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Materials and Methods
Study Population
The Chinese silica cohort has been described elsewhere. Briefly, the cohort included 74,040 workers who worked at 29 metal mines and pottery factories for 1 year or more between 1960 and 1974. All participants were followed up until they were lost to follow-up, died, or survived to 2003. Data on demography, lifestyle, work history, silicosis status, and cause of death were collected by trained investigators from 1986 onward. Monitoring of dust concentrations, polycyclic aromatic hydrocarbons, radon, and other occupational hazards was conducted.
In this study, we excluded 8,268 workers without detailed work histories. Participants without detailed smoking data were also excluded (n = 23,200). To minimize the effects of other carcinogenic confounders, we excluded 8,554 participants from copper mines (where exposure to radon and carcinogenic polycyclic aromatic hydrocarbons may occur) and tin mines (where exposure to arsenic may occur). Finally, this study includes 34,018 participants from 7 metal mines and 4 pottery factories with an average of 34.5 years of follow-up.
Ascertainment of Lung Cancer Deaths and Silicosis Cases
All participants were traced for vital status during the follow-up period. Information on underlying causes of death was obtained on the basis of the following 3 levels of evidence: medical records from a hospital (60.5%); employment registers, accident records, or death certificates (35.2%); or oral reports from relatives (4.3%). For participants who died from lung cancer, the diagnostic information was reconfirmed by using hospitals records.
Yearly radiographs for workers exposed to silica dust have been required by the Chinese government since 1963, and silicosis diagnoses were included in a silicosis registry. National diagnostic criteria for silicosis were standardized as stage I, II, or III. Silicosis was defined as stage I or higher. The agreement was 89.3% between the presence of radiological silicosis diagnosed by the International Labour Office and Chinese criteria.
Silica Exposure Assessment
We produced quantitative estimates of silica exposure by using historical data on dust concentrations and work histories. Total dust concentrations were available since 1950. A field study was conducted to convert Chinese total dust concentrations to silica concentrations. A job-exposure matrix with facility-, job-, and year-specific silica concentrations was then created. Lifetime work histories were retrospectively collected in 1986 and then updated yearly by industrial hygienists using employee rosters during follow-up. By linking the job-exposure matrix with the work history, cumulative silica exposure (in mg/m-years) was calculated as follows:
where n is the total number of job titles, Ci is the silica concentration for the ith job title, and Ti is the working years for the ith job title.
Smoking Information
Detailed lifetime smoking data were collected in 1986, 1995, and 2004. Overall, smoking data from next-of-kin or colleagues accounted for 11% of the study subjects. Data reliability was examined for 1,990 randomly selected subjects in 2004. The agreement on smoking status (yes or no) from next-of-kin and colleagues of decedents (n = 602) was 89.1%, and the agreement on smoking status from self-report and next-of-kin (or colleagues) for living subjects was 93.6%. The smoking data included the average number of cigarettes per day and the corresponding start and end dates, taking into consideration smoking intensity. The smoking amount for ever smokers of all smoking intensities was calculated by multiplying packs per day by smoking duration.
Statistical Analysis
Quantitative exposure-response analyses for silica exposure and lung cancer were conducted by using Cox proportional hazard models. We used age to define the risk set for each lung cancer death. The association was quantified by hazard ratios and their 95% confidence intervals with adjustment for potential confounding factors including facility, sex, year of birth, and smoking amount. We considered lag periods of 0, 5, 10, 15, 20, and 25 years for cumulative silica exposure. We used a minimized Akaike's information criterion statistic to select the optimal exposure-response models.
We conducted categorical analysis by quartiles of cumulative silica exposure. The overall risk of silica exposure was examined by including silica exposure as a dichotomous variable (exposed/unexposed). Continuous models were conducted by using unlogged or logged cumulative silica exposure. In a nested case-control sample, we used penalized splines to investigate the shape of the exposure-response relationship, avoiding parametric assumptions. The association was also evaluated after exclusion of silicotics.
To investigate the joint effect of silica and smoking, we estimated hazard ratios by crossed dichotomized silica exposure (exposed = A+, unexposed = A−) and smoking (ever smokers = B+, never smokers = B−). As suggested by Li and Chambless, the relative excess risk due to interaction (calculated as hazard ratio (HR)A+B+ – HRA+B− – HRA−B+ + 1) was used to evaluate departure from additivity. Departure from multiplicativity was examined by adding an interaction term of silica exposure (A+/A−) and smoking (B+/B−) to the model. A model with an interaction term of continuous exposure and smoking (B+/B−) was used to assess the multiplicative joint effect.
Risk assessment was conducted by using the results from the models and converting rates to risk. Excess lifetime risk of lung cancer was estimated by assuming an exposure of 0.1 mg/m for 45 years (from ages 20 to 65 years), and a lifetime was defined as 55 years (from ages 20 to 75 years). The 0.1-mg/m level is the compliance level for respirable silica exposure in the workplace published by the US Occupational Safety and Health Administration (Washington, DC). We also considered risks at 0.02 and 0.01 mg/m, as well as the occupational exposure limits in China, which range from 0.07 to 0.35 mg/m depending on the percentage of crystalline silica. Age-specific background mortality rates for lung cancer and all causes of death in the general population were adjusted. The penalized splines were fitted in S-PLUS, version 8.0, software (Insightful Corporation, Seattle, Washington); all other statistical analyses were conducted by using SAS, version 9.3, software (SAS Institute Inc., Cary, North Carolina). All statistical tests were 2-sided.
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