Urinary Glyphosate Exposure and Risk of Obstructive Airway Diseases in Youth and Adults: Population-Based Evidence from U.S. Biomonitoring Data

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for the invitation to review this manuscript. I read it with interest from the perspective of respiratory medicine and epidemiology. The authors aim to examine whether glyphosate exposure is associated with obstructive airway diseases in both adults and children using NHANES, categorizing exposure into tertiles and using multivariable logistic regression with age-stratified analyses and sensitivity analyses for recent asthma-related events. They found that in adults, a dose–response pattern, with higher glyphosate tertiles associated with higher odds of obstructive airway disease (highest tertile aOR ~1.29, statistically significant). In pediatrics, overall weak/uncertain associations, but stronger (though not statistically significant) point estimates in adolescents. Sensitivity outcomes in adults, a pattern suggesting higher odds of recent asthma attacks at the highest exposure tertile, though with wide uncertainty.

I appreciate the authors’ effort in leveraging a large, nationally representative dataset and in attempting stratified and sensitivity analyses, which strengthens the epidemiologic narrative. However, there are some points should be addressed.

1. Outcome definition

The authors appropriately acknowledge in the discussion that asthma/COPD outcomes are self-reported, which introduces misclassification risk (diagnostic access, recall, label bias, etc.). However, from a respiratory medicine standpoint, a major strength of NHANES is the potential availability of objective pulmonary function measures. NHANES includes spirometry (availability depends on cycle/age eligibility and quality grading).  Thus, I recommend that, if spirometry is available in the cycles used, it would be valuable to present and/or incorporate it in one or more of the following ways:

                1.1 Report baseline lung function (e.g., FEV₁, FVC, FEV₁/FVC, percent predicted if feasible) by glyphosate tertile.

                1.2 Define airflow obstruction using accepted criteria (fixed ratio and/or LLN) and run a sensitivity analysis using spirometry-defined obstruction.

                1.3 Alternatively, show spirometry descriptively to support construct validity of the self-reported outcomes.

 

However, if spirometry is not available for the selected cycles or is missing extensively, please state this clearly, quantify missingness, and explain why spirometry could not be used.

2. Age stratification

The manuscript states that analyses were stratified by age, and adolescents appear to be a key subgroup. Please clarify:

2.1. What exact age groups were used and why those cut-points were chosen.

2.2 Provide a citation to an external standard/guideline for these categories (as appropriate), such as WHO (or another widely accepted framework), or justify analytically (e.g., puberty-related differences, NHANES age bands, spirometry eligibility thresholds, or clinical relevance).

This is important because the pediatric results depend heavily on how “child” vs “adolescent” is defined, and readers will want to understand the rationale.

3) Table 1

In Table 1, please clarify whether “glyphosate level” and “glyphosate tertiles” refer to:

3.1 The **same exposure variable** presented in two formats (continuous concentration vs categorized tertiles), or

3.2 Two different metrics (e.g., raw vs creatinine-adjusted, serum vs urine, LOD-handling versions).

If it is the same exposure, please ensure terminology is consistent and specify the units, matrix (e.g., urine), any transformation, and how values below LOD were handled. Provide the tertile cut-points in the methods or a table footnote so the categorization is transparent and reproducible.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The authors examine the association of glyphosate exposure (based on urinary metabolites) and obstructive respiratory disease among youth and adults in the U.S. using NHANES data.  This is an interesting and important analysis, but it requires some thought in the presentation of the results as definitive.

 

The authors refer to participants under age 20 as “pediatrics.”  A strange use of the term.  They are children, adolescents and youth adults; the gloss “youth” would be more appropriate.

 

3.4 Subgroup Analysis by Age – the authors need to temper their statements.  None of the results reported in Table 5 attain statistical significance.  The pattern of results also raises concerns.  For example, among adults aged 20-39 years, those in the second tertile have 2.1 greater odds of COPD, but the UI includes zero and p=.07; those in the third tertile have an odds of 1.53, but this does not attain statistical significance.  Of the 18 comparisons in Table 5, none attain statistical significance; by chance alone, you would expect one to attain statistical significance.

 

3.5 Results of Sensitivity Analysis by Time-Bound Outcomes – again, the authors need to temper their statements.  They state, “Table 6 shows an increasing trend in the odds of asthma events in the past year with higher glyphosate tertiles in adults, suggesting a potential dose-response association.”  Yet none of the associations reported in Table 6 attain statistical significance (all the UIs include zero, all the p-values are >.05).  These results may be suggestive of a trend, but they are not proof of a trend.

 

4. Discussion – The authors need to temper their statements. They begin the discussion by stating, “Using NHANES data from 2013 to 2018, we found that higher urine glyphosate concentrations were associated with a greater likelihood of obstructive airway diseases, particularly among younger and middle-aged adults, as well as adolescents.” Such a definitive statement is difficult to support given that only two odds ratios across the 34 reported in Tables 3 through 6 attained statistical significance.

 

5. Conclusion – again the authors need to temper their claims concerning their results.

 

The results that the authors report are important, but their presentation needs to be tempered.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript be accepted for publication.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have responded appropriately to my comments.