Barriers to the use of toxicogenomics data in human health risk assessment: A survey of Canadian risk assessors

Accepted Manuscript Barriers to the use of toxicogenomics data in human health risk assessment: A survey of Canadian risk assessors Julien Vachon, Céline Campagna, Manuel J. Rodriguez, Marc-André Sirard, Patrick Levallois PII:

S0273-2300(17)30008-9

DOI:

10.1016/j.yrtph.2017.01.008

Reference:

YRTPH 3755

To appear in:

Regulatory Toxicology and Pharmacology

Received Date: 25 August 2016 Revised Date:

24 November 2016

Accepted Date: 25 January 2017

Please cite this article as: Vachon, J., Campagna, C., Rodriguez, M.J., Sirard, M.-A., Levallois, P., Barriers to the use of toxicogenomics data in human health risk assessment: A survey of Canadian risk assessors, Regulatory Toxicology and Pharmacology (2017), doi: 10.1016/j.yrtph.2017.01.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Barriers to the use of toxicogenomics data in human health risk assessment: A survey of Canadian risk

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assessors

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Authors:

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Julien Vachona, b, c, [email protected]

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Céline Campagnaa, b, [email protected]

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Manuel J. Rodriguezf, g, [email protected]

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Marc-André Sirardd, e, [email protected]

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Patrick Levalloisa, b, c, *, [email protected]

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*Corresponding author

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Affiliations:

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a

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Canada

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b

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Québec (INSPQ), Québec, QC, Canada

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c

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universitaire de Québec, Québec, QC, Canada

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d

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Laval, Québec, QC, Canada

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Département de médecine sociale et préventive, Faculté de médecine, Université Laval, Québec, QC,

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Direction de la santé environnementale et de la toxicologie, Institut national de santé publique du

Axe Santé des populations et pratiques optimales en santé, Centre de recherche du Centre hospitalier

Département des sciences animales, Faculté des sciences de l’agriculture et de l’alimentation, Université

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e

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recherche du Centre hospitalier de Québec, Québec, QC, Canada

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f

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d’architecture, d’art et de design, Université Laval, Québec, QC, Canada

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g

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Laval, Québec, QC, Canada

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Correspondence information:

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Patrick Levallois: [email protected], 1-418-650-5115 #5216

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Institut national de santé publique du Québec

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945 avenue Wolfe, 4e étage

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Québec, QC, Canada G1V 5B3

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Word counts:

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Abstract: 199

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Text: 3132

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References: 902

Centre de recherche en reproduction, développement et santé intergénérationnelle, Centre de

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École supérieure d'aménagement du territoire et de développement régional, Faculté d’aménagement,

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Chaire de recherche industrielle CRSNG, Gestion et surveillance de la qualité de l’eau potable, Université

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Abstract Regulatory agencies worldwide need to modernize human health risk assessment (HHRA) to

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meet challenges of the 21st century. Toxicogenomics is at the core of this improvement. Today, however,

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the use of toxicogenomics data in HHRA is very limited. The purpose of this survey was to identify

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barriers to the application of toxicogenomics data in HHRA by human health risk assessors. An online

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survey targeting Canadian risk assessors gathered information on their knowledge and perception of

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toxicogenomics, their current and future inclusion of toxicogenomics data in HHRA, and barriers to the

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use of such data. Twenty-nine (29) participants completed a questionnaire after 2 months of solicitation.

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The results show that the application of toxicogenomics data in Canada is marginal, with 85% of

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respondents reporting that they never or rarely used such data. Knowledge of toxicogenomics by

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Canadian risk assessors is also limited: about two-thirds of respondents (68%) were not at all or only

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slightly familiar with the concept. Lack of guidelines for toxicogenomics data interpretation, data quality

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assessment and on their use in HHRA, were found to be major barriers. In conclusion, there is a need for

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interventions aimed at facilitating the use of toxicogenomics data in HHRA, when available.

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Key Words

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Genomics, 21st century, regulatory toxicology, knowledge application

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Contents

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Introduction ..................................................................................................................................... 1

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Summary of methods ....................................................................................................................... 3

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Results and discussion ...................................................................................................................... 4 3.1 Response rate ................................................................................................................................ 4

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3.2 Characteristics of respondents ....................................................................................................... 4

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3.3 Frequency of use of toxicogenomics data in human health risk assessment.................................... 5

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3.4 Individual factors as potential barriers to the use of toxicogenomics in human health risk assessment .......................................................................................................................................... 5

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3.4.1 Training and knowledge of toxicogenomics ............................................................................. 5

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3.4.2 Perception of and confidence in using toxicogenomics data in human health risk assessment . 6

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3.5 Organizational support as potential barrier to the use of toxicogenomics in human health risk assessment .......................................................................................................................................... 7

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3.6 Barriers and facilitating factors highlighted by respondents............................................................ 8

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3.7 Insufficient guidelines for toxicogenomics data integration in human health risk assessment ......... 8

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Conclusion........................................................................................................................................ 9

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Declaration of interest.................................................................................................................... 10

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Authorship contributions................................................................................................................ 10

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Acknowledgements ........................................................................................................................ 10

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Supplementary material ................................................................................................................. 11

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References ..................................................................................................................................... 11

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Table ..................................................................................................................................................... 14

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Figure .................................................................................................................................................... 15

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1. Introduction Regulatory agencies worldwide have to adapt and improve human health risk assessment

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(HHRA) methods to meet challenges of the 21st century: a rapid increase in the number of chemicals to

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be assessed (in 2009, 87% of chemicals on the market lacked toxicity data) (Hartung, 2009), and the need

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for faster, more scientifically robust assessments. As such, they are encouraging the use of data

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generated by toxicogenomics technologies (Tralau and Luch, 2015). Large-scale programs aimed at

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exploiting toxicogenomics data in HHRA include the U.S. Environmental Protection Agency’s (EPA) Tox21

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(http://epa.gov/ncct/Tox21) launched after the publication of the National Research Council’s (NRC)

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report Toxicity Testing in the 21st Century: A Vision and a Strategy (NRC, 2007a). Besides, the SEURAT-1

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research initiative was launched to develop alternative methods to replace animal testing of cosmetic

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products in the European Union (Gocht and Schwarz, 2015). Health Canada also began reflecting on this

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matter (CCA, 2012).

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The potential of toxicogenomics in improving the HHRA process was recently examined in the

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literature (Bourdon-Lacombe et al., 2015; Chepelev et al., 2015; Goetz et al., 2011; Marx-Stoelting et al.,

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2015; McHale et al., 2010) and in various case studies (Bourdon et al., 2013; Burgoon et al., 2016; Euling

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et al., 2013; Moffat et al., 2015; Thomas et al., 2012; Wilson et al., 2013). Those studies showed that

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toxicogenomics research could be valuable at different stages of HHRA. First, toxicogenomics data can

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help in the hazard identification and characterization stages by facilitating the identification of

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mechanisms of action and allowing better in vitro to in vivo extrapolation and inter-/intra-species

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comparison. Secondly, toxicogenomics data can also contribute to the characterization of low-dose

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responses and thresholds, and help to investigate the transition between adaptive and toxic responses

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(Boverhof et al., 2011). Lastly, another significant advantage of toxicogenomics is the potential decrease

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in time and resources needed to generate toxicity data, compared to conventional testing on whole

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animals (NRC, 2007b).

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Despite this strong interest from regulatory agencies, the use of toxicogenomics in HHRA

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remains very limited. For instance, in Canada, Bourdon-Lacombe et al. (2015) reported that between

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2000 and 2013, only 2% of the evaluation from Health Canada Existing Substances Risk Assessment

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Bureau contained genomics information, and none in Canadian Drinking Water Quality programs

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(Bourdon-Lacombe et al., 2015). In the U.S., this proportion increases to 20% for EPA’s Integrated Risk

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Information System (IRIS) program (Bourdon-Lacombe et al., 2015). Only a few authors have investigated

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the reasons for this limited use of toxicogenomics data by human health risk assessors. Potential barriers

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have been postulated, such as: difficulty in interpreting toxicogenomics data (Goetz et al., 2011; McHale

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et al., 2010; Pettit et al., 2010), lack of training or insufficient knowledge in risk assessors, dearth of

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standards and guidelines for toxicogenomics data quality assessment or proper application in HHRA

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(Bourdon-Lacombe et al., 2015; Euling et al., 2013; Goetz et al., 2011; Moffat et al., 2015; Pettit et al.,

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2010; Sturla et al., 2014; Tong et al., 2015), uncertainties regarding the utility of toxicogenomics in HHRA

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(Goetz et al., 2011; Pettit et al., 2010), and availability of toxicogenomics data (Chepelev et al., 2015;

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Euling et al., 2013; Moffat et al., 2015). However, very few studies have investigated these barriers

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systematically. Therefore, a more comprehensive and systematic scrutiny is needed.

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One of those investigations surveyed mainly U.S. scientists regarding current and future use of

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toxicogenomics in risk assessment, as well as barriers to such a use (Pettit et al., 2010). However, it

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targeted scientists and decision-makers already involved in the field of toxicogenomics. Moreover, few

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respondents were from outside the U.S., leaving other countries, such as Canada, underrepresented. In

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order to fill this gap, a national survey was designed with the objectives of characterizing: 1) the current

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and future use of toxicogenomics data by Canadian human health risk assessors, 2) their knowledge of

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toxicogenomics, 3) their perceptions of the usefulness and potential impact of toxicogenomics on HHRA,

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and 4) the factors impeding the use of toxicogenomics data in HHRA in Canada.

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2. Summary of methods The complete methodology is described in the supplementary material. Briefly, an online

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questionnaire accessed through and completed on the FluidSurveysTM platform (http://fluidsurveys.com,

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Ottawa, ON, Canada) was designed based on a literature review of the topic (e.g. Bourdon-Lacombe et

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al., 2015; Boverhof et al., 2011; Chepelev et al., 2015; Goetz et al., 2011; Marx-Stoelting et al., 2015;

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McHale et al., 2010; Tong et al., 2015) and consultation with experts. To identify potential participants,

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queries including a short description of the project and asking for contact information (e-mails) of human

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health risk assessors were sent to ministries of health or environment and other public or non-profit

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health organizations across Canada. The survey invitation was sent by email directly or through

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organizations to about 200 potential participants. Participation was confidential. To be eligible,

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participants had to be professionals who contributed to a HHRA process at the Canadian federal or

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provincial level, either as manager, writer, reviewer, scientific expert or consultant, commentator, or any

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other relevant roles.

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Answers to the questionnaires were exported and merged into a single Microsoft Excel®

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spreadsheet where descriptive statistics were performed via Microsoft Excel® functions (e.g.

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frequencies, averages). Linear regressions were performed (regression function in Microsoft Excel®, 95%

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confidence level) to explore links between some of the questions. Some questions were analyzed using

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subsamples stratified for levels of knowledge (high versus low) of toxicogenomics. Both versions (French

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and English) of the questionnaire are available as supplementary material. This research project was

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approved by the Comité d’Éthique de la Recherche de l’Université Laval (CÉRUL): No. 2015-287/18-12-

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2015.

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3. Results and discussion

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3.1 Response rate On a total of 39 questionnaires returned, 29 questionnaires were used for the analysis. Others

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were incomplete or not eligible. The response rate was difficult to ascertain because of recruitment

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methods, but would probably be less than 15%.

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This sample is rather small, despite our recruitment efforts. The absence of a central list of

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Canadian human health risk assessors and the time constraints on the survey duration might have led to

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a possible selection bias which increased uncertainties regarding the validity of our results. We tried to

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reduce this limitation by including a snowball sampling procedure in the recruitment strategy to enhance

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the likelihood of reaching potential participants not identified beforehand.

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3.2 Characteristics of respondents

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Characteristics of respondents are available in Table S1 in the supplementary material. Briefly,

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mean age of the respondents was 44 years (range 28-63 years; n=27 [2 unreported]). Most of the

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participants had been working in the field of HHRA for 6 to 15 years and were from the government

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sector; the rest were divided between academic, private and non-governmental. The respondents’

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percentage of practice dedicated to HHRA was relatively well distributed between < 20% to > 80%, and

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most respondents had either a master’s or doctoral degree.

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The small sample size reduces our ability to extrapolate the results to all of Canada’s human

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health risk assessors. However, this is partly offset by the variety of professional settings represented by

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participant, which represents the professional context of HHRA (see supplementary material, Table S1).

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3.3 Frequency of use of toxicogenomics data in human health risk assessment Most respondents (62%) never considered toxicogenomics data or information in HHRA they

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worked on and only one respondent used them "all the time"; the others used them "a few times" (24%)

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or "sometimes" (7%). When asked about their potential future use of toxicogenomics in HHRA, one-third

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(34%) declared they did not plan to do so (Figure 1), and only about one-quarter (24%) asserted that they

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plan to use it. Assessors that reported high knowledge of toxicogenomics were more inclined to use

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toxicogenomics data in future HHRA. These results indicate that, until today, the use of toxicogenomics

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data by Canadian human health risk assessors remains marginal.

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3.4 Individual factors as potential barriers to the use of toxicogenomics in human health risk assessment

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3.4.1 Training and knowledge of toxicogenomics

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Most respondents reported having received no training in toxicogenomics. Among those

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untrained in toxicogenomics, about three-quarters (72%) did not plan to receive training in the near

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future, either because it is not available in their professional context or because of time and resource

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constraints. Only a few respondents (10%) considered that it was not relevant to their job. Moreover,

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respondents reported low-level knowledge of toxicogenomics: 69% of them stated that they were "not

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at all familiar" or "slightly familiar" with the concept. Overall, most respondents were only "slightly

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familiar" with concepts and methods in toxicogenomics, based on their level of familiarity with different

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concepts (e.g. transcriptomics), methods (e.g. microarray), and data analysis (e.g. heat maps). Only 21%

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of respondents reported high levels of familiarity ("very" or "extremely familiar") with the concepts in

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toxicogenomics. There was no statistical association between level of knowledge and either the age of

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respondents or their number of years of work in HHRA.

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As shown by Figure 1 above, when stratified for knowledge levels of toxicogenomics (low versus

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high), respondents with low-level knowledge were less likely to use toxicogenomics data in future HHRA.

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The high frequency of "N/A" answers could be explained by respondents expecting that they will not 5

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conduct HHRA anymore, or considering that it does not apply to them (e.g. if their role is to review only).

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Thus, human health risk assessors’ knowledge of toxicogenomics and the availability of training appear

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to be major factors influencing the use of toxicogenomics data in HHRA.

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These results are in agreement with results from Pettit et al. (2010), whose respondents

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(contacts related to the U.S. Health and Environmental Science Institute Genomics Committee) viewed

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biological understanding of toxicogenomics data and their interpretation by regulatory agencies as major

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hurdles. Training was also recognized by participants at the 2014 Global Coalition for Regulatory Science

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Research Workshop as being a key element for advancing regulatory science (Tong et al., 2015).

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Moreover, in our study, low level of familiarity with toxicogenomics was also associated with a much

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lower level of confidence in specific tasks related to the use of toxicogenomics (discussed in section

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3.4.2).

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3.4.2 Perception of and confidence in using toxicogenomics data in human health risk assessment

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This survey confirms the positive perception held by risk assessors about the usefulness and

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advantages of toxicogenomics data for HHRA. More than half of respondents (59%) considered that it

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was "somewhat" or "to a great extent" important for human health risk assessors to be knowledgeable

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about toxicogenomics, while fewer than a third (27%) considered it "not at all" or "only a little"

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important. They also had a rather positive perception of the impact of toxicogenomics on HHRA,

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although, when stratified for levels of knowledge (low versus high), the proportion of participants whose

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perception was positive was much higher in the high knowledge group (Table S2 in the supplementary

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material). HHRA aspects perceived as being most facilitated by the use of toxicogenomics were related to

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the HHRA phase of toxicological characterization (e.g. dose-response analysis, identification of the

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mechanisms of action, toxicity of mixture, predicting toxicity, and the selection of critical endpoints).

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However, up to half of respondents in the low knowledge subsample answered "don’t know" to different

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aspects of HHRA they had to rate. When asked about their level of confidence towards specific tasks related to the use of

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toxicogenomics in HHRA, respondents reported very low levels for most tasks (Table 1). Those who

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reported higher levels of knowledge of toxicogenomics were significantly more confident in their ability

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to perform different tasks. These results suggest that knowledge of toxicogenomics not only play a

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significant role in the perception of human health risk assessor about the usefulness of toxicogenomics

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in HHRA, but also in their ability to judge the potential impact of toxicogenomics on HHRA, as suggested

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by the high frequency of “don’t know” answers in the low knowledge subsample.

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3.5 Organizational support as potential barrier to the use of toxicogenomics in human health risk assessment

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Survey respondents were asked whether their organizations encouraged the use of

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toxicogenomics in HHRA and if they encouraged, supported or provided training in toxicogenomics: half

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of the respondents answered "not at all" to both questions (52% and 55% respectively). Only 10% of

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respondents reported that it was "somewhat" or "to a great extent" encouraged in their organizations.

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When asked about organizational efforts to develop guidelines for the use of toxicogenomics data in

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HHRA, 66% of respondents noted that their organization made "no effort", while 14% checked off "small

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efforts". Only one respondent acknowledged "considerable efforts" by his or her organization.

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Considering these results, it appears there is still a gap between assessors’ perceived value of

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toxicogenomics and regulatory agencies’ views, a situation also previously reported by Pettit et al. (2010)

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in the U.S. In fact, Canadian human health risk assessors seem to receive very little encouragement to

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use toxicogenomics data in HHRA. This lack of leadership by organizations in the application of

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toxicogenomics in HHRA is problematic, considering that organizational environment is recognized as

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critical in supporting and maximizing innovation and changes in practice (Davies and Nutley, 2000; 7

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Hamer, 2010). Efforts to modernize HHRA should not rest solely on the professionals’ willingness. All

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parties involved in HHRA should work together to create an innovative ecosystem (Hamer, 2010) where

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organizations support individuals who, in turn, participate in further shaping organizational vision and

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leadership.

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3.6 Barriers and facilitating factors highlighted by respondents

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Respondents were asked to rate potential barriers on a scale ranging from "not an obstacle" to

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"high hurdle". Barriers recognized as being most limiting (i.e. "high hurdle") to the use of toxicogenomics

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in HHRA were the lack of guidelines on how to consider toxicogenomics data in HHRA (66%), the lack of

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training in toxicogenomics (59%), difficulties with toxicogenomics data interpretation (41%), and the lack

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of acceptance by regulatory agencies (48%). Moderate hurdles reported include organizational

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conservatism, lack of acceptance by senior management, time required to implement regulatory

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changes, immature technologies, uncertainties associated with the data, toxicogenomics data quality

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assessment, and time required to analyze such data (see supplementary material, Figure S1).

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When asked to rate a series of potential facilitating factors, a majority of respondents reported

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that they would all be "highly helpful" (see supplementary material, Table S3). In agreement with the

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barriers identified above, the facilitating factors that were reported to potentially be the most helpful

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were Guidelines on how to integrate toxicogenomics data into HHRA and Established standards and

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guidelines for the interpretation of toxicogenomics data. These results were similar when stratified for

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knowledge of toxicogenomics (low vs high).

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3.7 Insufficient guidelines for toxicogenomics data integration in human health risk assessment

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The lack of guidance on acceptable toxicogenomics methods and on how to integrate this type of

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data in HHRA has been reported previously as a potential barrier to risk assessors (Bourdon-Lacombe et

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al., 2015; Euling et al., 2013; McConnell et al., 2014; Moffat et al., 2015; Pettit et al., 2010; Sturla et al., 8

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2014; Tong et al., 2015). About half of Pettit et al. (2010) respondents (mostly from the U.S.) were

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concerned that regulatory agencies did not have proper methodologies to analyze and interpret

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toxicogenomics data within the current risk assessment paradigm. In our survey, the lack of guidelines

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was the principal barrier identified by most respondents. Unfortunately, despite efforts made to develop

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such guidelines, particularly for systematic quality assessment and interpretation of toxicogenomics

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data, those tools do not seem to be known or used by assessors (Bourdon-Lacombe et al., 2015; Embry

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et al., 2014; Euling et al., 2013; Goetz et al., 2011; McConnell et al., 2014). The development and

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application of such guidelines will benefit from a consensus at national and international levels, and

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regulatory agencies are urged to collaborate and share expertise (Birnbaum et al., 2016; Marx-Stoelting

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et al., 2015; Tong et al., 2015). Although the availability of toxicogenomics data in the scientific literature

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was investigated in another study by the authors (unpublished), the absence of regulatory requirement

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to submit toxicogenomics data as a potential impeding factor to the use of toxicogenomics data in HHRA

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was not investigated in our survey. While guidance exists on toxicogenomics data submission (e.g.

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Genomics Data Submission (FDA, 2005), External Review Draft on the Interim Guidance for Microarray-

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Based Assays: Data Submission, Quality, Analysis, Management, and Training Considerations (U.S. EPA,

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2007), the lack of required submission might play a role in the low implication of organizations toward

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training of risk assessors. In fact, a majority of respondents from the regulatory sector in the study by

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Pettit et al. (2010) considered that required submission of toxicogenomics data to regulatory agencies

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would be beneficial to HHRA.

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4. Conclusion

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The use of toxicogenomics data in HHRA has the potential to better protect human populations

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from environmental exposure to toxicants through significantly improving the quality of HHRA

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conducted. This survey showed that human health risk assessors are quite positive about the use of

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toxicogenomics data in HHRA. However, its use in Canadian HHRA is very limited. This seems to be due in 9

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great part to: 1) human health risk assessors’ lack of knowledge of toxicogenomics, 2) absence of

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guidelines on how to efficiently interpret, assess and use toxicogenomics data in HHRA, and 3) lack of

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leadership and encouragement from organizations towards the application of toxicogenomics in HHRA

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and training of risk assessors. Although not generalizable to assessors from other countries, the results

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might be transposable to other industrialized countries that have limited experience with the use of

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toxicogenomics data in HHRA. Regulatory agencies are encouraged to engage in knowledge transfer

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interventions aimed at training and providing tools to support the expertise of human health risk

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assessors, as well as collaborating in rapidly developing standardized guidelines.

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5. Declaration of interest

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The authors’ affiliations are shown on the cover page. They declare they have no conflict of interest.

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6. Authorship contributions

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This work was undertaken as part of JV’s master’s degree in community health at Université

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Laval, under the supervision of PL and CC. JV prepared the study, conducted the data collection and

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analysis, and wrote the manuscript. PL and CC contributed to the design, analysis and interpretation of

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the data, and to the writing of the final manuscript. MJR and MAS contributed to the development of the

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original protocol and did a critical review of the draft manuscript.

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7. Acknowledgements

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The authors are thankful to SOTC and the Chapitre Saint-Laurent for their contribution to study

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recruitment. They also thank Reza Farmahin and Nikolai L. Chepelev of Health Canada for their review

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and comments on survey questions.

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Funding: This work was supported by Fonds de recherche du Québec - Nature et technologies

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(FRQNT) [Grant No. 174533].

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8. Supplementary material Supplemental details on the complete methodology and additional results (Tables S1 to S3,

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Figure S1) are available in the supplementary material. English and French copies of the survey

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administered in this study are also available as supplementary material.

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9. References

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Birnbaum, L.S., Burke, T.A., Jones, J.J., 2016. Informing 21st-Century Risk Assessments with 21st-Century Science. Environ. Health Perspect. 124, A60–A63. doi:10.1289/ehp.1511135

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Bourdon, J.A., Williams, A., Kuo, B., Moffat, I., White, P.A., Halappanavar, S., Vogel, U., Wallin, H., Yauk, C.L., 2013. Gene expression profiling to identify potentially relevant disease outcomes and support human health risk assessment for carbon black nanoparticle exposure. Toxicology 303, 83–93. doi:10.1016/j.tox.2012.10.014

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Bourdon-Lacombe, J.A., Moffat, I.D., Deveau, M., Husain, M., Auerbach, S., Krewski, D., Thomas, R.S., Bushel, P.R., Williams, A., Yauk, C.L., 2015. Technical guide for applications of gene expression profiling in human health risk assessment of environmental chemicals. Regul. Toxicol. Pharmacol. 72, 292–309. doi:10.1016/j.yrtph.2015.04.010

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Boverhof, D.R., Geter, D.R., Gollapudi, B.B., Hollnagel, H., 2011. Practical considerations for the application of toxicogenomics to risk assessment: ealy experience, current drivers, and a path forward, in: Applications of Toxicogenomics in Safety Evaluation and Risk Assessment. John Wiley & Sons, Hoboken, N.J, pp. 41–63.

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Burgoon, L.D., Druwe, I.L., Painter, K., Yost, E.E., 2016. Using In Vitro High-Throughput Screening Data for Predicting Benzo[k]Fluoranthene Human Health Hazards: Benzo[k]Fluoranthene Human Health Hazards. Risk Anal. doi:10.1111/risa.12613

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[CCA] Council of Canadian Academies, 2012. Integrating emerging technologies into chemical safety assessment. Council of Canadian Academies, Expert Panel on the Integrated Testing of Pesticides, Ottawa.

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Chepelev, N.L., Moffat, I.D., Labib, S., Bourdon-Lacombe, J., Kuo, B., Buick, J.K., Lemieux, F., Malik, A.I., Halappanavar, S., Williams, A., Yauk, C.L., 2015. Integrating toxicogenomics into human health risk assessment: Lessons learned from the benzo[a]pyrene case study. Crit. Rev. Toxicol. 45, 44– 52. doi:10.3109/10408444.2014.973935

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Davies, H.T.O., Nutley, S.M., 2000. Developing learning organisations in the new NHS. BMJ 230, 998– 1001.

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Embry, M.R., Bachman, A.N., Bell, D.R., Boobis, A.R., Cohen, S.M., Dellarco, M., Dewhurst, I.C., Doerrer, N.G., Hines, R.N., Moretto, A., Pastoor, T.P., Phillips, R.D., Rowlands, J.C., Tanir, J.Y., Wolf, D.C.,

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Doe, J.E., 2014. Risk assessment in the 21st century: Roadmap and matrix. Crit. Rev. Toxicol. 44, 6–16. doi:10.3109/10408444.2014.931924 Euling, S.Y., Thompson, C.M., Chiu, W.A., Benson, R., 2013. An approach for integrating toxicogenomic data in risk assessment: The dibutyl phthalate case study. Toxicol. Appl. Pharmacol. 271, 324– 335. doi:10.1016/j.taap.2013.03.013

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[FDA] Food and Drug Administration, 2005. Genomic Data Submission. U.S. Department of Health and Human Services, MD.

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Gocht, T., Schwarz, M. (Eds.), 2015. SEURAT-1 Annual report: Towards the Replacement of in vivo Repeated Dose Systemic Toxicity Testing, ARTTIC. ed. Paris, France.

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Goetz, A.K., Singh, B.P., Battalora, M., Breier, J.M., Bailey, J.P., Chukwudebe, A.C., Janus, E.R., 2011. Current and future use of genomics data in toxicology: Opportunities and challenges for regulatory applications. Regul. Toxicol. Pharmacol. 61, 141–153. doi:10.1016/j.yrtph.2011.07.012

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Hamer, S., 2010. Developing an innovation ecosystem: A framework for accelerating knowledge transfer. J. Manag. Mark. Healthc. 3, 248–255. doi:10.1179/175330310X12736578177607

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Hartung, T., 2009. Toxicology for the twenty-first century. Nature 460, 208–212. doi:10.1038/460208a

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Marx-Stoelting, P., Braeuning, A., Buhrke, T., Lampen, A., Niemann, L., Oelgeschlaeger, M., Rieke, S., Schmidt, F., Heise, T., Pfeil, R., Solecki, R., 2015. Application of omics data in regulatory toxicology: report of an international BfR expert workshop. Arch. Toxicol. 89, 2177–2184. doi:10.1007/s00204-015-1602-x

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McConnell, E.R., Bell, S.M., Cote, I., Wang, R.-L., Perkins, E.J., Garcia-Reyero, N., Gong, P., Burgoon, L.D., 2014. Systematic Omics Analysis Review (SOAR) Tool to Support Risk Assessment. PLoS ONE 9, e110379. doi:10.1371/journal.pone.0110379

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McHale, C.M., Zhang, L., Hubbard, A.E., Smith, M.T., 2010. Toxicogenomic profiling of chemically exposed humans in risk assessment. Mutat. Res. Mutat. Res. 705, 172–183. doi:10.1016/j.mrrev.2010.04.001

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Moffat, I., Chepelev, N.L., Labib, S., Bourdon-Lacombe, J., Kuo, B., Buick, J.K., Lemieux, F., Williams, A., Halappanavar, S., Malik, A.I., Luijten, M., Aubrecht, J., Hyduke, D.R., Fornace, A.J., Swartz, C.D., Recio, L., Yauk, C.L., 2015. Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water. Crit. Rev. Toxicol. 45, 1–43. doi:10.3109/10408444.2014.973934

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[NRC] National Research Council, 2007a. Toxicity testing in the 21st century: a vision and a strategy. National Academies Press, Washington, DC.

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[NRC] National Research Council, 2007b. Applications of toxicogenomic technologies to predictive toxicology and risk assessment. National Academies Press, Washington, D.C.

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Pettit, S., des Etages, S.A., Mylecraine, L., Snyder, R., Fostel, J., Dunn, R.T., Haymes, K., Duval, M., Stevens, J., Afshari, C., Vickers, A., 2010. Current and Future Applications of Toxicogenomics: Results Summary of a Survey from the HESI Genomics State of Science Subcommittee. Environ. Health Perspect. 118, 992–997. doi:10.1289/ehp.0901501

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Sturla, S.J., Boobis, A.R., FitzGerald, R.E., Hoeng, J., Kavlock, R.J., Schirmer, K., Whelan, M., Wilks, M.F., Peitsch, M.C., 2014. Systems Toxicology: From Basic Research to Risk Assessment. Chem. Res. Toxicol. 27, 314–329. doi:10.1021/tx400410s

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Thomas, R.S., Clewell, H.J., Allen, B.C., Yang, L., Healy, E., Andersen, M.E., 2012. Integrating pathwaybased transcriptomic data into quantitative chemical risk assessment: A five chemical case study. Mutat. Res. Toxicol. Environ. Mutagen. 746, 135–143. doi:10.1016/j.mrgentox.2012.01.007

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Tong, W., Ostroff, S., Blais, B., Silva, P., Dubuc, M., Healy, M., Slikker, W., 2015. Genomics in the land of regulatory science. Regul. Toxicol. Pharmacol. 72, 102–106. doi:10.1016/j.yrtph.2015.03.008

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Tralau, T., Luch, A., 2015. Moving from rats to cellular omics in regulatory toxicology: great challenge toward sustainability or “up-shit-creek without a paddle”? Arch. Toxicol. 89, 819–821. doi:10.1007/s00204-015-1511-z

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U.S. EPA, 2007. External Review Draft on the Interim Guidance for Microarray-Based Assays: Data Submission, Quality, Analysis, Management, and Training Considerations.

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Wilson, V.S., Keshava, N., Hester, S., Segal, D., Chiu, W., Thompson, C.M., Euling, S.Y., 2013. Utilizing toxicogenomic data to understand chemical mechanism of action in risk assessment. Toxicol. Appl. Pharmacol. 271, 299–308. doi:10.1016/j.taap.2011.01.017

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Table

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Table 1. Percentage (%) of respondents confident in their ability to perform tasks related to the use of

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toxicogenomics data in human health risk assessment, by knowledge level

1

n1 (%)

6/19 (32%)

8/9 (89%)

1/18 (6%)

7/9 (77%)

1/19 (5%)

6/9 (67%)

1/18 (6%)

6/9 (67%)

1/18 (6%) 0/19 (0%)

4/8 (50%) 2/9 (22%)

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Search the scientific literature for toxicogenomics studies Use toxicogenomic data from multiple sources (in vivo, in vitro, in silico) Assess the quality of toxicogenomics studies Determine the mode of action from gene expression data and online databases Determine point of departure from toxicogenomics data Identify health hazards based only on toxicogenomics data

High knowledge

n (%)

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Tasks

Differences in sample sizes across conditions explained by the removal of N/A answers

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Figure 1. Potential future use of toxicogenomics data by risk assessors in human health risk assessment,

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stratified for knowledge of toxicogenomics (low versus high)

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9

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2 2 0 Yes

No

Total

Low knowledge

N/A

High knowledge

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Study’s highlights : Use of toxicogenomics data in human health risk assessment is marginal Risk assessors’ knowledge limits toxicogenomics use in human health risk assessment Training and standardized guidelines are needed to support risk assessors Modernising human health risk assessment requires organisational leadership

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ACCEPTED MANUSCRIPT Toxicogenomics and Health Risk Assessment

Page #1 Simple Skipping Information    • If To participate in the survey, click the I AGREE bu... = I DISAGREE then Terminate survey  CONSENT FORM - ANONYMOUS PARTICIPATION

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PROJECT TITLE: Integrating toxicogenomics into health risk assessment: an exploratory study of its implementation in Canada LEAD RESEARCHER : Julien Vachon (Univeristé Laval INSPQ) PROJECT CONTEXT : Master’s degree, under the supervision of Patrick Levallois (MD, M.Sc.; INSPQ Université Laval) Céline Campagna (Ph.D ; INSPQ Université Laval) PROJECT SUMMARY This research project aims to explore the feasibility of integrating toxicogenomic data into health risk assessment (HRA). Toxicogenomics (the application of genomic technologies to toxicology) is a rapidly expanding field promising to impact and improve health risk assessments on multiple aspects. However, the utilisation of toxicogenomic data into HRA is lacking and its implementation is slow. The first step undertaken to explore the reasons behind this is to assess risk assessors’ knowledge and perception of genomics technologies, toxicogenomics, the available tools, and to characterise the factor facilitating or impeding the use of such data in HRA. Results will allow generating recommendations aiming at facilitating and improving the use of toxicogenomic data into HRA.     YOUR PARTICIPATION Your participation to this study consists in completing this questionnaire, which includes 29 questions (on average 15 minutes) about your profile, your risk assessment practice, and your knowledge of toxicogenomics. Although the answers to each question are important for this research, you remain free to choose not to answer to either of them or to end your participation at any time. However, since no data that identifies you (eg. name, address) will be collected by the survey, the data obtained from a participant who chooses to withdraw from the project after submitting his questionnaire will not be destroyed.   BENEFITS Your participation can be an opportunity to gain new knowledge about toxicogenomics, as a list of key readings, resources and tools will be provided at the end of the questionnaire, in the event that you would like to learn more about the subject. Your participation in this study will also beneficiate the field of health risk assessment by helping improve the knowledge transfer process between the fields of toxicogenomics and HRA.

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RISKS AND INCONVENIENCES This project is independent of your organisation and will not result in any prejudice for you. Your employer will not be informed about your consent or refusal to participate in the study or given any of the data from the questionnaire. This remains even if this invitation was transmitted to you by your employer or your manager. However, despite the measures taken to ensure confidentiality, integrity and security of the data transmitted online, using Internet involves certain risks of intrusion by third parties, and data loss, manipulation and identification.

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ANONYMITY AND DATABASE Your participation in this project is anonymous; it will never be possible to identify you.   ACKNOWLEDGEMENTS Your cooperation is valuable and allows us to conduct this study. That is why we want to thank you for your time and attention that you agree to dedicate to your participation.                                                             ETHICAL APPROBATION This research project was approved by the Ethics Research Committee of Laval University: approval No 2015-287 / 18-12-2015.   ATTESTATION OF CONSENT Selecting the “I agree” button below will be considered as the explicit expression of your consent to participate.   ADDITIONAL INFORMATION If you have any questions about the study or about the implications of your participation, please contact Julien Vachon (Project leader) at 1-481-650-5115 #5247, or by email at [email protected]; or Patrick Levallois (Research superviser) at 1-418-650-5115 #5216, or by email at [email protected].  

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COMPLAINTS OR COMMENTS If you have any complaints or criticisms related to your participation in this study, you may contact confidentially the Ombudsman office at the following:   Pavillon Alphonse-Desjardins, bureau 3320 2325, rue de l’Université Université Laval Québec (Québec) G1V 0A6 Information- Secretariat : (418) 656-3081 Toll free : 1-866-323-2271 Email : [email protected]  To participate in the survey, click the I AGREE button below. To exit the survey, click the I DISAGREE button.

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 I AGREE  I DISAGREE

ACCEPTED MANUSCRIPT Page #2 Simple Skipping Information    • If Verifying your admissibility = No then Terminate survey  Verifying your admissibility Please indicate if you satisfy the following criteria:

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You must participate in the provincial or federal human health risk assessment process, in part or for the whole process.

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Your implication in the process may be: - in the past, - currently, - in the near future,   and your role falls within one or many of the following: - editor/writer, - reviewer, - commentator, - expert/consultant.   Also, you can be from the following sector: - governemental, - academic, - private, - NGO. Do you satisfy the above criteria?  Yes  No

ACCEPTED MANUSCRIPT Page #3  Please note the following definition: Genomics, as opposed to genetics, is defined as the study of all of a person's genes (the genome), including interactions of those genes with each other and with the person's environment. (National Human Genome Research Institute) Toxicogenomics is defined as the application of genomic technologies to toxicology.  Q1. During your schooling, have you received training in genomics or toxicogenomics?(Q1)

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 Yes  No  If yes, please indicate how many hours of training: ______________________

 Q2. Have you received training in genomics or toxicogenomics in a professional context?(Q2)

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 Yes  No  If yes, please indicate how many hours of training:

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 Q3. In the near future, do you plan on receiving training in genomics or toxicogenomics?(Q3)  Yes  No  If No, please indicate why:

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ACCEPTED MANUSCRIPT Page #4  ABOUT TOXICOGENOMICS

 Not at all familiar  Slightly familiar  Moderately familiar  Very familiar  Extremely familiar

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 Q4. How familiar are you with the concept of toxicogenomics?(Q4)

 Q5. How familiar are you with the following concepts in genomics and toxicogenomics?(Q5) Slightly familiar

 

 

Transcriptomics

 

 

Proteomics

 

 

Metabolomics

 

 

Gene expression profilling

 

microRNA (miRNA)

 

messenger RNA (mRNA)

 

Non-coding RNA (ncRNA)

 

DNA Methylation

 

Histones

 

Molecular Initiating Event (MIE)

Upstream regulators Pathway perturbation

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Extremely familiar

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Gene ontology (GO)

Very familiar

 

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Molecular Key Events

 

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Epigenomics

Moderately familiar

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ACCEPTED MANUSCRIPT Page #5  Q6. How familiar are you with the following concepts in methods, data analysis and interpretation?(Q6) Not at all familiar

Slightly familiar

Moderately familiar

Very familiar

Extremely familiar

 

 

 

 

 

Real-Time quantitative Polymerase chain reaction (RT-qPCR)

 

 

 

 

 

RNA-sequencing

 

 

 

 

 

RNA extraction

 

 

 

 

 

RNA A280/A260 ratio

 

 

 

 

 

RNA Integrity Number (RIN)

 

 

 

 

 

Poly (A) capture

 

 

 

 

 

Ribosomal RNA depletion

 

 

 

 

 

Fold-change

 

 

 

 

 

Heat maps

 

 

 

 

 

Hierarchical or Supervised clustering

 

 

 

 

 

Principal component analysis (PCA)

 

 

 

 

 

Pathway and gene interaction network analysis

 

 

 

 

 

No Transcriptional Effect Level (NOTEL)

 

 

 

 

 

Lowest Transcriptomic Effect Level (LOTEL)

 

 

 

 

 

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DNA microarray

 Q7. How familiar are you with the following databases [D] or softwares [S] ?(Q7) Not at all familiar

Kyoto Encyclopedia of Genes and Genomes (KEGG) [D]

Slightly familiar

Moderately familiar

Very familiar

Extremely familiar

 

 

 

 

Comparative Toxicogenomics Database (CTD) [D]

 

 

 

 

 

Reactome [D]

 

 

 

 

 

Gene Expression Omnibus (GEO) [D]

 

 

 

 

 

ENCODE [D]

 

 

 

 

 

Database for Annotation, Visualization, and Integrated Discovery (DAVID) [D]

 

 

 

 

 

Panther [D]

 

 

 

 

 

Ingenuity Pathway Analysis (IPA) [S]

 

 

 

 

 

Metacore [S]

 

 

 

 

 

Cytoscape [S]

 

 

 

 

 

BMDExpress [S]

 

 

 

 

 

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ACCEPTED MANUSCRIPT Page #6  TOXICOGENOMICS IN HEALTH RISK ASSESSMENT  Q8. To this day, have you used toxicogenomic data or information in the risk assessments you worked on?(Q8)

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 Q9. Considering the health risk assessments you worked on, in how many of them have you used toxicogenomic data or information?(Q9)

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 Yes  No  N/A

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 Q10. In the future, do you plan on using toxicogenomic data or information in the health risk assessments you will work on?(Q10)

 Not at all  A little  Somewhat  To a great extent  Don't know

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 Q11. According to you, is it important for health risk assessors to be knowledgeable about genomics and toxicogenomics?(Q11)

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 Q12. Is the use of toxicogenomics in health risk assessment encouraged by your organisation?(Q12)  Not at all  A little  Somewhat  To a great extent  N/A

 Q13. Is training in genomics or toxicogenomics encouraged, supported or provided by your organisation?(Q13)  Not at all  A little  Somewhat  To a great extent  N/A

ACCEPTED MANUSCRIPT  Q14. How much effort does your organisation put into the development of guidelines for the utilisation of toxicogenomics in health risk assessment?(Q14)

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ACCEPTED MANUSCRIPT Page #7  Q15. What is your perception about the potential impact of toxicogenomics on the following?(Q15) Small negative impact

Small positive impact

No impact

The overall health risk assessment process

 

 

 

The quality of the risk assessments produced

 

 

 

The overall regulatory context

 

 

 

Your practice as risk assessor

 

 

 

Considerabl e positive impact

 

Don't know

 

 

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Considerabl e negative impact

 

 

 

 

 

 

 

 

 

Definitely not

Probably not

 

 

Chemical prioritization

 

 

Exposure assessment

 

Selection of risk assessment approach

 

Selection of critical endpoint(s)

 

Dose metric selection

 

Deriving a point of departure (PoD)

 

Low-dose extrapolation

 

Intra-species variations

Probably yes

Definitely yes

Don't know

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Read-across for chemical grouping

 

 

 

 

 

Toxicity of mixtures

 

 

 

 

 

Identification of mechanism of action (MoA)

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 Q16. Do you think toxicogenomics can improve or facilitate the following aspects of health risk assessment?(Q16)

ACCEPTED MANUSCRIPT Page #8  Q17. How confident are you in your ability to:(Q17) Moderately confident

 

 

 

Assess the quality of a toxicogenomic study?

 

 

 

Determine a point of departure (POD) from toxicogenomic data

 

 

 

Determine the mode of action (MoA) from gene expression data and online databases?

 

 

 

Use toxicogenomic data from multiple sources (in vivo, in vitro, in silico)?

 

 

 

Determine health hazards based on toxicogenomic data only?

 

 

Extremely confident

 

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 Q18. Please rate the following factors according to their current impact on the use of toxicogenomics in health risk assessment.(Q18) Not an obstacle Difficulties with toxicogenomic data interpretation

 

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Difficulties with assessing toxicogenomic data quality

 

Low hurdle

Moderate hurdle

High hurdle

Don't know

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Lack of training in toxicogenomics

 

 

 

 

 

Lack of toxicogenomic data on chemicals

 

 

 

 

 

Lack of toxicogenomic data of sufficient quality

 

 

 

 

 

Lack of guidelines on how to use toxicogenomic data

 

 

 

 

 

Immature technology requiring further validation

 

 

 

 

 

Lack of acceptance by senior management

 

 

 

 

 

Uncertainties associated with toxicogenomic data

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Conservative nature of organisation

 

 

 

 

 

Time required to implement regulatory change

 

 

 

 

 

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ACCEPTED MANUSCRIPT Page #9  Q19. If you plan on using toxicogenomics in your health risk assessment practice, how helpful would the following be?(Q19) Slighty helpful

Moderately helpful

Training in toxicogenomics (data interpretation)

 

 

 

Established standards and guidelines for the interpretation of toxicogenomic data

 

 

 

Established quality control standards for toxicogenomic data

 

 

 

Guidelines on how to integrate toxicogenomic data into health risk assessment

 

 

 

Working in collaboration with a toxicogenomic expert

 

 

Access to toxicogenomic software

 

 

Highly helpful

N/A

 

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 Q20. Are there any other factors that would allow you or help you use toxicogenomics in your work? If so, please indicate them.

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ACCEPTED MANUSCRIPT Page #10  YOUR EDUCATIONAL PROFIL  Q21. Your age(Q21) ______________________

 Bachelor's degree  Master's degree  Doctoral degree  Medical degree  Other, please specify... __________________________

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 Q22. Please select the levels of education you have achieved:(Q22)

 Q23. For each educational degree selected above, please indicate the disciplines you studied. ______________________

Master's

______________________

Doctoral

______________________

Medical

______________________

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ACCEPTED MANUSCRIPT Page #11  YOUR PROFESSIONAL PROFIL

 Academic sector  Govermental sector  Private sector  NGO  Other (please specify) __________________________  Q25. Please select the position(s) that correspond(s) best to your occupations.(Q25)

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 Q24. Please select the sector(s) that corresponds best to your professional occupation.(Q24)

 Q26. How many years have you been working in the field of human health risk assessment?(Q26)  1-5 years  6-10 years  11-15 years  16-20 years  21-25 years  26-30 years  > 30 years

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 Q27. Please select the choice that describes best your participation in health risk assessment(s).(Q27)

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 Editor/manager  Writer  Reviewer  Expert/consultant  Other (please specify) __________________________

 < 20 %  21-40 %  41-60 %  61-80 %  > 80 %

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 Q28. What pourcentage (%) of your professional practice is dedicated to human health risk assessment?(Q28)

 Q29. Have you worked, or do you currently work in the field of human health risk assessment for drinking water contaminants?(Q29)  Yes  No

 Congratulation, you reached the end of the survey! Please don't forget to press the ''SUBMIT'' button below.

ACCEPTED MANUSCRIPT Toxicogenomics and Health Risk Assessment

Page #1 Simple Skipping Information    • If Pour participer à l’étude et répondre au questionn... = Je refuse then Terminate survey  FORMULAIRE DE CONSENTEMENT ANONYME

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TITRE DE LA RECHERCHE : Intégration de la toxicogénomique à l’évaluation du risque pour la santé : une étude exploratoire de son application au Canada CHERCHEUR PRINCIPAL : Julien Vachon (Université Laval et INSPQ) CONTEXTE DU PROJET : Projet de maîtrise, dirigé par Patrick Levallois (M.D., M. Sc., Université Laval et INSPQ) et Céline Campagna (Ph. D., Université Laval et INSPQ)    RENSEIGNEMENTS SUR LE PROJET Ce projet de recherche vise à étudier la faisabilité d'intégrer des données toxicogénomiques dans le processus d'évaluation du risque pour la santé (ÉRS). La toxicogénomique (l'application des technologies génomiques en toxicologie) est un domaine en plein essor promettant d’influencer et d’améliorer l'évaluation du risque pour la santé sur de multiples aspects. Cependant, à ce jour l’utilisation de données toxicogénomiques en ÉRS est rare et son implantation est lente. La première étape visant à explorer les raisons derrière ce constat est d'évaluer, chez des évaluateurs de risque de tous horizons, leurs connaissances et leurs perceptions par rapport à la toxicogénomique et aux outils disponibles, ainsi que de caractériser les facteurs facilitant ou entravant l’utilisation de ces données dans l’ÉRS. Les résultats permettront de générer des recommandations visant à faciliter et améliorer l'utilisation des données toxicogénomiques en ÉRS.   VOTRE PARTICIPATION Votre participation à cette recherche consistera à remplir le présent questionnaire comprenant 29 questions (durée moyenne de 15 minutes) portant sur votre profil, votre pratique d’évaluateur de risque, et votre connaissance de la toxicogénomique. Bien que les réponses à chacune des questions soient importantes pour la recherche, vous demeurez libre de choisir de ne pas répondre à l’une ou l’autre d’entre elles, ou encore de mettre fin à votre participation à tout moment. Toutefois, puisqu’aucune donnée permettant de vous identifier (ex. : nom, coordonnées) ne sera recueillie par le questionnaire, les données obtenues d’un participant qui choisirait de se retirer du projet après avoir soumis son questionnaire ne pourront être détruites.   BÉNÉFICES Votre participation peut être une occasion d'acquérir de nouvelles connaissances sur la toxicogénomique, et une liste de lectures clés, de ressources et d’outils vous sera fournie à la fin du questionnaire si vous souhaitez en apprendre davantage sur le sujet. Votre participation à cette étude est aussi une contribution importante à la discipline de l'évaluation du risque pour la santé en aidant à améliorer le transfère de connaissances entre les domaines de la toxicogénomique et de l’ÉRS. RISQUES ET INCONVÉNIENTS Ce projet est indépendant de votre organisation et n’entrainera aucun préjudice pour vous. Votre employeur ne sera pas informé de votre consentement ou refus de participer à l’étude, et aucune donnée issue du questionnaire ne lui sera remise. Toutefois, en dépit des mesures prises pour assurer la confidentialité, l’intégrité et la sécurité des données transmises en ligne, l’utilisation d’Internet comporte certains risques d’intrusion par des tiers, de manipulations, de pertes de données et d’identification. ANONYMAT ET CONSERVATION DES DONNÉES Votre participation à ce projet étant anonyme, il ne sera jamais possible de vous identifier.   REMERCIEMENTS Votre collaboration est précieuse pour nous permettre de réaliser cette étude. C’est pourquoi nous tenons à vous remercier pour le temps et l’attention que vous acceptez de consacrer à votre participation.   APPROBATION ÉTHIQUE Ce projet a été approuvé par le Comité d’éthique de la recherche de l’Université Laval : No d’approbation 2015-287 / 18-12-2015. ATTESTATION DU CONSENTEMENT La sélection de l’option « J’accepte» ci-dessous sera considérée comme l’expression explicite de votre consentement à participer au projet.   RENSEIGNEMENTS SUPPLÉMENTAIRES Si vous avez des questions sur la recherche ou sur les implications de votre participation, veuillez communiquer avec Julien Vachon (Étudiant responsable du projet) au 1-481-650-5115 #5247, ou par courriel à [email protected]; ou Patrick Levallois (Directeur de recherche) au 1-418-650-5115 #5216, ou par courriel à [email protected].   PLAINTES OU CRITIQUES

ACCEPTED MANUSCRIPT Si vous avez des plaintes ou des critiques relatives à votre participation à cette recherche, vous pouvez vous adresser, en toute confidentialité, au bureau de l’Ombudsman de l’Université Laval aux coordonnées suivantes :

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Pavillon Alphonse-Desjardins, bureau 3320 2325, rue de l’Université Université Laval Québec (Québec) G1V 0A6 Renseignements - Secrétariat : (418) 656-3081 Ligne sans frais : 1-866-323-2271 Courriel : [email protected]

 J'accepte  Je refuse

 Vérification de votre éligibilité Indiquez si vous satisfaites aux critères suivants:

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 Pour participer à l’étude et répondre au questionnaire, sélectionnez «J’accepte». Pour quitter, sélectionnez «Je refuse».

Vous devez prendre part au processus fédéral ou provincial d'évaluation du risque pour la santé, en partie ou pour la totalité du processus.

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Votre implication dans le processus peut être: - dans le passé, - présentement, - dans un futur proche; et votre rôle peut se résumé par un ou plusieurs des suivants: - gestionnaire, - éditeur/rédacteur, - réviseur/commentateur, expert/consultant. Aussi, vous pouvez oeuvrer dans un ou plusieurs des secteurs suivants: - gouvernemental, - académique, - privé, - ONG. Satisfaites-vous aux critères énumérés ci-haut?  Oui  Non

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 Veuillez prendre note des définitions suivantes avant de poursuivre: La génomique, par opposition à la génétique, se définit comme l'étude de l'ensemble des gènes d'un individu (son génome), y compris les interactions entre les gènes et l'environnement. [traduction](National Human Genome Research Institute) La toxicogénomique se définit comme l'application des technologies génomiques en toxicologie.  Q1. Durant votre scolarité, avez-vous suivi des heures de formation en génomique ou en toxicogénomique?(Q1)  Oui  Non  Si oui, s'il vous plait indiquez le nombre d'heures de formation: ______________________  Q2. Avez-vous suivi des heures de formation en génomique ou en toxicogénomique dans un contexte professionnel?(Q2)  Oui

ACCEPTED MANUSCRIPT  Non  Si oui, s'il vous plait indiquez le nombre d'heures de formation: ______________________  Q3. Dans un futur proche, prévoyez-vous participer à des formations en génomique ou en toxicogénomique?(Q3)  Oui  Non

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 Si non, s'il vous plait indiquez pourquoi:

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 À PROPOS DE TOXICOGÉNOMIQUE

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_____________________________________________________________ _____________________________________________________________ _____________________________________________________________

 Q4. Comment qualifieriez-vous votre niveau de familiarité avec le concept de toxicogénomique?(Q4)  Pas du tout familier  Un peu familier  Modérément familier  Très familier  Extrêmement familier

 Q5. Comment qualifieriez-vous votre niveau de familiarité avec les concepts de génomique et de toxicogénomique suivants?(Q5) Un peu familier

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Pas du tout familier

L'épigénomique

Modérément familier

Très familier

Extrêmement familier

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ARN messager (ARNm)

 

 

 

 

 

ARN non codant (ARNnm)

 

 

 

 

 

La méthylation de l'ADN

 

 

 

 

 

Les histones

 

 

 

 

 

Les « Molecular Initiating Event (MIE) »

 

 

 

 

 

Les « Molecular Key Events »

 

 

 

 

 

Les « Upstream regulators »

 

 

 

 

 

« Pathway perturbation »

 

 

 

 

 

« Gene ontology (GO) »

 

 

 

 

 

La transcriptomique

La métabolomique L'expression génétique

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microARN (miARN)

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La protéomique

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Page #5  Q6. Comment qualifieriez-vous votre niveau de familiarité avec les concepts en méthodologies, analyses et interprétation de données toxicogénomiques suivants?(Q6) Un peu familier

Modérément familier

 

 

 

« Real-Time quantitative Polymerase Chain Reaction (RT-qPCR) »

 

 

 

« RNA-sequencing »

 

 

 

« RNA extraction »

 

 

 

« RNA A280/A260 ratio »

 

 

« RNA Integrity Number (RIN) »

 

 

« Poly (A) capture »

 

 

« Ribosomal RNA depletion »

 

« Fold-change »

 

« Heat maps »

 

« Hierarchical or Supervised clustering »

 

« Principal component analysis (PCA) »

 

« Pathway and gene interaction network analysis »

 

« Lowest Transcriptomic Effect Level (LOTEL) »

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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« No Transcriptional Effect Level (NOTEL) »

Extrêmement familier

 

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« DNA microarray »

Très familier

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Pas du tout familier

 

 

 

 

 

 

 

 

 

 

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 Q7. Comment qualifieriez-vous votre niveau de familiarité avec les bases de données [D] ou les programmes [P] suivants?(Q7) Pas du tout familier

Un peu familier

Modérément familier

Très familier

Extrêmement familier

 

 

 

 

 

Comparative Toxicogenomics Database (CTD) [D]

 

 

 

 

 

Reactome [D]

 

 

 

 

 

Gene Expression Omnibus (GEO) [D]

 

 

 

 

 

ENCODE [D]

 

 

 

 

 

Database for Annotation, Visualization, and Integrated Discovery (DAVID) [D]

 

 

 

 

 

Panther [D]

 

 

 

 

 

Ingenuity Pathway Analysis (IPA) [P]

 

 

 

 

 

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Kyoto Encyclopedia of Genes and Genomes (KEGG) [D]

ACCEPTED MANUSCRIPT Metacore [P]

 

 

 

 

 

Cytoscape [P]

 

 

 

 

 

BMDExpress [P]

 

 

 

 

 

 TOXICOGÉNOMIQUE ET ÉVALUATION DU RISQUE POUR LA SANTÉ

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 Q8. À ce jour, avez-vous utilisé de l'information ou des données toxicogénomiques dans des évaluations du risque pour la santé sur lesquelles vous avez travaillé?(Q8)

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 Jamais  Rarement  Parfois  Souvent  Toujours  N/A

 Q9. Considérant les évaluations du risque pour la santé sur lesquelles vous avez travaillé, dans quel pourcentage d'entre elles avez-vous utilisé de l'information ou des données toxicogénomique?(Q9)

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• N/A • 0% • 10% • 20% • 30% • 40% • 50% • 60% • 70% • 80% • 90% • 100%

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 Q10. Prévoyez-vous, dans le futur, utiliser des données ou de l'information toxicogénomique dans les évaluations du risque pour la santé sur lesquelles vous allez travailler?(Q10)

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 Oui  Non  N/A

 Q11. Selon vous, est-il important que les évaluateurs de risque connaissent bien les concepts et principes de génomique et de toxicogénomique?(Q11)  Pas du tout important  Peu important  Modérément important  Très important  Ne sais pas

 Q12. Est-ce que l'utilisation de la toxicogénomique en évaluation du risque pour la santé est encouragée dans votre organisation?(Q12)  Pas du tout  Un peu  Modérément

ACCEPTED MANUSCRIPT  Beaucoup  N/A  Q13. Est-ce que votre organisation encourage, supporte ou fournit des formations en génomique ou en toxicogénomique?(Q13)  Pas du tout  Un peu  Modérément  Beaucoup  N/A

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 Q14. Combien d'efforts votre organisation met-elle dans le développement de lignes directrices visant l'utilisation de la toxicogénomique en évaluation du risque pour la santé?(Q14)

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 Pas d'efforts  Peu d'efforts  Efforts modérés  Efforts considérables  N/A

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 Q15. Comment percevez-vous l'impact potentiel de la toxicogénomique sur les éléments suivants:(Q15) Impact négatif considérable L'ensemble du processus d'évaluation du risque pour la santé

Le contexte réglementaire entourant l'évaluation du risque pour la santé

 

Impact positif modeste

Impact positif considérable

Ne sais pas

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Votre pratique en tant qu'évaluateur de risque

Pas d'impact

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La qualité des évaluations du risque produites

 

Impact négatif modeste

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 Q16. Selon vous, la toxicogénomique peut-elle améliorer ou faciliter les étapes ou éléments suivants en évaluation du risque pour la santé?(Q16) Définitivement non

Probablement non

Probablement oui

Définitivement oui

Ne sais pas

Criblage des molécules (« Chemical screening »)

 

 

 

 

 

Priorisation des molécules (« Chemical prioritization »)

 

 

 

 

 

Caractérisation de l'exposition

 

 

 

 

 

Choisir l'approche d'évaluation du risque

 

 

 

 

 

Sélection des effets critiques

 

 

 

 

 

Sélection de la gamme de dose (« dose metric »)

 

 

 

 

 

Dériver un « point of departure » (PoD)

 

 

 

 

 

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Variations intra-espèces

 

 

 

 

 

Extrapolation inter-espèces

 

 

 

 

 

Identification des mécanismes d'action (MoA)

 

 

 

 

 

Analyse de la dose-réponse

 

 

 

 

 

Prédire la toxicité d'une molécule

 

 

 

 

 

Regroupement de substances et références croisées (« read across »)

 

 

 

Évaluer la toxicité de mélanges

 

 

 

 Q17. Quel est votre niveau de confiance quant à votre capacité à:(Q17)

 

Évaluer la qualité d'un article toxicogénomique?

 

Déterminer un « point of departure » (POD) à partir de données toxicogénomiques Déterminer le mode d'action (MoA) d'une molécule à partir de données d'expression génétique et de bases de données en ligne?

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Déterminer le risque pour la santé basé sur des données toxicogénomiques uniquement?

 

 

 

Très confiant

Extrêmemen t confiant

N/A

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Utiliser des données toxicogénomiques de différentes sources (in vivo, in vitro, in silico)?

Modérément confiant

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Chercher dans la littérature scientifique pour des articles toxicogénomiques?

Un peu confiant

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Extrapolation à faibles doses

 Q18. Selon vous, les éléments suivants sont-ils présentement des obstacles à l'utilisation de la toxicogénomique en évaluation du risque pour la santé?(Q18) Pas un obstacle

Obstacle légé

Obstacle modéré

Obstacle important

Ne sais pas

L'interprétation des données toxicogénomiques

 

 

 

 

 

L'évaluation de la qualité des données toxicogénomiques

 

 

 

 

 

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Les incertitudes dans le lien entre la toxicité d'une molécule et les niveaux de transcription, de protéines ou de métabolites

 

 

 

 

 

Le temps requis pour analyser des articles ou des données toxicogénomiques

 

 

 

 

 

Le manque de formation en toxicogénomique

 

 

 

Le manque de données toxicogénomiques sur les substances

 

 

 

Le manque de données toxicogénomiques de qualité adéquate

 

 

 

L'absence de lignes directrices guidant l'utilisation de données toxicogénomiques

 

 

La maturité et la validité des technologies génomiques

 

 

Le manque d'acceptation/d'encouragement de la part des gestionnaires

 

Le manque d'acceptation/d'encouragement de la part des organismes réglementaires

 

Le conservatisme des organismes

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Le temps requis pour appliquer les changements réglementaires nécessaires

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Les incertitudes associées aux données toxicogénomiques

 

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 Q19. Si vous prévoyez utiliser des données ou de l'information toxicogénomique dans les évaluations du risque sur lesquelles vous travaillerez, à quels points les éléments suivants vous seraient-ils utiles?(Q19) Pas utile

Un peu utile

Modérément utile

Très utile

N/A

Accès à des formations en toxicogénomique (interprétation des données)

 

 

 

 

 

Normes et lignes directrices guidant l'interprétation des données toxicogénomiques

 

 

 

 

 

Normes de qualité standardisées pour l'évaluation de données toxicogénomiques

 

 

 

 

 

ACCEPTED MANUSCRIPT Lignes directrices guidant l'utilisation de données toxicogénomiques en évaluation du risque pour la santé

 

 

 

 

 

Travailler en collaboration avec des experts en toxicogénomiques

 

 

 

 

 

Accès à des programmes informatiques de toxicogénomique

 

 

 

 

 

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 VOTRE PROFIL ACADÉMIQUE

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_____________________________________________________________ _____________________________________________________________ _____________________________________________________________

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 Q20. Y a-t-il d'autres facteurs ou éléments qui vous permettraient ou qui vous encourageaient à utiliser des données toxicogénomiques dans votre pratique d'évaluateur de risque? Si oui, s'il vous plaît indiquez-les.

 Q21. Votre âge(Q21) ______________________

 Q22. S'il vous plaît, indiquez chaque niveau d'éducation que vous avez atteint et complété.(Q22)

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 Baccalauréat  Maîtrise  Doctorat  Diplôme de médecine  Autre (s'il vous plaît, spécifiez) __________________________

 Q23. Pour chaque diplôme sélectionné précédemment, veuillez indiquer la discipline que vous avez étudiée. Baccalauréat

______________________ ______________________

Doctorat Diplôme de médecine

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Autre

______________________

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Maîtrise

______________________ ______________________

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 VOTRE PROFIL PROFESSIONNEL

 Q24. S'il vous plaît, veuillez indiquer le secteur d'activité qui correspond le mieux à votre occupation professionnelle.(Q24)  Milieu académique  Milieu gouvernemental  Secteur privé  ONG  Autre (S'il vous plaît, spécifiez) __________________________

ACCEPTED MANUSCRIPT  Q25. S'il vous plaît, veuillez indiquer la(es) position(s) professionnelle(s) qui correspond(ent) le mieux à votre occupation.(Q25)

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 Regulateur  Gestionnaire  Chercheur  Directeur de laboratoire  Chercheur en laboratoire  Professeur  Consultant/expert  Autre (s'il vous plaît, specifiez) __________________________  Q26. Depuis combien d'années travaillez-vous dans le domaine de l'évaluation du risque pour la santé?(Q26)

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 1-5 ans  6-10 ans  11-15 ans  16-20 ans  21-25 ans  26-30 ans  > 30 ans

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 Q27. S'il vous plaît, sélectionnez le rôle qui correspond le mieux à votre implication dans le processus d'évaluation du risque pour la santé.(Q27)  Éditeur/gestionnaire  Rédacteur  Réviseur  Expert/consultant  Autre (s'il vous plaît, spécifiez) __________________________

 < 20 %  21-40 %  41-60 %  61-80 %  > 80 %

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 Q28. Quel pourcentage (%) de votre pratique professionnelle est consacré à l'évaluation du risque pour la santé?(Q28)

 Oui  Non

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 Q29. Avez-vous oeuvré, ou oeuvrez-vous présentement dans le domaine de l'évaluation du risque pour la santé associé aux contaminants d'origine hydrique?(Q29)

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 Félicitation, vous avez atteint la fin du questionnaire! S'il vous plaît, n'oubliez pas de peser sur le bouton « SUBMIT » au bas de la page.