Respiratory cancer risks associated with low-level nickel exposure: an integrated assessment based on animal, epidemiological, and mechanistic data

Abstract

Increased lung and nasal cancer risks have been reported in several cohorts of nickel refinery workers, but in more than 90% of the nickel-exposed workers that have been studied there is little, if any evidence of excess risk. This investigation utilizes human exposure measurements, animal data from cancer bioassays of three nickel compounds, and a mechanistic theory of nickel carcinogenesis to reconcile the disparities in lung cancer risk among nickel-exposed workers. Animal data and mechanistic theory suggest that the apparent absence of risk in workers with low nickel exposures is due to threshold-like responses in lung tumor incidence (oxidic nickel), tumor promotion (soluble nickel), and genetic damage (sulfidic nickel). When animal-based lung cancer dose–response functions for these compounds are extrapolated to humans, taking into account interspecies differences in deposition and clearance, differences in particle size distributions, and human work activity patterns, the predicted risks at occupational exposures are remarkably similar to those observed in nickel-exposed workers. This provides support for using the animal-based dose–response functions to estimate occupational exposure limits, which are found to be comparable to those in current use.

Introduction

Nickel (Ni) in various forms is used in a wide range of products, including electric batteries, catalytic converters for automobiles, coins, and innumerable items containing stainless steel and other nickel alloys. In the production of nickel and nickel-bearing products, workers are often exposed to nickel and nickel compounds in the form of airborne dust and small particles. Epidemiological studies conducted on more than 100,000 nickel workers indicate that inhalation of certain nickel compounds can significantly increase lung and nasal sinus cancer risk if the exposure is sufficiently high. Increased respiratory risks have been observed predominantly in workers in dusty, high-exposure refinery processes, most of which are no longer in use today. Less than 8% of the workers that have been studied were exposed to these high-exposure operations with airborne nickel concentrations of more than 1–10 mg Ni/m³, depending on nickel compound. By contrast, little, if any evidence of increased respiratory cancer risk has been found in more than 90,000 workers with substantially lower nickel exposures, including those engaged in nickel mining and smelting, nickel alloy production, and the use of metallic nickel.

The purpose of this paper is to investigate whether the lack of evidence of respiratory cancer risk in most nickel workers (as compared to those involved in high-exposure refinery processes that are largely obsolete) is simply the result of a proportionally lower level of exposure and a lack of statistical power to detect small, but relevant risks, or whether there is evidence to suggest strongly non-linear or threshold carcinogenic responses to nickel and its compounds. In the latter case, cancer risks at relatively low occupational exposures would be non-existent or vanishingly small. Human epidemiology, current occupational exposure measurements, animal bioassay data, and mechanistic theory are used to explore the relative merits of these two propositions.