Concise Review of Nickel Human Health Toxicology and Ecotoxicology

Round 1

Reviewer 1 Report

Ms No. 523613

“Concise Review of Nickel Human Health Toxicology and Ecotoxicology” by Buxton et al.

In this review, the authors stated about the detail of toxicity and effects of nickel on human and environments. 

Major comments:

This review includes enough information about biological effects of nickel.  However, it was not clear what the recent progress is.  The authors should emphasize the recent  progress in this field that made the authors decide to prepare this review.  In addition, the main part of the review should be based on the authors' findings.  The findings by authors should also be emphasized.

Author Response

Thank you for the review comments. We have implemented some changes in the manuscript in response to the reviewers' comments and addressed the comments below.

*Reviewer 1 questioned the recent progress that prompted this review. Firstly, this is the first review article to integrate the toxicity of nickel to human health and the environment. We have included a sentence in the abstract and in the conclusions to emphasize this point. This review is not just a review of 'old' literature, as demonstrated by the fact that over 70 of our references are published in the last 5 years. Additionally, we have a whole section dedicated to "Emerging Issues", which detail two areas of importance for both regulators and toxicologists, namely "Mixtures" and "Nanoparticles." Throughout this review manuscript, therefore, there is ample demonstration of the recent progress. This review is unlike other reviews on nickel toxicology, in scope and content.

*Reviewer 1 stated that "the main part of the review should be based on the authors' findings. The findings by authors should also be emphasized." We want to emphasize that this is a review manuscript, and our approach was to interpret and integrate the references into a coherent story, rather than just summarize authors' findings. However, it is worth noting that we do indeed summarize the findings of authors throughout the manuscript. 

Reviewer 2 Report

It is a well written comprehensive overview of the problem,  but one rather inportant aspect of the latter is neglected, namely nanotoxicology of nickel. I believe  you know, that not only are engineered NiO nanoparticles produced for various industrial applications (such as photoelectric and recording materials, catalysts, sensors, and ceramics), but they also make up a substantial proportion in the particle size distribution of condensation aerosolsgenerated by traditional metallurgical and arc-welding technologies. Meantime what you write about Ni respirastolry toxicokinetics  (your Section 2.2.2) is misleading as far as it concerns nanoparticles.

Besides, I'd recommend to touch peculiarities of Ni toxicity in combinatkion with some other metals typical of occupational exposures.

You may find relevant the following  publications:

Minigaliyeva I.A., Katsnelson B. A., Privalova L.I., Gurvich V.B., Panov V. G., Varaksin A.N., Makeyev O. H.,   Sutunkova M.P., Loginova N.V.,   Kireyeva E. P., Grigoryeva E.V., Slyshkina T. V., Ganebnykh E. V., Grebenkina S. V. Toxicodynamic and toxicokinetic descriptors of combined chromium (VI) and nickel toxicity. International Journal of Toxicology, 2014, V. 33(6), P. 498-505.         

Katsnelson B.A., Minigaliyeva I.A., Panov V.G.,  Privalova L.I.,  Varaksin A.N., Gurvich V.B., Sutunkova M.P., Shur V.Ya., Shishkina E.V., Valamina I.E.,  Makeyev O.H. Some patterns of metallic nanoparticles’ combined subchronic toxicity as exemplified by a combination of nickel and manganese oxide nanoparticles. Food and Chemical Toxicology, 2015, V.86, P. 351-364.

Minigalieva I.A., Katsnelson B.A., Privalova L.I., Sutunkova M.P.,  Gurvich V.B.,  Shur V.Y., Shishkina E.V.,  Valamina I.E.,  Makeyev O.H., Panov V.G.,  Varaksin A.N., Grigoryeva E.V., Meshtcheryakova E.Y. Attenuation of combined nickel (II) oxide and manganese (II,III) oxide nanoparticles’ adverse effects with a complex of bioprotectors. International Journal of Molecular Sciences, 2015, V. 16(9), P. 22555-22583

Minigalieva I.A, Bushueva T.V, Fröhlich E., Meindl C., Panov V.G, Varaksin A.N, Shur V. Ya, Shishkina E.V., Gurvivh V.B., Katsnelson B.A. Are in vivo and in vitro assessments of comparative and combined toxicity of the same metallic nanoparticles compatible, or contradictory, or both? A juxtaposition of data obtained in some experiments with NiO and Mn3O4 nanoparticles. Food and Chemical Toxicology, 2017, 109 (1): 393-404

Marina P. Sutunkova , Svetlana N. Solovyeva , Ilzira A. Minigalieva , Vladimir B. Gurvich, Irene E. Valamina , Oleg H. Makeyev , Vladimir Ya. Shur, Ekaterina V. Shishkina , Ilya V. Zubarev , Renata R. Saatkhudinova, Svetlana V. Klinova , Anastasia E. Tsaregorodtseva , Artem V. Korotkov, Eugene A. Shuman , Larisa I. Privalova  and Boris A. Katsnelson . Toxic effects of low-level long-term inhalation exposures of rats to nickel oxide nanoparticles. Int. J. Mol. Sci. 2019, 20, 1778

Author Response

Thank you to reviewer 2 for the comments on our review manuscript. We have made changes in the manuscript in response to the reviewer comments. Please find below our responses to the reviewers' comments.

*Reviewer 2 requested that we include more information under the nanoparticle section, especially in combination with other nanoparticles. We included more information on the "Mixtures" section to include studies on nickel in combination with other metals. We included a short review on welding fumes under this section, as an example of a mixture for which complementary human and animal data are available. We have also expanded on the "Nanoparticles" section to include the references provided by the reviewer. We included comparisons between micron and nano forms of nickel, as well as a discussion on the toxicity of nano nickel particles in combination with other metal nanoparticles.

*Reviewer 2 indicated that our discussion under section 2.2.2 on "Respiratory" toxicokinetics of nickel is misleading. We focused on the toxicokinetics and toxicity of micron-sized particles, which is why we limited the discussion on nanoparticles to a separate section. However, we understand how that may be misleading. As such, we included a sentence in section 2.2 to hopefully clear this up; "while most of the historically available information relates to micron size particles of nickel-containing substances, recent studies have looked at the toxicokinetics of nickel nanoparticles to characterize how they differ from those of the corresponding micron size. This is further discussed under section 5.2." We hope this explanation clarifies the discussion.