PONE-D-24-41161Arsenic exposure is associated with elevated sweat chloride concentration and airflow obstruction among adults in Bangladesh: a cross sectional studyPLOS ONE

Dear Dr. Mazumdar,

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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: No

Reviewer #3: Yes

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

Reviewer #1: No

Reviewer #2: N/A

Reviewer #3: Yes

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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: No

Reviewer #3: Yes

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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: Yes

Reviewer #3: 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: Major Comment:

This study investigates the relationship between arsenic exposure, sweat chloride levels (a marker of cystic fibrosis transmembrane conductance regulator [CFTR] function), and pulmonary function among adults in Bangladesh. The study presents intriguing findings suggesting that elevated sweat chloride may be a novel biomarker for arsenic exposure while raising questions about the role of CFTR dysfunction in arsenic-induced lung disease. The study is generally well-conducted, with a clear focus, appropriate methodology, and comprehensive data analysis. However, there are areas where the manuscript could be improved in terms of clarity, precision, and discussion of the limitations and implications of the findings.

Advantage:

1) The study addresses a significant public health issue: arsenic exposure and its potential impact on lung health in a highly exposed population. However, PM2.5 and other co-morbidities with air pollutants should be adjusted and discussed as confounding factors.

2) The study design, including the recruitment of participants, collection of biological samples, and measurement of variables, is appropriate for addressing the research question. The multiple exposures should reveal the relationship and interaction between lung function and CFTR in the design of further studies.

3) The statistical analysis is comprehensive and appropriate for the data collected. The authors have explored the relationships between the variables of interest using various statistical methods, including linear regression, logistic regression, and mediation analysis. The internal and external doses of arsenic should be discussed comprehensively, and distribution should fit the assumption of normal distribution. Thus, the un-transformation and transformation of indicators should be listed in tables, and the non-parametric methods should even be chosen.

4) The study provides novel evidence suggesting that elevated sweat chloride may be a potential biomarker for arsenic exposure. This finding has important implications for the screening and diagnosing arsenic-related health issues. The concordance of arsenic exposure between sweat chloride and blood or urine arsenic metabolites, such as DMA and MMA levels, should be discussed.

5) The manuscript is generally well-written and organized, making it easy to follow the study's rationale, methods, results, and conclusions; however, the correlation between sweat chloride and arsenic exposure should also identify the time-lapse changes.

6) The study population is drawn from a specific region in Bangladesh with high arsenic exposure. The authors need to explicitly acknowledge that the findings may need to be more generalizable to other populations with different levels of arsenic exposure or genetic backgrounds.

7) The study's cross-sectional nature limits the ability to draw definitive conclusions about causality. The authors must emphasize this limitation and suggest future longitudinal studies to establish a temporal relationship between arsenic exposure, sweat chloride levels, and lung function.

8) The manuscript needs more detailed information on the types of lung function tests conducted and the criteria used to define airflow obstruction. More specific information about the lung function assessment would strengthen the study's validity.

9) The study adjusts for several potential confounders. Still, other unmeasured factors, such as nutritional status, socioeconomic status, and exposure to different environmental pollutants, may influence the relationship between arsenic and lung function. The authors should address this limitation.

10) While the study did not find evidence of CFTR mutations in participants with elevated sweat chloride, it does not fully explore other potential mechanisms of CFTR dysfunction that may be induced by arsenic exposure. Expanding the discussion on this aspect would enhance the study's contribution to understanding arsenic toxicity.

Minor Comments:

1) Introduction: The introduction provides a good overview of the problem and the rationale for the study. However, it could be strengthened by briefly mentioning the specific aims and hypotheses of the study.

2) Methods: The methods section is generally well-described. However, providing more details on the quality control measures used for the sweat chloride and lung function testing would be helpful.

3) Results: The results are presented clearly and concisely. However, more information on the distribution of sweat chloride levels in the study population, such as the interquartile range or the 95% confidence interval, would be helpful.

4) Discussion: The discussion reasonably interprets the findings and their implications. However, it could be improved by discussing the study's limitations more explicitly and suggesting future research directions.

This study provides impressive insights into the relationship between arsenic exposure, sweat chloride levels, and lung function. The findings have important implications for public health, particularly in regions with high arsenic contamination. By addressing the negative comments and incorporating specific suggestions, the authors can significantly enhance their manuscript's clarity, precision, and impact.

Reviewer #2: 

- Please provide the IRB approval information of this study.

- In Figure 1, I may assume the comparison did not consider the impact of other factors on levels of sweat chloride. If this is true, then how to convince the readers the difference was mainly driven by arsenic exposure?

- Please verify the linearity assumption for association between As exposure and levels of sweat chloride.

- In mediation analysis, please specify what covariates were adjusted for mediator and outcome models. Usually the confounding factors in these two models should be different.

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Reviewer #3: The manuscript titled "Arsenic exposure is associated with elevated sweat chloride concentration and airflow obstruction among adults in Bangladesh: a cross-sectional study" investigates the link between arsenic exposure, CFTR dysfunction (as measured by sweat chloride levels), and pulmonary function in Bangladeshi adults. The authors hypothesize that arsenic exposure impairs CFTR function, reflected in elevated sweat chloride concentrations, and that this dysfunction may mediate arsenic’s impact on lung function. Through comprehensive measurements of arsenic levels in toenails and water, sweat chloride testing, pulmonary function testing, and CFTR genotyping, the study aims to establish sweat chloride as a biomarker for arsenic exposure and explore the mechanisms underlying arsenic-associated lung disease. This study is significant due to its focus on an underexplored potential biomarker (sweat chloride) for arsenic exposure and its implications for screening arsenic-related diseases in low-resource settings. However, the manuscript should only be considered after proper adjustments and corrections have been made including clarity in methodology, coherence in data interpretation, and justification of certain scientific claims. Kindly see attachement for all comments.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Attachments

Attachment

Submitted filename: response - arsenic exposure and sweat chloride.pdf

<p>Arsenic exposure is associated with elevated sweat chloride concentration and airflow obstruction among adults in Bangladesh: a cross sectional study

PONE-D-24-41161R1

Dear Dr. Mazumdar,

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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Kind regards,

Aaron Specht

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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: (No Response)

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: Partly

Reviewer #3: Yes

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

Reviewer #1: Yes

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: Yes

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: Yes

Reviewer #3: Yes

**********

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: The authors would not discuss the PM2.5 and arsenic exposure interaction, and the comprehensive view was not standing on the solid evidence, so the previous study demonstrated the PM2.5 existing arsenic fraction and represented elevation of risk (https://doi.org/10.1016/j.envpol.2019.113881), which authors should not omitted; thus, the biases should not null and need to discuss the PM2.5 and arsenic exposure interaction, even the cumulative external dose might be played as fallacy for assessment risk for arsenic exposure, which represented why authors need to convince us on scientific view. From a comprehensive point of view, the overall evidence might not stand on solid ground; authors need to discuss this in as much detail as possible. So the previous study demonstrated that the PM2.5 existing arsenic fraction and represented elevation of risk was not a coincidence; thus, the biases should not be null. I encourage these authors to find surrogate markers to adjust PM2.5 levels and re-analyse the risk of external arsenic exposure. Even with no more evidence, they should be humble enough to face the weakness in the present study.

Reviewer #3: The in-text citations should be formatted consistently throughout the manuscript. Currently, there are inconsistencies, such as in line 120 and line 420, and throughout the manuscript, the citations are placed directly after the last word without a space. To ensure clarity and adherence to proper citation formatting, the authors should include a single space between the last word and the citation number in all instances.

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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

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