|
| |
 |
|
| ORIGINAL ARTICLE |
|
| Year : 2019 | Volume
: 37
| Issue : 3 | Page : 123-128 |
|
Contact allergy to preservatives in Taiwan between 1996 and 2015
Yen-Kai Huang1, Yu-Hung Wu2, Po-Hsuan Lu2, Mei-Eng Tu1
1 Department of Dermatology, Mackay Memorial Hospital, Taipei, Taiwan
2 Department of Dermatology, Mackay Memorial Hospital, Taipei; Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
| Date of Submission | 08-Jun-2018 |
| Date of Acceptance | 21-Nov-2018 |
| Date of Web Publication | 23-May-2019 |
Correspondence Address:
Dr. Mei-Eng Tu
Department of Dermatology, Mackay Memorial Hospital, 92, Sec. 2, Zhongshan North Road, Taipei, 10449
Taiwan
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/ds.ds_21_18
Background: Preservatives are widely used in personal and industrial products. Frequent and sustained exposure to preservatives can cause contact allergy. Objective: We investigated the prevalence of contact allergic reactions to common preservatives in Taiwan over a 20-year period. Methods: A retrospective analysis was conducted among patients with allergic contact dermatitis who underwent patch testing at our clinic between 1996 and 2015. Patients who showed positive reactions to preservatives were enrolled. The location of the reaction, likely source of the allergen, and patient occupation, sex, and age were recorded. Thirteen common preservatives, including methylchloroisothiazolinone/methylisothiazolinone (MCI/MI), MI, formaldehyde (FA), paraben mix, and quaternium-15, were investigated. Results: Of 757 enrolled patients, 151 showed at least one positive reaction to preservatives. Allergy to MCI/MI (12.5%), the most frequent allergen in the standard series, showed a steeply increasing trend over time. FA (4.8%) and paraben mix (2.1%) were the next common allergens. Cosmetic products were the most common source of exposure (63.6%), while hairdressers and massage therapists were most commonly associated with occupational contact dermatitis. A sharp increase of sensitivity to MCI/MI was observed after 2006 and that of allergy to MI after 2013. Conclusions: In Taiwan, the prevalence of contact allergy to MCI/MI, MI, and parabens has increased in recent years. Individuals who are frequently exposed to cosmetic products should consider precautions against sensitization.
Keywords: Contact dermatitis, methylchloroisothiazolinone, methylisothiazolinone, parabens, preservatives
How to cite this article:
Huang YK, Wu YH, Lu PH, Tu ME. Contact allergy to preservatives in Taiwan between 1996 and 2015. Dermatol Sin 2019;37:123-8 |
| Introduction | |  |
Preservatives are common ingredients used in daily-use products, such as cosmetics, shampoos, cleansing solutions, perfumes, paint, glue, and ink. Preservatives are used to stabilize the products and prevent their deterioration. The first epidemic of contact allergy to preservatives occurred when many individuals experienced cutaneous exposure to formaldehyde (FA) in textile finishes and cosmetics between 1950 and 1960.[1] The introduction of methylchloroisothiazolinone (MCI), methylisothiazolinone (MI), and methyldibromo glutaronitrile (MDBGN) subsequently resulted in widespread preservative dermatitis.[1],[2] Other common preservatives that result in contact allergy are parabens, quaternium-15, FA releasers, and iodopropynyl butylcarbamate (IPBC). The frequency of sensitization and ranking of these allergens differs worldwide.[1],[2],[3],[4],[5],[6],[7],[8] Recently, a mixture of MCI and MI (MCI/MI) or MI alone has increasingly been reported as a specific sensitizer, and the prevalence of the resultant contact dermatitis shows increasing trends.[9],[10],[11],[12],[13] Several epidemiology reports on contact allergy to preservatives have been published based on studies conducted in the United States,[14] Europe,[2],[3],[5] and Asia.[4] However, information regarding contact allergies to these substances in Taiwan is limited. Therefore, we conducted a retrospective analysis of data obtained from patients with contact allergy to understand the trends of contact allergy to different preservatives among the Taiwanese population.
| Methods | | |
We retrospectively enrolled patients who had a history of contact dermatitis and who underwent a European standard series patch test (Chemotechnique Diagnostics, Malmö, Sweden) at a referral center in Northern Taiwan between 1996 and 2015. Some patients were also tested using additional series tests, such as the cosmetic series or hairdresser series if clinically indicated. The results of the patch test and clinical data including sex, age, occupation, personal history, and the location of the skin problem were retrieved from medical records. The clinical relevance of the positive reaction was assessed by personal exposure history, occupation, and physical examination. For each positive allergen, the possible sources of exposure were also recorded.
The preservatives in the European standard series included MCI/MI, FA, paraben mix, 1, 2-dibromo-2, 4-dicyanobutane, and quaternium-15. The preservatives in the additional series included Kathon CG (MCI/MI 0.02% aqueous), dimethyloldimethyl hydantoin, 2-bromo-2-nitropropane-1,3-diol (bronopol), diazolidinyl urea, and imidazolidinyl urea; 1,2-dibromo-2,4-dicyanobutane was included in the European standard series starting in 2008, and MI, MDBGN, and IPBC were included in the cosmetic series starting in 2011. The concentration of these preservatives in the patch test is shown in [Table 1]. | Table 1: The Prevalence of contact allergy to preservatives between 1996 and 2015 in Taiwan, stratified by sex
Click here to view |
The patch testing materials were applied with Finn chambers (Epitest Ltd Oy, Tuusula, Finland), with the upper back covered with Scanpor tape (Norgesplaster A/S, Vennesla, Norway). The testing materials were removed after 48 h. Readings were taken at 48 h, 72 h, and 7 days, according to the protocol recommended by the International Contact Dermatitis Research Group.[15]
All data were analyzed using SPSS™ version 12.0 (SPPS™ Statistics Chicago, IL, USA; IBM PASW Statistics) for Windows™. Fisher's exact test was used where applicable. The P values were two-sided, and a P ≤ 0.05 indicated statistical significance in all analyses.
| Results | | |
We included a total of 757 patients examined at the clinic between January 1996 and December 2015. Their mean age was 39.6 years, and 71.9% of them were female (544/757). In total, 151 patients (19.9%) showed positive reactions to at least one preservative. The mean age of the patients with a positive reaction was 39.2 years, and most of these patients were female (n = 136, 90.1%).
The prevalence of positive reactions to individual preservatives and the prevalence stratified by sex are summarized in [Table 1]. MCI/MI (12.5%) was the most frequent allergen identified in the standard series; FA (4.8%) and the paraben mix (2.1%) were less frequently identified. Among patients tested with the additional series, MI (40.7%) and Kathon CG (38.4%) showed the highest reaction prevalence. Compared to men, women had a significantly higher prevalence of contact allergy to MCI/MI 0.01% (P < 0.001) and Kathon CG (P = 0.018). However, there was no significant difference between men and women in the prevalence of contact allergy to other preservatives [Table 1].
The frequencies of positive reactions to preservatives in the standard series in the first decade (1996–2005) were compared with those in the second decade (2006–2015) [Table 2]. The prevalence of contact allergy to FA decreased significantly from 7.0% ( first decade) to 3.2% (second decade) (P = 0.023). Conversely, the prevalence of contact allergy to parabens increased significantly from 0.6% ( first decade) to 3.2% (second decade) (P = 0.019). In particular, the prevalence of hypersensitivity to MCI/MI increased significantly from 3.8% ( first decade) to 18.6% (second decade) (P < 0.001). Positive reactions to quaternium-15 were infrequent during both periods. We were unable to compare the prevalence of contact allergy to preservatives between the two periods in the additional series, as not all patients were routinely tested for the additional series, and many preservatives were added to the patch test after 2006. | Table 2: Comparison of the frequency of positive reactions to preservatives between 1996-2005 and 2006-2015 in Taiwan
Click here to view |
[Figure 1] shows the prevalence of contact allergy to different preservatives over the course of 20 years in Taiwan. The prevalence of allergy to FA followed a decreasing trend. Contact allergy to parabens appeared in 1996 and 1997 and then remained at 0% until 2007, after which it gradually increased. The prevalence of contact allergy to quaternium-15 was low and stable across the study period. There was a steep increase in the prevalence of contact allergy to MCI/MI after 2006, which reached approximately 30% between 2013 and 2015. 1,2-dibromo-2,4-dicyanobutane was included in our standard series in 2008, and contact allergy to this preservative remained at 0% from 2008 to 2011, after which it gradually increased to 5.6% in 2015. MI was added to the cosmetic series in 2011; contact allergy to MI remained at 0% for the first 3 years, before steeply increasing to 50% in 2014 and 66.7% in 2015. | Figure 1: Annual prevalence of contact allergy to preservatives in Taiwanese patients between 1996 and 2015. *Only tested in cosmetic series
Click here to view |
The sites of dermatitis in patients with a positive reaction are shown in [Table 3]. The most commonly affected location was the face (70.9%), and it was more frequently observed in women (P < 0.001). In contrast, hand and foot dermatitis was more common in men (P < 0.001 in hands and P = 0.004 in feet). | Table 3: Localization of dermatitis in 151 patients (15 males and 136 females) with positive reaction to preservatives
Click here to view |
Analysis of patient occupation and the possible source of exposure revealed that 96 cases (63.6%) were related to cosmetic products and 35 cases (23.2%) were the result of occupational contact dermatitis [Table 4]. Hairdressers (15 cases) and massage therapists (6 cases) were the most commonly affected. Further, the ratio of patients with contact allergy associated with cosmetic products increased significantly from 35.3% during 1996–2005 to 71.8% during 2006–2015. [Figure 2] shows that the number of cosmetic product-related allergic cases increased significantly after 2006. | Table 4: Possible source of exposure in 151 patients with positive reaction
Click here to view |
 | Figure 2: Number of preservative-allergic patients classified by source of exposure over 20 years
Click here to view |
| Discussion | | |
This study revealed the trends in the annual prevalence of contact allergy to preservatives over a course of two decades in Taiwan. In the first decade (1996–2005), FA was the most significant sensitizer. It was replaced by MCI/MI in the second decade of the study (2006–2015). The prevalence of contact dermatitis resulting from parabens and MI also significantly increased in recent years. The face was the most frequent location of reaction, observed more commonly in women, which was likely associated with contact allergy to facial cosmetics. These findings were supported by an increase in the number of patients with allergies to cosmetics after 2006, and by the fact that cosmetics were the most common source of allergen exposure.
MCI and MI were initially compounded in a 3:1 ratio for industrial use. Although MCI/MI has been gradually replaced by MI over recent years, MCI/MI is still widely used in personal products, such as cleansers, shampoos, beauty preparations, sunscreens, and moisturizing creams, and is considered a common sensitizer.[10],[12],[13],[16],[17],[18],[19],[20] The rate of sensitization to MCI/MI in Taiwan, compared to that in other countries, between 1996 and 2005 indicates that the sensitization rate of MCI/MI observed at our institution (3.8%) was slightly higher than the rates reported by the North American Contact Dermatitis Group (NACDG; which recorded a prevalence of 2.2%–3%),[1] the Information Network of Departments of Dermatology (IVDK; 2.2%),[3] and in Denmark (1.8%);[2] however, it was similar to the rates reported for Israel (3.7%–4%).[6] However, the rate of sensitization to MCI/MI gradually increased, and several reports from the United Kingdom,[18] Spain,[21] and Thailand[11] have all shown that the prevalence of allergy to MCI/MI is >10%, with an increasing trend.
The prevalence of allergy to MCI/MI in our survey was 18.6% between 2006 and 2015, which increased to approximately 30% between 2012 and 2015. In our standard series patch test, the sensitization to MCI/MI in men (2.8%) was similar to that reported in other countries; however, it was markedly higher in women (16.3%). MCI/MI was the only preservative that had a significantly different sensitization rate among men and women (P < 0.001 for 0.01% aqueous, P = 0.018 for 0.02% aqueous). Moreover, the number of preservative-related allergic contact dermatitis cases associated with cosmetics increased after 2006, in parallel to the trend of contact allergy to MCI/MI. These findings suggest that MCI/MI may be strongly associated with cosmetics-related allergic contact dermatitis in the women in our cohort.
We have been testing MI at a concentration of 0.02% in our cosmetic series since 2011, and we have found that the rate of allergy to MI steeply increased after 2013. The sensitization to Kathon CG and MI in the additional series was dramatically higher compared to that in other geographic regions. In a study on contact allergy to cosmetics in Spain, about 27.4% (172/629) of the patients had a positive reaction to Kathon CG.[22] A possible explanation is that we tested Kathon CG and MI only in select patients, and most cases were associated with exposure to cosmetics. A survey from Thailand also revealed a high prevalence of allergy to MI (40.7%), which was also likely the result of exposure to cosmetics.[11]
Although the recommended concentration of MCI/MI has been restricted to 15 ppm in the European Union, and up to 100 ppm of MI is allowed in cosmetics since 2005, many investigations still show an increasing prevalence of isothiazolinone (MCI/MI or MI) allergy across regions, and some articles have highlighted its association with cosmetics.[5],[9],[10],[23] [Table 5] summarizes the prevalence of contact allergy to preservatives in different countries. Compared to data from other countries, our data show a higher prevalence of contact allergy to MCI/MI and MI from 2006 to 2015. This could be attributed to a possible lack of comprehensive regulations or restrictions on the use of preservatives such as MCI/MI or MI in cosmetic products before 2013 in Taiwan.[24] | Table 5: Frequency of sensitization (%) to preservatives across countries during the periods of 1996-2005 and 2006-2015
Click here to view |
The prevalence of allergy to FA over the course of the study was 4.8%, and it did not show any difference between men and women. The prevalence of allergy to FA was slightly lower than that reported by NACDG (5.8%–9.3% between 1994 and 2010)[1] but higher than that reported by IVDK (1.54% between 1996 and 2009)[3] and in Denmark (3.1% between 1985 and 2008).[2] The rate of sensitization to FA was the highest among the rates of sensitization to all the preservatives tested by our institution before 2006, after which it gradually decreased. This decrease could be attributed to the use of fewer products containing FA, which is increasingly being replaced by FA releaser or other preservatives. The rate of sensitization to all FA releasers was also <2%, whereas most of the FA releasers were tested for patients who underwent patch tests with the cosmetic series. Quaternium-15 was the only FA releaser tested in our standard series, and it is a frequently identified sensitizer in the United States;[1] however, the rate of sensitization to quaternium-15 in our survey was relatively low (0.2%).
Parabens are widely used in cosmetics and personal products. In a European study, parabens were found in 99% of leave-on products and 77% of rinse-off products.[30] Since the 1990s, the prevalence of sensitization has been relatively low and stable, ranging from 0.5% to 1.7% in Europe and North America.[1] However, a higher rate of allergic reactions to parabens is observed in Asian countries. A survey conducted in Singapore from 2006 to 2011 showed that the rate of sensitization to parabens was 2.6%,[4] while another investigation of cases of cosmetics-related allergies from Thailand[31] and Korea[32] showed that the sensitization rates of parabens were 9.2% and 3.1%, respectively. Our analysis found that the sensitization rate of parabens was low and stable (0.6%) in the first decade but significantly increased to 3.2% in the second decade of the study.
1,2-dibromo-2,4-dicyanobutane, known as MDBGN, was tested in our standard series since 2008. The prevalence of 1,2-dibromo-2,4-dicyanobutane was much lower than that of MCI/MI, FA, and parabens. Despite the small number of tested patients, an increasing annual trend of patients was observed.
The most common occupation of the patients in our cohort who had occupational contact allergy was hairdressers, followed by massage therapists. These data were similar to those from a case series on contact allergy to MCI/MI reported from another institution in Northern Taiwan.[33] The study revealed that the most relevant sources of exposure were essential oils, hairdressing products, and cosmetics.[33] A similar result was reported in a Finnish study from 2002 to 2013 that demonstrated that hairdressers and beauticians were the most significantly affected by MCI/MI.[19] However, the occupational contact allergy to MCI/MI and/or MI is also observed in manufacturing workers and painters,[19],[29],[34] indicating that isothiazolinone must be present in other products in addition to cosmetics. In our study group, we did not find a strong association between preservatives and occupational contact allergy, probably because most of our patients were female and were allergic to their personal daily use products.
There were several limitations to this study. The patients were enrolled from a single institution and the patient number was limited. The analyzed group of patients may not reflect the characteristics of the general population. Nevertheless, very few institutions can provide a patch test in Taiwan owing to the test materials being strictly regulated by the government; hence, this test is limited to only a few medical centers. Therefore, our data provide important information regarding the trends of contact allergy to preservatives in Taiwan.
| Conclusions | | |
The burden of preservative dermatitis has substantially increased over the course of two decades in Taiwan. There was a distinct rise in the prevalence of contact allergy to MCI/MI, MI, and parabens after 2006. Cosmetics were the most important sources of exposure, and hairdressers and massage therapists were the two most common occupations that experienced contact allergy to preservatives. Such information should be reported regularly to help devise informed policies related to the regulation of preservative usage.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Yim E, Baquerizo Nole KL, Tosti A. Contact dermatitis caused by preservatives. Dermatitis 2014;25:215-31.  |
| 2. | Thyssen JP, Engkilde K, Lundov MD, Carlsen BC, Menné T, Johansen JD, et al. Temporal trends of preservative allergy in denmark (1985-2008). Contact Dermatitis 2010;62:102-8. |
| 3. | Schnuch A, Lessmann H, Geier J, Uter W. Contact allergy to preservatives. Analysis of IVDK data 1996-2009. Br J Dermatol 2011;164:1316-25. |
| 4. | Cheng S, Leow YH, Goh CL, Goon A. Contact sensitivity to preservatives in Singapore: Frequency of sensitization to 11 common preservatives 2006-2011. Dermatitis 2014;25:77-82. |
| 5. | Schwensen JF, White IR, Thyssen JP, Menné T, Johansen JD. Failures in risk assessment and risk management for cosmetic preservatives in Europe and the impact on public health. Contact Dermatitis 2015;73:133-41. |
| 6. | Zoller L, Bergman R, Weltfriend S. Preservatives sensitivity in israel: A 10-year overview (1995-2004). Contact Dermatitis 2006;55:227-9. |
| 7. | Pontén A, Goossens A, Bruze M. Recommendation to include formaldehyde 2.0% aqua in the European baseline patch test series. Contact Dermatitis 2013;69:372-4. |
| 8. | Suzuki K, Matsunaga K, Yagami A, Adachi A, Ikezawa Y, Ito A, et al. Positive rates in 2013 and 2014 of Japanese standard allergens 2008. J Environ Dermatol Cutan Allergol 2017;11:234-47. |
| 9. | Garcia-Hidalgo E, Sottas V, von Goetz N, Hauri U, Bogdal C, Hungerbühler K, et al. Occurrence and concentrations of isothiazolinones in detergents and cosmetics in Switzerland. Contact Dermatitis 2017;76:96-106. |
| 10. | Isaksson M, Ale I, Andersen KE, Elsner P, Goh CL, Goossens A, et al. Multicenter patch testing with methylisothiazolinone and methylchloroisothiazolinone/methylisothiazolinone within the international contact dermatitis research group. Dermatitis 2017;28:210-4. |
| 11. | Puangpet P, Chawarung A, McFadden JP. Methylchloroisothiazolinone/methylisothiazolinone and methylisothiazolinone allergy. Dermatitis 2015;26:99-102. |
| 12. | Yu SH, Sood A, Taylor JS. Patch testing for methylisothiazolinone and methylchloroisothiazolinone-methylisothiazolinone contact allergy. JAMA Dermatol 2016;152:67-72. |
| 13. | Zirwas MJ, Hamann D, Warshaw EM, Maibach HI, Taylor JS, Sasseville D, et al. Epidemic of isothiazolinone allergy in North America: Prevalence Data from the North American Contact Dermatitis Group, 2013-2014. Dermatitis 2017;28:204-9. |
| 14. | DeKoven JG, Warshaw EM, Belsito DV, Sasseville D, Maibach HI, Taylor JS, et al. North American contact dermatitis group patch test results 2013-2014. Dermatitis 2017;28:33-46. |
| 15. | Wilkinson DS, Fregert S, Magnusson B, Bandmann HJ, Calnan CD, Cronin E, et al. Terminology of contact dermatitis. Acta Derm Venereol 1970;50:287-92. |
| 16. | Bruze M, Isaksson M, Gruvberger B, Andersen KE, Gonçalo M, Goossens A, et al. Patch testing with methylchloroisothiazolinone/methylisothiazolinone 200 ppm aq. Detects significantly more contact allergy than 100 ppm. A multicentre study within the European Environmental and Contact Dermatitis Research Group. Contact Dermatitis 2014;71:31-4. |
| 17. | Isaksson M, Hauksson I, Hindsén M, Pontén A, Svedman C, Bruze M, et al. Methylisothiazolinone contact allergy is rising to alarming heights also in Southern Sweden. Acta Derm Venereol 2015;95:31-4. |
| 18. | Johnston GA; Contributing Members of the British Society for Cutaneous Allergy (BSCA). The rise in prevalence of contact allergy to methylisothiazolinone in the British isles. Contact Dermatitis 2014;70:238-40. |
| 19. | Vauhkala AR, Pesonen M, Suomela S, Kuuliala O, Suuronen K, Aalto-Korte K, et al. Occupational contact allergy to methylchloroisothiazolinone/methylisothiazolinone and methylisothiazolinone. Contact Dermatitis 2015;73:150-6. |
| 20. | Warburton KL, Wilkinson M. Contact allergy to methylisothiazolinone: Has there been any change? Experience of a UK centre. Contact Dermatitis 2015;72:398-400. |
| 21. | Gameiro A, Coutinho I, Ramos L, Gonçalo M. Methylisothiazolinone: Second 'epidemic' of isothiazolinone sensitization. Contact Dermatitis 2014;70:242-3. |
| 22. | Zaragoza-Ninet V, Blasco Encinas R, Vilata-Corell JJ, Pérez-Ferriols A, Sierra-Talamantes C, Esteve-Martínez A, et al. Allergic contact dermatitis due to cosmetics: A clinical and epidemiological study in a tertiary hospital. Actas Dermosifiliogr 2016;107:329-36. |
| 23. | Gallo R, Signori A, Gervasio S, Riva S, Parodi A. Methylisothiazolinone contact allergy - are rinse-off cosmetics and household products relevant sources of exposure? Contact Dermatitis 2016;75:319-21. |
| 24. | |
| 25. | Wilkinson JD, Shaw S, Andersen KE, Brandao FM, Bruynzeel DP, Bruze M, et al. Monitoring levels of preservative sensitivity in Europe. A 10-year overview (1991-2000). Contact Dermatitis 2002;46:207-10. |
| 26. | Kaplan J, Burgin S, Sepehr A. Granulomatous pigmented purpura: Report of a case and review of the literature. J Cutan Pathol 2011;38:984-9. |
| 27. | Uter W, Geier J, Bauer A, Schnuch A. Risk factors associated with methylisothiazolinone contact sensitization. Contact Dermatitis 2013;69:231-8. |
| 28. | Pontén A, Bruze M, Engfeldt M, Hauksson I, Isaksson M. Concomitant contact allergies to formaldehyde, methylchloroisothiazolinone/methylisothiazolinone, methylisothiazolinone, and fragrance mixes I and II. Contact Dermatitis 2016;75:285-9. |
| 29. | Warshaw EM, Maibach HI, Taylor JS, Sasseville D, DeKoven JG, Zirwas MJ, et al. North American contact dermatitis group patch test results: 2011-2012. Dermatitis 2015;26:49-59. |
| 30. | Alani JI, Davis MD, Yiannias JA. Allergy to cosmetics: A literature review. Dermatitis 2013;24:283-90. |
| 31. | Boonchai W, Desomchoke R, Iamtharachai P. Trend of contact allergy to cosmetic ingredients in thais over a period of 10 years. Contact Dermatitis 2011;65:311-6. |
| 32. | Lee SS, Hong DK, Jeong NJ, Lee JH, Choi YS, Lee AY, et al. Multicenter study of preservative sensitivity in patients with suspected cosmetic contact dermatitis in Korea. J Dermatol 2012;39:677-81. |
| 33. | Liao SL, Tseng YH, Chu CY. Contact allergy to methylisothiazolinone/methylchloroisothiazolinone: A retrospective case series in a referral center in Northern Taiwan. Dermatol Sin 2017;35:201-5. |
| 34. | Urwin R, Warburton K, Carder M, Turner S, Agius R, Wilkinson SM, et al. Methylchloroisothiazolinone and methylisothiazolinone contact allergy: An occupational perspective. Contact Dermatitis 2015;72:381-6. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
|
Search Pubmed for