Carcinogenicity assessment of water-soluble nickel compounds

Abstract

IARC is reassessing the human carcinogenicity of nickel compounds in 2009. To address the inconsistencies among results from studies of water-soluble nickel compounds, we conducted a weight-of-evidence analysis of the relevant epidemiological, toxicological, and carcinogenic mode-of-action data. We found the epidemiological evidence to be limited, in that some, but not all, data suggest that exposure to soluble nickel compounds leads to increased cancer risk in the presence of certain forms of insoluble nickel. Although there is no evidence that soluble nickel acts as a complete carcinogen in animals, there is limited evidence that suggests it may act as a tumor promoter. The mode-of-action data suggest that soluble nickel compounds will not be able to cause genotoxic effects in vivo because they cannot deliver sufficient nickel ions to nuclear sites of target cells. Although the mode-of-action data suggest several possible non-genotoxic effects of the nickel ion, it is unclear whether soluble nickel compounds can elicit these effects in vivo or whether these effects, if elicited, would result in tumor promotion. The mode-of-action data equally support soluble nickel as a promoter or as not being a causal factor in carcinogenesis at all. The weight of evidence does not indicate that soluble nickel compounds are complete carcinogens, and there is only limited evidence that they could act as tumor promoters.

Keywords::

• Causal association
• human exposure
• mode of action
• tumor promotion
• weight of evidence

Acknowledgments

We thank Lynne Haber of TERA and Steven Seilkop of SKS Consulting Services for comments and suggestions on a draft of this article. This work was supported by the Nickel Producers Environmental Research Association (NiPERA). This review represents the individual professional views of the authors and not necessarily the views of Haber, Seilkop, or NiPERA.

Declaration of interest: This work was funded by the Nickel Producers Environmental Research Association (NiPERA).

Notes

¹Acronyms used: ACGIH, American Conference of Governmental Industrial Hygienists; CHO, Chinese hamster ovary; CI, confidence interval; DNA, deoxyribonucleic acid; EHEN, N-ethyl-N-hydroxyethylnitrosamine; EU, European Union; FDA, Food and Drug Administration; GLP, Good Laboratory Practice; HIF-1, hypoxia-inducible factor-1; HT, high-temperature; IARC, International Agency for Research on Cancer; ICNCM, International Committee on Nickel Carcinogenesis in Man; IOM, Institute of Occupational Medicine; IRIS, Integrated Risk Information System; LT, low-temperature; MMAD, mass median aerodynamic diameter; MTD, maximum tolerated dose; NTP, National Toxicology Program; OECD, Organisation for Economic Co-operation and Development; RSC, roasting, smelting, and calcining; ROS, reactive oxygen species; RR, relative risk; SCE, sister chromatid exchange; SEM, scanning electron microscopy; SIR, standardized incidence ratio; SMR, standardized mortality ratio; U.S. EPA, U.S. Environmental Protection Agency; UV, ultraviolet; XANES, x-ray absorption near-edge structure; XRD, X-ray diffraction.

²Throughout this article, “nickel” refers to either the metal or nickel-containing compounds.

³Although the proportion of soluble nickel is higher in the electrolysis department, the concentration of soluble nickel (as well as other forms) is higher in other departments. If soluble nickel were the primary cause of the lung cancer, one would expect the risk to be higher in the departments with higher soluble nickel concentrations. This was not the case in this study.

⁴ Individuals who worked in both the smelter and the refinery at different times were included in the analyses at both sites.

⁵Easton et alet al. (1992) used geometric means because only the ranges of exposure estimates were available.

⁶This line of reasoning also applies for comparing SMRs and SIRs under other circumstances, such as across studies.