The nickel ion bioavailability model of the carcinogenic potential of nickel-containing substances in the lung

Abstract

The inhalation of nickel-containing dust has been associated with an increased risk of respiratory cancer in workplaces that process and refine sulfidic nickel mattes, where workers are exposed to mixtures of sulfidic, oxidic, water-soluble, and metallic forms of nickel. Because there is great complexity in the physical and chemical properties of nickel species, it is of interest which specific nickel forms are associated with carcinogenic risk. A bioavailability model for tumor induction by nickel has been proposed, based on the results of animal inhalation bioassays conducted on four nickel-containing substances. The nickel ion bioavailability model holds that a nickel-containing substance must release nickel ions that become bioavailable at the nucleus of epithelial respiratory cells for the substance to be carcinogenic, and that the carcinogenic potency of the substance is proportional to the degree to which the nickel ions are bioavailable at that site. This hypothesis updates the nickel ion theory, which holds that exposure to any nickel-containing substance leads to an increased cancer risk. The bioavailability of nickel ions from nickel-containing substances depends on their respiratory toxicity, clearance, intracellular uptake, and both extracellular and intracellular dissolution. Although some data gaps were identified, a weight-of-evidence evaluation indicates that the nickel ion bioavailability model may explain the existing animal and in vitro data better than the nickel ion theory. Epidemiological data are not sufficiently robust for determining which model is most appropriate, but are consistent with the nickel ion bioavailability model. Information on nickel bioavailability should be incorporated into future risk assessments.

Keywords::

• Mechanism of action
• metals
• respiratory cancer
• risk assessment
• tumor induction
• weight of evidence

Acknowledgments

An Expert workshop was convened by TERA in February, 2010 to provide input into the manuscript. The workshop report is available at the TERA Web site (http://www.tera.org/Peer/NiBioavailability/). We thank all workshop participants (Dr. Ambika Bathija, Dr. John Bukowski, Dr. Harvey Clewell, Dr. Max Costa, Dr. Michael Dourson, Dr. Lynne Haber, Dr. Andrea Hartwig, Dr. Uwe Heinrich, Ms. Melissa Kohrman-Vincent, Dr. Joseph R. Landolph, Jr., Dr. Len Levy, Dr. Günter Oberdörster, Ms. Jacqueline Patterson, Mr. Steven K. Seilkop, and Dr. Zong-Can Zhou) for their helpful discussions and insightful comments on a draft of the manuscript.

Declaration of interest

This paper was prepared with financial support to Gradient, a private environmental consulting firm, by the Nickel Producers Environmental Research Association, Incorporated (NiPERA, Inc.). NiPERA, Inc., is a not-for-profit research organization funded by the global nickel-producing industry through the Nickel Institute. The work reported in the paper was conducted during the normal course of employment. The authors have the sole responsibility for the writing and contents of this paper. The Expert workshop was also funded by NiPERA, and participants received an honorarium and were reimbursed for their expenses. One of the authors (A.R.O.) has appeared before government agencies to present information regarding classification or risk assessment of nickel metal and/or nickel compounds.