Lung cancer risk associated with occupational exposure to nickel, chromium VI, and cadmium in two population-based case-control studies in Montreal

Nickel, chromium VI and cadmium were designated as IARC class 1 lung carcinogens in the early 1990s. However, the study results informing this designation have not been consistently replicated in the past two decades, and there remain some important questions about these metals’ effects at low levels of exposure. Further empiric research is therefore required to confidently reaffirm the carcinogenicity of these agents and to understand the circumstances in which they may be harmful.  The objective of this study was to investigate the relationship between exposure to either nickel, chromium VI or cadmium and subsequent risk of lung cancer among workers exposed to these substances at a variety of levels and in a wide range of occupations. Two large population-based case-control studies conducted in Montreal provided the data to investigate the carcinogenicity of these substances. Study I was conducted from 1979 to 1986, and included males aged 35 to 70 diagnosed with cancer at any of 19 selected cancer sites. Study II was conducted from 1996 to 2001 and included men and women aged 35 to 75 diagnosed with lung malignancies. In both studies, cases were ascertained in all hospitals on the island of Montreal, while age- and sexstratified population controls were selected from electoral lists. Detailed job histories, as well as lifestyle and socioeconomic measures, were elicited by interviewers with each subject. Job descriptions were then evaluated by an expert team of chemists and hygienists in order to determine whether the subject was exposed to each agent, and if so, to create measures of concentration, duration, and cumulative exposure over the course of each participant’s lifetime. In order to determine whether lifetime exposure to any of the metals of interest was associated with increased incidence of lung cancer, exposure data were analysed by logistic regression, adjusting for relevant confounders including detailed smoking history. Categorical measures of cumulative exposure were analysed, and effect modification by smoking was also explored. Study I and II were first analysed separately, and then combined when appropriate to increase statistical power.  At the exposure levels experienced by this population, subjects exposed to nickel incurred a small but significantly increased risk of cancer compared to those unexposed. Meanwhile, there did not appear to be any excess risk of lung cancer among workers exposed to chromium VI. Lung cancer risk was somewhat elevated, albeit not significantly so, after cadmium exposure. For each of the three metals, lung cancer risk was significantly elevated among non smokers, but not among smokers. The joint effect of smoking and exposure to each of the metals was compatible with an additive excess risk. However, confidence limits in this study tended to be wide, and lack of statistical power may limit interpretation of some of the results.  This study is unique in providing empiric evidence on lung cancer risks associated with low levels of exposure to nickel, chromium VI, or cadmium originating from a variety of occupational contexts. While many studies have failed to control for important co-exposures, this study benefited from the collection and availability of detailed histories of exposure to tobacco and other potential confounders. The results of this study have important public health implications, both in terms of determining ongoing risk experienced by exposed workers, and in terms of assessing risk to the general population exposed to these metals by means of pollution and cigarette smoke. This analysis will likely contribute to an upcoming IARC re-evaluation of the carcinogenicity of these metals. Examination of the relationship between exposure to cadmium, chromium VI and nickel and subsequent risk of lung cancer is therefore timely and pertinent.

Keyphrases: Cancer, Cadmium, Nickel, Epidemiology, Metals, Chromium, Occupational exposure, Lung neoplasms