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Latex Protein Allergy : The current issues (Paper presented at the Seminar "Malaysian latex-based industry : review, competitions and opportunities "help on 22 September, 1997 at Sheraton Subang Hotel, sponsored by the Malaysian rubber product Manufacturers’’ Association) Since the recognition of the latex protein allergy problem in relation to use of latex-dipped products in the early nineties, much efforts have been undertaken by both the medical profession and the latex industry in addressing it. Better understanding of the allergy and considerable advancements in the development of more sensitive diagnostic tests for latex hypersensitive persons, as well as the manufacture of more biocompatible latex products especially gloves, have now been achieved However, a number of related issues still exist, namely:
All these are relevant issues of importance. Unless they are resolved, overcoming of the problem could be hindered. These are being examined in the present paper. Furthermore, the influence of the allergy on NR dry rubber product, is also discussed. Idendification of latex hypersensitive persons Although the incidence of occurrence of the allergic reaction is estimated to be less than 1% among the general population, the prevalence is higher among high risk groups, such as the healthcare workers and spina bifida children. Table 1 gives some indication of the prevalence studies done on the various high risk groups, using skin prick testing, the best diagnostic technique by this type of allergy. Table 1. Prevalence of latex protein allergy in different population (by skin prick testing)1
Atopy seems to be a pricipal determinant for sensitization and pre-existing food allergy condition of a person is an addition risk factor. It is generally acknowledged that once sensitized, there is presently no known cure for it, except to avoid contact with the allergens concerned. Hence, these people should not come into contact with whatever allergens they are sensitive to. Their continual exposure to these allergens could lead to very unpleasant, if not serious experiences. This would certainly aggravate the allergy situation. Therefore, if the allergy problem were to be contained effectively, it is vital importance that the relatively small group of latex sensitive individuals should be properly diagnosed and identified, so that proper precautions could be taken, as in the case of those who are allergic to penicillin or some plant pollens. For the majority of non-affected users (> 90%) of latex products, intensive efforts should be made to reduce or prevent further sensitization among them. This should best be achieved via the production of low extractable protein gloves by the manufacturers and the selective purchases of these gloves by the users. Standardized method(s) for evaluatioon of allergic potential of latex gloves The production of low protein gloves and their subsequet selection require an adequate indication of the allergic potential of the gloves, be that expressed in terms of their extractable protein contents or allergen levels. Unfortunately, a universally standardized method for such measurements in still lacking to-date. In fact, a number of tests are being adopted, each generating their own values which are strictly not comparable between tests for the same sample analyzed. These included the determinations of total extractable proteins, total antigenic protein content and allergenic protein content. The one test that is considered to be the most suitable in that of the assessment of allergic response elicited in latex hypersensitive subjects, by the skin prick test. However, this test necessitates the presence of latex hypersensitive persons who are not always easily available. Hence a more practical method has to be sought. Since the allergy reaction in one that involves the immunological between the allergen and latex specific IgE antibodies, it is thought that the in-vitro serological immunoassays, eg. The RAST-inhibition and ELISA-inhibition test using IgE from latex hypersensitive persons could serve such a purpose. However, the lack of good standardized reference mixtures of both the latex specific IgE antibodies and latex allergens, which are necessary and important for reliable measurements , has prevented the development of a standardized test method. Furthermore these immunoassay procedures are somewhat tedious and highly sophisticated, not to mention that they are also very costly for testing of a large number of samples. Generally, for routine analysis fo a great number of latex products, particularly gloves, the simpler colorimetric assay of modified Lowry method for determination of total extractable proteins (EP) is preferred. Even with this test, three variations presently exist namely, the RRIM (MS 1392:96P) test, the ASTM (D 5712-95) test, and the very CEN (PrEN455-3) test. Owing to the variations adopted in parts of the protocol, the protein values generated by the three tests for the test sample are not identical. Although a good correlation has been established between those of the RRIM and the ASTM2, such information is not yet available for the CEN test which is a recent addition to the protein test methods. Allergic potential of a given latex glove as indicated by protein values determined by different test in various analytical laboratories, has indeed caused considerable confusion currently, not only to the latex product industry but also to the consumers. There is therefore a dire need to adopt a single standardized routine modified Lowry test, and perhaps a standardized immunoassay protocol at a later date. This would certainly give a clearer indication of the protein / allergen of the latex gloves. It may be mentioned that in view of the good correlations demonstrated by EPRRIM with allergen contents as well as with the clinical (SPT) response, the RRIM Lowry test may be considered a good candidate3. "Low-risk" levels of EPW While it is essential that EP values of latex products be adequately indicated, it is equally important that "low-risk" levels at which majority of latex hypersensitive persons show no allergic response, be defined. This could certainly help to make more focussed the manufacture of improved products, as well as the choice of gloves by users. To accomplish this, EP values obtained by whatever method, should be evaluated in relation to their inability in allergic response in latex hypersensitive subjects. Since EP values differ for the different tests, the definition of "safe" levels would not be expected to be the same. Hence by each test should be investigated. Presently, with the exception of EPRRIM (obtained by the RRIM modified Lowry test), none of the other EP values have been investigated for their relationship with allergenicity as assessed by the skin prick test Studies4 have shown that at EPRRIM of less than 400 µg/g of glove, more than 60% of no response was observed when latex hypersensitive subjects in Europe in were skin prick tested. It was further found that at even lower EPRRIM of about 100 µg/g glove and below, very little or no allergic response was detected. Sush observations were further substantiated when gloves with EPRRIM of about 100 µg/g and less were shown to have very low allergen levels (< 10 AU/ml) by the IgE latex specific ELISA-inhibition test5, a test which has been validated clinically by the prick test. These have indeed provided useful guidelines for the identification of low protein gloves with low allergen content / allergenicity. Although the quantity of allergens required to cause sensitization (which is thought to vary from person) is not yet know, the use of gloves with such EP RRIM levels could minimize or prevent further sensitization among majority of the users. It may be pointed out however, that these may not be applicable to the minority of the very latex hypersensitive people, some of whom may react to the presence of slightest amount of the allergen concerned. Presently, the food and Drug Administration (FDA) of USA has permitted a low protein labelling claim for the 510k application6 although it is clearly stated that the claim should not be lower than EPASTM of 50 µg/g, the sensitivity limit of the ASTM modified Lowry test, no maximum EPASTM level has been specified, but an EPASTM level of 400 µg/g may be considered. Powder Issue
Constarch powder, used in the manufacture of glove to facilitate easy donning, has been thought to be another cause of allergy reaction, via aerosolization whereby some soluble proteins bind to the powder and become airborne. Inhalation of these powder particles could thus bring about sensitization. However, such theory of sensitization seems to be somewhat controversial. While some dismissed it as being speculative, many considered it to be one of the main routes for sensitization. It is learned that three States in the USE (New York, Oregon and more recently. Minnesota) have proposed to ban the sales of powdered glove. Such as ban would be a case of over-reaction on account of the allergy problem. Firstly, the cornstarch powder itself is not an allergen. Secondly, its presence in low-protein glove (the current new generation of glove with greatly improved quality) has been shown to have no adverse effect on the allergic potential of the gloves. In fact, these gloves have not only very low extractable protein content, but also allergen levels and allergenicity4,5, as in the case of the powder-free gloves. Hence, the allergy problem may be contained by proper selection of powdered gloves, as been proven by some hospital in Europe and USA The presence of powder in surgical gloves during operations has also been reported to give rise to post surgery adhesion formation leading to bowel obstruction and has adverse effect on the healing of abdominal incisional wounds7. It has also been said to have caused misdiagnosis of "cancer-like" growth in tissues which is not cancerous8. All these adverse reactions are associated with the presence of foreign microbodies deposited in the tissues. A Recent study9 carried out by a hospital in Paris, reported that foreign microbodies are present in 93% of all the re-operated patients in which adhesions were analyzed for evidence of external contamination. It futher revealed that there were many types of foreign bodies associated with human adhesions. The main culprit was gauze lint (80%), cornstarch constituted only 3%, surgical sutures 2%, polyester fibbers from surgeon mask 2% and oil 1%. Therefore, based on these findings, it would appear that aliminating powder in gloves alone would clearly notbe able to minimize tissue contamination during operation. Nevertheless, in response to this powder issue, the latex glove industry in Malaysia is moving towards the production of powder-free gloves. According to a survey by the Malaysian Rubber Glove Manufacturers’ Association10, two-thirds of the manufacturers which account for 60% of Malaysia’s glove production, have the capability to do so. A transition time of about one year is however, required for the changes. Labelling of Latex Products In view of the allergy reaction associated with some users, latex labelling was first suggested in 1992. A statement on the label of medical devices identifying their contents and risks, is considered to be necessary for the safe and effective use of such devices. The FDA Proposed Rule was published in the Federal Register only in June 1996, three options regarding wording of the statement and comments from the public were invited. The Finale Rule out in September 1997, stating that all medical devices containing latex and are likly to come in contact with humans, have to be labelled with the following wordings: "Caution: This product contains natural rubber latex which cause allergic reation". Similarly with packaging carrying the device, it should be lablelled as: "Caution: The packaging the this Product contains natural rubber latex which maty cause allergic reaction" Furthermore, the "hypoallergenic" claim allowed earlier for latex devices, is now removed. Manufacturers are given one year to comply with these rulings. Presently, many large latex glove manufacturers in USA have been sued for negligence in selling products that triggered crippling sensitivities11. The number of law by latex allergy sufferers is reported to have increased. Over the last two years, there were about 123 plaintiffs in the US state courts and another 25 in the federal courts. Thus, labelling of NR latex products may at first seem disadvantageous, but in order to prevent the undesirable spiralling of such litigation, it may be inevitable to do so. NIOSH Alert In the wake of the increasing outcry of the various latex sensitive sufferers, the National Institute of Occupational Safety and Health (NIOSH) in USA has published an alert12 entitles: "Preventing allergic reactions to natural rubber latex in the workplace". It gives brief information on the three adverse reactions associated with the use of latex gloves, routes of sensitization in the case of latex protein allergy, diagnosis and treatment. Six case reports on latex sensitized workers were described, and a number of recommendations were made, which included reducing exposures, using appropriate work practices, training and educating workers, monitoring symptoms, and substituting non-latex product when appropriate. The Alert, as it is written, may serve as a good document for minimizing latex-related health problems among the latex hypersensitive workers and the potentially sensitive candidates, protecting them from the infectious they need to avoid. But to indiscrimatively apply to all could raise unnecessary alarm and fear in majority of the normal unaffected population. Further more, recommending all workers to use non-latex glove for industries such as food service may lead to an increase materials which would undoubtedly pose a serious pollution problem in time to come, unlike the NR products which are known to be environmentally-friendly. Dry rubber products It has been recently reported that tyre debris and dust contained residual extractable proteins which demonstrated some IgE binding activities13. It was thus suggested that these materials could cause health hazards resulting in sensitization. However, findings by the RRIM14 showed that such residual exractable protein levels were associared with not only very low allergen levels, but also negligible allergenicity when skin prick tested on latex sensitive persons. Hence, dry rubbers and dry rubber products can be considered to be "non-allergenic" and are generally not affected by the protein allergy problem. However, it must be mentioned that this may not be so for some highly sensitive individuals who may react to the presence of slightest amount of the relevant allergens. It may be of interest to note that for labelling of such products, FDA required the following wordings for dry natural rubber products that may come in contact with humans: "This product contains dry natural rubber", and for the packaging:"The packaging "This packaging of this product contains dry natural rubber". As in latex products, manufacturers of dry rubber products are also given one year to comply with these rulings. Summary o In order that the allergy problem to be effectively contained, latex hypersensitive persons should be properly diagnosed as and identified, so that they could be alerted to avoid the allergen concerned. This would minimize aggravation of the allergy situation. Acknowledgement The author wishes to thank the Director of the Research Institute of Malaysia for permission to present this paper. She also likes to show her appreciation to Dr. E.L. Ong, the Assistant Director of Chemistry and Technology Department, and Dr. P.F. Lai, Head of latex Technology Division, for their encouragement and support extended to her in workReferences
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