PONE-D-21-34278Development of an observational exposure human biomonitoring study to assess Canadian children's DEET exposure during protective use.PLOS ONE

Dear Dr. Gibson,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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ACADEMIC EDITOR: This is an interesting manuscript, and  based on the publication criteria of PLOS ONE's  several questions highlighted by the reviewers should be clarified by authors.

best regards .

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Kind regards,

José Luiz Fernandes Vieira

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have done a lot of work for this field study, and earned some good results. The major issue, however, is the objective of this study, which is not very clear. The authors established three exposure scenarios for data analysis, but did not conduct a good comparison between them and suggest better ones (at least not seen in Abstract, but in Conclusion). The authors need to indicate the chosen scenarios explicitly by showing some good approaches of comparison, and make this paper more valuable.

Other issues are listed as follows:

Line 37, please give full names of DHMB and DCBA here.

DHMB is an intermediate product on the way to DCBA, and thus, inconsistent recovery rates for it are acceptable. Other than DCBA, a final product of ring methyl oxidation, why not choose a metabolite from N-deethylation?

Lines 95-96, please add approval information, such as number, date.

Line 121, please cite references for the literature mentioned here.

Please give purchase information for standards of DEET, DCBA and DHMB.

Please make a table for QA/QC results (i.e., recovery rates).

Reviewer #2: Important and innovative study. Very good scientific contribution. The authors demonstrate knowledge about the subject. Well explored article. All figures should be improved. The presentation of tables could be improved. It would be important to add their hypothesis in the introduction.

Reviewer #3: Some suggestions/additional comments to the authors:

There are some abbreviations throughout the manuscript. Consider making a list of abbreviations and meanings.

What is the toxic relevance of DEET and its metabolites, DCBA and DHMB ?

Line 172 - Analytical methods for urine samples – was based on which reference ?

Was any internal standard used in the analysis?

Pilot study

Line 299 – of the 14 children ... (age?)

8 participants only? Were there not 13 remaining participants? It didn't seem clear to me...

Reviewer #4: The manuscript intitled "Development of an observational exposure human biomonitoring study to assess

Canadian children's DEET exposure during protective use" by Gibson et. presents an interesting issue, however needs profound modifications, including statistical and sample data, as foolow below:

1) Why the authors chose the children age. Besides, sometimes the authors refers as 6-12 years old, and sometimes 7-12 years old;

2) Phisiologically, these chosen ages may reflect different toxicological effects. These issue is fundamental and underlies the importance of the study;

3) The authors should stratify the samples (i.e., 7-10 and 11-13), if the commentary above is positive physiologically;

4) Line 55-56: such kind of justification should not be raised;

5) The concentration of repelent applied should be considered in the measurement of urine DEET and metabolites concentration, since that higher concentrations induces higher concentrations in urine (first-order knetics processes);

6) What is the novelty of the work? This issue was not clear;

7) The title did not reflects the study;

8) The number of the license of Health Canada’s Research Ethics Board approvation;

9) What means QA/QC samples?

10) What the consequences of body system bioavaliablity of DDET and its metabolites for Human health?

11) What the secure blood levels of DEET and its metabolites? Are the metabolites bioactive compounds toxic for the Human?

12) Conclusion needs to be more direct, with the conclusion and importance of the study.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

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Development of an observational exposure human biomonitoring study to assess Canadian children's DEET exposure during protective use.

PONE-D-21-34278R1

Dear Dr. Gibson

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

José Luiz Fernandes Vieira

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #3: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #3: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #3: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #3: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: No