The Difficulties in Demonstrating That Aflatoxin Reduction Improves Stunting in Developing World Regions
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis is a comprehensive review on the challenges of correlating reduction of Aflatoxin levels with reduction in stunting in developing countries. Some observation:
-At the beginning of the article there should a paragraph mentioning some of potential mechanisms for aflatoxin growth stunting proposed in the literature. IGFBP-3 binding is already mentioned further down but it would be better to also briefly mention these in the introduction.
-There are two captions for Figure 3 on page 14, if both refer to the same figure above, they could be merged and gave them assigned letters like Figure 3A and 3B.
-Some units of measurements should be checked: for example, mg/ul would be better as mg/uL.
Author Response
Comment 1: -At the beginning of the article there should a paragraph mentioning some of potential mechanisms for aflatoxin growth stunting proposed in the literature. IGFBP-3 binding is already mentioned further down but it would be better to also briefly mention these in the introduction.
Response 1: Respectfully disagree - the mechanism discussed remains speculative thus it would seem odd to bring up in the introduction - ahead of introducing the topic of what the toxins are - few studies have even looked at this - so no change
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Comment 2: -There are two captions for Figure 3 on page 14, if both refer to the same figure above, they could be merged and gave them assigned letters like Figure 3A and 3B.
Response 2: I deleted the second Figure title - however the article reads better with the language scenario 1 and scenario 2, so this is one figure - but no change to 3a and b.
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Comment 3: Some units of measurements should be checked: for example, mg/ul would be better as mg/uL
Response 3: Units are correct mg/ul - the ul use is appropriate as it links into the occasiosn where aflatoxin-lysine in the a few studies is measured per ul of serum - aiding reader conversion - no change to manuscript
Reviewer 2 Report
Comments and Suggestions for AuthorsThe document is well written; however, I suggest some modifications to improve its readability.
Keywords: I suggest replacing the words that are also in the article title with others, in order to increase the document's searchability.
I suggest that the first section be about mycotoxins, followed by aflatoxins and then the consequences of intoxication, which would be the topics associated with clinical effects (1,4,5...).
Line 163: reference
I suggest replacing "personal communication" with published references.
I suggest reformulating the conclusions into a single topic that highlights the main consequences of the findings of this study and suggestions for future research. This should exclude repetitions of the main results and remove references from the section.
Line 37. A period is missing at the end of the sentence.
Author Response
Comment 1: Keywords: I suggest replacing the words that are also in the article title with others, in order to increase the document's searchability.
Response 1: Some additional key words are added
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Comment 2: I suggest that the first section be about mycotoxins, followed by aflatoxins and then the consequences of intoxication, which would be the topics associated with clinical effects (1,4,5...).
Response 2: Respectfully disagree - the manuscript is about stunting and suggestive that aflatoxin maybe causative - thus a the paper logically introduces some basics of stunting (in brief) but highlights the the traditional nuytrition/hygiene model explains only a modest amount - it then introduces mycotoxins and focuses on aflatoixns and epidemiological studies thereof - no change.
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Comment 3: Line 163: reference
Response 3: this sentence is about using the ref 74 albumin concentration and in relation to 1pg AF-lys/ul serum - thus it reports me doing a simple math convsersion - no additional ref would make sense - no chnage
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Comment 4: I suggest replacing "personal communication" with published references.
Response 4: I have included the only reference - I added personal communication as this was a widely discussed topic at a recent mycotoxin section of an international conference in New Orleans, - no change
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Comment 5: I suggest reformulating the conclusions into a single topic that highlights the main consequences of the findings of this study and suggestions for future research. This should exclude repetitions of the main results and remove references from the section.
Response 5: Agree - see track changes to that section
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Comment 6: Line 37, missing period
Response 6: period added - now line 38
Reviewer 3 Report
Comments and Suggestions for AuthorsThis review addresses a critical and intersection of environmental toxicology and global child health: the link between aflatoxin exposure and childhood stunting in low-resource settings. However, there are some questions that should be answered.
Major concerns
1. As a review paper, author has added one color Figure in this manuscript, including cartoon images, for the mechanism of aflatoxin action, including the source of aflatoxin.
2. Clarify the threshold hypothesis. The idea of a toxicological threshold (~50 pg/mg AF-alb) is central but remains speculative.
3. The manuscript briefly mentions fumonisins as a co-occurring mycotoxin but does not fully explore the synergistic effects of AF and other contaminants on stunting.
4. Clarify Figures. Revise Figures 3 and 4 to include quantitative data from published studies rather than hypothetical values, to enhance reproducibility.
5. There is no a section of Introduction, and aim of this manuscript should be added in the end of Introduction section.
6. Merge Figure 1a and Figure 1b, as well as Table 1a and Table 1b
7. English grammar and writing should be checked and revised throughout the manuscript. There are many low wrongs.
Minor concerns
1. Line 25, correct ‘growth;’.
2. Line 89, correct ‘8,9 position’.
3. Line 102, correct ‘ide(27)’.
4. Line 132, correct ‘(19)’.
5. Line 151, correct ‘[73,’.
6. Line 132, correct ‘29pg/mg’ to ’29 pg/mg’. please check this throughout the manuscript.
7. Line 173, correct ‘(19,’.
8. Table 1b, correct ‘75percentile’.
9. Table 1b, clarify what “n/d” means.
10. Line 216, ‘(p<0.001)’. ‘p’ should be italic. Please check and revise it throughout the manuscript.
11. Line 227, delete ‘Figure 2 here’.
12. Lines 278-279. Different font.
13. Line 308, correct ‘0·003’ and ‘0·04’.
14. Line 508, check ‘Figure 3. Postulated distributions….’.
15. Lines 545–546, check ‘Review Toxin 2025 Fig 4 Hypothetical….’.
16. Lines 584-604, revise ‘1., 2., …’ to ‘I, II, III, …’ or others.
17. Before the References section, add ‘Conflict of Interest Statement’ and others.
18. The format of references should be based on MDPI style.
Author 1, A.B.; Author 2, C.D. Title of the article. Abbreviated Journal Name Year, Volume, page range.
Comments on the Quality of English LanguageThe English could be improved to more clearly express the research.
Author Response
Comment 1: As a review paper, author has added one color Figure in this manuscript, including cartoon images, for the mechanism of aflatoxin action, including the source of aflatoxin.
Response 1: no response - unclear if this is a comment or a query
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Comment 2: Clarify the threshold hypothesis. The idea of a toxicological threshold (~50 pg/mg AF-alb) is central but remains speculative.
Response 2. In general a threshold for toxic action for non-cancer effects is neither hypothetical nor speculative - to our knowledge no paper has suggested what this might be - the 50pg/mg is based on a study in Benin - but there is clear explanation in the text on this - indicative that the 50 pg/mg is based on the ELISA data - and that this may only be relevant for this population, The text describes this in detail - and the point is to draw the reader to the idea that they could do an aflatoxin intervention that reduces exposure but has no effect on growth - the discussion is modified slightly to reinforce this this - but it is expected that readers know about dose-response without a further discussion on what a treshold means .
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Comment 3: . The manuscript briefly mentions fumonisins as a co-occurring mycotoxin but does not fully explore the synergistic effects of AF and other contaminants on stunting.
Response 3: Authors are not aware of studies reporting synergistic effects of AF and fumonsins on stunting - there is scant evidence of that interaction on liver cancer, and the evidence of fumonisins causing stunting is extremely limited - thus this review mentions it - but further discussion becomes so speculative as to be a distraction. no chnage.
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Comment 4: Clarify Figures. Revise Figures 3 and 4 to include quantitative data from published studies rather than hypothetical values, to enhance reproducibility.
Response 4: Figure 3 scenario 1 is purely hypothetical to make a point, scenario 2 is based on data from Benin as referenced. It is explained that this is used as an illustartion of how dose-response and thresholds work - going back to comment 2. Figure 4 is based on several studies as indicated where we observe both seasonality and chnages based on diet - again this figure is ilustartive deliberately - no change
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Comment 5: There is no a section of Introduction, and aim of this manuscript should be added in the end of Introduction section.
Response 5: Section 1 is converted to an introduction, with the addition of a set of aims to the review
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Comment 6: Merge Figure 1a and Figure 1b, as well as Table 1a and Table 1b
Response6: Figures 1a and 1b are deliberately distinct as initially the toxins and introduced and then key metabolites are discussed - no change. The manuscript is very purposefully laid out to introduce a modest study design - allowing readers to understand that data, and then studies that follow a cohort - stonger design. Merging these tables would significantly impact reasdability and understanding - additionally these tables become overly large and cumbersome - therfore less readable- no change
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Comment 7: English grammar and writing should be checked and revised throughout the manuscript. There are many low wrongs.
Response 7: we have edited the manuscript using track changes to correct these issues
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Minor concerns
- Line 25, correct ‘growth;’. RESPONSE - DONE
2. Line 89, correct ‘8,9 position’.RESPONSE - DONE now line 95
3. Line 102, correct ‘ide(27)’.RESPONSE - DONE now line 108
4. Line 132, correct ‘(19)’. RESPONSE - DONE now line 138
5. Line 151, correct ‘[73,’. RESPONSE - DONE now line 157
6. Line 132, correct ‘29pg/mg’ to ’29 pg/mg’. please check this throughout the manuscript. RESPONSE - DONE
7. Line 173, correct ‘(19,’. RESPONSE - DONE now line 179
8. Table 1b, correct ‘75percentile’. RESPONSE - DONE
9. Table 1b, clarify what “n/d” means. RESPONSE - defined already as no data
10. Line 216, ‘(p<0.001)’. ‘p’ should be italic. Please check and revise it throughout the manuscript. RESPONSE - DONE
11. Line 227, delete ‘Figure 2 here’. RESPONSE - DONE
12. Lines 278-279. Different font. RESPONSE - this is deliberatly highlighted - but if innappropriate can be adjusted?
13. Line 308, correct ‘0·003’ and ‘0·04’. RESPONSE - DONE now line 315
14. Line 508, check ‘Figure 3. Postulated distributions….’. RESPONSE - removed
15. Lines 545–546, check ‘Review Toxin 2025 Fig 4 Hypothetical….’. RESPONSE - adjusted
16. Lines 584-604, revise ‘1., 2., …’ to ‘I, II, III, …’ or others. RESPONSE - DONE
17. Before the References section, add ‘Conflict of Interest Statement’ and others.RESPONSE - DONE
18. The format of references should be based on MDPI style. RESPONSE - Modified all
Author 1, A.B.; Author 2, C.D. Title of the article. Abbreviated Journal Name Year, Volume, page range.
Round 2
Reviewer 3 Report
Comments and Suggestions for AuthorsThanks for author’s responses. However, there are STILL some concerns.
- As a review paper, author should added one color Figure in this manuscript, including cartoon images, for the mechanism of aflatoxin action, including the source of aflatoxin.
- Figures 1a and 1b are from other papers. Permission is required.
- This manuscript should greatly benefit from professional English language editing services. There are STILL many low wrongs throughout the manuscript.
For example,
- Lines 48-49, delete ‘(IYCF)’ and ‘(WASH)’. If the abbreviation only appears once in the text, please delete it, and check this throughout the manuscript.
- Line 108, correct ‘(27)’.
- Line 167, correct ‘mg/ul’ and ‘1pg/ul’ to ‘mg/μl’ and ‘1 pg/μl’. Please check others throughout the manuscript.
- Lines 283-284, different font.
- Line 306, correct ‘p<0.001’. ‘p’ should be italic. Please check and revise it throughout the manuscript.
- Line 515, ‘(Gong et al., 2002, 2003, 2004)’, please add the Reference numbers.
- Line 617, ‘CONCLUSIONS’, does not use full capitalization.
- The format of references should be based on MDPI style.
Author 1, A.B.; Author 2, C.D. Title of the article. Abbreviated Journal Name Year, Volume, page range.
For example,
Ref. 2, revise ‘2013;382(9891):525-34’ to 2013, 382, 525-534’. Please revise others.
Ref. 44, delete ‘(Basel)’.
Comments on the Quality of English LanguageThe English could be improved to more clearly express the research.
Author Response
Comment 1: As a review paper, author should added one color Figure in this manuscript, including cartoon images, for the mechanism of aflatoxin action, including the source of aflatoxin.
RESPONSE: Disagree - we know the mechanism for cancer, but not for stunting, only unproven suggestions - thus it seems in appropropriate
Comment 2. Figures 1a and 1b are from other papers. Permission is required.
RESPONSE: These are actually produced by me more than a decade ago - and should not be referenced - ref removed from subtitles
Comment 3: This manuscript should greatly benefit from professional English language editing services. There are STILL many low wrongs throughout the manuscript.
RESPONSE: Manuscript has been uodated as indicated in additional track changes
Additional
- Lines 48-49, delete ‘(IYCF)’ and ‘(WASH)’. If the abbreviation only appears once in the text, please delete it, and check this throughout the manuscript. RESPONSE _ DONE
- Line 108, correct ‘(27)’. RESPONSE REMOVED
- Line 167, correct ‘mg/ul’ and ‘1pg/ul’ to ‘mg/μl’ and ‘1 pg/μl’. Please check others throughout the manuscript. RESPONSE - DONE
- Lines 283-284, different font. RESPONSE DONE
- Line 306, correct ‘p<0.001’. ‘p’ should be italic. Please check and revise it throughout the manuscript. RESPONSE DONE
- Line 515, ‘(Gong et al., 2002, 2003, 2004)’, please add the Reference numbers. RESPONSE DONE
- Line 617, ‘CONCLUSIONS’, does not use full capitalization. RESPONSE - DONE
- The format of references should be based on MDPI style. RESPONSE - MODIFIED
Author 1, A.B.; Author 2, C.D. Title of the article. Abbreviated Journal Name Year, Volume, page range.
For example,
Ref. 2, revise ‘2013;382(9891):525-34’ to 2013, 382, 525-534’. Please revise others.
Ref. 44, delete ‘(Basel)’.
