Letter to the Editor

Dear Editor, There are two aspects of the recent MiniReview Is nickel chloride really a non genotoxic carcinogen? by Stannard et al. (DOI: 10.1111/bcpt.12689) that merit some consideration. One aspect relates to the incomplete presentation of the existing animal carcinogenicity studies with soluble nickel (Ni) compounds, and the second one to the inclusion of new in vitro study results without providing information on materials and methods. As the subject of this review is the carcinogenicity mode of action of a water-soluble Ni compound (NiCl2), it was appropriate for the authors to review the outcome of animal carcinogenicity studies with other water-soluble compounds (e.g. sulphate, acetate) by relevant routes of exposure. All water-soluble compounds have similar bioavailability of the nickel ion (i.e. the toxic moiety). Yet, while the MiniReview describes some oral studies with Ni acetate and chloride, other substantial ones were omitted. The negative results from the U.S. National Toxicology Program inhalation studies of Ni sulphate in mice and rats 1 and the negative results from an oral carcinogenicity study of Ni sulphate in rats 2 were not mentioned. Furthermore, the authors did not mention that in the oral studies of Uddin et al. (2007) 3 with NiCl2 in mice, no tumours were induced by exposure to this water-soluble Ni compound alone. Any proposed mode of action for carcinogenicity of a water-soluble Ni compounds has to be consistent with the negative results from these animal studies. The reliance on previous review articles could have contributed to missing some key studies and could also have been responsible for some unintended miscitations. For example, after detailed tumour data from an epidemiological study of UK workers are presented, the article indicates that ‘This study also stated that smoking and nickel exposure had a synergistic effect on cancer risk’. While the reference given for the UK data is a review article and not a primary report for that cohort (e.g. such as 4 or 5, the citation for the second sentence is a primary report for a different study of Norwegian workers (Andersen et al., 1996) 6. There are many instances in the MiniReview where statements are made without proper citation. The MiniReview concludes in its Abstract that ‘NiCl2 has previously been classified as a non-genotoxic carcinogen (NGTC); however, after studying the effect of NiCl2 on many mechanistic endpoints, it has become clear that NiCl2 behaves more like a genotoxic carcinogen’. Within the text of the manuscript, the wording is more cautious: ‘More data is needed to make an accurate conclusion on the genotoxic potential of NiCl2’. The paper concludes that ‘A chronic dosing system may be able to detect the potential genotoxicity of previously classified non-genotoxic carcinogens which act via the accumulation of ROS, such as NiCl2’. The latter statement seems to be based on new data presented by the authors in figs. 3 and 4. The results from the in vitro studies (e.g. 4 hr or 24 hr of exposure to NiCl2) looking at toxicity, micronucleus formation and ROS generation are shown in figs. 3 and 4a. No information on protocols, description of the TK6 cell line or any details on methods are provided. Surprisingly, fig. 3 indicates that there was no micronucleus formation up to 600 μM NiCl2 for 4 or 24 hr. While the Abstract states that there were positive micronucleus results after 5-day repeated exposure to NiCl2, suggesting that repeated exposure was needed to see positive results, these 5-day micronucleus data were not included or discussed at all in the manuscript beyond the Abstract. This weakens the manuscript conclusions. In this context, and as in vitro positive results do not always translate into in vivo positive results, it is surprising that the authors did not mention the study where rats were exposed orally for three consecutive days to Ni sulphate and micronucleus formation in bone marrow was examined 7. Even at the maximum tolerated dose that resulted in increased measured Ni levels in target tissue, no induction of micronucleus was observed in this study. In summary, this manuscript relied extensively in older reviews, was imprecise in its citations and incomplete in the new data presentation. Overall, it missed an opportunity to include all relevant data in its assessment of the mode of action (non-genotoxic, indirect genotoxic or direct genotoxic) for the respiratory carcinogenicity of water-soluble nickel compounds.

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