-->PONE-D-25-50711-->-->Cadmium Exposure and Hepato-renal Injury in Response to Cigarette Smoking in Apparently Healthy Active Smokers in Buea-Cameroon-->-->PLOS One

Dear Dr. Kouam,

Thank you for submitting your manuscript to PLOS ONE. Two expert reviewers in the field have evaluated the manuscript and provided constructive feedback that will enhance its quality. 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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Reviewer #1: Yes

Reviewer #2: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: Reviewer’s Comments

Cadmium Exposure and Hepato-renal Injury in Response to Cigarette Smoking in Apparently Healthy Active Smokers in Buea-Cameroon.

PONE-D-25-50711

Dear Editor-in-Chief,

This manuscript addresses a relevant public health concern by assessing cadmium exposure from cigarette smoking and its association with liver and kidney biomarkers in Buea, Cameroon. The study design and exposure assessment are appropriate, and findings are clearly presented and biologically plausible. Only minor clarifications are needed. The manuscript is acceptable with minimal revision.

Comments:

Abstract

Lines 31-34: I suggest authors rephrase objective to “This study, conducted in Buea (Southwest Region, Cameroon), aimed to assess cadmium inhalation exposure from cigarette smoking and its association with altered liver and kidney function biomarkers in apparently healthy smokers.”.

Line 34: rephrase to “A survey was used to recruit smokers and collect data on their smoking habits.”

Lines 34-35: rephrase to “Cadmium contents in the major cigarette brands selected were used to estimate daily cadmium exposure (DE)…..”

Line 38: replace “active” with “smokers”

Line 50: delete “active”

Introduction

Line 54-55: rephrase to “……to many organs and systems of the body” [1].

Lines 71-72: Some vital information on tobacco consumption and health in Cameroon are missing. I suggest you cite all tobacco papers from Cameroon e.g., https://www.ijtsrd.com/papers/ijtsrd46334.pdf and https://doi.org/10.56557/jodagh/2025/v18i29850

Line 73: rephrase to “Cigarette smoking can harm nearly all organs and systems of the human body.”

Line 74: insert “which are” to read as “…smoking can damage the liver and kidneys, which are two important organs..”

Line 80: rephrase to “…can lead to liver injury and fibrosis, a condition in which liver tissue becomes thickened and scarred.”

Lines 83-85: delete “an”, and “a” to read as “...including increased blood pressure, reduced renal blood flow, glomerular damage, and a gradual loss of kidney function”

Line 85: delete “activity”

Line 86: delete “, a state of irreversible kidney injury”

Line 88: replace “abnormal increased levels of blood urea and creatinine” to “abnormally elevated levels of blood urea and creatinine”

Line 83: Insert the statement from Line 90-92 “In the ……[20]” in line 83 after the reference “[16]”.

Lines 101-105: this objective is not the same as in the abstract section – make it uniform/the same.

Methods

Lines 111-113: what is the association between Cd levels/exposures with seasons? Did you show that in this work? I though population size of Buea could be vital mentioning here, so readers understand the scope of the study and potential damage due to Cd from smoking – or better still insert the data on population size

Lines 115-117: the statement “The area was therefore 116 chosen to raise awareness among the young and old alike that smoking can potentially damage vital 117 organs like the kidneys and the liver.” appears as if you knew the results of this work and as if the aim of your work was to raise awareness! I suggest you rephrase.

Lines 118-122: some vital information/components are missing on the study design, for example, the variables (independent/dependent), sampling methods, etc. kindly consider re-writing this section.

Lines 124-125: if that was the primary aim, what about the effects on hepatocellular/kidney functions etc

Line 129: is this “Cameroon [23] (Njoumeni et al., 2020)” or “Cameroon [23]” or “Cameroon [23, 24]” reference 24 being Njoumeni et al., 2020?

Line 131: N of 78 (95) is too small for such studies! Well, lets deal with it.

Lines 133-137: Inclusion and exclusion criteria not well stated eg., did you include smokers with known illnesses?

Line 140: Are there smoking areas in Buea???

Line 140: replace “a” with “each”

Lines 141-142: Not only is the statement too long, it has repetitions e.g. gave their consent by signing the informed consent … therefore, kindly shorten the statement and rephrase the second part of that statement from “..were clearly explained; and only participants who gave their consent by signing the informed consent were admitted to the study.” to read as “..were clearly explained. Participation in the study was limited to individuals who signed the informed consent form.”

Lines 138-149: What were the inclusion and exclusion criteria? This is missing from the manuscript. This information was attempted on lines 118-122.

Line 154: How was “pre-testing” done? I suggest you provide a statement on that. For example – “During the pre-testing phase, the questionnaire was randomly administered to five market women and ten primary school pupils in classes five and six. This process aimed to ensure that the language used in the questionnaire was simple, clear, and unambiguous, and that it could be easily understood by all participants. As more than 80% positive responses were obtained, the questionnaire was considered valid. The results of the pre-testing phase were not included in the findings of this study.”

Lines 151-163: The heading on line 151 does not adequately reflect the content in lines 152-163. Lines 158-163 deserve a separate subheading “Sampling of biological specimens (blood and urine)”. Meanwhile, the square brackets in Line 158 needs to be adjusted.

Line 164: replace “of” with “in”

Line 184: capital use “C” for the first “cadmium”

Line 186: something is wrong with the phrase “The estimation of DE (µg Cd/day) DIE (µg) and DIE (µg Cd/kg b.w. per day)” – please correct it – perhaps delete “DIE (µg)”

Line 189: this statement is a result (“Only four of the most consumed brands of cigarettes based on the responses”) and so should be taken to the results section where you would specify them. So rephrase by deleting “four of”

Line 190: put a full stop at the end of the statement.

Lines 191-192: I think De and DIE have been defined on line 186 and need not to be defined anymore.

Line 191: provide references for the formula 2 and 3 used.

Line 213: provide references for the formula 5 used.

Lines 214-215: items like “DIE” which have been defined needs not to be defined again.

Results

Lines 262-163: age range provided in square brackets is confusing as it appears as intext citation – use normal brackets.

Line 268 and 273: on table 1 and 2, use simple brackets and not square brackets for example - age range on table 1 and number of cigarettes for table 2 – it is confusing with intext citation

Line 278: use simple/normal brackets and not square brackets – do same through out the manuscript to differentiate intext citations from manuscript content information

Line 282: replace “1/4th” with “a quarter”. What do you mean by “nearly”? be specific!

Line 294: delete the phrase “an observation was that”

Line 325: close the bracket that is opened.

Lines 393-395: were these levels higher than the normal range? If not, then, although there was a difference, it doesn’t necessarily imply toxicity risk! Its good to compare with normal range first!

Lines 412-413: what does the figures “(37)”, “(38)”, “(39)” and “(25)” mean under the “Smoker Category” in the table headings.

Lines 457-461: On table 8 and table 9, what do you means by [0.00 - ] ??

Discussion

Lines 472-473: replace “these young individuals” with “smokers”

Overall, proofread the entire manuscript for grammer

Reviewer #2: In addition to Cadmium (Cd), cigarette smoke also contains PAHs: Polycyclic Aromatic e.g. B(a)P: Benzo (a) pyrene, B(a)A: Benzo (a) anthracene and TSNAs: Tobacco Specific Nitrosamines e.g. NNN: Nitrosonornicotine, NNK:4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone etc and Volatile components: CO, hydrocyanide, methane, ethylene, phenol, 1,3-butadiene etc. Authors must acknowledge presence of PAHs and aromatic amines as co-toxicants and confounders and state that combined exposure is likely to potentiates organ dysfunction.

Authors have observed alterations in serum ALT, urea, creatinine, albuminuria and glucosuria level which may be reflected with PAHs and aromatic amines toxicity. To distinguish cigarette smoke inhalation associated cadmium (Cd)-specific toxicity from effects of PAHs and aromatic amines also present in cigarette smoke, authors must rely on a combination of biomonitoring, mechanistic biomarkers, experimental modeling, and statistical adjustment. For this they must perform more experiments and add results.

Below is a structured scientific approach suitable to incorporate some of the following experiments and results in the manuscript.

1. DNA adduct formation, carcinogenesis mutagenesis via CYP 450 activation Hence, it may be checked as cadmium does not form DNA adducts like PAHs and aromatic amines

2. Measuring blood cadmium level (provide recent exposure) and urinary cadmium (will provide body burden). Some of the other cadmium specific biomarkers are metallothionein levels, renal tubular dysfunction, urinary β2-microglobulin, N-acetyl-β-D-glucosaminidase (NAG), Kidney Injury Molecule-1 (KIM-1) etc.

Results of some of above major tests may be incorporated in the manuscript.

Brand names of cigarette must bot be written, instead they can be coded like A, B, C .....

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Reviewer #1: Yes: Wilfred Angie Abia

Reviewer #2: Yes: Prof.(Dr.) Lakshmi Bala

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-->PONE-D-25-50711R1-->-->Cadmium Exposure and Hepato-renal Injury in Response to Cigarette Smoking in Apparently Healthy Active Smokers in Buea-Cameroon-->-->

PLOS One

Dear Dr. Kouam,

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.

Thank you for revising the manuscript and carefully addressing most of the reviewers’ comments, including the minor revisions suggested by Reviewer #1. The manuscript has improved substantially.

However, before the manuscript can be considered for acceptance, please carefully address the remaining concerns raised by Reviewer #2, particularly regarding the interpretation of cadmium-specific effects in the context of cigarette smoke as a complex mixture of toxicants. The title and relevant sections of the manuscript should be revised accordingly to avoid overstating cadmium as the sole causative factor.

Please submit your revised manuscript by Jun 22 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at 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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We look forward to receiving your revised manuscript.

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PLOS One

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Reviewer #2: (No Response)

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Reviewer #2: Partly

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: In context of the presence of co-toxicants in addition to Cadmium (Cd) in cigarette smoke as PAHs

(Polycyclic Aromatic Hydrocarbons) e.g. B(a)P: Benzo (a) pyrene, B(a)A: Benzo (a) anthracene and

TSNAs (Tobacco Specific Nitrosamines) e.g. NNN: Nitrosonornicotine, NNK:4(methylnitrosamine)-1-(3-pyridyl)-1-butanone etc and Volatile components as CO, hydrocyanide, methane, ethylene, phenol, 1,3-butadiene etc. The cadmium exposure stands as one of the contributing factor for the observed hepato-renal injury in apparently healthy individuals.

1. It is recommended that the “Title” should be changed as:

“Cadmium exposure as a contributing factor causing hepato-renal Injury in apparently healthy active cigarette smokers in Buea-Cameroon.”

2. Authors must acknowledge and explicitly write and incorporate it at various places (e.g. in Abstract, Introduction, Methods and Discussion) in addition to cadmium, presence of PAHs and aromatic amines etc. (as mentioned above) as co-toxicants and confounders. It should be stated that combined exposure may likely to potentiates/contribute organ dysfunction. However, in a resource-limited setting (Cameroon), this study acknowledges a significant limitation to evaluate the effect of other co-toxicants on liver and kidney. The present revolves around evaluation of cadmium exposure of individuals while active cigarette smoking and its effect on hepatic and renal functions.

3. In the conclusion, it should be added that to distinguish cadmium-specific effects from effects caused by PAHs and aromatic amines would require additional biomonitoring (e.g., blood and urinary cadmium levels), mechanistic biomarkers (e.g., metallothionein, β2microglobulin), and DNA adduct analysis [4,5]. Additional bioassays incorporating these measurements are needed to identify the specific contribution of cadmium to smoking-induced liver and kidney injury. Exposure to cadmium may cause carcinogenesis/mutagenesis via CYP 450 activation and may not directly form stable DNA adduct but may induce oxidative stress and interfere with DNA repair mechanisms.

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Reviewer #2: Yes: Lakshmi Bala

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Attachments

Attachment

Submitted filename: Lakshmi Bala_comments.docx

Cadmium Exposure as a Contributing Factor Causing Hepato-Renal Injury in Apparently Healthy Active Cigarette Smokers in Buea-Cameroon

PONE-D-25-50711R2

Dear Dr. Kouam,

The reviewers’ and editorial comments have been adequately addressed, and I am pleased to inform you that the manuscript is acceptable for publication pending final production checks. During proof correction, please revise the title slightly by deleting the word “causing” to avoid implying direct causality. The title should read: Cadmium Exposure as a Contributing Factor to Hepato-Renal Injury in Apparently Healthy Active Cigarette Smokers in Buea-Cameroon

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,

Iman Al-Saleh

Academic Editor

PLOS One

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