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The Association Between Domestic Water Hardness, Chlorine and Atopic Dermatitis Risk in Early Life: a Population-Based Cross-Sectional Study King’s Research Portal DOI: 10.1016/j.jaci.2016.03.031 Document Version Peer reviewed version Link to publication record in King's Research Portal Citation for published version (APA): Perkin, M. R., Craven, J., Logan, K., Strachan, D., Marrs, T., Radulovic, S., Campbell, L. E., MacCallum, S. F., McLean, W. H. I., Lack, G., & Flohr, C. (2016). The Association between Domestic Water Hardness, Chlorine and Atopic Dermatitis Risk in Early Life: A Population-Based Cross-Sectional Study. Journal of Allergy and Clinical Immunology, 138(2), 509-516. https://doi.org/10.1016/j.jaci.2016.03.031 Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. 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Sep. 2021 Accepted Manuscript The Association between Domestic Water Hardness, Chlorine and Atopic Dermatitis Risk in Early Life: A Population-Based Cross-Sectional Study Michael R. Perkin, PhD, Joanna Craven, MPH, Kirsty Logan, PhD, David Strachan, MD, Tom Marrs, BM BS, Suzana Radulovic, MD, Linda E. Campbell, BSc, Stephanie F. MacCallum, MSc, W.H. Irwin McLean, DSc, Gideon Lack, MD, Carsten Flohr, PhD PII: S0091-6749(16)30187-7 DOI: 10.1016/j.jaci.2016.03.031 Reference: YMAI 12078 To appear in: Journal of Allergy and Clinical Immunology Received Date: 4 November 2015 Revised Date: 8 March 2016 Accepted Date: 16 March 2016 Please cite this article as: Perkin MR, Craven J, Logan K, Strachan D, Marrs T, Radulovic S, Campbell LE, MacCallum SF, McLean WHI, Lack G, Flohr C, on behalf of the EAT Study Team, The Association between Domestic Water Hardness, Chlorine and Atopic Dermatitis Risk in Early Life: A Population- Based Cross-Sectional Study, Journal of Allergy and Clinical Immunology (2016), doi: 10.1016/ j.jaci.2016.03.031. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1 ACCEPTED MANUSCRIPT 1 Title: The Association between Domestic Water Hardness, Chlorine and 2 Atopic Dermatitis Risk in Early Life: A Population-Based Cross-Sectional Study 3 4 Michael R. Perkin, PhD 1, Joanna Craven, MPH 2, Kirsty Logan, PhD 2, David Strachan, MD, 1 Tom 5 Marrs, BM BS 2, Suzana Radulovic, MD 2, Linda E. Campbell, BSc 3, Stephanie F. MacCallum, 6 MSc 3, W.H. Irwin McLean, DSc 3, Gideon Lack, MD 2, Carsten Flohr, PhD 2,4 , on behalf of the 7 EAT Study Team 8 9 From 1the Population Health Research Institute, St George's, University of London, 2the 10 Children’s Allergies Department, Division of Asthma, Allergy and Lung Biology, King’s College 11 London, UK, 3the Centre for Dermatology and Genetic Medicine, Division of Molecular 12 Medicine, University of Dundee, Dundee, UK; and 4the St John’s Institute of Dermatology, 13 Guy’s and St Thomas’ Hospital NHS Foundation Trust,MANUSCRIPT London, UK. 14 15 Conflict of interest: none 16 Word count: 3122 17 18 Corresponding author: 19 Carsten Flohr 20 Unit for Population-Based Dermatology Research, St John’s Institute of Dermatology 21 Guy’s and St Thomas’ NHS Foundation Trust and King’s College London 22 London, UK ACCEPTED 23 Tel: 020 7188 7188, extension 51601 24 Fax: 020 7188 6334 25 Email: [email protected] 26 27 2 ACCEPTED MANUSCRIPT 28 Funding: 29 The main components of the EAT Study are jointly funded by the UK Food Standards Agency 30 (FSA, grant code T07051) and the Medical Research Council (MRC). The skin-related aspects 31 of the study are supported by the UK National Institute for Health Research (NIHR). CF holds 32 a NIHR Clinician Scientist Award (NIHRCS/01/2008/009). The views expressed in this 33 publication are those of the authors and not necessarily those of the FSA, MRC, the NHS, the 34 NIHR, the Wellcome Trust or the UK Department of Health. 35 MANUSCRIPT ACCEPTED 3 ACCEPTED MANUSCRIPT 36 ABSTRACT 37 Background: Domestic water hardness and chlorine have been suggested as important risk 38 factors for atopic dermatitis (AD). 39 Objective: To examine the link between domestic water calcium carbonate and chlorine 40 concentrations, skin barrier dysfunction (raised TEWL) and AD in infancy. 41 Methods: We recruited 1303 three month old infants from the general population and 42 gathered data on domestic water calcium carbonate (CaCO 3 mg/L) and chlorine (Cl 2 mg/L) 43 concentrations from local water suppliers. At enrolment, infants were examined for AD and 44 screened for filaggrin ( FLG ) skin barrier gene mutation status. Transepidermal water loss 45 (TEWL) was measured on unaffected forearm skin. 46 Results: CaCO 3 and chlorine levels were strongly correlated. A hybrid variable of above and 47 below median levels of CaCO 3 and total chlorine was constructed: a baseline group of low MANUSCRIPT 48 CaCO 3/low total chlorine (CaL/ClL), high CaCO3/low total chlorine (CaH/ClL), low CaCO 3/high 49 total chlorine (CaL/ClH) and high CaCO 3/high total chlorine (CaH/ClH). Visible AD was more 50 common in all three groups versus the baseline group: CaH/ClL adjusted OR (AOR) 1.87 51 (95%CI 1.25-2.80, p=0.002), CaL/ClH AOR 1.46 (95%CI 0.97-2.21, p=0.07) and CaH/ClH AOR 52 1.61 (95%CI 1.09-2.38, p=0.02). The effect estimates were greater in children carrying 53 filaggrin mutations but formal interaction testing between water quality groups and filaggrin 54 status was not statistically significant. 55 Conclusions: HighACCEPTED domestic water CaCO 3 levels are associated with an increased risk of AD in 56 infancy. The influence of elevated total chlorine levels remains uncertain. An intervention 57 trial is required to see whether installation of a domestic device to lower CaCO 3 levels 58 around the time of birth can reduce this risk. 59 4 ACCEPTED MANUSCRIPT 60 Clinical Implications 61 Domestic water hardness is an important risk factor for AD development and skin barrier 62 dysfunction already during the first three months of life, especially in genetically 63 predisposed infants. 64 65 Capsule Summary 66 In a cohort recruited from the general population, visible AD was more common in three 67 month old infants exposed to domestic water with raised levels of calcium carbonate. 68 69 Keywords: Filaggrin, eczema, atopic dermatitis, transepidermal water loss, water hardness 70 71 Abbreviations: 72 AD – atopic dermatitis MANUSCRIPT 73 CI – confidence interval 74 FLG – Filaggrin 75 OR – odds ratio 76 AOR – adjusted odds ratio 77 SCORAD - Scoring Atopic Dermatitis Index 78 TEWL – transepidermal water loss 79 ACCEPTED 5 ACCEPTED MANUSCRIPT 80 Introduction 81 Atopic dermatitis (AD: syn. ‘atopic eczema’, ‘childhood eczema’) is the commonest 82 inflammatory skin disease and affects around 20% of children in the UK. 1 Skin barrier 83 impairment and dry skin are hallmarks of AD and likely to be important triggers of 84 eczematous skin inflammation in early life, partly through genetic predisposition, in 85 particular inheritance of filaggrin ( FLG ) skin barrier gene mutations. We have previously 86 shown that carriage of FLG skin barrier mutations is associated with an increase in 87 transepidermal water loss (TEWL) and xerosis already by three months of life, even in 88 unaffected children. 2 In addition to FLG mutation inheritance, there are a number of 89 potential environmental exposures that may contribute to the breakdown of the skin barrier 1 90 in early life, including domestic water hardness (CaCO 3) and chlorine concentration. 91 Rain water is naturally low in CaCO 3 but it collects minerals, such as calcium, as it percolates 92 through rock. The local geology therefore has a majMANUSCRIPTor impact on the hardness of the water 93 supply. In the UK, domestic water tends to be harder in the south compared to the north. 94 Chlorine is universally added to tap water and is a potential skin irritant. 3 95 Ecological studies in the UK, Spain and Japan have shown consistent positive associations 96 between domestic water hardness and AD risk among schoolchildren. 4-6 However, the link 97 between domestic water hardness and AD has not been studied in early infancy, when 98 around 50% of all AD cases manifest clinically for the first time, 7 and furthermore, FLG 99 mutation inheritanceACCEPTED and skin barrier impairment (raised TEWL) have not been considered 100 in this context either.
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