Domestic use of hypochlorite bleach, atopic sensitization,and respiratory symptoms in adults

Jan-Paul Zock, PhD,a,b,c Estel Plana, MSc,a,b,c Josep M Anto, MD,a,b,c,d Geza Benke, PhD,e Paul D. Blanc, MD,f

Aurelia Carosso, MD,g Anna Dahlman-H€oglund, PhD,h Joachim Heinrich, PhD,i Deborah Jarvis, MD,j

Hans Kromhout, PhD,k Linnea Lillienberg, PhD,h Maria C. Mirabelli, PhD,a,b,c Dan Norback, PhD,l Mario Olivieri, MD,m

Michela Ponzio, PhD,o Katja Radon, PhD,p Argo Soon, MD,q Marc van Sprundel, MD,r Jordi Sunyer, MD,a,b,c,d

Cecilie Svanes, MD,s Kjell Toren, MD,h Giuseppe Verlato, MD,n Simona Villani, PhD,o and

Manolis Kogevinas, MDa,b,c,t Barcelona, Spain, Victoria, Australia, San Francisco, Calif, Turin, Verona, and Pavia, Italy, G€oteborg,

Sweden, Neuherberg and Munich, Germany, London, United Kingdom, Utrecht, The Netherlands, Uppsala, Sweden, Tartu, Estonia, Antwerp,

Belgium, Bergen, Norway, and Heraklion, Greece

Background: Professional use of hypochlorite (bleach) has beenassociated with respiratory symptoms. Bleach is capable ofinactivating allergens, and there are indications that itsdomestic use may reduce the risk of allergies in children.Objective: To study the associations between household use ofbleach and atopic sensitization, allergic diseases, andrespiratory health status in adults.Methods: We identified 3626 participants of the EuropeanCommunity Respiratory Health Survey II in 10 countries whodid the cleaning in their homes and for whom data on specificserum IgE to 4 environmental allergens were available.

Frequency of bleach use and information on respiratorysymptoms were obtained in face-to-face interviews. House dustmite and cat allergens in mattress dust were measured in asubsample. Associations between the frequency of bleach useand health outcomes were evaluated by using multivariablemixed logistic regression analyses.Results: The use of bleach was associated with less atopicsensitization (odds ratio [OR], 0.75; 95% CI, 0.63-0.89). Thisassociation was apparent for specific IgE to both indoor (cat)and outdoor (grass) allergens, and was consistent in varioussubgroups, including those without any history of respiratory

From athe Centre for Research in Environmental Epidemiology, Barcelona; bthe Munic-

ipal Institute of Medical Research (IMIM-Hospital del Mar), Barcelona; cCIBER Epi-

demiologıa y Salud Publica, Barcelona, Spain; dthe Department of Experimental and

Health Sciences, Pompeu Fabra University, Barcelona; ethe Department of Epidemi-

ology and Preventive Medicine, Monash University, Victoria, Australia; fthe Division

of Occupational and Environmental Medicine, University of California San Francisco;gthe Division of Pneumology and Allergology, ASL 2 Regione Piemonte, Turin; hthe

Department of Occupational and Environmental Medicine, Sahlgrenska University

Hospital, G€oteborg; iHelmholtz Zentrum M€unchen, German Research Center for En-

vironmental Health, GmbH, Neuherberg; jthe Respiratory Epidemiology and Public

Health Group, National Heart and Lung Institute, Imperial College, London; kthe En-

vironmental Epidemiology Division, Institute for Risk Assessment Sciences, Univer-

sity of Utrecht; lthe Department of Medical Science, Occupational and Environmental

Medicine, Uppsala University; mthe Department of Medicine and Public Health, Unit

of Occupational Medicine, and nthe Unit of Epidemiology and Medical Statistics, De-

partment of Medicine and Public Health, University of Verona; othe Department of

Health Sciences, Section of Epidemiology and Medical Statistics, University of Pavia;pthe Unit for Occupational and Environmental Epidemiology and NetTeaching, Insti-

tute for Occupational and Environmental Medicine, Ludwig-Maximilians-University,

Munich; qthe Department of Public Health, University of Tartu; rthe Department of Ep-

idemiology and Community Health, University of Antwerp; sthe Department of Tho-

racic Medicine, Institute of Medicine, University of Bergen; and tthe Department of

Social Medicine, Medical School, University of Crete, Heraklion.

The coordination of the European Community Respiratory Health Survey II was

supported by the European Commission as part of their Quality of Life program.

This work was also funded by the US National Institutes of Health (grant

1R01HL062633) and the Carlos III Health Institute of the Spanish Ministry of Health

and Consumption (Fondo de Investigaciones Santarias [FIS] grant 01/3058). The

following bodies funded the local studies in the European Community Respiratory

Health Survey II included in this article: Albacete, FIS (grants 97/0035-01, 99/0034-01,

and 99/0034-02), Hospital Universitario de Albacete, Consejeria de Sanidad; Antwerp,

Fund for Scientific Research, Flanders, Belgium (grant G.0402.00), University of

Antwerp, Flemish Health Ministry; Barcelona, SEPAR, Public Health Service (grant

R01 HL62633-01), FIS (grants 97/0035-01, 99/0034-01, and 99/0034-02), CIRIT

(grant 1999SGR 00241), Red Respira ISCII; Basel, Swiss National Science Founda-

tion, Swiss Federal Office for Education and Science, Swiss National Accident Insur-

ance Fund, USC NIEHS Center (grant 5P30 ES07048); Bergen, Norwegian Research

Council, Norwegian Asthma and Allergy Association, Glaxo Wellcome AS, Norway

Research Fund; Erfurt, GSF-National Research Centre for Environment and Health,

Deutsche Forschungsgemeinschaft (grant FR 1526/1-1); Galdakao, Basque Health

Department; G€oteborg, Swedish Heart Lung Foundation, Swedish Foundation for

Health Care Sciences and Allergy Research, Swedish Asthma and Allergy Foundation,

Swedish Cancer and Allergy Foundation; Grenoble, Programme Hospitalier de Re-

cherche Clinique-DRC de Grenoble 2000 no. 2610, Ministry of Health, Direction de

la Recherche Clinique, Ministere de l’Emploi et de la Solidarite, Direction Generale

de la Sante, CHU de Grenoble, Comite des Maladies Respiratoires de l’Isere; Hamburg,

GSF-National Research Centre for Environment and Health, Deutsche Forschungsge-

meinschaft (grant MA 711/4-1); Ipswich and Norwich, Asthma UK (formerly known as

the National Asthma Campaign); Huelva, FIS (grants 97/0035-01, 99/0034-01, and 99/

0034-02); Oviedo, FIS (grants 97/0035-01, 99/0034-01, and 99/0034-02);Paris, Minis-

tere de l’Emploi et de la Solidarite, Direction Generale de la Sante, UCB-Pharma

(France), Aventis (France), Glaxo France, Programme Hospitalier de Recherche Clin-

ique-DRC de Grenoble 2000 no. 2610, Ministry of Health, Direction de la Recherche

Clinique, CHU de Grenoble; Pavia, GlaxoSmithKline Italy, Italian Ministry of Univer-

sity and Scientific and Technological Research, Local University Funding for research

1998 and 1999; Tartu, Estonian Science Foundation; Turin, ASL 4 Regione Piemonte,

AO CTO/ICORMA Regione Piemonte, Italian Ministry of University and Scientific

and Technological Research; GlaxoSmithKline Italy; Umea, Swedish Heart Lung

Foundation, Swedish Foundation for Health Care Sciences and Allergy Research,

Swedish Asthma and Allergy Foundation, Swedish Cancer and Allergy Foundation;

Uppsala, Swedish Heart Lung Foundation, Swedish Foundation for Health Care Sci-

ences and Allergy Research, Swedish Asthma and Allergy Foundation, Swedish Can-

cer and Allergy Foundation; Verona, University of Verona; Italian Ministry of

University and Scientific and Technological Research; GlaxoSmithKline Italy.

Disclosure of potential conflict of interest: G. Benke has received research support from

the National Health and Medical Research Council of Australia. P. D. Blanc has

received research support from the National Institutes of Health, UC Tobacco Related

Diseases, and FAMRI and has served as an expert witness on hepatotoxicity and inha-

lation injury. J. Sunyer has received research support from the European Union, Min-

istry of Health, Spain, and the Ministry of Health, Catalonia. The rest of the authors

have declared that they have no conflict of interest.

Received for publication October 31, 2008; revised May 22, 2009; accepted for publica-

tion June 1, 2009.

Available online August 10, 2009.

Reprint requests: Jan-Paul Zock, PhD, Centre for Research in Environmental Epidemi-

ology, Barcelona Biomedical Research Park, Dr Aiguader, 88, E-08003 Barcelona,

Spain. E-mail: jpzock@creal.cat.

0091-6749/$36.00

� 2009 American Academy of Allergy, Asthma & Immunology

doi:10.1016/j.jaci.2009.06.007

731

J ALLERGY CLIN IMMUNOL

OCTOBER 2009

732 ZOCK ET AL

problems (OR, 0.85). Dose-response relationships (P < .05) wereapparent for the frequency of bleach use and sensitization rates.Lower respiratory tract symptoms, but not allergic symptoms,were more prevalent among those using bleach 4 or more daysper week (OR, 1.24-1.49). The use of bleach was not associatedwith indoor allergen concentrations.Conclusion: People who clean their homes with hypochloritebleach are less likely to be atopic but more likely to haverespiratory symptoms. (J Allergy Clin Immunol 2009;124:731-8.)

Key words: Hypochlorite bleach, household, atopy, allergy,respiratory

Chlorine-derived substances have been used for more than 200years for bleaching, cleaning, and disinfection. Currently, dilutehypochlorite solutions constitute the most common bleachingproduct type in use in private households around the world, withuses including surface cleaning and disinfection and laundrybleaching.1

The use of hypochlorite solution, hereafter referred to simply asbleach, has been associated with adverse respiratory health ef-fects. Mixing bleach with acids or ammonia results in a rapid re-lease of free chlorine or chloramines, respectively.2,3 There arenumerous reports of acute inhalation events related to inappropri-ate bleach mixing, in some cases resulting in chronic respiratorydisorders4,5 including reactive airways dysfunction syndrome, aform of irritant-induced asthma.6-8 In addition, epidemiologicstudies have shown associations between professional use ofbleach and respiratory symptoms suggestive of asthma.9-11 Al-though acute inhalations may partially explain these associations,recurrent lower-grade exposures to chlorine-derived respiratoryirritants may also induce asthmalike disorders.12 Chloraminesare typically released during cleaning activities when hypochlo-rite reacts with organic matter, and are likely to play a role inthis effect mechanism.13

On the other hand, bleach has been found to be effective in theinactivation of cat and other indoor allergens, probably throughthe fragmentation of antigenic proteins.14,15 It has also beenshown that bleach is able to reduce skin prick test reactivity to As-pergillus allergens in sensitized individuals when it is used to pre-treat mold-contaminated material.16 It is not clear, however,whether such inactivation of antigenic material has any clinicalrelevance. A single epidemiologic study investigated the risk ofatopic sensitization in school children age 10 to 13 years in rela-tion to domestic use of bleach.17 Children living in homes thatwere cleaned at least weekly with bleach had less atopic sensiti-zation to indoor allergens (odds ratio [OR], 0.5; 95% CI, 0.3-1.0), with a potentially prominent role of house dust mite allergy.Cleaning with bleach was also associated with lower rates ofasthma and eczema. The authors hypothesized that inactivationof indoor allergens by bleach could be the underlying factor ex-plaining these findings.

The main aim of this study is to assess the use of bleach in thehome in relation to respiratory and atopic health status in theEuropean Community Respiratory Health Survey (ECRHS)follow-up (ECRHS II), a large, multicenter, population-basedstudy of European adults. In particular, we studied the associationbetween the use of household bleach and specific serum IgE toselected indoor and outdoor allergens, allergic diseases, respira-tory symptoms, and bronchial responsiveness. We considered

potentially confounding and effect modifying factors, and alsoanticipated possible selection bias caused by the avoidance ofbleach use by individuals with symptomatic airway disease.Finally, we evaluated potential effects of bleach use on house dustmite and cat allergen concentrations in the home.

METHODS

Study design and participantsThe ECRHS is a multicenter study designed to identify risk factors for

asthma and allergy. Participants age between 20 and 44 years were recruited

from 1992 to 1994 by random sampling from a community-based sampling

frame in each center. A random sample of responders to a short postal

questionnaire was invited for clinical testing. In 2001 and 2002, participants

who had taken part in these clinical investigations were invited for further

study (ECRHS II).18 Twenty-two centers from 10 European countries agreed

to take part in the assessment of selected occupational and domestic exposures

at the ECRHS II by using modular questionnaires. The follow-up study in

these 22 centers was performed in 7263 participants (response rate, 63%)

with an average follow-up time of 8.9 years. Responders tended to be some-

what older, less likely to come from less-advantaged socioeconomic classes,

and less likely to be former or current smokers; however, there were no differ-

ences in sensitization rates.19 The study protocol was approved by all local in-

stitutional committees on ethical practice, and participants provided written

informed consent.

QuestionnaireAt the face-to-face interview of ECRHS II, participants were asked, ‘‘Since

the last survey, have you been the person doing the cleaning and/or washing in

your home?’’ The 4267 participants (59%) who answered affirmatively

completed a questionnaire module that asked about the use of specific

products for domestic cleaning and washing. A specific question about the

frequency of use of bleach for cleaning was included, and it referred to the

average use during the follow-up period. The frequency was recorded as never,

less than 1 day per week, 1 to 3 days per week, or 4 to 7 days per week. More

details of this module have been described elsewhere.20

Participants’ history of allergic diseases included ever having had asthma,

having nasal allergies or hay fever, and ever having had eczema or any kind of

skin allergy. Family history of allergic disease was defined as reporting either

parent having ever had asthma, eczema, skin or nasal allergy, or hay fever.

Respiratory symptoms experienced in the last 12 months included wheezing

and nocturnal attacks of shortness of breath. An asthma symptom score was

calculated as the sum of the answers (0 5 no; 1 5 yes) to 5 asthma symptoms

in the last 12 months (wheeze with breathlessness, woken up with chest

tightness, attack of shortness of breath at rest, attack of shortness of breath

after exercise, woken up by attack of shortness of breath). Validity and

determinants of this score have been described elsewhere.21 Chronic cough

was defined as an affirmative answer to both, ‘‘Do you usually cough during

the day, or at night, in the winter?’’ and ‘‘Do you cough like this on most

days for as much as three months each year?’’ Allergic symptoms were defined

as ever having cough, wheeze, chest tightness, shortness of breath, runny or

stuffy nose or sneezing, and/or itchy or watering eyes that participants re-

ported when (1) ‘‘being near animals, such as cats, dogs or horses’’; (2) ‘‘in

a dusty part of the house, or near pillows or duvets’’; (3) or ‘‘near trees, grass

or flowers, or when there is a lot of pollen about.’’ Socioeconomic status (SES)

Abbreviations used

BHR: Bronchial hyperresponsiveness

ECRHS: European Community Respiratory Health Survey

OR: Odds ratio

SES: Socioeconomic status

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ZOCK ET AL 733

was based on the longest held job during the follow-up interval between

ECRHS I and ECRHS II.22

Nonspecific bronchial responsiveness testingAt the ECRHS II, FEV1 was recorded by means of spirometry using a stan-

dardized method,18 and methacholine challenge testing was carried out with a

dosimeter (Mefar, Brescia, Italy). Bronchial hyperresponsiveness (BHR) was de-

fined as a 20% fall in FEV1 associated with a methacholine dose of 1 mg or less.

Atopic sensitizationBlood samples were provided by 3626 ECRHS II participants, 85% of

those answering the specific questionnaire on home cleaning. Specific serum

IgE against 4 common environmental aeroallergens (the house dust mite Der-matophagoides pteronyssinus, cat, timothy grass, and the mold Cladosporium

herbarium) was determined by using the Pharmacia CAP system (Pharmacia

Diagnostics, Uppsala, Sweden). Atopy was defined as a specific IgE level of

0.35 kU/L or higher to at least 1 out of these 4 allergens.

Measurement of house dust mite and cat allergenMaximum 200 ECRHS II participants in 21 of the 22 centers who did not

move home during the follow-up period and provided a blood sample for

serum specific IgE determination had house dust samples measured. More

details of dust sampling and determination of allergen levels have been

described elsewhere.23,24 Briefly, a sample of dust was taken from the partic-

ipant’s mattress by vacuuming an area of 1 m2 for a period of 2 minutes using a

1300-W vacuum cleaner with an attached ALK dust collection filter (ALK-

Abello, Hørsholm, Denmark). Samples were sealed in a plastic bag, frozen

for 24 hours at 2208C, and then forwarded with a silica gel desiccant to a cen-

tral laboratory, where they were sieved and extracted in borate-buffered saline.

House dust mite allergens (Der p 1 and Der f 1) and cat allergen (Fel d 1) were

assayed by using a standardized ELISA technique.

Statistical analysesAll analyses were performed by using the subset of ECRHS II participants

who did the cleaning and/or washing in their homes with complete informa-

tion on both bleach use and atopic sensitization at the time of the ECRHS II (N

5 3626). Cross-sectional associations between the frequency of bleach use

and binary outcomes assessed at the time of the ECRHS II were evaluated by

using mixed logistic regression analysis adjusted for potential confounders

sex, age, and smoking status, with a random intercept for study center. Models

for atopic sensitization were additionally adjusted for family history of

allergic disease and number of siblings, because these 2 factors were

associated with atopy and with bleach use in preliminary analyses. For the

asthma score, negative binomial regression models assessing the adjusted ratio

of the mean score for exposed and nonexposed were applied.19 Statistical sig-

nificance of linear trend for the frequency of bleach use in 4 categories was

evaluated by the Wald x2 test from the adjusted regression models with bleach

use a continuous variable (0, 1, 2, 3). Potential modification of an association

by a third factor was evaluated by calculating the P value for multiplicative

interaction when entered into adjusted regression models. Potential heteroge-

neity between countries for selected associations was examined by using stan-

dardized methods for random-effects meta-analysis. Associations between the

frequency of use of bleach and log-transformed concentrations of dust mite

and cat allergens were investigated by using mixed Tobit regression models

controlling for the housing and sampling characteristics as described else-

where.23,24 Analyses were performed by using Stata SE 10.0 (Stata Corp, Col-

lege Station, Tex).

RESULTSAbout two thirds of the study population were women (Table I).

Twenty-eight percent had any atopic sensitization, predominantlyagainst grass and house dust mite. Allergic conditions (rhinitis,

eczema, and to a lesser extent, asthma) and associated symptomswere common.

Sixty-three percent of the study population reported ever usingbleach in their homes; approximately 1 in 4 (28%) used bleach ona weekly basis, and 1 in 10 did so at least every second day, if notdaily (Table II). The use of bleach was consistently associatedwith less atopic sensitization. There was a significant dose-relatedtrend of lower risks of specific IgE to different aeroallergens andof overall atopic sensitization with more frequent use of bleach.Results were essentially similar when the regression modelswere additionally adjusted for a range of potential confounders in-cluding SES, type of home and other dwelling characteristics,mold growth, pet keeping, the frequency of home cleaning activ-ities, and the use of cleaning products other than bleach (data notpresented). The number of participants sensitized to Cladospo-rium was too small to be analyzed independently.

Most atopics were sensitized to more than 1 allergen. Whenconsidering monosensitization (that is, specific IgE to only 1 ofthe 4 allergens), inverse associations with ever using bleach wereapparent for IgE to cat (prevalence rate, 3.7%; OR, 0.62; 95% CI,0.40-0.97) and for IgE to grass (prevalence rate, 1.8%; OR, 0.58;95% CI, 0.32-1.08), but not, however, for IgE to house dust mite(prevalence rate, 8.8%; OR, 1.10; 95% CI, 0.80-1.50). Thefollowing models are based on the variables atopy (any sensiti-zation) and any bleach use to perform stratified analyses withsufficient statistical power.

TABLE I. Demographic, allergic, and respiratory health charac-

teristics of the study population of ECRHS II participants doing

the cleaning and/or washing in their homes (N 5 3626)

Age (y), mean (SD) 42.9 (7.16)

Women 2471 (68.2)

Current smokers 1061 (29.3)

Exsmokers 934 (25.8)

Specific IgE to house dust mite 527 (14.5)

Specific IgE to cat 354 (9.8)

Specific IgE to timothy grass 599 (16.5)

Specific IgE to C herbarium 40 (1.1)

Atopy* 1010 (27.9)

Family history of allergic disease 1316 (36.3)

Ever asthma 413 (11.4)

Nasal allergies or hay fever 1103 (30.5)

Ever eczema or skin allergy 1701 (47.0)

Allergic symptoms� triggered by

contact with animals

580 (16.0)

Allergic symptoms� triggered by

contact with house dust

1027 (28.5)

Allergic symptoms� triggered by

contact with trees/grass/flowers/pollen

1142 (31.6)

Wheeze 771 (21.3)

Nocturnal shortness of breath 239 (6.6)

Chronic cough 263 (7.3)

Symptom score, mean (range)� 0.55 (0-5)

Bronchial hyperresponsiveness,§ 354 (13.4)

Units are n (%) unless otherwise stated.

*Specific sensitization to at least 1of the 4 allergens.

�Cough, wheeze, chest tightness, shortness of breath, runny or stuffy nose or sneezing,

and/or itchy or watering eyes.

�Sum of the answers (0 5 no; 1 5 yes) to 5 symptoms in the last 12 months (wheeze

with breathlessness, woken up with chest tightness, attack of shortness of breath at

rest, attack of shortness of breath after exercise, woken up by attack of shortness of

breath).

§Methacholine dose of 1 mg or less causing a 20% fall in FEV1 (n 5 2643).

J ALLERGY CLIN IMMUNOL

OCTOBER 2009

734 ZOCK ET AL

TABLE II. Associations between the frequency of bleach use and atopic sensitization

Frequency of bleach use n (%)

IgE to house

dust mite IgE to cat IgE to timothy grass Atopy*

Never 1340 (37.0) 1.00 (Referent) 1.00 (Referent) 1.00 (Referent) 1.00 (Referent)

Less than 1 d/wk 1267 (34.9) 0.85 (0.67-1.08) 0.76 (0.59-0.99) 0.65 (0.53-0.82) 0.76 (0.63-0.91)

1-3 d/wk 669 (18.4) 0.81 (0.60-1.10) 0.62 (0.43-0.90) 0.66 (0.49-0.90) 0.77 (0.61-0.99)

4-7 d/wk 350 (9.7) 0.58 (0.38-0.89) 0.49 (0.29-0.86) 0.55 (0.36-0.86) 0.62 (0.44-0.87)

P for linear trend .017 .001 <.001 .002

ORs and 95% CIs adjusted for sex, age, smoking status, family history of allergic disease, number of siblings (fixed), and study center (random).

*Specific sensitization to at least 1 of 4 allergens (mite, cat, grass, Cladosporium).

TABLE III. Associations between the use of bleach (ever) and atopy stratified by sex, smoking status, and history of allergic diseases

Stratum n Bleach use (%) OR (95% CI) P for interaction

All 3626 63 0.75 (0.63-0.89)

Men 1155 49 0.70 (0.54-0.92)

Women 2471 70 0.80 (0.65-1.00) .60

Never smokers 1595 63 0.70 (0.55-0.90)

Ever smokers 1995 63 0.81 (0.64-1.01) .76

High SES (ISCO Major Groups 1-3*) 1642 59 0.64 (0.50-0.82)

Low SES (ISCO Major Groups 4-9�) 1683 65 0.88 (0.68-1.13) .05

Never asthma 3209 63 0.79 (0.65-0.95)

Ever asthma 413 64 0.51 (0.31-0.84) .19

No nasal allergies or hay fever 2511 65 0.86 (0.67-1.10)

Nasal allergies or hay fever 1103 59 0.81 (0.61-1.06) .17

Never eczema or skin allergy 1914 62 0.75 (0.59-0.95)

Ever eczema or skin allergy 1701 64 0.72 (0.56-0.92) .11

No family history of allergic disease 1943 64 0.79 (0.62-1.00)

Family history of allergic disease 1316 64 0.65 (0.50-0.84) .16

Any respiratory problem� 2053 64 0.74 (0.60-0.91)

No respiratory problems 1402 62 0.85 (0.61-1.19) .39

ORs and 95% CIs relative to those who never used bleach (n 5 1340), adjusted for sex, age, smoking status, family history of allergic disease, number of siblings (fixed), and study

center (random).

*International Standard Classification of Occupations (ISCO) 1988: nonmanual workers including legislators, senior officials, managers, professionals, technicians, and associate

professionals.

�ISCO 1988: clerks, service workers, shop and market sales workers, and manual workers.

�Participants who (1) ever had asthma; and/or (2) had a symptom score of >0, indicating symptoms suggestive of asthma in the previous year; and/or (3) ever had a problem with

sneezing or a runny or a blocked nose when not having a cold or the flu.

First, the association between bleach use and atopy wasstratified by several independent risk factors for atopy. Theobserved inverse association between bleach use and atopy wasconsistent for men and women, for smokers and nonsmokers,and after stratification for allergic diseases or family history ofallergy (Table III). There was statistical evidence (P < .2) foreffect modification by SES and allergic diseases; there were in-dications that the inverse association under study was strongeramong the more advantaged SES groups and perhaps amongthose having an allergic disease and a family history of allergy.To address potential selection bias caused by health-relatedavoidance of bleach use, we defined a subgroup of participantswithout any history of respiratory conditions and no upper orlower respiratory tract symptoms in the previous year. The

OR for the association between bleach use and atopy withinthis subgroup was below unity (0.85) and was not statisticallydifferent from the subgroup with any of these respiratory prob-lems (OR, 0.74; Table III).

Second, the association between bleach use and atopy wasassessed separately for each country. The use of bleach variedlargely between countries (Fig 1), ranging from 17% in Switzerlandto 92% in Spain. Meta-analysis of the country-specific associationsshowed that the risk of atopy among bleach users was reduced inmost countries. There were no indications that the associationswere systematically different between countries where bleach wasused more or less frequently. Differences in OR between somecountries seemed apparent, but the test for heterogeneity did notreach conventional levels of statistical significance (P 5 .20).

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ZOCK ET AL 735

The use of bleach was inversely associated with reported nasalallergies and with allergic symptoms (Table IV). However, thiswas not apparent when bleach was used on 4 or more days perweek. Asthma was not clearly associated with bleach use, al-though it tended to be more common among the most frequentbleach users. Eczema was associated with sporadic bleach use(OR, 1.25), but not with common use. Very frequent use of bleachwas associated with a higher prevalence of lower respiratory tractsymptoms and possibly BHR. There was a significant dose-re-sponse relationship between the frequency of bleach use andthe symptom score, with the mean score significantly higher infrequent bleach users compared with never-users (Table IV).These associations were similar for atopics and nonatopics (re-sults not shown).

The use of bleach was not associated with mattress house dustmite allergen concentrations (Table V). There were some indica-tions that cat allergen levels were lower in homes with a cat wherebleach was used; however, this association was based on smallnumbers and was not statistically significant. Fel d 1 concentra-tions were overall more than 100-fold lower in homes without acat and were not associated with the use of bleach in those homes(results not shown).

DISCUSSIONIn this large observational study among adults from 10

European countries, we found that the use of hypochlorite bleachin the home was associated with lower rates of sensitization tocommon environmental allergens. This inverse association waspresent for specific IgE to both indoor and outdoor allergens, andwas consistent in various subgroups including those withoutclinically apparent respiratory disease, and the effect was strongerwhen bleach was used more frequently. Allergic symptoms andallergic rhinitis were also less prevalent among bleach users. Bycontrast, nonspecific lower respiratory tract symptoms and

Spain (92%)

UK (85%)

France (83%)

Italy (77%)

Belgium (76%)

Norway (60%)

Sweden (50%)

Estonia (38%)

Germany (34%)

Switzerland (17%)

Combined

0.5 0.75 1 1.5

Odds Ratio

FIG 1. Association between the use of bleach (ever) and atopy by country.

OR and 95% CI, adjusted within countries for study center, sex, age,

smoking status, family history of allergic disease, and number of siblings,

are shown. The size of each square is proportional to the reciprocal of the

variance of the estimate for the country. The diamond indicates 95% CI of

the combined OR from the model, with country as the random effect (P 5

.20, test for heterogeneity). Countries are ranked from high (top) to low

(bottom) by the frequency of bleach use (percentages indicated between

brackets). UK, United Kingdom.

bronchial hyperresponsiveness tended to be more prevalentamong those using bleach on 4 or more days per week.

To our knowledge, this is the first report studying the relation-ship between domestic use of bleach and atopic sensitization inadults. Our finding that bleach use is associated with less atopicsensitization is consistent with another epidemiologic study inBelgian children.17 Sensitization to indoor allergens, predomi-nantly house dust mite, in that study was less common in childrenwho lived in homes that were cleaned at least weekly with chlo-rine bleach. However, an inverse association between bleach useand sensitization to outdoor (pollen) allergens or hay fever wasnot observed. In our study, we did show reduced risks of sensiti-zation to timothy grass and of hay fever in bleach users. Anotherdifference with the Belgian study is that we could not demonstratean inverse association between the use of bleach and asthma or ec-zema. The latter 2 conditions are more strongly related to atopy inchildren than adults and could therefore explain the difference inobserved patterns between the 2 studies.

Our findings are consistent for 3 different allergens. However,most atopics were sensitized to more than 1 allergen. The risk ofsensitization to only cat or only grass was low, but was inverselyassociated with bleach use. Sensitization to house dust miteexclusively was more common, but was not related to the use ofbleach. Interestingly, this pattern is similar to that observed for theassociation between cigarette smoking and specific sensitizationusing the same base population.25 Smoking was inversely associ-ated with sensitization to cat or to grass, and positively associatedwith sensitization to mite. The hypothesis was put forward thattobacco smoke may inhibit lung antiproteases, and as a result,specific IgE production may be enhanced because house dustmite allergens contain enzymes with proteolytic activity.25 It isunknown, however, whether bleach-related exposures couldalso inhibit antiproteases and hence modify the risk of mite sen-sitization through these complex immunologic pathways.

Very frequent use of bleach was associated with nonspecificrespiratory symptoms and possibly with BHR. The use of thecontinuous asthma symptom score resulted in a more powerfulanalysis than dichotomous symptoms,21 and this indeed led to a sta-tistically significant association for the score. Importantly, the bor-derline significant association found for individual symptoms,chronic cough among others, was consistent with the score. Thesefindings are consistent with studies in professional cleaners9-11,26

and also with the Belgian study in which symptoms of wheezeand chronic bronchitis were more common in children from homeswhere bleach was used.17 When bleach is used appropriately andnot mixed with other (acid) products, the release of free chlorineduring or after cleaning should be minimal.1 However, even whennot combined with ammonia or other nitrogenous agents, chlora-mines may be formed during bleach use when hypochlorite reactswith organic material during cleaning activities. Chloramines, inparticular the most volatile and less water-soluble trichloramine,are potent respiratory irritants, and exposure to chloramines inswimming pool workers has been associated with irritant-inducedoccupational asthma.13,27 Thus, it can be hypothesized that recur-rent exposure to chloramines, rather than chlorine, during cleaningactivities with bleach may lead to adverse respiratory effects.

Experimental studies have shown that hypochlorite bleach caninactivate indoor allergens.14-16 We investigated whether cat andmite allergen levels in house dust were influenced by the fre-quency of bleach use. Our findings do not indicate that domesticuse of bleach may reduce indoor allergen exposure levels. There

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TABLE IV. Associations between the frequency of bleach use and allergic diseases, respiratory symptoms, and BHR

Frequency of bleach use

Less than 1 d/wk (n 5 1267) 1 to 3 d/wk (n 5 669) 4 to 7 d/wk (n 5 350) P for linear trend

Ever asthma 0.93 (0.72-1.21) 0.88 (0.62-1.23) 1.30 (0.86-1.96) .61

Nasal allergies or hay fever 0.76 (0.64-0.91) 0.76 (0.60-0.97) 0.91 (0.66-1.25) .07

Ever eczema or skin allergy 1.25 (1.06-1.47) 1.12 (0.89-1.41) 1.07 (0.80-1.44) .32

Allergic symptoms* triggered by contact with animals 0.87 (0.70-1.08) 0.71 (0.51-0.99) 0.93 (0.59-1.46) .16

Allergic symptoms* triggered by contact with house dust 0.90 (0.74-1.08) 0.75 (0.58-0.97) 0.93 (0.66-1.30) .15

Allergic symptoms* triggered by contact with trees/

grass/flowers/pollen

0.70 (0.58-0.83) 0.76 (0.60-0.97) 0.96 (0.69-1.33) .09

Wheeze 1.01 (0.82-1.24) 1.00 (0.76-1.31) 1.24 (0.88-1.74) .40

Nocturnal shortness of breath 0.73 (0.52-1.03) 1.09 (0.74-1.59) 1.38 (0.88-2.16) .21

Chronic cough 0.75 (0.54-1.04) 1.19 (0.81-1.76) 1.49 (0.94-2.37) .11

Symptom score (ratio of the mean score)� 0.88 (0.76-1.02) 1.06 (0.89-1.27) 1.37 (1.11-1.68) .02

BHR� 1.06 (0.79-1.42) 1.03 (0.70-1.50) 1.30 (0.82-2.06) .38

OR and 95% CI relative to those who never used bleach (n 5 1340), adjusted for sex, age, smoking status (fixed), and study center (random).

*Cough, wheeze, chest tightness, shortness of breath, runny or stuffy nose or sneezing, and/or itchy or watering eyes.

�Sum of the answers (0 5 no, 1 5 yes) to 5 symptoms in the last 12 months (wheeze with breathlessness, woken up with chest tightness, attack of shortness of breath at rest, attack

of shortness of breath after exercise, woken up by attack of shortness of breath).

�Methacholine dose of 1 mg or less causing a 20% fall in FEV1.

TABLE V. Associations between the frequency of bleach use and house dust mite and cat allergen concentrations in mattress dust

Der p 1 (N 5 1223) Der f 1 (N 5 1191) Fel d 1 (N 5 300*)

Use of bleach GM (mg/g)y GM ratio (95% CI)z GM (mg/g)y GM ratio (95% CI)z GM (mg/g)y GM ratio (95% CI)z

Never 0.19 1 (Referent) 0.22 1 (Referent) 108 1 (Referent)

<1 d/wk 0.16 0.87 (0.58-1.29) 0.21 0.96 (0.62-1.49) 63 0.61 (0.31-1.19)

1-3 d/wk 0.20 1.06 (0.68-1.66) 0.29 1.28 (0.76-2.14) 104 0.95 (0.46-1.97)

4-7 d/wk 0.22 1.01 (0.58-1.75) 0.16 0.69 (0.35-1.35) 87 0.88 (0.32-2.45)

Ever 0.18 0.94 (0.65-1.35) 0.22 1.01 (0.67-1.52) 77 0.76 (0.43-1.34)

*Participants with a cat in their home.

�Geometric mean (GM) with random-effects adjustment for study center.

�GM ratio from multivariable mixed Tobit regression models with random-effects adjustment for study center and fixed adjustment for relevant sampling and home characteristics

as described elsewhere.23,24

was perhaps a tendency of somewhat lower Fel d 1 concentrationsin homes with a cat when bleach was used, but there was notenough statistical power to demonstrate this formally. In anycase, we previously failed to show any association between expo-sure to house dust mite or cat allergen and specific sensitization inthis population,28 and it is therefore unlikely that a modest reduc-tion in indoor allergen level would result in a notable reduction ofsensitization. Thus, our study does not provide evidence that lessatopic sensitization in relation to bleach use can be explained bythe inactivation of indoor allergens. The fact that IgE to grass andhay fever were also reduced in bleach users can also be usedagainst this hypothesis. We cannot exclude, however, that com-plex interactions between allergens and bleach-derived chlorinecompounds in the epithelial lining fluid of the respiratory tractmay influence sensitization and hence play a role here.

In this cross-sectional analysis, the inverse association betweenbleach use and sensitization might partly be explained byselection bias if atopic individuals with symptomatic airwaydisease avoided using bleach. However, there are a number ofobservations that argue against this explanation. First, the resultsdid not change when individuals who had asthma and/or reportedlower or upper respiratory tract symptoms were excluded from theanalysis. It is very unlikely that atopics without any clinicallyapparent disease would avoid bleach only because of the presence

of IgE, of which many are not even aware. The observation thatthe most frequent bleach users had more asthma and respiratorysymptoms but less atopic sensitization is an additional counter-weight to selection bias.

Further, asthmatic patients with atopy in many countries aretypically recommended to clean their homes thoroughly, inparticular when sensitized to house dust mite. Public awarenessof possible adverse respiratory health effects of normal use ofbleach may be generally limited. We therefore do not have strongreasons to believe that such patients would not use bleach if thatis a common practice in their country. Finally, we evaluated therelationship between bleach use and atopy longitudinally. Theproportion of participants who developed atopy during follow-upwas nonsignificantly lower among ever bleach users than amongnever-users (adjusted OR, 0.86; 95% CI, 0.60-1.24). Thus, astrong selection bias caused by health-related avoidance ofbleach use seems unlikely; however, we cannot exclude that itplayed some part in the inverse association between bleach useand atopy.

Our results could have been influenced by confounding if theuse of bleach was associated with host or environmental deter-minants of atopic sensitization. We controlled for potential hostconfounders (potentially associated with both bleach use andatopy) including sex, age, smoking status, and family history of

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allergic diseases. It is important to note that additional adjustmentfor SES did not affect the association, even though the lessadvantaged social class groups used more bleach and have beensuggested to have less atopy. In addition, adjustment for a varietyof household characteristics (including type and age of the home,type of floor covers, dust mite control measures, mold growth, petkeeping, using gas for cooking, and passive smoking) that couldinfluence the use of bleach did not change the results. Thisincluded the overall frequency of cleaning, indicating that ourobservations were specific for bleach and did not reflect generalcleanliness of the home. It is difficult to hypothesize other possiblehost or environmental factors that could have strongly confoundedthe observed association between bleach use and atopy.

Bleach use was common in most countries of our study, andwas probably used for a variety of cleaning purposes in thehome. A potential limitation was that we did not collect moredetails about bleach use. We asked for the frequency of use,but there was probably an additional large quantitative andqualitative variability in exposure within the population.Anecdotally, applications may have varied from pouring adash of undiluted bleach into the toilet bowl to intensivelymopping floors with diluted bleach.9 Using the frequency ofbleach use as a proxy of exposure could have led to misclas-sification of actual exposure and hence to a bias in the associ-ations under study. Another limitation is that we collectedinformation about the active use of bleach by the study partic-ipant only, and not about the use of bleach in the house byothers. Therefore, potential effects of passive exposure couldhave influenced our findings. Although it has been suggestedthat such passive exposure may be relevant,17 we believethat personal exposures related to active use are much higher,and that it is therefore unlikely that passive exposure to bleachcaused an important bias.

Overall loss to follow-up was 37%, and some differencesbetween responders and nonresponders to the ECRHS II had beenobserved.19 We do not have information on bleach use among thenonresponders but, importantly, baseline sensitization rates werecomparable between responders and nonresponders. Further-more, in this cross-sectional analysis, we do not have specificdata to evaluate a potential previous negative selection effect inwhich less healthy individuals had quit doing home cleaning ac-tivities. Nevertheless, the current study population did not haveless atopy (OR,1.1; CI, 0.9-1.3) than the excluded subgroup ofthose who did not do the cleaning in their homes (n 5 1511).This observation argues against such selection.

Our study suggests that health effects of bleach use may beparadoxical, because it is at the same time associated with morerespiratory symptoms and with less atopy. This phenomenon,however, is not completely novel; apparently ambiguous associ-ations with respiratory and allergic health outcomes have beenreported for other environmental exposures. In adults, an increasein respiratory symptoms and at the same time a reduction in atopicsensitization have been associated with cigarette smoking,25 ex-posure to endotoxins,29 and other farming-related organic dust ex-posures.30 Studies in children have shown that health effects ofpet keeping31 and respiratory infections32 can also be paradoxi-cal. Our observational study does not provide specific informationto speculate on the underlying (immunologic or nonimmuno-logic) effect mechanisms in relation to bleach.

We conclude that the use of bleach in the home is related toless allergic sensitization but also to more nonallergic

respiratory symptoms in adults who do the cleaning in theirhomes. Although we cannot exclude that cleaning with bleachreduces allergic triggers in the home environment, this isunlikely to be the principal explanation for this observation.It is possible that exposure to bleach can also reduce the risk ofclinically manifest allergic diseases. However, results need tobe confirmed in other studies, and potential effect mechanismsshould be evaluated before balanced public health implicationsof our finding can be made.

See this article’s Online Repository at www.jacionline.org for

acknowledgments.

Key messages

d Adults who use hypochlorite bleach to clean their homesare less likely to have atopic sensitization.

d This observation is unlikely to be explained by reductionof indoor allergen concentration.

d Very frequent use of bleach was associated with more res-piratory symptoms.

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COORDINATING CENTER OF ECRHS IIProject Leader: P. Burney; Statistician: S. Chinn; Principal

Investigator: D. Jarvis; Project Coordinator: J. Knox; PrincipalInvestigator: C. Luczynska; Assistant Statistician: J. Potts; DataManager: S. Arinze.

STEERING COMMITTEE FOR ECRHS IIProfessor Josep M. Anto, Institut Municipal d’Investigacio

Medica (IMIM-IMAS), Universitat Pompeu Fabra (UPF);Professor Peter Burney, King’s College London (ProjectLeader); Dr Isa Cerveri, University of Pavia; Professor SusanChinn, King’s College London; Professor Roberto de Marco,University of Verona; Dr Thorarinn Gislason, IcelandUniversity Hospital; Dr Joachim Heinrich, GSF—Institute ofEpidemiology; Associate Professor Christer Janson, UppsalaUniversity; Dr Deborah Jarvis, King’s College London;Dr Nino K€unzli, University of Basel and University ofSouthern California Los Angeles; Dr Benedicte Leynaert,Institut National de la Sante et de la Recherche Medicale(INSERM); Dr Christina Luczynska, King’s College London;Dr Francxoise Neukirch, INSERM; Dr J. Schouten, Universityof Groningen; Dr Jordi Sunyer, IMIM-IMAS, UPF; Dr CecilieSvanes, University of Bergen; Professor Paul Vermeire,University of Antwerp; Dr Matthias Wjst, GSF—Institute ofEpidemiology.

PRINCIPAL INVESTIGATORS AND SENIOR

SCIENTIFIC TEAMBelgium: South Antwerp and Antwerp City (P. Vermeire,

J. Weyler, M. Van Sprundel, V. Nelen). Estonia: Tartu (R. Jogi,A. Soon). France: Paris (F. Neukirch, B. Leynaert, R. Liard, M.Zureik), Grenoble (I. Pin, J. Ferran-Quentin). Germany: Erfurt(J. Heinrich, M. Wjst, C. Frye, I. Meyer). Italy: Turin (M. Bugiani,P. Piccioni, A. Carosso, W. Arossa, E. Caria, G. Castiglioni,E. Migliore, C. Romano, D. Fabbro, G. Ciccone, C. Magnani,P. Dalmasso, R. Bono, G. Gigli, A. Giraudo, M. C. Brussino,C. Bucca, G. Rolla), Verona (R. de Marco, G. Verlato, E. Zanolin,S. Accordini, A. Poli, V. Lo Cascio, M. Ferrari), Pavia (A. Marinoni,S. Villani, M. Ponzio, F. Frigerio, M. Comelli, M. Grassi, I. Cerveri,A. Corsico). Norway: Bergen (A. Gulsvik, E. Omenaas, C. Svanes,B. Laerum). Spain: Barcelona (J. M. Anto, J. Sunyer, M. Kogevinas,J. P. Zock, X. Basagana, A. Jaen, F. Burgos), Huelva (J. Maldonado,A. Pereira, J. L. Sanchez), Albacete (J. Martinez-Moratalla Rovira,E. Almar), Galdakao (N. Muniozguren, I. Urritia), Oviedo(F. Payo). Sweden: Uppsala (C. Janson, G. Boman, D. Norback,M. Gunnbjornsdottir), G€oteborg (K. Toren, L. Lillienberg,A. Dahlman-H€oglund, R. Sundberg), Umea (E. Norrman,M. Soderberg, K. Franklin, B. Lundback, B. Forsberg, L. Nystrom).Switzerland: Basel (N. K€unzli, B. Dibbert, M. Hazenkamp,M. Brutsche, U. Ackermann-Liebrich). United Kingdom: Norwich(D. Jarvis, B. Harrison), Ipswich (D. Jarvis, R. Hall, D. Seaton).