An expert panel met in a public workshop on February 15 and 16 in Cincinnati, Ohio to discuss a proposed hypothesis for lung tumor induction after inhalation exposure to various nickel substances.  The workshop provided a critical evaluation of the Nickel ion bioavailability hypothesis for lung tumor induction, as outlined in a draft paper prepared by Goodman and coworkers (Gradient). The goal was to determine whether the hypothesis is biologically plausible and coherent and is supported by the available data.  In particular, the workshop facilitated discussions of this model compared to the hypothesis known as “nickel ion theory.” Relevant epidemiological, animal and in vitro data will be reviewed and discussed.  Workshop participants also identified areas of consensus and areas of disagreement regarding the ability of the different hypotheses to explain the preponderance of the available data (epidemiology, animal, in vitro), the strengths and weaknesses of existing data to support or refute the hypotheses, the overall weight of evidence assessment regarding the respective hypotheses, and their utility in aiding the hazard assessment and/or risk assessment of nickel substances.  Suggestions for alternative models that better support the available data were also considered.  Participants were asked to identify data gaps and specific research studies that could be undertaken to validate or disprove the nickel ion bioavailability hypothesis. 

Toxicology Excellence for Risk Assessment (TERA) worked with the Nickel Producers Environmental Research Association (NiPERA, Inc.) to organize the workshop.  NiPERA, Inc. is a not-for-profit organization and an independently incorporated division of the Nickel Institute (see www.nipera.org).  NiPERA, Inc. was formed to develop and disseminate information on human health an environmental effects that might be associated with the production and use of nickel, its compounds and alloys. As such, NiPERA, Inc is committed to supporting scientifically sound research and promoting general awareness of the care required in the production, handling, use and disposal of nickel-containing materials.  Funding for the workshop was provided by NiPERA, Inc.

Workshop Panel Conclusions

An expert panel evaluated a proposed “nickel ion bioavailability” hypothesis for part of the mode of action of lung tumor induction after inhalation exposure to various nickel substances, as described by Gradient (2010; published post-meeting as Goodman et al., 2011). The panel attributed the carcinogenesis of nickel compounds to freely available nickel ion (i.e., nickel ion not bound to proteins) at the target cellular sites. The panel agreed that the subcellular targets of nickel's carcinogenicity are unknown, but that the dose metric of interest is the amount of free nickel ion that reaches the target. While the mechanism of action is not known, the panel agreed unanimously that nickel does not act by direct DNA reactivity. The panel concluded that, despite the limitations of the epidemiology data, it is clear that some forms of nickel at some concentrations do cause cancer, and that the observed tumors cannot be completely attributed to the effects of confounding exposures. The weight of evidence provides clear support for the carcinogenicity of insoluble forms, and fairly strong evidence that metallic nickel is not carcinogenic; however, the data are equivocal regarding soluble nickel. The potential for tumor promotion by soluble nickel was also noted.

Workshop Materials & Report

Agenda
Abstract of Goodman et al. Paper

Discussion Questions

Workshop Report Volume 1 - Report

Workshop Report Volume 2 - Appendices

For more information, contact Jacqueline Patterson (patterson@tera.org or 513-521-7426)