Prof Thomas Behrens
email: thomas.behrens@dguv.de

LOD Limit of detection OR Odds ratio RERI Relative excess risk due to interaction SCOEL European Union Scientific Committee on Occupational Exposure Limits

Keywords: Metals, Pulmonary Cancer, Smoking, SYNERGY, Welders CI Confidence interval Cr

III) Trivalent chromium

Cr(VI)

Hexavalent chromium

INTRODUCTION

The hexavalent form of chromium (Cr(VI)) has been long recognized as human carcinogen. 1 Exposure mainly arises in hot metal processes, during the processing of stainless steel, during surface treatment by polishing, sanding, and grinding, and, historically, during the manufacture of chromium pigment. 2,[START_REF] Sciannameo | Cancer mortality and exposure to nickel and chromium compounds in a cohort of Italian electroplaters[END_REF] In previous analyses of the German MEGA measurement database, we observed the highest Cr(VI) concentrations in spray painting and hard-chromium plating, and also in welding fumes from shielded metal arc welding and flux-cored arc welding. [START_REF] Pesch | Airborne exposure to inhalable hexavalent chromium in welders and other occupations: Estimates from the German MEGA database[END_REF] Determination of Cr(VI) is difficult as it is frequently deoxidized to the more stable trivalent chromium (Cr(III)). [START_REF] Unceta | Chromium speciation in solid matrices and regulation. A review[END_REF] In contrast to Cr(III), Cr(VI) readily passes cell membranes. Intracellular reduction to Cr(III) may lead to oxidative stress, resulting in protein and DNA damage, genomic instability, cytotoxicity, tissue damage, chronic inflammation, and epigenetic changes such as microRNA, histone modification, and DNA methylation which all may trigger carcinogenesis. [START_REF] Proctor | Assessment of the mode of action for hexavalent chromium-induced lung cancer following inhalation exposures[END_REF] The European Union Scientific Committee on Occupational Exposure Limits (SCOEL) estimated an "acceptable" lifetime excess risk of four additional lung-cancer cases per 1,000 after a 40-year occupational exposure to 1 μg/m 3 of Cr(VI) (40 μg/m 3 -years). [START_REF] Hartwig | SCOEL/REC/386 Chromium VI compounds: Recommendation from the Scientific Committee on Occupational Exposure Limits[END_REF] Nickel is a widespread occupational exposure in various jobs and industries, frequently with coexposure to chromium. 1 Exposure frequently occurs in nickel alloy and battery production. [START_REF] Hayes | The carcinogenicity of metals in humans[END_REF] It has been demonstrated that workers in several industrial processes (e.g. metal-cutting and metalforming activities, metal spraying, sintering, chemical production, manufacturing of glass, batteries and accumulators, as well as certain welding processes) have experienced exposures at median nickel concentrations above 10 μg/m 3 , which is the recommended SCOEL threshold limit value to protect workers from carcinogenicity. [START_REF]Social Affairs and Inclusion[END_REF][START_REF] Kendzia | Modelling of occupational exposure to inhalable nickel compounds[END_REF] As early as 1979, working in nickel refineries was classified as Group 1 carcinogen by the International Agency for Research on Cancer (IARC), [START_REF]IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Chemicals and Industrial Processes Associated with Cancer in Humans (IARC Monographs Volumes 1 to 20)[END_REF] and the same classification was later also assigned to various nickel compounds. 1 So far, epidemiological evidence on the exposure-effect relationship between occupational exposure to Cr(VI) or nickel with lung-cancer risk primarily has been obtained from studies among workers in chromate production and in nickel refining. [START_REF] Crump | Dose-response and risk assessment of airborne hexavalent chromium and lung cancer mortality[END_REF][START_REF] Gibb | Extended followup of a cohort of chromium production workers[END_REF][START_REF] Grimsrud | Lung cancer incidence among Norwegian nickel-refinery workers 1953-2000[END_REF] Increased lung-cancer risks were also described in chromate pigment production and among chrome plating workers. 2 At-risk occupations with exposures to Cr(VI) and nickel comprise welders as the largest workforce. Welding fumes have been classified as a Group 1 carcinogen, [START_REF]IARC Monographs on the Evaluation of Carcinogenic Risks to Humans[END_REF] and several job titlebased analyses have demonstrated increased risks for lung cancer among professional, [START_REF] Honaryar | Welding fumes and lung cancer: a metaanalysis of case-control and cohort studies[END_REF][START_REF] Pesch | Exposure to Welding Fumes, Hexavalent Chromium, or Nickel and Risk of Lung Cancer[END_REF][START_REF] Kendzia | Welding and lung cancer in a pooled analysis of case-control studies[END_REF] but also occasional welders. [START_REF] Kendzia | Welding and lung cancer in a pooled analysis of case-control studies[END_REF] Due to the complex composition of welding fumes, it is challenging to attribute lung-cancer risk to one of its major components, which may be illustrated by the inability of many studies to demonstrate consistently elevated lung-cancer risks to Cr(VI) or nickel exposure in association with welding activities. [START_REF] Honaryar | Welding fumes and lung cancer: a metaanalysis of case-control and cohort studies[END_REF][START_REF] Pesch | Exposure to Welding Fumes, Hexavalent Chromium, or Nickel and Risk of Lung Cancer[END_REF] There is little evidence showing quantitative, measurement-based exposure-effect relationships between Cr(VI) or nickel and lung cancer across a wide array of job activities, while adjusting for smoking habits. We therefore took advantage of data from the pooled SYNERGY case-control study of occupational lung cancer to estimate relative risks related to occupational exposure to Cr(VI) or nickel. The objectives of this paper were: 1) to estimate lung-cancer risk associated with quantitative indices of occupational exposure to Cr(VI) and to nickel; 2) to assess the shape of the exposure-effect relationship between each metal and lung cancer separately; and 3) to assess their joint effects with smoking habits.

METHODS

SYNERGY Project

The detailed objectives, methods, and aims of SYNERGY are described elsewhere. [START_REF] Olsson | Exposure-Response Analyses of Asbestos and Lung Cancer Subtypes in a Pooled Analysis of Case-Control Studies[END_REF][START_REF] Ge | Respirable Crystalline Silica Exposure, Smoking, and Lung Cancer Subtype Risks A Pooled Analysis of Case-Control Studies[END_REF] Briefly, SYNERGY was established as an international pooled case-control study to investigate joint effects of occupational carcinogens (asbestos, [START_REF] Olsson | Exposure-Response Analyses of Asbestos and Lung Cancer Subtypes in a Pooled Analysis of Case-Control Studies[END_REF] respirable crystalline silica, 20 polycyclic aromatic hydrocarbons, 21 chromium, nickel) and smoking [START_REF] Pesch | Cigarette smoking and lung cancer--relative risk estimates for the major histological types from a pooled analysis of case-control studies[END_REF] in the development of lung cancer. Over the years, this study has developed into an international platform for research on occupational lung cancer with 16 case-control studies from 22 study centers. For this analysis, we used data from the 14 original SYNERGY studies from Europe and Canada (Table S1), including 16,901 lungcancer cases and 20,965 control subjects. More information about SYNERGY is available at http://synergy.iarc.fr.

Assessment of occupational exposure to Cr(VI) and nickel

The development of the quantitative job-exposure matrix SYN-JEM to assess occupational exposure to Cr(VI) and nickel followed a protocol which has been described in detail elsewhere. [START_REF] Peters | SYN-JEM: A Quantitative Job-Exposure Matrix for Five Lung Carcinogens[END_REF] Briefly, personal measurements of chromium (n=24,150) and nickel (n=22,081), covering a period from the 1970s to 2009, were collected in the participating countries, compiled in the ExpoSYN database, and tagged with an ISCO-68 job title. Overall, 35% of the chromium and 28% of the nickel measurements were below the limit of detection (LOD). [START_REF] Peters | SYN-JEM: A Quantitative Job-Exposure Matrix for Five Lung Carcinogens[END_REF] We substituted these measurements with a random figure between 0 and the LOD, assuming that they followed the same log-normal probability distribution as the measurements above LOD. [START_REF] Lubin | Epidemiologic evaluation of measurement data in the presence of detection limits[END_REF] A standard linear mixed-effects model was developed to assign region-and time-specific exposure levels for each ISCO-68-based job title that was solicited from the subjects' selfreported job histories. Region/country and job title were used as random effects, whereas year of measurement, sampling duration, and a prior exposure rating from a semi-quantitative expertbased job-exposure matrix (DOMJEM) assigning no, low, or high exposure levels [START_REF] Offermans | Comparison of expert and job-exposure matrix-based retrospective exposure assessment of occupational carcinogens in the Netherlands Cohort Study[END_REF] were included as fixed effects. The DOMJEM rating was used as an override for non-routine measurements to set jobs considered to be non-exposed to 0 μg/m 3 . In addition, models for Cr(VI) and nickel included the analytical method as fixed effect. Measurements conducted for jobs that were assumed by SYN-JEM to be non-exposed were retained in the model for the overall assessment of time trends and regional differences in Cr(VI) and nickel levels. Model-based estimates were used to calculate the amount of Cr(VI) based on specific Cr(VI) (n=8,363) and total chromium measurements (n=15,787). For total chromium values a conversion factor set at a total chromium:Cr(VI) ratio of 3:1 was applied. [START_REF] Peters | SYN-JEM: A Quantitative Job-Exposure Matrix for Five Lung Carcinogens[END_REF] The model yielded a linear temporal trend with an annual decrease of Cr(VI) concentrations of -2.7% and -1.2% per year for nickel. When there were <5 measurements for a specific job, the mean estimate of all jobs within the same unit or major group was used to base a job-specific exposure estimate on information from similar jobs. [START_REF] Peters | SYN-JEM: A Quantitative Job-Exposure Matrix for Five Lung Carcinogens[END_REF] It should be noted that assigning quantitative exposure data as part of a job-exposure matrix may lead to a combined classical measurement and Berkson-type of error structure, which may cause over-or underestimation of coefficients in logistic-regression analysis. [START_REF] Kim | Bias in the estimation of exposure effects with individual-or group-based exposure assessment[END_REF] Lifetime cumulative exposure to Cr(VI) or nickel was calculated as the sum of the country/regionspecific SYN-JEM estimates for each job and year. Cumulative indices were categorized according to quartiles based on the distribution among all (both sexes combined) control subjects.

For interaction analyses a cutoff at the median was applied to define low and high exposure categories.

Statistical analysis

We calculated odds ratios (OR) with 95% confidence intervals (CI) by unconditional logistic regression analysis. The main models included either Cr(VI) or nickel as the exposure variable, in addition to a number of covariates. Mutual adjustment was not performed in the main models, because a strong correlation between cumulative Cr(VI) and nickel levels was observed in subjects with co-exposure to both metals (Pearson r=0.75; 95% CI 0.74-0.76). The reference category therefore consisted of subjects who were not exposed occupationally to either Cr(VI) or to nickel.

To control for confounding, we employed two different models: OR1 was adjusted for study and age group (<45, 45-49, 50-54, 55-59, 60-64, 65-69, 70-74, 75+ years) and OR2 was additionally adjusted for cumulative cigarette consumption (log(cigarette pack-years+1), smoking status including time-since-quitting smoking cigarettes (current smokers, stopping smoking 2-7 years, 8-15 years, 16-25, 26+ years before interview/diagnosis, never smokers), and ever employment in a "list A" job (yes/no). List A includes occupations and industries with an established lung cancer risk. [START_REF] Ahrens | A standard tool for the analysis of occupational lung cancer in epidemiologic studies[END_REF][START_REF] Mirabelli | Database di occupazioni e attività industriali che comportano rischio di tumore del polmone [Database of occupations and industrial activities that involve the risk of pulmonary tumors[END_REF] This approach is consistent with the other analyses in SYNERGY. [START_REF] Olsson | Exposure-Response Analyses of Asbestos and Lung Cancer Subtypes in a Pooled Analysis of Case-Control Studies[END_REF][START_REF] Ge | Respirable Crystalline Silica Exposure, Smoking, and Lung Cancer Subtype Risks A Pooled Analysis of Case-Control Studies[END_REF][START_REF] Olsson | Occupational exposure to polycyclic aromatic hydrocarbons and lung cancer risk: results from a pooled analysis of case-control studies (SYNERGY)[END_REF] Cigarette pack-years were calculated as smoking duration (years) x average cigarette smoking intensity per day/20. Current smokers included smokers who had stopped smoking within the last two years before the interview/diagnosis. Never smokers were defined as lifelong non-smokers and subjects with a smoking history of <1 pack-year.

To visualize the functional form of the adjusted exposure-effect relationship between each agent (Cr(VI) or nickel) and lung-cancer risk for the fully adjusted model (OR2), we estimated restricted cubic spline functions and associated 95% CI. The optimal smoothing parameter was selected based on generalized cross-validation and under the assumption that the total number of degrees of freedom required for a biologically plausible model would not exceed three. Restricted cubic spline analyses also included lagged analyses, neglecting exposures that occurred 5, 10, 15, or 20 years before diagnosis (cases) or the interview (control subjects).

We assessed the additive interaction between smoking and Cr(VI) and nickel by estimating the 'relative excess risk due to interaction' (RERI). [START_REF] Richardson | Estimation of the relative excess risk due to interaction and associated confidence bounds[END_REF] Possible departure from a multiplicative joint effect was assessed by testing a multiplicative interaction term in the statistical model. Statistical analyses were carried out using R statistical software (version 3.6.1).

RESULTS

Among men, lifetime prevalence of exposure to Cr(VI) was 30% among cases and 23% among controls. Exposure prevalence to nickel was 24% (cases) and 19% (controls), of whom 77.7% of cases and 83% of controls were also exposed to Cr(VI). As expected, exposure prevalence was much lower among women than men (5% to Cr(VI) in both cases and controls). The exposure prevalence to nickel in females was 3% among both cases and controls (Table 2). 1).

We observed similarly increased lung-cancer ORs for ever exposure to Cr(VI) and nickel among both sexes. Assessment of cumulative exposure revealed a a close to monotonic exposure-effect trend among men in the fully adjusted model (ORs for the highest exposure category: Cr(VI): 2). For women, the exposure-effect relationships were less consistent with OR=1.04; 95% CI 0.48-2.24 in the highest Cr(VI) category and OR=1.29; 95% CI 0.60-2.86 in the highest nickel-exposure category (Table 2).

In men, we also observed a monotonic trend towards higher risk estimates with increasing duration of exposure to Cr(VI). Exposure for 30 years and more, compared to never exposed, showed increased ORs in the fully adjusted model (OR=1.37; 95% CI 1.23-1.51 for Cr(VI) and OR=1.23; 95% CI 1.09-1.38 for nickel). Risks peaked 10-19 years after cessation of exposure to Cr(VI) or nickel and then continuously declined towards baseline risk. The findings for women were less consistent (Table 2). Subgroup analyses among males revealed more cases and slightly higher ORs in populationbased studies than hospital-based studies (Tables 3a and3b). Compared with the full model, restricting the study base to male blue-collar workers and workers who started their job after 1960 showed a weaker exposure-effect relationship for Cr(VI) and nickel, although the highest exposure category still resulted in significantly increased ORs for lung cancer. Analyses restricted to workers starting after 1970 showed similar risk patterns, albeit less strong. Subgroup analyses among female subjects were based on few cases only, and the results were quite imprecise (Tables S3a andS3b). Lagging exposure by 5, 10, 15, and 20 years generated similar results (Table S4) compared to the unlagged risk estimates.

Center-specific results revealed some heterogeneity between study regions where results from Southern Europe matched those from the North European region showing increased ORs, whereas the picture was less homogeneous and the number of cases smaller in the other geographically similar study centers (see Tables S2a andS2b and Figures S1a andS1b).

Analyses using cubic splines showed a nearly linear exposure-effect relationship for nickel among males. The exposure-effect for Cr(VI) among males and among female subjects for both metals were linear (Figure 1).

When we stratified the analyses by smoking status, we observed similarly increased ORs for Cr(VI) exposure above the median (40.23 μg/m 3 -years) among current smokers, former smokers, and never smokers (Tables S5-S7). In men, ORs were strongest for squamous-cell and smallcell lung cancer subtypes, whereas there was no consistent association between Cr(VI) exposure and adenocarcinoma. Risk estimates in never smokers appeared to be strongest for small-cell cancer of the lung (Table S5). Similar patterns were observed for occupational nickel exposure above the median of 30.75 μg/m 3 -years (Table S6).

Among men, the joint effect of smoking and Cr(VI) on the risk of all lung-cancer subtypes was larger than additive (RERI=2.10; 95% CI 1.41-2.79; Table 4). RERI was particularly high for squamous-cell and small-cell cancer of the lung (supplementary table S8). For women, these associations were similar, however estimates were less precise compared to men (Tables 4 andS8). When using a multiplicative model as framework, no statistical siginificance for the interaction term in the model was observed except for small-cell lung cancer in men, implying that there is no significant deviation of the joint effect between smoking and occupational exposure to Cr(VI) or nickel from multiplicativity (Tables 4 andS8). Analysis of the interaction between Cr(VI) and nickel exposure was impaired by a high correlation between these agents, and, as stated above, we refrained from adjusting mutually for the other metal in these analyses.

Although the main analyses contained only one of the two exposure variables of interest, we conducted a set of sensitivity analyses that mutually adjusted for both, Cr(VI) and nickel. The OR for Cr(VI) was similar in the two-variable model compared to the one-variable model. By contrast there was some difference between the two models for the OR estimate for nickel. In men, ORs for nickel were attenuated to OR=1.05; 95% CI 0.97-1.14 and ORs for women slightly increased (OR=1.39; 95% CI 0.99-1.94). Analysis of subjects solely exposed to Cr(VI), but not nickel yielded an OR of 1.40; 95% CI 1.25-1.57 for men and 0.59; 95% CI 0.24-1.42 for women, but the latter analysis was based on only 10 exposed cases and 15 exposed controls. Subjects solely exposed to nickel were too few to conduct a sound sensitivity analysis (four male cases and three controls, but no exposed female case subject, all results not shown).

DISCUSSION

We studied the associations between occupational Cr(VI) and nickel exposure with lung cancer in the pooled SYNERGY case-control study. Increasing duration and increasing cumulative exposure to Cr(VI) or nickel were associated with increasing ORs for lung cancer. As it can be expected from welding and various metalwork-related activities, 1 Cr(VI) and nickel exposures were highly correlated in our data so that we did not adjust mutually for both metals in our analyses. Increased risks for Cr(VI) and nickel were found in never smokers, former smokers, and current smokers. The joint effect of smoking and Cr(VI) or nickel exposure was generally more than additive, particularly for squamous-cell and small-cell cancer of the lung. All these effects were clearly seen in men with narrow confidence intervals. Women showed similar risks, but analyses were limited by smaller numbers of exposed subjects, and subsequently analyses yielded wider confidence intervals in ever-never comparisons and exposure-effect trends.

Hexavalent chromium and at least some forms of nickel compounds are established lung carcinogens which have been repeatedly evaluated by IARC. 1,2,[START_REF]IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Chemicals and Industrial Processes Associated with Cancer in Humans (IARC Monographs Volumes 1 to 20)[END_REF][START_REF]IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1-42[END_REF][START_REF]IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Cadmium, nickel, some epoxides, miscellaneous industrial chemicals and general considerazions on volatile anaesthetics[END_REF] IARC's classification as Group 1 carcinogens relied mainly on industrial cohort studies of chromium production and nickel refinery workers.

Two of the largest chromium cohorts from Baltimore, MD, and Painsville, OH, have been repeatedly updated and re-analyzed with respect to lung-cancer risk. These studies unanimously indicated some increase in lung-cancer risk with respect to occupational Cr(VI) exposure. [START_REF] Crump | Dose-response and risk assessment of airborne hexavalent chromium and lung cancer mortality[END_REF][START_REF] Gibb | Lung cancer among workers in chromium chemical production[END_REF][START_REF] Park | Hexavalent chromium and lung cancer in the chromate industry: a quantitative risk assessment[END_REF][START_REF] Park | A search for thresholds and other nonlinearities in the relationship between hexavalent chromium and lung cancer[END_REF][START_REF] Luippold | Lung cancer mortality among chromate production workers[END_REF] We here add to the evidence by supporting these observations with analyses in a large pooled case-control study.

Although the exact nickel compounds responsible for an increased lung-cancer risk are unknown, results of studies among Norwegian refinery workers, suggest the strongest evidence for total nickel and water-soluble nickel compounds. 2,[START_REF] Grimsrud | Lung cancer incidence among Norwegian nickel-refinery workers 1953-2000[END_REF][START_REF] Grimsrud | Exposure to different forms of nickel and risk of lung cancer[END_REF] Additional analyses of this Norwegian cohort revealed a clear dose-effect relationship with lung-cancer risk for water-soluble compounds, but little support for metallic, oxidic, or sulfidic forms of nickel as risk factors, when mutually adjusting for water-soluble nickel compounds. [START_REF] Grimsrud | Exposure to different forms of nickel and risk of lung cancer[END_REF] Although epidemiological studies are limited in disentangling, which form is associated with an increased lung-cancer risk due to exposure to multiple forms of nickel, our findings in SYNERGY compare well with findings from these cohorts (see OR1 in table 2). However, exposure levels were in general lower than in these industries.

More recently, a semi-quantitative approach was undertaken by a population-based Canadian case-control study, whose data partially also contributed to this analysis. The study also showed increased lung-cancer risks in relation to occupational Cr(VI) or nickel exposure, but only among non-smokers and former smokers quitting smoking over 20 years prior to inclusion into the study. [START_REF] Beveridge | Lung Cancer Risk Associated With Occupational Exposure to Nickel, Chromium VI, and Cadmium in Two Population-Based Case-Control Studies in Montreal[END_REF] This finding is probably due to the strong effects of smoking on lung-cancer risk, leading to relative risks for occupational exposures being superimposed by the higher risk for lung cancer from smoking.

The median cumulative exposure level of 40 μg/m 3 -years for Cr(VI) observed in this study corresponds with the current SCOEL benchmark value of 1 μg/m 3 associated with 4/1,000 excess lung-cancer cases during 40 years of working life, [START_REF] Hartwig | SCOEL/REC/386 Chromium VI compounds: Recommendation from the Scientific Committee on Occupational Exposure Limits[END_REF] indicating that in the past a substantial part of the occupational workforce was exposed to Cr(VI) above these levels. The SCOEL benchmark value [START_REF] Hartwig | SCOEL/REC/386 Chromium VI compounds: Recommendation from the Scientific Committee on Occupational Exposure Limits[END_REF] was based on the mean value from the individual slope estimates of β=1.75, [START_REF] Seidler | Systematic review and quantification of respiratory cancer risk for occupational exposure to hexavalent chromium[END_REF] as derived from the studies by Crump and co-workers (β=0.68) [START_REF] Crump | Dose-response and risk assessment of airborne hexavalent chromium and lung cancer mortality[END_REF] and Park et al. (β=2.82). [START_REF] Park | Hexavalent chromium and lung cancer in the chromate industry: a quantitative risk assessment[END_REF] Kauermann and others, [START_REF] Kauermann | Exploring the statistical uncertainty in acceptable exposure limit values for hexavalent chromium exposure[END_REF] using a variety of model specifications, derived a combined slope estimate of 0.63 based on a pooled analysis of aggregated data from these studies. Using these two reported slope estimates, we can calculate an expected relative risk of 1.19 and 1.07 for men at an exposure level of 0.1 mg/m 3 -years, respectively, which is in line with our finding of an OR of 1.24 at this exposure level. In contrast, median cumulative nickel concentrations in SYNERGY (20 μg/m 3years) were much lower than the current SCOEL threshold limit value of 10 μg/m 3 , if taking into account a 40-year occupational exposure period.

Strengths of our analysis include a large study population with sufficient power to detect potentially increased risks in subgroups such as women, non-smokers, and for histological lungcancer subtypes, while taking into account detailed information on smoking habits. The use of a database of measurements from different countries and industries and modelling of an exposure time trend enabled us to assess cumulative exposures over the entire job histories and across jobs and industries quantitatively. [START_REF] Peters | SYN-JEM: A Quantitative Job-Exposure Matrix for Five Lung Carcinogens[END_REF] Although we included a high number of personal measurements to assess occupational exposure to Cr(VI) and nickel, limitations related to exposure assessment are that the measurements for a particular job did not necessarily correspond with the jobs reported in the study subjects' occupational history. [START_REF] Peters | SYN-JEM: A Quantitative Job-Exposure Matrix for Five Lung Carcinogens[END_REF] This will cause some degree of measurement error of the Berkson type, which will primarily weaken the precision of our estimates. Likely, the effect on point estimates will be rather small and lead to attenuation of ORs. [START_REF] Heid | Two dimensions of measurement error: Classical and Berkson error in residential radon exposure[END_REF] However, we cannot rule out the possibility of a combined error structure of classical measurement and Berkson-type of error, which may occur when estimating quantitative exposure-effect associations using random exposuregrouping methods. This is frequently the case in job-exposure matrices in which exposure levels are estimated for various occupational groups instead a fixed occupational setting. This situation may cause a non-differential measurement error turning into differential bias, thus leading to overor underestimation of risk estimates. As it has been shown, decreasing between-group variance usually leads to an increase in bias, which may also have affected our estimates that were situated in the low-exposure range. [START_REF] Kim | Bias in the estimation of exposure effects with individual-or group-based exposure assessment[END_REF] Exposure assessment in SYNERGY was performed to capture a wide array of exposed jobs, which may have resulted in assigning exposure levels to subjects who were only occasionally exposed to Cr(VI) or nickel or not at all. We therefore cannot rule out that our risk estimates, at least partially, entail a "blue-collar" effect associated with multiple exposures to several coccupational carcinogens. Restricting analyses to blue-collar workers, indeed revealed reduced ORs compared to the full sample. In addition, the relatively low response proportions in many of the population-based case-control studies may have resulted in a general under-representation of blue-collar workers in the control group, potentially inflating the observed associations when including white-collar workers. However, positive associations were seen for the highest exposure groups, and trends across exposure categories were consistent.

CONCLUSIONS

Summarizing, we observed positive exposure-effect associations between lung-cancer risk and occupational exposure to Cr(VI) and to nickel in the large SYNERGY study in men. Women showed similar tendencies, albeit with less statistical precision due to the smaller numbers of exposed female subjects. We estimated exposure-risk relationships over a wide range of exposed jobs, using a comprehensive measurement-based JEM. Among men, increased lung-cancer risks were associated with both longer exposure duration and higher cumulative exposure to Cr(VI) or nickel. Similar results were also observed across smoking group strata. The joint effect of smoking and Cr(VI) or nickel generally exceeded additivity. Various sensitivity analyses corroborated the robustness of these results. Although differential bias in our results due to combined Berkson and classical error structure cannot be ruled out, our results warrant a continuing awareness to monitor the impact of occupational metal exposure on human cancer by epidemiologic, toxicological, and experimental investigations.

Cigarette pack-years (current and former smokers) • Assessment of lung-cancer risk after occupational exposure to Cr(VI) and nickel in a pooled case-control study to investigate quantitative exposure-effect relationships using secondary measurement data.

<10 202 (5) 594 (20) 490 (5) 2,130 (24) 10
• Cubic-spline analyses showed linear exposure-effect relationship for nickel and Cr(VI)among women, and also for Cr(VI) among men. The exposure-effect relationship for nickel among men was sublinear at lower cumulative exposure levels.

• Exploring various lagging periods did not change results.

• Various sensitivity analyses corroborated the robustness of these results.

  We conducted several subgroup and sensitivity analyses to assess the robustness of our results: a) We stratified analyses by hospital-based and population-based studies and study region (Northern Europe (Germany, Sweden, France, UK, The Netherlands); Southern Europe (Italy, Spain); East Europe (Czech Republic, Hungary, Poland, Romania, Russia, Slovakia); and Canada). b) We restricted the study base to blue-collar workers to rule out a general blue-collar worker effect (i.e., an increased risk associated with multiple hazardous exposures in blue-collar job activities). c) We excluded welders and d) we restricted analyses to workers who started working in 1960 as well as 1970 or later, because exposure data were scarce before the 1970s. e) Although the main analyses contained only one of the two exposure variables of interest, we conducted a set of sensitivity analyses that included both Cr(VI) and nickel.

  Differences in median cumulative exposure levels to Cr(VI) and nickel were less pronounced. The median Cr(VI) exposure in men was: 42.8 μg/m 3 -years (cases) and 40.8 μg/m 3 -years (controls) and in women 26.2 μg/m 3 -years (cases) and 26 μg/m 3 -years (controls). Median nickel exposure among men was 22.7 μg/m 3 -years among cases and 21.5 μg/m 3 -years among controls. Women showed 16.7 μg/m 3 -years (cases) and 14.2 μg/m 3 -years (controls), respectively (Table

>99. 5

 5 μg/m 3 -years; OR=1.32, 95% CI 1.19-1.47 and nickel: >78.1 μg/m 3 -years, OR=1.29; 95% CI 1.15-1.45) (Table

Figure 1 :

 1 Figure 1: Exposure-response relationships among males and females for cumulative hexavalent chromium and nickel exposure with different lag periods, adjusted for study, age group, cigarette pack-years, time-since-quitting smoking, and ever employment in a 'list A' job. The histograms on the x-axis show the distribution of the cumulative exposure in the respective sub-populations.

TABLES : Table 1 .

 :1 Descriptive characteristics of the study participants (16,901 lung-cancer cases, 20,965 control subjects) by exposure to hexavalent chromium (Cr(VI)) and nickel

			Exposed to Ni or Cr(VI)	Unexposed to Ni and Cr(VI)
	Characteristic	Exposure category	Cases No. (%) Median (IQR)	Controls No. (%) Median (IQR)	Cases No. (%) Median (IQR)	Controls Median No. (%) (IQR)
	MEN		4,135	3,823	9,470	12,628
		Median (IQR)	63 (13)	63 (13)	64 (12)	63 (13)
	Age [years]	<45 45-65	132 (3) 2,260 (55)	177 (5) 1,955 (51)	354 (4) 4,725 (50)	718 (6) 6,227 (49)
		65+	1,743 (42)	1,691 (44)	4,391 (46)	5,683 (45)
		Never smoker	116
	Smoking status

Characteristic Exposure category Exposed to Ni or Cr(VI) Unexposed to Ni and Cr(VI)

			Cases	Controls	Cases	Controls
			No. (%)	Median (IQR)	No. (%)	Median (IQR)	No. (%)	Median (IQR)	No. (%)	Median (IQR)
	WOMEN		161		146		3,135		4,368
	Age [years]	Median (IQR)		63 (14)		62 (15)		61 (16)	61 (17)
		<45	11 (7)		5 (3)		218 (7)		471 (11)
		45-64	82 (51)		75 (51)		1,696 (54)		2,097 (48)
		65+	68 (42)		66 (45)		1,221 (39)		1,800 (41)
	Smoking status	Never smoker	35 (22)		76 (52)		844 (27)		2,640 (60)
		Former smoker	24 (15)		35 (24)		621 (20)		857 (20)
		Current smoker	102 (63)		35 (24)		1,670 (53)		871 (20)
	Cigarette pack-years (current and former smokers)	<10 10-19 20-<40 40+	9 (7) 19 (15) 53 (42) 45 (36)		20 (29) 17 (24) 25 (36) 8 (11)		222 (10) 377 (16) 906 (40) 786 (34)		629 (36) 403 (23) 464 (27) 232 (13)
	Years-since-quitting smoking (former smokers)	-<20 2-7 years 8-15 years 16-25 years 26+ years	411 (10) 9 (38) 6 (25) 6 (25) 3 (12)		586 (20) 7 (20) 5 (14) 13 (37) 10 (29)		837 (9) 271 (44) 170 (27) 121 (19) 59 (10)		1,746 (19) 197 (23) 202 (24) 238 (28) 220 (26)
	20-<40 40+ Employed in 'List A' job Ever	1,533 (39) 1,873 (47) 17 (11)		1,067 (36) 730 (24) 16 (11)		3,336 (37) 4,433 (49) 41 (1)		3,004 (33) 2,157 (24) 24 (1)
	Years-since-quitting smoking (former smokers) Lung-cancer cell type	>2 -7 Not available 8 -15 Adenocarcinoma 16 -25 >25 Squamous cell carcinoma Small-cell lung cancer	521 (37) 1 (1) 394 (28) 56 (35) 297 (21) 185 (13) 37 (23) 37 (23)		306 (17) 429 (24) 516 (29) 538 (30)		1,225 (36) 14 (1) 961 (28) 1,371 (44) 747 (22) 457 (13) 638 (20) 493 (16)		912 (16) 1,262 (23) 1,579 (29) 1,786 (32)
	Employed in 'List A' job Ever Other/unspecified Nickel [μg/m 3 -years] Median (IQR)	922 (22) 30 (19)	16.7 (30)	668 (17)	14.2 (29)	807 (9) 619 (20)		656 (5)
	Lung-cancer cell Cr(VI) [μg/m 3 -years] IQR = Interquartile range Adenocarcinoma Median (IQR) Squamous cell carcinoma Cr(VI) = Hexavalent chromium	896 (22) 1,885 (46)	26.2 (46)		26.0 (46)	2,429 (26) 3,943 (42)
	type	Small-cell lung cancer	703 (17)				1,497 (16)
		Other/unspecified	625 (15)				1,548 (16)
		Not available	26 (1)				53 (1)
	Nickel [μg/m 3 -years]			22.7 (64)		21.5 (60)
	Cr(VI) [μg/m 3 -years]			42.8 (91)		40.8 (86)

Table 2 .

 2 Lung cancer odds ratios (OR) and 95% CI in relation to indices of occupational exposure to nickel and hexavalent chromium in the SYNERGY Study OR 1 is adjusted for study and age group OR2 is adjusted for study, age group, smoking (log(cigarette pack-years+1), time-since-quitting smoking (current smokers, stopping smoking 2-7 years, 8-15 years, 16-25, 26+ years before interview/diagnosis, never smokers)), and List A jobs * OR2 in "time since last exposure" is in addition adjusted for duration (continuous) of exposure °99.4%CI Bonferroni-corrected for 9 subtests

	Indices of exposure occupational	category Exposure	Men

>30.9-≤78.1 914 790 1.44 1.30-1.59 1.20 1.07-1.35 1.02-1.41 29 28 1.45 0.85-2.48 0.97 0.53-1.76 0.41-2.25 >78.1 881 804 1.42 1.29-1.57 1.29 1.15-1.45 1.10-1.52 21 14 1.91 0.97-3.90 1.29 0.60-2.86 0.43-3.87

Table 4 .

 4 Lung-cancer odds ratios and 95% CI, p-value for multiplicative interaction and relative excess risk due to interaction (RERI) and 95% CI in relation to occupational chromium (VI) and nickel exposure and smoking among men and women

		Exposure status			Men					Women
			Cases Controls	OR*	95%CI	99.4%CI° Cases	Controls OR*	95%CI	99.4%CI°
	Chromium (VI)
		Never smoker and never Cr(VI)	374	3,592	1.0	Ref.	Ref.	844	2,640	1.0	Ref.	Ref.
		Never smoker and Cr(VI)	116	845	1.22	0.98-1.53	0.89-1.68	35	76	1.13 0.73-1.73	0.62-2.08
		Ever smoker and never Cr(VI)	9,100	9,039	9.31	8.34-10.42 7.95-10.89 2,293	1,728	4.77 4.29-5.31	4.10-5.55
		Ever smoker and ever Cr(VI)	4,015	2,975	11.63 10.34-13.11 9.83-13.75	124	70	6.22 4.54-8.57	3.97-9.73
		p-value multiplicative interaction			0.86					0.60
	RERI with linear model**			2.10	1.41-2.79				1.31 -0.66-3.29
	Nickel
		Never smoker and never nickel	402	3,735	1.0	Ref.	Ref.	847	2,650	1.0	Ref.	Ref.
		Never smoker and nickel	88	702	1.08	0.84-1.38	0.76-1.53	32	66	1.27 0.80-1.97	0.67-2.39
		Ever smoker and never nickel	9,987	9,576	9.31	8.37-10.38 7.99-10.84 2,298	1,733	4.77 4.29-5.31	4.10-5.55
		Ever smoker and ever nickel	3,128	2,438	10.63 9.46-11.98 9.00-12.56	119	65	6.60 4.78-9.18 4.16-10.46
		p-value multiplicative interaction			0.66					0.76
	RERI with linear model**			1.25	0.56-1.93				1.56 -0.60-3.72
	* OR adjusted for study, age group and "List A" jobs
	** Confidence intervals are based on 1,000 bootstrap samples
	°	99.4%CI Bonferroni-corrected for 9 subtests

ACKNOWLEDGEMENTS

Isabelle Stücker will be remembered for her professionalism and generosity regarding the SYNERGY project. The authors thank Mrs. Veronique Benhaim-Luzon at IARC for pooling of data and data management.

FUNDING

This study was supported by the German Social Accident Insurance, grant FP 271. Grant sponsors of the individual studies were the Canadian Institutes of Health Research and Guzzo-SRC Chair in Environment and Cancer, the Fondation de France, the German Federal Ministry of Education, Science, Research, and Technology (grants 01 HK 173/0 and 01 HK 546/8) and the Ministry of Labour and Social Affairs (grant IIIb7-27/13), EC's INCO-COPERNICUS Program, Polish State Committee for Science Research, Roy Castle Foundation, NIH/NCI/DCEG Intramural Research Program, Lombardy Region, INAIL and the European Union Nuclear Fission Safety Program, Italian Association for Cancer Research, Region Piedmont, Compagnia di San Paolo, Europe Against Cancer Program, the Swedish Council for Work Life Research and the Swedish EPA, the University of Oviedo, the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101), the Ministry of Health of the Czech Republic-MH CZ -DRO (MMCI, 00209805), CIBERESP, and FISS-PI060604.

DATA AVAILABILITY STATEMENT

The data are from a pooled study, and the data right owners are the individual study groups whose authors may be contacted at synergy@iarc.fr. Further information is available from the corresponding author upon request.

AUTHOR CONTRIBUTIONS

KS, T. Brüning, HK, and RV contributed to the original conception and acquired funding for the project. KS, J. Schüz, HK, RV, AO, BP, T. Brüning, and T. Behrens developed the methodology for this analysis. T. Behrens. wrote the draft, by integrating suggestions from CG, AO, SP, J.

ETHICS STATEMENT

The IARC Institutional Review Board provided ethical approval for the pooled study, while national ethics committees approved the local case-control studies. All study subjects gave written informed consent.