for preventing latex allergy. A large-scale latex allera prevalence study is underway in collaboration with the Veterans Administration (VA). This study is expected to screen a population of over 4000 HCWs from 3 VA hospitals via skin prick tests, serological tests, and questionnaires. In subsequent years, the study will investigate the effects of various risk factors on the prevalence of latex allergy and document the natural history of the disease. A latex allergy prevention study is ongoing with researchers from the Medical College of Wisconsin. In this study, intervention strategies at 2 hospitals, one a children’s hospital that switched to nonlatex gloves with the exception of surgical gloves in 1992, and an adult hospital in the process of switching to powder-free low protein latex gloves, will be evaluated. In the area of methods development and evaluation, studies are underway with scientists from Guthrie Research Institute and the FDA to develop a latex-specific enzyme-linked immunosorbent assay to quantify the amount of latex allergen in medical products. Other immunological assays are being developed to provide sensitive and reproducible methods for environmental monitoring of workplace latex allergens. Studies conducted in collaboration with scientists from John Hopkins University compared the sensitivity and specificity of com-

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in vitro serological

assays used to diagnose NRL allergy via latex-specific IgE levels.75 Animal models of latex allergy and in vitro percutaneous penetration models are being established to address more mechanistic questions that cannot be directly answered in human studies. Murine models of respiratory, dermal, and subcutaneous (to mimic surgical exposure) exposure have been developed and are being used to answer questions related to the role of route of exposure, the role of dextran glove powder, and the role of concurrent exposure to endotoxin and other chemicals (i.e., gluteraldehyde, disinfectants, etc.) on latex sensitization. These models will also be useful in testing interventional strategies. Allergy to natural rubber latex remains a serious occupational health concern. Increased public awareness of the problem and knowledge gained through scientific research are key to developing interventional strategies to prevent further sensitization and reduce the elicitation of symptoms in already sensitized individuals. Efforts are underway to control the levels of protein and powder in latex gloves and to develop alternative nonlatex products. Powder-free and nonlatex gloves are available and are increasingly being utilized in interventional strategies. The balance between providing appropriate barrier protection and desired tactile properties of gloves and protecting individuals from unnecessary latex exposure will only be reached through continued education and research. References 1. Warshaw, E. I. Am. Acad. Dermatol. 1998,39 (1) 1. 2. Levy, D. A.; Charpin, D.; Pecquet, C.; Leynadier, F.; Vervloet, D. AlEergy 1992,47, 579. L. P.; Boguniewicz, M. 3. Landwehr, 1. Pediatr. 1996, 128, 305. 4. Stem, G. Klin. Wochenschr. 1927, 6, 1096. 5. Nutter, A. F. Br. J. Dermatol. 1979, 101, 597. 6. Slater, J. E. J. Allergy Clin. Immunol. 1994,94, 139. 7. Gawchik, S. “The Role of Organizations.” Presented at The 1998 National

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