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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?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

Reviewer #4: Partly

Reviewer #5: Yes

Reviewer #6: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: No

Reviewer #5: Yes

Reviewer #6: Yes

**********

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

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: No

Reviewer #5: Yes

Reviewer #6: Yes

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Reviewer #1: The author may revise the manuscript with proper scientific evidence and supporting data to arrive at definite conclusions. The reasons are to be clearly defined and stated in the conclusions part.

Reviewer #2: Dear authors,

I read your manuscript"Reference Values of Urinary Metabolites of Organophosphate in Healthy Iranian Adults"

To improve the article's quality, I recommended the following comments:

1. In the materials and method section, the type of metabolites and their properties such as purity have not been written.

2. The name of the internal standard has not been mentioned. Please add the name of the internal standard along with a reference.

3. what do you mean by reference value? About reference value, I think that you should cite to new references. References of 17, 18, and 19 for this keyword are very old. What is the difference between reference dose and reference value?

4. Please cite new references for all materials and methods subtitles. Almost, more of them are without reference.

5. In the results section, numerical data lack unit. please check all of them.

6. All references are very old. I think it is better to discuss new references. The discussion section is written poorly.

7. Results are very poor. Except for Table 7( Visceral fat ), other results are without any significant relationship.

8. I think that the conclusion could be written better.

Best regards,

Reviewer #3: This manuscript presents a study on the urinary levels of organophosphate pesticide metabolites among a healthy Iranian adult population. The study provides valuable data on exposure levels across different regions and demographic groups within Iran. However, the manuscript requires significant revisions to meet the publication standards.

Title

Make the title more descriptive and specific about the study's focus, such as "Assessment of Organophosphorus Pesticide Exposure Among Iranian Adults Using Urinary Biomarkers."

Abstract

Abstract does not cover the main aim of the study which is derivation of reference values (RV95s). why this is not reported?

Ensure the abstract is concise and free from redundancy. Simplify complex sentences and use straightforward language to enhance readability.

Define any abbreviations or acronyms.

Clarify the results. For instance: Metabolite levels ranged from 0-24.9 µg/l for TCP (median: 2.8 µg/l, 2.9 µg/gcrt….

What 0 means in the range? Below detection limit? Please clarify.

Introduction

- The text adequately highlights the importance of the issue but could be more specific about the context of Iran (a more detailed explanation of the current state of pesticide use and exposure in Iran), and the gap in biomonitoring data specific to this region.

- Expand the literature review to include more recent studies and data on pesticide exposure and its health effects, particularly those relevant to the Iranian context.

- The introduction lacks citations in some areas, and some references are not formatted correctly (e.g., "(10())").

- Clearly state the study's objectives at the end of the introduction. This helps to provide a clear direction for the paper.

Please revise the line 115-119 as following:

“ In Iran, the use of pesticides has increased significantly over the last decade, raising serious concerns about their toxicological and detrimental effects. Despite this, there has been no national biomonitoring study or reported RV95 for pesticides in Iran. This study aims to fill this gap by calculating RV95s using data from an HBM study that measured pesticide metabolites in urine and examined effective demographic factors in Iran.”

The introduction lacks clear structure and flow, with some sentences being long and complex, making it difficult to follow. The transition between general information and the specific focus of the study is not smooth. Some examples:

Please revise the sentence line as: “The annual use of pesticides in agriculture continues to rise due to the expansion of agricultural activities”

And the following sentence as “ While pesticides are essential tools in modern agriculture for improving food supply, protecting crops, and controlling pests and disease vectors, their widespread use poses significant risks to human health and the environment”.

Material and method

Age range of the participants should be mentioned.

The methods section briefly mentions that "after data cleaning, 490 samples were used for statistical analysis." There are no details on the specific data cleaning procedures (checking for outliers, inconsistencies, duplicates, and invalid data entries) or criteria used to determine which samples were included or excluded (Samples with incomplete demographic data or urine samples with insufficient volume). How is the data cleaning process done? How did you handle the missing information? Describe the methods used for imputing missing data and justify the choice of imputation method.

Line 135-137: delete this sentence. It does not belong here.

Provide the durations at various temperatures to ensure sample integrity.

Information on validation procedures for analytical methods, including recovery rates, precision, accuracy, are missing.

I could not find use of quality control samples to monitor method performance. Please elaborate on descriptions of how calibration curves are validated and the specific acceptance criteria for QC sample

Line 165 remove “ 200”: The limit of detection 165 (LOD) and limit 200 of quantification (LOQ) for these compounds are indicated in table 2.

Line 182: what do you mean with “physical measurements” ? Anthropometry?

was any sensitivity analysis conducted to assess the impact of for example different cofounders or missing data on the study results?

Lots of grammatical error and long and complex sentences. Please revise the text.

Method for calculating of RV is missing.

While the importance of lifestyle factors, or food patterns or other factors in interpretation of the results is mentioned by the author in the introduction section but it seems no data on these aspects is collected in this study. This is one of the limitations of the study that should be mentioned in the discussion.

Results

The results are comprehensive but somewhat difficult to follow due to the dense text and lack of clear subsections. Clear headings and subheadings would improve readability.

The descriptive statistics for anthropometric measurements and body composition are well-presented. However, including more comparative statistics (e.g., t-tests or ANOVAs) could provide insight into whether these differences are statistically significant.

Line 200- revise as following:

“ The study population was predominantly female (58.09%). However, in the age group 55-65, the gender distribution was equal”

Revise line 204

“ Men were taller and weighed more than women, whereas women had higher BMI and body fat percentages. Detailed statistics are provided in Table 4.”

It is mentioned that the population in the study broken down into five quintiles, from the income/wealth ladder perspective. But the method used, and rationale is not mentioned in the method section. Question is why this approach is taken while relationship between pesticide concentrations in urine and this factor is not assesses.

Discussion:

The discussion disproportionately focuses on chlorpyrifos, with less detailed analysis of diazinon and malathion. A more balanced discussion would provide a comprehensive understanding of all three pesticides.

Discussion on the potential source of exposure to these pesticides is missing. Did author collect any data on lifestyle and dietary habits?

Occupational exposure to pesticide is excluded however information on the job of participants are missing.

The discussion of non-significant findings, especially regarding demographic factors, is lacking. Providing potential explanations or considerations for these results is recommended.

While comparisons with previous studies are made, more in-depth analysis and discussion of why differences might exist (e.g., differences in study populations, methodologies, and environmental factors) would be beneficial.

There is limited discussion on the potential biological mechanisms underlying the observed associations, particularly for the significant correlation between visceral fat and chlorpyrifos levels.

The discussion is somewhat disorganized, with some points repeated and others not clearly linked to the results. Clearer subheadings and a more structured approach would improve readability.

A more detailed evaluation of the study's limitations (including the cross-sectional design, potential biases in self-reported data, among others) and their potential impact on the results is required.

Discussion on RV95 is limited. More detailed information and comparison with other available RVs is required. are there any HBMGVs for these pesticides? please add more information on interpretation of the results.

Conclusion:

Expand the conclusion to discuss the broader public health implications of the findings and how they can inform future research and policy.

How this study filled the gap mentioned in the introduction?

Reviewer #4: The article reported metabolites of specific pesticides among 490 healthy Iranian adults to established reference values. Please, see my comments below.

1. The pesticides measured in this study include chlorpyrofos TCP, Diazinon, and Malathion. Are these four organophosphorus pesticides the most commonly used in Iran? In addition are there other pesticides and why are they not reported here. Furthermore, metabolites identified the only ones observed?

2. In the abstract the authors clearly state what the objective of the study is

3. #94: what is large quantities? Are you inferring that exposure to low levels do not safe?

4. There is the need to improve the language at several places in the text (e.g., #98-113)

5. #117: which definition?

6. #118-119 not clear

Methods

1. how can eligibility criteria help achieve representativeness. It's your sample strategy. Please, provide a brief description of your sample, sample size calculation, and data collection. I am concern about the eligibility criteria. I, For comparison among/between studies can you explain why adult was defined here as 25+ , (ii) the inclusion criteria not exposed to second hand smoke is a bit strange. How will you ensure this. Just inquiring about this with a questionnaire is not enough. Besides, it’s now established that combustion of biomass for cooking and heating produces similar chemicals as found in cigarette smoke. What about those exposed to household air pollution, (ii) what is your definition os healthy and how will you ensure this, (. iv) I find your eligibility criteria as too arbitrary. And also the one on occupational exposire

2. Provide detailed description on how the data was collected, by who and when?

3. The information provided on urine sampling is woefully inadequate

4. A bit of clarification is needed here about the exact instructions that were given to participants concerning the urine collection. The explanation should clarify for males and females.

5. Provide soe detail information about the questionniare and its administration in the text

6. provide a detail description of the analysis and the models that were used

Results

1. were females over-sampled? since the purpsoe of this study was to generate a reference for the iranian population, is the current population representative enough?

2. one of the serious flaws of this study was selection bias and not too sure if this study is suitable for the development of a reference

Discussions

1. discuss the reasons for the differences between communities. Else, it will appear as if the results are repeated

2. #291: what type of milk?

3. The authors should carefully discuss their results

4. The strength and limitations of thr study should be thoroughly discussed in the light of selection bias, information bias and confounding where possible

Reviewer #5: The study focuses on the metabolites of Chlorpyrifos (TCP), Diazinon (IMPY), and Malathion (Malathion dicarboxylic acid). Key parameters recorded include age, gender, wealth index, and body composition metrics such as body fat, muscle, visceral fat, and BMI. Urine samples were collected and analyzed using LC-MS/MS, and the data were processed through descriptive statistics and multiple linear regression.

However there are some limitations:

a.Sample Size and Representativeness: This study included 490 people from six provinces in Iran. Iran has 31 provinces with different geographical environments and agricultural distributions. Is the selected population representative?please explain.

b.Single-Time Urine Sample Collection: Urine samples were collected only once from each participant. Pesticide levels can fluctuate based on agricultural cycles, dietary changes, or seasonal variations.Urine samples should be collected three times on different days.

c.In disscusion,lack of recent references: please add the latest references and remodify discussion section.

d.The English in this article is not academic or standard enough. the language should be polished.

Reviewer #6: Abstract

authors provide urinary concentrations adjusted for creatinine. Authors should specify this so reader understands difference between concentrations in units of µg/L and µg/gcrt

Introduction

Line 94 – "when used in large quantities" – risk from pesticides is related to level of exposure and not quantities used.

Line 97 – different pesticides have different toxic properties. Authors should report toxic properties based on pesticide group (organophosphates, pyrethroids, etc) and not all pesticides together

General – introduction should include more information on status of registration of pesticides in Iran. Is chlorpyrifos approved for use on food crops? Do you have data on amount used? In EU for example this pesticide is no longer approved for plant protection.

Sampling

Was study population adults? Children? Although this appears in Table 1 authors should state in text that study population was adults

Were there questions in the questionnaire about diet? Distance of home from agricultural fields? If not this should be mentioned in limitations of study

Results

Lines 203-210 – findings of less interest to reader in context of this study

Line 244 – does this mean people with higher visceral fat had lower levels of TCPy?

Discussion

For readers to understand the findings, it is important to present study results in comparison to current studies in general populations from different countries worldwide. Table 8 includes mostly studies from the US, and many studies in occupational populations. I would encourage authors to look for more recent data emerging from HBM4EU study. Data is available on HBM4EU dashboard. Comparison of results for population in Iran should be compared to current studies (not from 1990s) and not from occupational studies.

Also, it is worth mentioning results in context of risk assessment. How do results compare to risk based HBM thresholds? See https://www.sciencedirect.com/science/article/pii/S143846392300010X#bib105

Line 295 – why do you think exposure levels were higher in Kermanshah region? Previous studies have shown that diet is major source of exposure to Chlorpyrifos. Is it possible that there are dietary differences between regions? Or do certain regions have more agriculture and possible drift exposure of the general population?

In policy discussion – it is worth mentioning that chlorpyrifos has been phased out in many countries, see recent decisions in EU and US.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: Yes:  Reginald Quansah

Reviewer #5: Yes:  Wan Long

Reviewer #6: No

**********

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Attachments

Attachment

Submitted filename: PONE-D-24-11112.docx

Dear Dr. Alireza Mesdaghinia,

plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Murtada D. Naser

Academic Editor

PLOS ONE

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

Reviewer #6: (No Response)

**********

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

Reviewer #2: No

Reviewer #6: Yes

**********

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

Reviewer #2: No

Reviewer #6: Yes

**********

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

The PLOS Data policy

Reviewer #2: Yes

Reviewer #6: Yes

**********

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

Reviewer #2: Yes

Reviewer #6: Yes

**********

Reviewer #2: Dear authors,

please follow these comments:

1. In the abstract section, the following sentences should be placed after the aim of the article: "We measured metabolites for Chlorpyrifos (TCP: 2-isopropyl-4-methyl-6-hydroxypyrimidine), Diazinon (IMPY: 2-isopropyl-4-methyl-6-hydroxypyrimidine), and Malathion (Malathion dicarboxylic acid) in 490 healthy Iranian adults. Additionally, we recorded age, gender, wealth index, and body composition parameters including body fat, muscle mass, visceral fat, and BMI. Fasting urine sampling, along with body composition and demographic measurements, were conducted. Urine samples were subsequently analyzed."

2. What do you mean by "Our analysis included 300 ml of morning urine collected from participants on the fourth sampling day"?

3. Please correct Table 3, as the data presented is unclear. It is essential to apply appropriate statistical tests and analyses for comparing the data effectively.

4. In Tables 4, 5, and 6, please utilize a means comparison test to analyze the differences among the various variables, along with the corresponding P-values.

Reviewer #6: Authors should revise Table 8 to include more recent studies. Authors should consider removing occupational studies from this table. Authors mention HBM4EU study but should present data as well (perhaps in Table 8)

Line 325 - there have been studies showing toxicity of chlorpyrifos at levels lower than those that inhibit cholinesterase. Consider citing more recent studies here

Line 327 - "Studies in China and the U.S. reported higher pesticide poisoning rates in women than men" - this does not seem related to low level exposure (which is the topic of the current study) but perhaps suicide attempts? consider taking this statement out

**********

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Reviewer #2: No

Reviewer #6: No

**********

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Reference Values of urinary metabolites of organophosphate in healthy Iranian adults

PONE-D-24-11112R2

Dear Dr. Alireza Mesdaghinia,

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.

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Kind regards,

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Academic Editor

PLOS ONE

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