Orianne Dumas
email: orianne.dumas@inserm.fr

Objectives: To investigate the association between occupational exposure to disinfectants/antiseptics used for hand hygiene and asthma control in nurses.

Methods:

In 2014, we invited female nurses with asthma drawn from the Nurses' Health Study II to complete two supplemental questionnaires on their occupation and asthma (crosssectional study, response rate: 80%). Among 4,055 nurses (mean age: 59 years) with physician-diagnosed asthma and asthma medication use in the past year, we examined asthma control, as defined by the Asthma Control Test (ACT). Nurses were asked about the daily frequency of hand hygiene tasks: "wash/scrub hands with disinfectants/hand sanitizers" (hand hygiene) and "wash/scrub arms with disinfecting products" (surrogate of surgical hand/arm antisepsis). Analyses were adjusted for age, race, ethnicity, smoking status, and body mass index.

Results: Nurses with partly controlled asthma (ACT: 20-24, 50%) and poorly controlled asthma (ACT≤19, 18%) were compared to nurses with controlled asthma (ACT=25, 32%). In separate models, both hand and arm hygiene were associated with poorly controlled asthma.

After mutual adjustment, only arm hygiene was associated with poorly controlled asthma:

Odds Ratio [95%CI] for <1 time/day, 1.38[1.06-1.80]; ≥1 time/day, 1.96[1.52-2.51], vs. never. We observed a consistent dose-response relationship between frequency of arm hygiene tasks (never to >10 times/day) and poor asthma control. Associations persisted after further adjustment for surfaces/instruments disinfection tasks.

Conclusions: Frequency of hand/arm hygiene tasks in nurses was associated with poor asthma control. Results suggest an adverse effect of products used for surgical hand/arm antisepsis. This potential new occupational risk factor for asthma warrants further study.

Association of hand and arm disinfection with asthma control in U.S. nurses

Orianne Dumas 1,2 , Raphaëlle Varraso 1,2 , Krislyn M Boggs 3 , Alexis Descatha 1,2,4 , Paul K Henneberger 5 , Catherine Quinot 1,2 , Frank E Speizer 3 , Jan-Paul Zock 6,7,8 , Nicole Le Moual 1,2 , Carlos A Camargo Jr 3,9 1. INSERM, U1168, VIMA: Aging and chronic diseases. Epidemiological and public health approaches, F-94807, Villejuif, France

What this paper adds

What is already known about this subject?

Healthcare workers have an increased risk of asthma, partly attributed to agents used for cleaning/disinfection of surfaces and medical instruments. However, little is known regarding the potential respiratory risks associated with disinfectants/antiseptics used for hand hygiene.

What are the new findings?

In a cross-sectional study of more than 4,000 U.S. nurses with asthma, we found that frequency of hand and arm hygiene tasks was associated with poor asthma control. Results suggest an adverse effect of products used for surgical hand/arm antisepsis.

How might this impact on policy or clinical practice in the foreseeable future?

If our findings are confirmed, some hand/arm hygiene tasks and the identified hygiene products would need to be added to current strategies of occupational illness prevention among healthcare workers.

INTRODUCTION

Healthcare workers have an increased risk of asthma, partly attributed to exposure to cleaning products and disinfectants [START_REF] Arif | Association between cleaning-related chemicals and workrelated asthma and asthma symptoms among healthcare professionals[END_REF][START_REF] Gonzalez | Asthma among workers in healthcare settings: role of disinfection with quaternary ammonium compounds[END_REF]. Exposure to several agents used for cleaning/disinfection of surfaces and medical instruments (e.g., bleach, hydrogen peroxide, aldehydes, quaternary ammonium compounds), has been associated with increased risk of asthma and poor asthma control [START_REF] Arif | Association between cleaning-related chemicals and workrelated asthma and asthma symptoms among healthcare professionals[END_REF][START_REF] Gonzalez | Asthma among workers in healthcare settings: role of disinfection with quaternary ammonium compounds[END_REF][START_REF] Dumas | Occupational exposure to disinfectants and asthma control in U.S. nurses[END_REF].

Hand hygiene practices in healthcare workers also involve chemical exposures. In hospitals, employees wash their hands 5-30 times per shift [START_REF] Centers For | Guideline for Hand Hygiene in Health-Care Settings: Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force[END_REF]. Products used for hand hygiene in U.S. healthcare are most often alcohol-based solutions [START_REF] Centers For | Guideline for Hand Hygiene in Health-Care Settings: Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force[END_REF][START_REF] Weber | Occupational health risks associated with the use of germicides in health care[END_REF]. For surgical personnel, hand antisepsis further involves washing/scrubbing their hands and forearms with water-or alcohol-based preparations generally containing chlorhexidine or povidone iodine [START_REF] Centers For | Guideline for Hand Hygiene in Health-Care Settings: Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force[END_REF]6,[START_REF] Tanner | Surgical hand antisepsis to reduce surgical site infection (Review)[END_REF].

The irritant and allergenic properties of antiseptic agents have been well-examined in relation to skin disorders [6]. In contrast, little is known regarding the potential respiratory risks associated with hand hygiene practices among healthcare workers. To address this question, we aimed to study the association between occupational exposures related to hand hygiene practices and asthma control in a large cohort of U.S. female nurses.

METHODS

The Nurses' Health Study II (NHSII) began in 1989 with the inclusion of 116,430 female registered nurses from 15 U.S. states, aged 25-44 years. Follow-up questionnaires have been sent every 2 years since. In 2014-2015, all nurses who ever reported physiciandiagnosed asthma in biennial questionnaires and who recently returned a biennial questionnaire (2013 or 2015) were invited to complete two questionnaires, on their current occupation and on asthma (response rate: 80%). Details of data collection have been published elsewhere [START_REF] Dumas | Occupational exposure to disinfectants and asthma control in U.S. nurses[END_REF]. This investigation was approved by the Institutional Review Board at the Brigham and Women's Hospital (Boston, MA, USA).

Based on the asthma questionnaire, we selected participants who reiterated that a physician had diagnosed her as having asthma, and who reported use of asthma medication in the past year (asthma case definition). Asthma control was defined by the Asthma Control Test (ACT), based on activity limitations, frequency of symptoms, and frequency of use of quick-relief medication in the past four weeks [START_REF] Schatz | Asthma Control Test: Reliability, validity, and responsiveness in patients not previously followed by asthma specialists[END_REF].

In the occupational questionnaire, nurses were asked about the daily frequency of hand/arm hygiene tasks involving disinfectants (i.e., nurses were specifically asked not to include tasks only involving use of soap): "In your current job, how many times per day, on average, do you …": "wash/scrub your hands with disinfectants or hand sanitizers" (later referred to as "hand hygiene"), to evaluate frequency of hand hygiene tasks; and "wash/scrub your arms with disinfecting products" (later referred to as "arm hygiene"), a surrogate to evaluate frequency of surgical hand/arm antisepsis [START_REF] Centers For | Guideline for Hand Hygiene in Health-Care Settings: Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force[END_REF]. Exposure to other disinfectants, i.e. used to clean surfaces/instruments, was evaluated by questionnaire and by a job-task-exposure matrix (JTEM) [START_REF] Quinot | Development of a job-task-exposure matrix to assess occupational exposure to disinfectants among US nurses[END_REF].

Associations between the frequency of hand and arm hygiene and asthma control were evaluated by multinomial logistic regressions adjusted for age, race, ethnicity, smoking status, and body mass index (BMI). Observations with missing values for covariates (all <1%) were excluded from multivariable analyses. Separate models were first used for each of the exposures of interest (hand / arm hygiene); then the two variables were entered in the same model for mutual adjustment. Additional models were further adjusted for exposure to disinfectants to clean surfaces/instruments. A two-sided P<0.05 was considered statistically significant. Analyses were run using SAS V.9 (SAS Institute, Cary, NC, USA).

RESULTS

Among 4,237 nurses who returned both questionnaires on asthma and occupation, and who met our asthma case definition, participants with missing data for ACT (n=135) or for hand and arm hygiene tasks (n=47) were excluded. This yielded an analytic sample of 4,055 women. Participants were on average 59 years of age, 94% were white, 2% where Hispanic, 42% were obese (BMI≥30 kg/m2), 4% were current smokers and 29% were ex-smokers.

Reported frequency of hand hygiene tasks (never, 15%; <1 time/day, 4%; 1-3 times/day, 11%; 4-10 times/day, 24%; and >10 times/day, 46% -n=4,031) was higher than frequency of arm hygiene (never, 62%; <1 time/day, 17%; 1-3 times/day, 12%; 4-10 times/day, 5%; and >10 times/day, 4% -n=4,006). Thus, different cut-offs were chosen to classify exposure variables into three categories for hand hygiene (never, 15%; ≤10 times/day, 39%; and >10 times/day, 46%) and arm hygiene (never, 62%; <1 time/day, 17%; and ≥1 time/day, 21%). Among nurses who reported arm hygiene tasks ≥1 time/day, 78% reported hand hygiene tasks >10 times/day; among those who reported hand hygiene >10 times/day, 35% reported arm hygiene ≥1 time/day (table E1, online supplement).

In main analyses, nurses with partly controlled asthma (ACT 20-24, 50%) and poorly controlled asthma (ACT ≤19, 18%) were compared to nurses with controlled asthma (ACT =25, 32%). When using separate models for the two exposure variables, both hand hygiene (>10 times / day vs. never) and arm hygiene (≥1 time / day vs. never) were associated with partly and poorly controlled asthma (Figure 1A). Results were consistent when examining more detailed categories of asthma control (Table E2, online supplement). Moreover, similar associations persisted after further adjustment for other disinfection tasks: self-reported use of disinfectants to clean surfaces or medical instruments (Figure 1B; and Table E3, online supplement) or exposure to specific disinfectants evaluated by a JTEM (Table E4, online supplement). However, after mutual adjustment (Figure 1C), only arm hygiene was associated with poorly controlled asthma: odds ratio [95% confidence interval] for <1 time/day vs. never, 1.38 [1.06-1.80]; and for ≥1 time/day vs. never, 1.96 [1.52-2.51]. Furthermore, among nurses who reported never doing arm hygiene tasks (n=2,443), no association was observed between hand hygiene and poor asthma control (>10 times / day vs. never, 1.10 [0.79-1.53]). In contrast, among nurses who reported infrequent hand hygiene (never or ≤10 times/ day, n=2,119), arm hygiene was associated with poorly controlled asthma (≥1 time/day vs. never, 2.59 [1.65-4.07]). Finally, when examining exposure frequency using more detailed categories (Figure E1, online supplement), we observed a consistent dose-response relationship between frequency of arm hygiene tasks (never to >10 times/day) and poor asthma control. This clear trend was not observed for hand hygiene.

Findings were confirmed for arm hygiene in sensitivity analyses using a more stringent asthma definition based on medication (Figure E2), and in models with further adjustment for nursing job types, household income, or husband's education (not shown).

Moreover, the association between hand and arm hygiene and poor asthma control were similar in participants with or without allergy (defined by report of ever having had hay fever, seasonal allergy or allergic rhinitis; p interaction for hand hygiene: 0.32; for arm hygiene: 0.29).

DISCUSSION

In a study of 4,055 nurses with asthma, increased frequency of hand/arm hygiene tasks was associated with poor asthma control. The strongest evidence was found for an association between arm hygiene, a surrogate of surgical hand/arm antisepsis, and poor asthma control. This association remained statistically significant after adjustment for other disinfectant exposures and general hand hygiene tasks. It was further supported by a clear dose-response relationship across categories of arm hygiene tasks frequency.

To our knowledge, we are the first to report an association between hand hygiene tasks and adverse respiratory outcomes in healthcare workers. We used a validated asthma definition in this large population of nurses [START_REF] Camargo | Prospective study of body mass index, weight change, and risk of adult-onset asthma in women[END_REF], and a standardized, validated, and commonly used measure of asthma control (ACT) which integrates several domains of the disease (symptoms, use of rescue therapy, sleep disorders, activity limitations) [START_REF] Schatz | Asthma Control Test: Reliability, validity, and responsiveness in patients not previously followed by asthma specialists[END_REF]. The main exposures of interest were evaluated by questionnaire. To reduce potential misclassification bias, we asked about frequency of hand hygiene tasks rather than use of specific agents (e.g., chlorhexidine), which may not be known by the nurses. Nonetheless, our results may be subject to differential misclassification bias (i.e., differential recall of exposure according to asthma control [START_REF] Delclos | Occupational exposures and asthma in healthcare workers: comparison of self-reports with a workplace-specific job exposure matrix[END_REF]). Although such bias cannot be completely ruled out, it would probably affect both exposures of interest similarly and lead to spurious associations for both hand and arm hygiene; however, after mutual adjustment, only frequency of arm hygiene was associated with poor asthma control. This pattern of associations is consistent with the hypothesis of an effect of agents specifically used for surgical hand/arm antisepsis, rather than regular hand hygiene products (alcohols). Latex exposure may be a cause of occupational asthma in healthcare workers. However, preventive efforts in the past decade, such as reduction in the use of powdered latex gloves, have led to a reduction of occupational asthma cases due to latex [START_REF] Vandenplas | Occupational Latex Allergy: the Current State of Affairs[END_REF]. As reported earlier [START_REF] Dumas | Occupational exposure to disinfectants and asthma control in U.S. nurses[END_REF], use of latex gloves was not associated with poor asthma control in NHSII nurses, and is unlikely a confounder in the current study.

Limitations of the current study include its cross-sectional design, and the absence of information regarding the specific agents used for hand/arm hygiene tasks or test for sensitization to workplace agents. We are thus limited in drawing conclusions regarding potential agent(s) responsible for the observed association. However, chlorhexidine and povidone iodine are currently the agents the most commonly used for surgical hand/arm antisepsis [START_REF] Tanner | Surgical hand antisepsis to reduce surgical site infection (Review)[END_REF]. Moreover, in a survey of a sample of the hospitals where NHSII nurses work, a chlorhexidine solution was used for surgical hand/arm antisepsis in 7 out of 8 hospitals surveyed [START_REF] Dumas | Determinants of disinfectant use among nurses in U.S. healthcare facilities[END_REF]. Chlorhexidine is a skin sensitizer [6], and cases of occupational asthma or occupational airway allergy due to chlorhexidine have been reported in nurses [START_REF] Wittczak | Chlorhexidine -still an underestimated allergic hazard for health care professionals[END_REF]. Povidoneiodine also has been involved in skin allergies, although such cases are thought to be rare [6].

Beside allergenic potential, chlorhexidine and povidone iodine have well-documented skin irritation properties [6] and may also cause airway irritation [START_REF] Baur | A compendium of causative agents of occupational asthma[END_REF]. Thus, mechanisms for a potential impact of antiseptic agents on respiratory health may include both sensitization and irritation, either through the dermal or inhalation route of exposure [START_REF] Arrandale | Occupational contact allergens: Are they also associated with occupational asthma?[END_REF].

In conclusion, increased frequency of hand and arm hygiene tasks in nurses was associated with poor asthma control. Results suggest a role of products used for surgical hand/arm antisepsis, but not of common hand hygiene tasks. The potential respiratory risks of products used for hand hygiene merit further investigation, to confirm our results and to clarify the putative agents and mechanisms. If our findings are confirmed, hand hygiene tasks (and the identified hygiene products) would need to be added to current strategies of occupational illness prevention among healthcare workers, which may require the development of new approaches to maintain infection control standards in healthcare settings [START_REF] Quinn | Cleaning and disinfecting environmental surfaces in health care: Toward an integrated framework for infection and occupational illness prevention[END_REF]. Multinomial logistic regressions, adjusted for age, smoking status in 2013, body mass index in 2013, race and ethnicity. Results are presented as odds ratio and 95% confidence intervals (lines). Reference category was "never" for hand/arm hygiene and "controlled asthma" for asthma control.

2 .

 2 Univ Versailles St-Quentin-en-Yvelines, UMR-S 1168, F-78180, Montigny le Bretonneux, France 3. Channing Division of Network Medicine, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA 4. AP-HP UVSQ, Occupational Health Unit/Population-Based Epidemiological Cohorts Unit, UMS 011, University Hospital of Poincaré, Garches, France 5. Respiratory Health Division, National Institute for Occupational Safety and Health, Morgantown, WV, USA 6. ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain 7. Universitat Pompeu Fabra (UPF), Barcelona, Spain 8. CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain 9. Department of Emergency Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

Figure legend Figure 1 .

 legend1 Figure legend

Acknowledgments

The Nurses' Health Study II is coordinated at the Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA. We would like to thank the participants and staff of the Nurses' Health Study II for their valuable contributions. In particular, we would like to thank Aleta Wiley, Lisa Abramovitz, Charlotte Marsh, Chidiogo Onwuakor and Christina Staffiere for their help with data cleaning and management. We also thank Francine Kauffmann for her participation in the study conception. ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. UM1 CA176726. The research leading to these results has received funding from the People Program (Marie Curie Actions) of the European Union's Seventh Framework Program (FP7/2007-2013) under REA grant agreement n. PCOFUND-GA-2013-609102, through the PRESTIGE program coordinated by Campus France.

Funding

Centers for Disease Control and Prevention R01 OH-10359; National Institutes of Health

Authors' contributions: OD contributed to the study conception, the acquisition, analysis and interpretation of the data, and primary manuscript preparation. RV, AD, PKH, CQ, and JPZ were involved in the data interpretation and critical revision of the manuscript. KB and FES contributed to the acquisition and interpretation of the data and critical revision of the manuscript. NLM contributed to the study conception, data interpretation and critical revision of the manuscript. CAC participated in the study conception, acquisition of the data, data interpretation and critical revision of the manuscript. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Competing Interests: None.

Disclaimer

The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health.


Nicole Le Moual
email: nicole.lemoual@inserm.fr

Jan-Paul Zock

Orianne Dumas

Theodore Lytras

Eva Andersson

Linnéa Lillienberg

Vivi Schlünssen

Geza Benke

Hans Kromhout

Update of an occupational asthma-specific job exposure matrix to assess exposure to 30 specific agents

Keywords: Asthma, Occupational exposure assessment, Job-Exposure Matrix, Asthmagens Objectives, Methods, Results, and Conclusions) -

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

3

WHAT THIS PAPER ADDS?

 What is already known about this subject?

To evaluate the burden of work-related asthma in community-based epidemiological studies, assessment of occupational exposures is a crucial issue.

An asthma-specific job-exposure-matrix (JEM) was constructed in the late 1990s and applied successfully in various studies on asthma or other immunological diseases. However, the number of identified asthmagens has tripled since the end of 1990s and an update of this JEM is warranted.

 What are the new findings?

A new Occupational Asthma-specific JEM (OAsJEM) was created to evaluate exposure to 30 specific agents, based on consensus from international experts in the field.

 How might this impact on policy or clinical practice in the foreseeable future?

This new OAsJEM, developed to improve exposure assessment to occupational asthmagens, may be a valuable tool to improve evaluations of associations between occupational exposures and asthma phenotypes in epidemiological studies, and contribute to assessment of the burden of disease due to exposure to occupational asthmagens.

INTRODUCTION

Work-related asthma is the most common occupational lung disease in industrialized countries [START_REF] Tarlo | Occupational asthma[END_REF] . The proportion of asthma in adults attributable to occupational exposures is estimated to be around 15% [START_REF] Siracusa | Asthma and exposure to cleaning products -a European Academy of Allergy and Clinical Immunology task force consensus statement[END_REF] .

The burden of work-related asthma is underestimated partly due to limited knowledge about occupational exposure to well-established asthmagens [START_REF] Dumas | Do chronic workplace irritant exposures cause asthma?[END_REF] . In addition, new asthmagens are constantly being reported [START_REF] Cartier | New causes of immunologic occupational asthma, 2012-2014[END_REF] . Occupational asthma is classically described as induced by a sensitizer (immunological asthma) or by a unique high level accidental exposure to an irritant agent (nonimmunological asthma) at work [START_REF] Tarlo | Occupational asthma[END_REF][START_REF] Dumas | Do chronic workplace irritant exposures cause asthma?[END_REF] . However, recently also chronic low-to-moderate level of exposure to irritants has been recognized as a cause of work-related asthma [START_REF] Vandenplas | EAACI position paper: irritant-induced asthma[END_REF][START_REF] Ghosh | Asthma and occupation in the 1958 birth cohort[END_REF][START_REF] Dumas | Occupational irritants and asthma: an Estonian crosssectional study of 34,000 adults[END_REF][START_REF] Cullinan | Occupational lung diseases: from old and novel exposures to effective preventive strategies[END_REF][START_REF] Andersson | Incidence of asthma among workers exposed to sulphur dioxide and other irritant gases[END_REF] . Underlying biological mechanisms are complex and partly unknown especially for reactive chemicals and irritants [START_REF] Dumas | Do chronic workplace irritant exposures cause asthma?[END_REF][START_REF] Malo | An official American Thoracic Society Workshop Report: presentations and discussion of the fifth Jack Pepys Workshop on Asthma in the Workplace. Comparisons between asthma in the workplace and non-work-related asthma[END_REF] . It has been suggested that irritant-induced asthma may represent between 10% and 20% of occupational asthma, with an increase in recent years [START_REF] Dumas | Do chronic workplace irritant exposures cause asthma?[END_REF][START_REF] Chan-Yeung | Proceedings of the first Jack Pepys occupational asthma symposium[END_REF] .

The deleterious role of cleaning agents and disinfectants in asthma has been recognized in recent decades [START_REF] Siracusa | Asthma and exposure to cleaning products -a European Academy of Allergy and Clinical Immunology task force consensus statement[END_REF][START_REF] Folletti | Update on asthma and cleaning agents[END_REF][START_REF] Matteis | Occupational asthma in cleaners: a challenging black box[END_REF] . Other potential risk factors for asthma have received more attention recently especially occupational exposures to endotoxins, organic solvents, pesticides and chronic exposure to irritants in general [START_REF] Tarlo | Occupational asthma[END_REF][START_REF] Vandenplas | EAACI position paper: irritant-induced asthma[END_REF][START_REF] Mamane | Occupational exposure to pesticides and respiratory health[END_REF][START_REF] Lillienberg | Occupational exposure and new-onset asthma in a population-based study in Northern Europe (RHINE)[END_REF][START_REF] Levan | Vapor, dust, and smoke exposure in relation to adult-onset asthma and chronic respiratory symptoms: the Singapore Chinese Health Study[END_REF][START_REF] Lemiere | Occupational asthma: new deleterious agents at the workplace[END_REF] . Studying associations between such kinds of agents, which may be sensitizers (low molecular weight chemicals) and/or lung irritants, and asthma is important for a better understanding of the disease [START_REF] Dumas | Do chronic workplace irritant exposures cause asthma?[END_REF][START_REF] Malo | An official American Thoracic Society Workshop Report: presentations and discussion of the fifth Jack Pepys Workshop on Asthma in the Workplace. Comparisons between asthma in the workplace and non-work-related asthma[END_REF][START_REF] Folletti | Update on asthma and cleaning agents[END_REF][START_REF] Lemiere | Occupational asthma: new deleterious agents at the workplace[END_REF] . Improvement of exposure assessment, especially for newly-recognized agents, is a crucial but challenging issue [START_REF] Dumas | Do chronic workplace irritant exposures cause asthma?[END_REF][START_REF] Heederik | Cleaning agents and disinfectants: moving from recognition to action and prevention[END_REF] when studying work-related asthma in community-based cohorts. Kennedy et al. [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] proposed at the end of the last century an asthma-specific JEM combined with an expert step, to evaluate occupational exposures to common asthmagens [START_REF] Chan-Yeung | Table of major inducers of occupational asthma[END_REF] . This method, by favouring specificity over sensitivity via an expert re-evaluation step, improved asthmagen assessment and reduced misclassification errors [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] . In some studies limited improvement of the additional expert reevaluation step was observed, possibly due to imprecise available information regarding tasks [START_REF] Zock | Evaluation of specific occupational asthma risks in a community-based study with special reference to single and multiple exposures[END_REF] . This asthma-specific JEM is the most commonly used method in various populations both in and outside Europe [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] and has been adapted to country-specific workplace environments in Northern Europe and the UK [START_REF] Lillienberg | Occupational exposure and new-onset asthma in a population-based study in Northern Europe (RHINE)[END_REF][START_REF] Abrahamsen | Association of respiratory symptoms and asthma with occupational exposures: findings from a population-based cross-sectional survey in Telemark, Norway[END_REF][START_REF] Tagiyeva | Parental occupation is a risk factor for childhood wheeze and asthma[END_REF][START_REF] Tagiyeva | Occupational exposure to asthmagens and adult onset wheeze and lung function in people who did not have childhood wheeze: A 50-year cohort study[END_REF] . Since the Asthma-specific JEM was developed the number of suspected asthmagens has tripled [START_REF] Dumas | Do chronic workplace irritant exposures cause asthma?[END_REF][START_REF] Cartier | New causes of immunologic occupational asthma, 2012-2014[END_REF] .

We aimed to develop a new Occupational Asthma-specific JEM (OAsJEM), combined with an expert re-evaluation step, to assess exposure to 30 specific sensitizers and/or irritants.

METHODS

The original Asthma-specific JEM

Briefly, the original Asthma-specific JEM [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] , is a two dimensional table with a 2-to 4-digit ISCO-88 (International Standard Classification of Occupations, 1988) job codes [START_REF]International standard classification of occupations[END_REF] axis crossed with a second axis of 18 asthmagens and four agents classified at low risk for asthma. Agents were classified into four broad groups: low molecular weight (LMW), high molecular weight (HMW) asthmagens, mixed environments and irritants peaks. In addition, job codes poorly defined and/or with heterogeneous exposures (88 out of all 506 2-to 4-digit ISCO-88 job codes; 17%) were identified and classified as requiring 'an expert re-evaluation step' with linked comments and specific recommendations for reviewing each specific exposure (see online supplement Figure E1). When re-evaluation was needed in a study, the exposure attributed by the JEM was checked and modified if necessary by the expert directly, at individual level, according to participant's job, industry and tasks descriptions.

Two major strengths of this method were: (i) specificity favoured over sensitivity, i.e. a job was classified as exposed to a specific asthmagen only if the probability to be exposed was high for an important number of subjects in that job. (ii) an expert re-evaluation step, performed after applying the JEM, for an a priori list of jobs (poorly defined or with heterogeneous exposures) [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] . The JEM combined with expert re-evaluation step provided a more specific exposure assessment, by correcting for heterogeneity of exposures within occupations and thereby avoiding a classical drawback of most JEMs, and by so doing reducing the impact of misclassification error.

The asthma-specific JEM is commonly used (see online supplement Table E1 for more detail) and is freely available on a website (http://asthmajem.vjf.inserm.fr/), which was developed and launched in Vancouver in 2005 and hosted in France since 2011.

The new Occupational Asthma-specific JEM (OAsJEM)

A standardised procedure was used to develop the updated OAsJEM. First the list of agents was updated from the previous one (22 agents, categorised from a list of 150 substances from Chan-Yeung and Malo [START_REF] Chan-Yeung | Table of major inducers of occupational asthma[END_REF] ) based on the recent literature [START_REF] Tarlo | Occupational asthma[END_REF][START_REF] Dumas | Do chronic workplace irritant exposures cause asthma?[END_REF][START_REF] Vandenplas | EAACI position paper: irritant-induced asthma[END_REF][START_REF] Dumas | Occupational irritants and asthma: an Estonian crosssectional study of 34,000 adults[END_REF][START_REF] Lillienberg | Exposures and asthma outcomes using two different job exposure matrices in a general population study in northern Europe[END_REF][START_REF] Schlunssen | Workplace exposure to wood dust and the prevalence of wood-specific sensitization[END_REF][START_REF] Quirce | Old and new causes of occupational asthma[END_REF] . The list was further improved during the process (Online supplement, Table E2) resulting in a final version consisting of 7 large groups with 30 specific agents in total (Table 1). The new agents were identified based on recent literature knowledge, using mostly information from two major literature reviews [START_REF] Tarlo | Occupational asthma[END_REF][START_REF] Vandenplas | EAACI position paper: irritant-induced asthma[END_REF] for sensitiser and irritant -induced asthma, respectively.

A working group of three experts was assigned to each agent: each expert evaluated exposure to a number of specific agents varying from 3 to 19 agents, according to their agent of choice and expertise.

Indoor cleaning# 1 Bleach 1 1 1 Organic Solvents 1 1
Exhaust fumes 1

The 12 new agents (out of 30), identified in bold, were chosen based on the knowledge from recent literature [START_REF] Tarlo | Occupational asthma[END_REF][START_REF] Vandenplas | EAACI position paper: irritant-induced asthma[END_REF] .

# Animals: exposure to animals in agriculture industry, research labsland mammals and birds ; Foods: work with milk, eggs, peanuts, tree nuts, soy, … mostly powders (process used to obtain powder may affect allergenic properties) -Fish/Shellfish and Flour are not included in foods ; Other plants-related dusts : Flour is not included; Enzyme: those used as improver in bread dough, or in washing detergents manufacturing … ; Textile: work with cotton or synthetic fibers, which explain its classification in 3 groups (HMW, microbes, irritants) ; Drugs : mostly HMW agents [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] (Kennedy, personal communication) but potentially also LMW [START_REF] Tarlo | Occupational asthma[END_REF] ; Wood : mostly LMW agents [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] but potentially also HMW [START_REF] Tarlo | Occupational asthma[END_REF][START_REF] Schlunssen | Workplace exposure to wood dust and the prevalence of wood-specific sensitization[END_REF][START_REF] Quirce | Old and new causes of occupational asthma[END_REF] ; Chronic exposure to irritants (n=19 agents including 9 agents also classified as LMW sensitizers because for these 9 agents both mechanisms are possible [START_REF] Tarlo | Occupational asthma[END_REF][START_REF] Dumas | Do chronic workplace irritant exposures cause asthma?[END_REF][START_REF] Vandenplas | EAACI position paper: irritant-induced asthma[END_REF][START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] ), of which Highly reactive chemicals (8 agents) and Biocides (5 agents) are 2 sub-categories. 7

Classification of exposures was refined from yes/no to semi-quantitative metrics i.e, high: high probability of exposure and moderate to high intensity; medium: low to moderate probability or low intensity of exposure, such as 'high probability and low intensity' or 'low probability and moderate to high intensity'; no: unlikely to be exposed (low probability and low intensity). Experts classified a job as 'high probability of exposure' when they considered that at least 50% of the workers were exposed.

The expert re-evaluation recommendations were also improved with a checking for (i) ISCO code for selected jobs (mostly the larger 2-and 3-digit ISCO-88 codes) and (ii) exposure assessment for selected jobs (poorly defined and/or heterogeneous jobs). For the expert re-evaluation recommendations, period and country-specific work situations were taken into account, in addition to job, industry and tasks recorded by each participant.

In addition, we addressed important methodological points during the process: (a) all experts evaluated exposure independently from each other. In case of disagreement, the final decision was taken by consensus within the experts' team. (b) specificity was favoured over sensitivity for high level of exposure only (not for 'medium' exposure).

At the beginning, all ISCO job codes were classified as 0: 'non exposed', if these jobs were classified unlikely to be exposed according to three existing JEMs (Asthma-specific [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] , ALOHA [START_REF] Matheson | Biological dust exposure in the workplace is a risk factor for chronic obstructive pulmonary disease[END_REF][START_REF] Sunyer | Pulmonary ventilatory defects and occupational exposures in a population-based study in Spain. Spanish group of the european community respiratory health survey[END_REF] and Northern [START_REF] Lillienberg | Occupational exposure and new-onset asthma in a population-based study in Northern Europe (RHINE)[END_REF][START_REF] Lillienberg | Exposures and asthma outcomes using two different job exposure matrices in a general population study in northern Europe[END_REF] ) or 1: 'exposure assessment warranted', if classified by one of these three JEMs as potentially exposed to asthmagens, irritants or dusts, gases and fumes. In a first step, for all job classified as 'exposure assessment warranted', for a given agent a first evaluation of exposure (high, medium, no) was attributed by each of the three experts independently. The experts decision were based on assessments from existing JEMs and especially the Asthma-specific, N-JEM and ALOHA JEMs [START_REF] Lillienberg | Occupational exposure and new-onset asthma in a population-based study in Northern Europe (RHINE)[END_REF][START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF][START_REF] Matheson | Biological dust exposure in the workplace is a risk factor for chronic obstructive pulmonary disease[END_REF][START_REF] Sunyer | Pulmonary ventilatory defects and occupational exposures in a population-based study in Spain. Spanish group of the european community respiratory health survey[END_REF] and on recent literature. In a second step, all exposure assessments were reviewed and compared. If the assessment was unanimous and consistent with previous evaluations (for 'old' agents from the Asthma-specific JEM) the job was classified as such; if not (jobs with at least one expert disagreeing or inconsistent with the previous evaluation), we used a standardised procedure and send to the three experts : an EXCEL file including information on the 3 initial evaluations, an exposure rating proposed by NLM with comments/justifications, and opportunities for further comments/ justifications from each expert, who were asked to send back the file completed with comments on the proposal. If all experts agreed, a final rating was made; in case of disagreement, the final decision was taken by consensus after a discussion (using information from the file) with the three experts during a conference call or a face to face meeting. Decisions regarding evaluations and recommendations are illustrated for latex in the online supplement (Tables E3,E4). The final step consisted of a complete review and feedback by all experts on the assigned exposures, their consistency and expert-step recommendations on exposure and code checking.

Basic characteristics of the Asthma-specific JEM and the new OAsJEM are compared in Table 2.

Data analysis

The initial evaluations of exposure to a specific agent obtained by each of the three experts were independently compared. Comparisons of chance-corrected agreement between of three pairs of experts per agent were undertaken by estimating Cohen's Kappa. The agreement was interpreted as follow: poor (<0), slight (0-0.2), fair (0.2-0.4), moderate (0.4-0.6), substantial (0.6-0.8) and almost perfect (0.8-1.0) agreement [START_REF] Landis | The measurement of observer agreement for categorical data[END_REF] . Prevalence of jobs classified exposed and with an expert-re-evaluation step, for each agent, was assessed after the final assessment of exposure at ISCO-88 code level. 9

RESULTS

The revised occupational asthma-specific JEM (Table 1) included exposure evaluations to 30 specific asthmagens (HMW (n=13) and LMW (n=10) agents) and exposure to irritants (n=19). The twelve new agents evaluated through the OAsJEM are marked in bold (such as acrylates, epoxy resins). Exposures were classified into seven broad groups (Table 1): HMW sensitizers, mites (sub-category of HMW), microbial exposures, LMW sensitizers, chronic exposure to irritants, highly reactive chemicals, biocides (last two sub-categories of irritants). Two agents were classified as both potentially HMW and LMW sensitizers (drugs, wood) as their classification was inconsistent in the literature [START_REF] Tarlo | Occupational asthma[END_REF][START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF][START_REF] Schlunssen | Workplace exposure to wood dust and the prevalence of wood-specific sensitization[END_REF][START_REF] Quirce | Old and new causes of occupational asthma[END_REF] .

Most LMW sensitizers were also classified as irritants. Compared to the previous Asthma-specific JEM [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] , 'mixed environments' and 'low risk exposure' as well as to 'high irritant peaks', 'environmental tobacco smoke' were no longer included in the OAsJEM (online supplement Table E2).

Values of initial agreement between two experts varied strongly by agent (Table 3; e.g. the 3 Kappa's values varied from 0.08 to 0.54 for fish/shellfish and from 0.21 to 0.29 for plants) and were mostly fair-to-moderate (0.2 -0.5). The Kappa's values varied overall from -0.01 to 1.00. Agreement could not be estimated for agents added after the first step (three categories of mites and pesticides, online supplement Table E2). For mites, experts decided by consensus after comparison of their first evaluations to split them into three sub-categories. We also decided a posteriori to assess exposures to three sub-categories of pesticides (herbicides, insecticides, fungicides).

Table 4 illustrates the percentage of jobs classified as exposed at high or medium level and at high level for the 30 agents. Out of 506 2 to 4 digit ISCO-88 job codes, agents classified as exposed ranged from 0.2% (persulphates/henna) to 17.4% (organic solvents) and as highly-exposed from 0%

(acrylates, enzymes, storage mites) to 2.6% (organic solvents, exhaust fumes). For 14 agents, such as epoxy resins (1.8%) and flour (0.6%), less than 3 % of the jobs were classified exposed at high or medium level. Overall, more jobs were classified exposed with the OAsJEM, compared to the original JEM (Table 4), mostly explained because specificity was not favoured to evaluate medium level.

However, for high level exposure the percentage were mostly lower with the OAsJEM (0.2 to 2.6%) than with the old JEM (0.2 to 5.5%). Examples of jobs classified at high exposure level are given in the online supplement (Table E5). Overall, the percentage of jobs classified with an expert reevaluation by the new OAsJEM (Table 4) varied from 0% (persulphates/henna) to 8.1% (metal).

Considering only the 390 4-digit ISCO-88 job codes (Table E6), after exclusion of the 116 less precise codes (2-and 3-digits), the percentages of jobs classified as highly exposed were similar. In addition, around 20% of the jobs (113 out of 506 codes, mostly 2-and 3-digit codes) were identified as 'code checking required'. E2) for specific mites (house dust, storage, plant) and specific pesticides (herbicide, insecticide, fungicide). For evaluation of mites in general the 3 values varied from 0.15 to 0.29. # Animals: exposure to animals in agriculture industry, research labsland mammals and birds ; Foods: work with milk, eggs, peanuts, tree nuts, soy, … mostly powders (process used to obtain powder may affect allergenic properties) ; -Fish/Shellfish and Flour are not included in foods ; Other plants-related dusts : Flour is not included; Enzyme: those used as improver in bread dough, or in washing detergents manufacturing … ;Textile: work with cotton or synthetic fibers, which explain its classification in 3 groups (HMW, microbes, irritants) ; Drugs : mostly HMW agents [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] (Kennedy, personal communication) but potentially also LMW 1 ; Wood : mostly LMW agents [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] but potentially also HMW [START_REF] Tarlo | Occupational asthma[END_REF][START_REF] Schlunssen | Workplace exposure to wood dust and the prevalence of wood-specific sensitization[END_REF][START_REF] Quirce | Old and new causes of occupational asthma[END_REF] 4.0 11.9 2.6 7.1 * percentage of jobs classified exposed at high or medium level and at high level, respectively out of 506. For 14 agents, the percentages of jobs classified exposed were less than 3%. In the second column, in italic: percentage of jobs classified exposed by the original Asthma-specific JEM [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] . ** 0.4 for mites and insect antigen in general according to the original Asthma-specific JEM [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] 12

DISCUSSION

We developed an OAsJEM to update and to improve occupational exposure assessment for 30 specific asthmagens and irritants, classified into seven large groups, for 506 2-to 4-digit ISCO-88 job codes. The initial agreement observed between three experts per agent was fair-to-moderate in most cases and final decisions regarding exposure assessment were taken by consensus. These results stress the importance of evaluating occupational exposures among a working group of at least two experts.

The expert re-evaluation step was improved and country and time specific issues (e.g. replacement of latex powered gloves) were taken into account.

A priori or a posteriori choice of specific exposures evaluation

Agents included in the category 'at low risk for asthma' in the original JEM [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] may be considered instead as 'chronic low-to-moderate level of exposure to irritants' which may also induce asthma [START_REF] Dumas | Do chronic workplace irritant exposures cause asthma?[END_REF][START_REF] Ghosh | Asthma and occupation in the 1958 birth cohort[END_REF][START_REF] Dumas | Occupational irritants and asthma: an Estonian crosssectional study of 34,000 adults[END_REF][START_REF] Lillienberg | Exposures and asthma outcomes using two different job exposure matrices in a general population study in northern Europe[END_REF] .

Improvement of occupational exposure assessment during the entire working life is crucial [START_REF] Heederik | Cleaning agents and disinfectants: moving from recognition to action and prevention[END_REF] for a better understanding of the underlying mechanisms of irritant-induced asthma.

Therefore, for the new OAsJEM we excluded the 'Low risk' category and added specific irritants potentially at risk for asthma such as indoor cleaning agents, pesticides, endotoxin, aliphatic amines, acrylates, epoxy resins, persulphates/henna and organic solvents [START_REF] Tarlo | Occupational asthma[END_REF][START_REF] Dumas | Do chronic workplace irritant exposures cause asthma?[END_REF] . In the original JEM [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] , the literature at the time suggested that only industrial cleaning products, which contain highly reactive chemicals, mostly used in hospitals, were associated with asthma compared to cleaning products used at home or in offices. However, this has been refuted in recent literature [START_REF] Siracusa | Asthma and exposure to cleaning products -a European Academy of Allergy and Clinical Immunology task force consensus statement[END_REF][START_REF] Dumas | Do chronic workplace irritant exposures cause asthma?[END_REF][START_REF] Folletti | Update on asthma and cleaning agents[END_REF][START_REF] Matteis | Occupational asthma in cleaners: a challenging black box[END_REF] . Cleaning products and disinfectants are ubiquitous agents used in many places (such as hospital, office, home) and are now considered amongst the most common lung irritants [START_REF] Dumas | Do chronic workplace irritant exposures cause asthma?[END_REF][START_REF] Malo | An official American Thoracic Society Workshop Report: presentations and discussion of the fifth Jack Pepys Workshop on Asthma in the Workplace. Comparisons between asthma in the workplace and non-work-related asthma[END_REF] . Bleach is considered one of the main airway irritants among cleaning products and has been shown to induce acute irritative asthma earlier known as RADS [START_REF] Lemiere | Occupational asthma: new deleterious agents at the workplace[END_REF] . Therefore, we have added Bleach as a sub-category of indoor cleaning products.

In addition, we excluded unspecific exposure categories: one a priori, agriculture, and five a posteriori, bacteria, high peaks exposure to irritants, environmental tobacco smoke, highly reactive chemicals and dusts, gases, fumes in general. Agriculture workers are exposed to many agents associated with asthma 3 . These agents are often heterogeneous in term of mechanisms, as they may include both allergens, such as animal proteins, and irritants, such as pesticides and cleaning products.

Large groups make it difficult to disentangle immunological or non-immunological mechanisms involved in occupational asthma. Following discussion within the expert group, it was decided a posteriori to exclude Bacteria assessment because it was closely linked to endotoxins. In addition, we assumed that associations observed between bacteria and asthma may be explained by the presence of endotoxin. For high peak exposure to irritants many workers may be exposed such as freight handlers (gassed containers), police officers, farmers, animal care takers and animal transporters. However, only one study in which the Asthma-specific JEM was applied (a case-control study in Taiwan 32 , Table E1), found an association between irritant peaks and non-atopic asthma (odds ratio 4.2 [1.5-11.8]). Given that these peaks are induced during incidents, we considered that the JEM methodology is not the best approach to evaluate such exposure. In the same way, we decided to exclude the category Environmental Tobacco Smoke (ETS) from this new OAsJEM, because ETS assessment at job level might be of poor quality. Indeed, nowadays workers are unexposed to ETS in most workplaces, due to new smoking regulations, which may depend strongly on country and period. In addition, the large group highly reactive chemicals was evaluated through exposure assessment to eight specific agents (see Table 1). We have not evaluated exposure to dusts, gases and fumes as a group as it may not be relevant for asthma [START_REF] Moual | Occupational exposures and asthma in 14,000 adults from the general population[END_REF] , and it is especially important to define groups that allow disentangling sensitizers from irritating agents when studying underlying mechanism.

The study experts decided by consensus a posteriori (at step 2) to split 'mites' into 3 sub-categories and to add an evaluation of exposures to three sub-categories of pesticides (herbicides, insecticides, fungicides) based on the existing ALOHA JEM [START_REF] Matheson | Biological dust exposure in the workplace is a risk factor for chronic obstructive pulmonary disease[END_REF][START_REF] Sunyer | Pulmonary ventilatory defects and occupational exposures in a population-based study in Spain. Spanish group of the european community respiratory health survey[END_REF] .

Evaluations of specific exposures

Initial agreement between exposure evaluations of two experts (out of three) varied according to agents and was mostly fair to moderate, which is consistent with previous observations [START_REF] Martin-Bustamante | Job-exposure matrix for the assessment of alkylphenolic compounds[END_REF][START_REF] Teschke | Occupational exposure assessment in case-control studies: opportunities for improvement[END_REF] . However, it is difficult to compare agreement for each specific agent to earlier findings as few comparable studies are available. The lack of initial congruence between experts underlines the importance of evaluating occupational exposures within a review team of at least two experts. For all the agents, a small percentage of jobs, out of 506, were classified exposed at high level. For half of the agents, less than 3% of the jobs were classified exposed at high or medium level. Compared to the original JEM, more jobs were classified exposed in general but less at high level with the OAsJEM. In the original JEM less than 3% of the jobs were classified exposed, except for three agents (textile, metals, exhaust fumes). As expected, the exposure assessment evaluated through the new OAsJEM was more specific for high level of exposure but more sensitive for medium level.

Occupational Asthma-specific JEM

Due to the lack of a gold standard, a formal validation of the OAsJEM estimates is not possible, which is a classical limitation of JEMs [START_REF] Teschke | Occupational exposure assessment in case-control studies: opportunities for improvement[END_REF][START_REF] Mcguire | Assessment of occupational exposures in community-based case-control studies[END_REF] . It has been suggested that updating a JEM may increase the validity [START_REF] Kauppinen | Construction of job-exposure matrices for the Nordic Occupational Cancer Study (NOCCA)[END_REF] . In addition, the development of the OAsJEM was based on recent literature and knowledge from multidisciplinary international experts, using a standardized procedure to take final decision by consensus. The OAsJEM has been updated from the original Asthma-specific JEM, which has been used in at least 51 publications to date, has been regarded as a valuable and robust standardised tool for evaluating exposure to asthmagens [START_REF] Ghosh | Asthma and occupation in the 1958 birth cohort[END_REF][START_REF] Kogevinas | Exposure to substances in the workplace and new-onset asthma: an international prospective population-based study (ECRHS-II)[END_REF] . Published papers using this method allowed evaluating (1) efficiency and accuracy of the method but also (2) healthy worker effect, asthma-and allergy-related 14 phenotypes, occupational exposures in other diseases such as lymphoma and autism, maternal occupational exposure and child health (Table E1, online supplement). The original Asthma-specific JEM [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] was the sole JEM set-up to evaluated exposure to asthmagens in epidemiological surveys, and was previously adapted twice to take into account country-occupation specificities [START_REF] Lillienberg | Occupational exposure and new-onset asthma in a population-based study in Northern Europe (RHINE)[END_REF][START_REF] Tagiyeva | Parental occupation is a risk factor for childhood wheeze and asthma[END_REF] . This updated OAsJEM may improve the evaluation of associations between occupational exposures and asthma phenotypes in epidemiological studies and contribute to assessment of the burden of disease due to occupational asthmagens. In order to use the OAsJEM in optimal conditions, we recommend the following steps previously advised in the original JEM [START_REF] Kennedy | Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA)[END_REF] : first coding jobs by an experienced occupational coder and then applying the JEM with an expert re-evaluation step, blinded to disease status. In order to limit misclassification errors and to perform both job coding and the expert re-evaluation step in an optimal way, recording well described tasks for each job is crucial in epidemiological surveys. During the expert re-evaluation step it is important to keep in mind that the OAsJEM was built to promote specificity for high level of exposure to asthmagen. Other important points include (i) taking into account, for some identified exposures, time of exposure occurrence and in which country, (ii) following the recommendations of the re-evaluation step written for each job, for both ISCO code and exposure assessment checking and (iii) performing the expert re-evaluation step with at least two experts, independently. In the update, we have tried to limit the number of expert reevaluations to improve feasibility of this additional step. Some analyses [START_REF] Dumas | Occupational irritants and asthma: an Estonian crosssectional study of 34,000 adults[END_REF][START_REF] Moual | Occupational exposures and asthma in 14,000 adults from the general population[END_REF] performed in large cohorts suggest that it is possible to use the JEM without an expert re-evaluation step, especially after exclusion of poorly defined or heterogeneous jobs (such as those classified as needing an expert reevaluation step). In addition, information regarding task descriptions, specific workplace conditions (ventilation, personal respiratory protection use … ) or target tasks, as recorded in occupational epidemiology studies [START_REF] Clavel | Standardization in the retrospective evaluation by experts of occupational exposure to organic solvents in a population-based case-control study[END_REF] , may improve evaluations of exposure assessment from the OAsJEM agents by decreasing misclassification errors at the re-evaluation step.

The new OAsJEM is available for free on the website (http://asthmajem.vjf.inserm.fr/). In order to keep it up to date, we would appreciate receiving a notification through the website or by email to the corresponding author, when the application of the OAsJEM in an epidemiological study will result in a publication.

Strengths and limitations

The major strength of this OAsJEM is that initial exposure assessments were undertaken by experts independently from each other and final evaluations were taken by consensus, through a standardized procedure. Furthermore, we incorporated improvements based on other JEMs, such as ALOHA and Northern-JEM developed by experts from our team, to evaluate exposure assessment to pesticides and acrylates or epoxy resins, respectively. We finally checked that for all jobs with an expert reevaluation step the default exposure assessment for a specific agent was the most likely one. In addition, the standardisation of an expert re-evaluation step with precisely written recommendations may be helpful for non-experts. Furthermore, this method has previously shown its efficiency and usefulness to evaluate associations between occupational exposures and diseases (online supplement Table E1).

The present method also has limitations. As with any JEM, non-differential misclassification remains but is somewhat reduced by incorporating up-to-date knowledge from eight experts for the evaluated agents. We acknowledge that the additional expert assessment step may be time and money consuming which may induce difficulties to apply the method in large epidemiological studies.

However, the expert step is mostly intended to improve precision of exposure estimates in studies of moderate size and limited power. Our list of 30 asthmagens was not exhaustive but in accordance with most agents identified in recent papers [START_REF] Tarlo | Occupational asthma[END_REF][START_REF] Vandenplas | EAACI position paper: irritant-induced asthma[END_REF][START_REF] Crewe | A comprehensive list of asthmagens to inform health interventions in the Australian workplace[END_REF] . This method does not intend to identify new occupational risks, but may improve estimates for the most common agents known or suspected to have an adverse effect on work-related asthma till now [START_REF] Dumas | Do chronic workplace irritant exposures cause asthma?[END_REF][START_REF] Cartier | New causes of immunologic occupational asthma, 2012-2014[END_REF] . We developed the OAsJEM for the 2-to 4-digit ISCO-88 job codes, the most commonly used classification in Europe [START_REF] Martin-Bustamante | Job-exposure matrix for the assessment of alkylphenolic compounds[END_REF] . However, ISCO-88 classification was originally defined for economic statistical purposes, which may not be optimal for evaluation of occupational exposures. For example, the 5-digit ISCO-68 is a much more detailed classification and might be more accurate to evaluate occupational exposures, in spite of its lack of representation of more contemporaneous jobs. In future developments, it would be useful to adapt the OAsJEM for ISCO-68 and potentially ISCO-08 job codes. For certain agents, OAsJEM exposure assessment may be improved by applying agent-specific JEMs with quantitative exposure assessment, for example for endotoxin [START_REF] Basinas | O46-4 Development of a quantitative job exposure matrix for endotoxin exposure in agriculture[END_REF] , wood dusts [START_REF] Basinas | P096 Statistical modelling and development of a quantitative job exposure matrix for wood dust in the wood manufacturing industry[END_REF] , solvents and exhaust fumes (FINJEM). Applying the new OAsJEM in ongoing prospective epidemiological respiratory health studies, such as EGEA 43 and ECRHS [START_REF] Kogevinas | Exposure to substances in the workplace and new-onset asthma: an international prospective population-based study (ECRHS-II)[END_REF] studies, in which the original JEM has been applied will allow for comparisons of the original and updated Asthma JEMs.

Conclusions

In conclusion, we have developed an updated OAsJEM that allows evaluation of retrospective occupational exposure assessment to 30 specific asthmagens and irritants for all ISCO-88 job codes. This OAsJEM, developed to improve occupational asthmagen exposure assessment, may improve the evaluation of the association between occupational exposures and asthma phenotypes in epidemiological studies and contribute to assessment of the burden of work-related asthma.

Table 1 -List of individual agents classified in 7 large groups -New Occupational Asthma-specific JEM Agents, n=30 HMW sensitizer*

 1

			Mites	Microbial exposure*	LMW sensitizer*	Irritants*	Highly chemicals reactive	Biocides
	Animals#	1
	Fish/ Shellfish	1
	Flour	1
	Foods#	1
	Plants-related dusts#	1
	House dust Mites	1	1
	Storage Mites	1	1
	Plant Mites	1	1
	Enzymes	1
	Latex	1
	Textile #	1		1		1
	Moulds			1		1
	Endotoxin			1		1
	Drugs#	1			1
	High level chemical disinfectants #				1	1	1	1
	Aliphatic Amines				1	1	1
	Isocyanates				1	1	1
	Acrylates				1	1	1
	Epoxy resins				1	1	1
	Persulphates/Henna				1	1	1
	Wood#	1			1	1
	Metal				1	1
	Metal Working Fluids			1	1	1
	Herbicides					1	1
	Insecticides					1	1
	Fungicides					1	1

Table 2 -Comparison of basic characteristics of the Asthma-specific JEM and the new OAsJEM Asthma-specific JEM 19 New OAsJEM Number of agents or groups of agents

 2

	22	30

Table 3 -Cohen's Kappa values -New Occupational Asthma-specific JEM (OAsJEM)

 3

	Agents, n= 24*	Cohen's Kappa values between pairs of experts
		(1&2/ 1&3/ 2&3 ; ordered by ascending Kappa's
		values)
	Animals#	0.39 / 0.47 / 0.56
	Fish/shellfish	0.08 / 0.52 / 0.54
	Flour	0.50 / 0.67 / 0.83
	Foods#	0.18 / 0.24 / 0.78
	Plants-related dusts#	0.21 / 0.26 / 0.29
	Enzymes	0.00 / 0.22 / 0.33
	Latex	0.48 / 0.53 / 0.59
	Textile#	0.36 / 0.45 / 0.69
	Moulds	0.18 / 0.18 / 0.44
	Endotoxin	0.15 / 0.18 / 0.31
	Drugs#	0.22 / 0.42 / 0.44
	High level chemicals disinfectants#	0.09 / 0.15 / 0.37
	Aliphatic amines	-0.01 / 0.14 / 0.18
	Isocyanates	0.08 / 0.21 / 0.35
	Acrylates	0.31 / 0.34 / 0.80
	Epoxy resins	0.35 / 0.43 / 0.85
	Persulphates and henna	1.00 / 1.00 / 1.00
	Wood#	0.35 / 0.37 / 0.41
	Metal	0.25 / 0.31 / 0.52
	Metal working fluids	0.35 / 0.39 / 0.49
	Indoor cleaning#	0.28 / 0.40 / 0.50
	Bleach	0.16 / 0.28 / 0.32
	Organic solvents	0.24 / 0.26 / 0.41
	Exhaust fumes	0.29 / 0.40 / 0.53
	Unweighted Cohen's Kappa values of three pairs of experts (expert1 & expert2/ expert1 & expert3/ expert2
	& expert3) per agent. For each agent, Cohen's Kappa's were calculated between pair of experts, using
	exposure evaluations for 506 job codes, and reported in ascending values
	* No evaluation of Kappa were available (see online supplement, Table

; High level chemical disinfectants:

  High level disinfectant or chemical sterilizing agents (eg, glutaraldehyde, chlorhexidine, ethylene oxide, hydrogen peroxide); Indoor cleaning: Cleaning products/ detergents or low/intermediate level disinfectants

Table 4 -Percentage of jobs classified exposed or with an expert re-evaluation Asthma-specific JEM

 4

	New OAsJEM

Acknowledgements:

We thank Catherine Quinot (Inserm U1168) for checking analysis.

Contributors: NLM contributed to the study design, acquisition, analysis and interpretation of the data, drafting and revising the manuscript. JPZ and HK contributed to the study design, analysis and interpretation of the data and critically revised the manuscript. OD, TL, EA, LL, VS, GB contributed to analysis and interpretation of the data and critically revised the manuscript. All authors approved the final version of the manuscript.

Fundings: PHC Van Gogh programme, EP-Nuffic, Campus France 33653RF (2015-2016); 7th programme-EU (Marie-Curie) [FP7/2007-2013], REA (PCOFUND-GA-2013-609102), PRESTIGE-2015-3-0029 -Campus France. ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya.

Competing interests: N Le Moual reports grants from PHC Van Gogh programme, Campus France ; O Dumas reports grants from Prestige, Campus France; H Kromhout reports grants from PHC Van Gogh programme, EP-Nuffic, during the conduct of the study ; None declared for others co-authors.