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• Nickel related lung cancer: confounding a minor problem
  Tom K. Grimsrud
  Published on: 27 April 2016
• Smoking and lung cancer risk in Clydach nickel refinery report
  David F. Andrews
  Published on: 27 April 2016

• Published on: 27 April 2016

  Nickel related lung cancer: confounding a minor problem

  • Tom K. Grimsrud, Researcher

  Dear Editor,

  I thank Andrews and Heller for showing an interest in nickel related lung cancer in their electronic letter of 7 July 2006.[1] A large body of evidence exists on the link between nickel exposure and lung cancer. Among the most informative occupational cohorts were the one from Clydach, South Wales (where the risk was first observed); several cohorts of Canadian nickel workers; and the refinery cohort...

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  Dear Editor,

  I thank Andrews and Heller for showing an interest in nickel related lung cancer in their electronic letter of 7 July 2006.[1] A large body of evidence exists on the link between nickel exposure and lung cancer. Among the most informative occupational cohorts were the one from Clydach, South Wales (where the risk was first observed); several cohorts of Canadian nickel workers; and the refinery cohort from Kristiansand, Norway.[2] No data on smoking was necessary to identify dose-related risks from nickel exposure at these plants.

  Andrews and Heller mainly focused on a nested case-control study among the Norwegian refiners, published elsewhere.[3] For that study, we calculated individual cumulative nickel exposures for 738 employees, of whom 213 were diagnosed with lung cancer between 1952 and 1995. Exposure estimates were derived from personnel files and a revised job-exposure matrix.[4] Detailed smoking histories were collected from the participants or their closest relatives. There was a participation rate of 94% of all known cases and their matched controls.

  The aim of our study was to sort out the effect of exposure to different forms of nickel. The smoking data showed a strong, well-known association with lung cancer, and when this effect was adjusted for, we found a statistically significant effect from inhalation of nickel. The risk of lung cancer in the highest exposure group was between three and four times higher than that of the unexposed. The strongest dose-related effect was seen for water-soluble nickel compounds. More than half the number of lung cancers would have been avoided in the absence of nickel exposure. There was low to moderate confounding from smoking.[3] The effect of other potential confounders was negligible.[5]

  Two tables from this study caught the attention of Andrews and Heller, particularly the one intended to illustrate the joint effect of nickel and tobacco.[1] In this subanalysis, the confidence intervals were quite wide (omitted in Andrews’ and Heller’s letter) indicating that further splitting of the data would be of limited interest.[3] We agree with Andrews and Heller that some questions remain as regards the possible pattern of interaction between smoking and nickel exposure, and we conclude that the effect of nickel is seen most clearly in the group of former smokers and light to moderate current smokers, comprising the majority of the work-force.

  Our case-control data were analysed with conditional logistic regression, implying the use of multiplicative models. We explored our final model for interaction, but the product terms were not statistically significant.[3]

  Tom K Grimsrud

  Author’s affiliation

  Cancer Registry of Norway, Oslo

  Competing interests

  None declared

  References

  1 Andrews DF, Heller JG. Smoking and lung cancer risk in Clydach nickel refinery report (Electronic letter). Occup Environ Med 2006. http://oem.bmjjournals.com/cgi/eletters/63/5/365

  2 Doll R, Andersen A, Cooper WC et al. Report of the International Committee on Nickel Carcinogenesis in Man. Scand J Work Environ Health 1990;16(1, special issue):1-82.

  3 Grimsrud TK, Berge SR, Haldorsen T et al. Exposure to different forms of nickel and risk of lung cancer. Am J Epidemiol 2002;156:1123-32.

  4 Grimsrud TK, Berge SR, Resmann F et al. Assessment of historical exposures in a nickel refinery in Norway. Scand J Work Environ Health 2000;26(4):338-45.

  5 Grimsrud TK, Berge SR, Haldorsen T et al. Can lung cancer risk among nickel refinery workers be explained by occupational exposures other than nickel? Epidemiology 2005;16(2):146-54.

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  Conflict of Interest:
  None declared.

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• Published on: 27 April 2016

  Smoking and lung cancer risk in Clydach nickel refinery report

  • David F. Andrews, Professor
  • Other Contributors:
    • James G. Heller

  Dear Editor,

  The authors conclude that 'there was evidence of a persisting risk among process workers first employed since 1953' in the Clydach, South Wales, refinery. Unfortunately, they were unable to incorporate the confounding influence of such well-known predictors of health as attained education, income level and smoking status. An analysis of their data, stratified finely by smoking status, would yield use...

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  Dear Editor,

  The authors conclude that 'there was evidence of a persisting risk among process workers first employed since 1953' in the Clydach, South Wales, refinery. Unfortunately, they were unable to incorporate the confounding influence of such well-known predictors of health as attained education, income level and smoking status. An analysis of their data, stratified finely by smoking status, would yield useful information on the independent effect of exposure. The confounding role of smoking behaviour on inferences concerning nickel exposure can be demonstrated by examining a recently published case-control study by one of the authors of lung cancer risk in Norwegian nickel refinery workers.[1]

  

  Table 1, abridged from a corresponding table in Grimsrud et al. (2002)¹, shows clearly that lung cancer risk increases with amount smoked, reaching a 30-fold higher level for the Norwegian study's heaviest smokers.

  

  Table 2 shows that total nickel exposure risk decreases with increasing smoking level, clearly illustrating the complex interaction of disease, exposure and smoking behaviour. The highest exposure risk appears for the Never/Former smokers. However, for this group, the counts of cases in Table 2 (3,23) are almost the same as the counts (4,22) of the cases in Table 1. The significant odds ratios (ORs) for lung cancer were 3.8 for smoking and 5.0 for exposure. Without adjusting for smoking in this group, it is not possible to assess the separate contribution of either exposure or smoking. However, as will be seen, most of the risk associated with exposure comes from this small subset.

  This confounding of smoking and exposure effects is not surprising since there was a higher proportion of non-smokers among the controls in the Never/Former smoker group (93 of 234 controls or 40%) than among the cases (4 of 26 cases or 15%) (Table 1). The Light/Medium smoker group also shows relatively more light smokers among its controls (106 of 253 controls or 42%) than among its cases (49 of 146 cases or 34%). The OR for total nickel exposure in this group rises from 12.3 to 22.1 or 1.8 (Table 2). This estimate can be compared with the smoking OR for this group, which rises from 11.7 in Light smokers to 17.7 in Medium smokers or 1.5 (Table 1). These OR values are also not significantly different. The lung cancer risk in the Light/Medium smokers of the study could be attributed to smoking behaviour. Finally, the odds ratio of 0.9 in the heavy smoking group (Table 2) also provides no evidence of risk associated with nickel exposure.

  

  The complete Norwegian case/control dataset would have been required to duplicate exactly the odds ratios estimated using conditional logistic regression models to analyze lung cancer risk as a function of smoking status and total nickel exposure in Table 7 of Grimsrud et al. (2002). However, a simple logistic analysis (Table 3) closely approximates those ORs and their confidence intervals. This good agreement allows us to use our logistic models to examine the relationships between smoking and exposure in the Norwegian study.

  These odds ratios by smoking status lead to a conclusion very different from Grimsrud et al.'s. Significantly elevated lung cancer risks are seen for the Never/Former and Light/Medium smoker groups and, for the reasons discussed above, the attribution of this risk to smoking and/or exposure is unknown. These findings could be due to differences in the smoking histories of cases and controls.

  A comparison of two logistic models, each containing additive terms for total nickel exposure (2 levels) and smoking (3 levels) as explanatory factors, but one of which also includes a linear interaction term for exposure and smoking, shows that the interaction term is significant (p=0.016).[3] The significance of the interaction term indicates that an analysis that omits it will yield measures of exposure risk that include interaction effects.

  Smoking and exposure are strongly related in the Norwegian study. Its authors used a simple model in which the effects of smoking and exposure on lung cancer risk were presumed additive. Our analysis has shown the exposure/smoking interaction effect is significant. When one factor (smoking) has a large effect relative to that of the factor of interest (nickel exposure), the analysis is more informative if done separately for each level of the influential factor.[4] The failure to include this step in the analysis makes it impossible to assess the risk of nickel exposure. This calculation, which could be simply done with available Norwegian data, would inform our understanding of exposure risk in this and other studies, including the current Clydach study.

  D.K. Andrews and J.G. Heller

  Authors' affiliations

  D.K. Andrews, Dept. of Statistics, University of Toronto

  J.G. Heller, James G. Heller Consulting Inc., Toronto, Canada, and Dept. of Public Health Sciences, University of Toronto

  Competing interests

  Inco Ltd financially supported preparation of this letter by the authors. Falconbridge Ltd financially supported research² by the authors underlying this letter.

  References

  1 Grimsrud TK, Berge SR, Haldorsen T, et al. Exposure to different forms of nickel and risk of lung cancer. Am J Epidemiol 2002; 156: 1123- 1132.

  2 James G. Heller Consulting Inc. Report for Falconbridge Limited on Occupational Exposure Limits for Nickel. Falconbridge Ltd., Toronto, Canada. April 8, 2005. [unpublished]

  3 The SAS code yields output for two logistic models with and without an interaction term. The first model without the term has a chi squared likelihood ratio of 99.1857 with 4 degrees of freedom (df). The second with the term has a likelihood ratio of 93.4049 with 3 df. Consequently, the addition of the interaction term accounts for a decrease of (99.1857 - 93.4049) = 5.5808 with 1 df. The probability that a chi- square with 1 df exceeds this value is 0.016202, rounded to 0.016 in the text. Alternatively, SAS code yields a p-value of 0.0211 for the test of significance of the interaction term, based on an asymptotic approximation of normality for the distribution.

  4 Cox DR, Planning of Experiments. John Wiley and Sons, New Jersey. April 1992. ISBN: 0-471-57429-5.

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  Conflict of Interest:
  None declared.

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