Risk of Lymphohematopoietic Malignancies in Uranium Miners

Referencing: Incidence of Leukemia, Lymphoma, and Multiple Myeloma in Czech Uranium Miners: A Case-Cohort Study

Rericha et al. (2006) analyzed data from Czech uranium miners with respect to incidence of malignancies of the lymphohematopoietic system. Their results, however, do not correspond with those of two recent studies on German uranium miners (Kreuzer et al. 2004; Möhner et al. 2006). Rericha et al. (2006) used a case–cohort design, in which the subcohort was stratified by attained age and duration of employment. Stratification by age is a standard approach in case–cohort studies to optimize data ascertainment in the subcohort. However, stratification by duration of employment is problematic, because in occupational epidemiology it should be assumed that the duration of employment is highly correlated with cumulative exposure. Therefore, this kind of stratification contradicts the general demand for a random selection of controls with respect to exposure under study. Comparing the ratios of sampling fractions (< 12 months vs. ≥ 12 months duration of employment) between age groups results in a heterogeneous picture (Table 1).

Table 1.

It is not uncommon in occupational cohort studies to include only subjects with a duration of employment of at least a certain number of months into the cohort. An analysis of only those miners with an employment duration of at least 12 months would be in line not only with the standard methodology but also with earlier published results of the authors (Rericha et al. 1998). Hence, the authors should have at least explained their reasoning for including the remaining miners in a second set of strata. In addition, they should have presented separate results for both duration strata to validate the result of the combined analysis.

Given the above-mentioned assumption concerning the relationship between duration of employment and cumulative exposure, I calculated crude incidence rate ratios using data from Table 1 of Rericha et al. (2006). The age-specific odds ratios cover a wide range (0.29–7.16), and a corresponding test yields only borderline homogeneity. Consequently, completeness of matching with the cancer registry needs to be discussed.

According to the study design, the time period between last exposure and begin of follow-up can span up to 27 years; therefore, the healthy-worker survivor effect could be an important issue in this study (Rericha et al. 2006). In light of the discussion on the magnitude of the latency period for leukemia, more detailed results would be useful to get an impression on, for example, the effect of the year of last exposure.

The author declares he has no competing financial interests.

References

Kreuzer M, Schnelzer M, Tschense A, Grosche B. 2004. Risk of lung cancer and other cancers in the German uranium miners cohort study. 11th IRPA-Congress. Available: http://irpa11.irpa.net/pdfs/1b16.pdf [accessed 8 March 2007].

Möhner M, Lindtner M, Otten H, Gille HG. 2006. Leukemia and exposure to ionizing radiation among German uranium miners. Am J Ind Med 49:238–248.

Rericha V, Kulich M, Rericha R. Shore DL, Sandler DP. 2006. Incidence of leukemia, lymphoma, and multiple myeloma in Czech uranium miners: a case–cohort study. Environ Health Perspect 114:818–822.

Rericha V, Sandler DP, Shore DL, Solansky I, Hnizdo E, Sram R. 1998. Non-lung cancer incidence in Czech uranium miners [Abstract]. Epidemiology 9:S99.

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Lymphohematopoietic Malignancies in Uranium Miners: Kulich et al. Respond

We read with interest the comments by Möhner regarding the analysis and interpretation of the case–cohort study of Czech uranium miners (Rericha et al. 2006). He noted that our results do not agree with two recent German studies that also investigated the link between leukemia and radiation exposure in uranium miners. Kreuzer et al. (2004) conducted a mortality study based on death certificates (although combined with autopsy records) and reported standardized mortality ratios. As noted in our article (Rericha et al. 2006), studies relying on vital statistics underestimate the incidence of cancers such as chronic lymphocytic leukemia (CLL), which are not rapidly fatal or systematically diagnosed. For example, compare our 84 leukemia cases to the 95 cases reported by Kreuzer et al. (2004) that were based on a total follow-up period that was more than 4 times longer. The incidence rates or age differences between Czech and German miners cannot be that different. Möhner et al. (2006) published a well-designed, matched case–control study of cancer incidence with a large number of cases. Their reported results from grouped analyses and excess relative risk models indicated some elevated risk for CLL, which does not conflict with our conclusions. The lack of statistical significance can be explained by the relatively poor power of grouped analyses compared with the nongrouped Cox model we applied. Another important point that can explain seemingly conflicting results of different studies is the high sensitivity of the results to measurement error in exposures. A study that uses less precise estimates of radiation exposures is less likely to identify an existing exposure effect. This affects leukemia analyses more than lung cancer analyses because the effect of radon on lung cancer is much stronger and more difficult to miss.

In his letter, Möhner mentioned several other issues that need clarification. First, is stratification by duration of employment problematic, given the strong association of this variable with exposure? In fact, as shown, for example, by Borgan et al. (2000) and Kulich and Lin (2004), stratification on variables correlated with exposure is always highly desirable because it can substantially increase the precision of the analysis at little cost. As long as a correct procedure for estimating parameters from stratified samples is used, the estimates are valid and their standard errors are reduced. Stratification by age is a similar case; in these data, age is also strongly related to exposure.

The reasoning for including miners who worked < 12 months was that they represent a natural comparison group with low exposures. Many occupational studies exclude workers with short employment periods [Kreuzer et al. (2006) included those with ≥ 6 months exposure]. Both approaches have pros and cons. Including miners with short working periods may increase power and is relevant when the primary interest is to compare incidences at high exposures with those at low exposures. In contrast, miners who left their jobs early may have done so because of health reasons, which could induce a healthy-worker effect. We decided to include all miners before the data were analyzed, and we presented the planned analysis in our article (Rericha et al. 2006). We did a separate analysis of miners who worked > 12 months underground and found generally stronger radiation effects on incidence. For example, for CLL the estimated relative risks comparing 110 working level months (WLM) to 3 WLM would be 3.13 [95% confidence interval (CI), 1.22–8.08; p = 0.02] based on 39 cases and 1,596 subcohort subjects. The CI was wide but the conclusion was not changed.

The odds ratios (ORs) in Möhner's Table 1 would look less extreme if the last three groups were combined. The OR of 7.16 is based on a single case and the OR of 0.29 is based on three cases. Hence, the alleged heterogeneity does not look very convincing to us. Finally, the issue of latency period and late follow-up was addressed by separate analyses based on time since exposure. As we reported (Rericha et al. 2006), exposures acquired > 25 years ago had no noticeable effect on current incidence, whereas the most recent exposures (2–15 years ago) showed the strongest association.

In conclusion, we believe that our study (Rericha et al. 2006) offers the important advantage of having included incident cases and that the analysis was appropriate. The conclusions of the study do not depend on whether or not the analyses are restricted to miners with longer working periods.

The authors declare they have no competing financial interests.

References

Borgan Ø, Langholz B, Samuelsen SO, Goldstein L, Pogoda J. 2000. Exposure stratified case-cohort designs. Lifetime Data Anal 6:39–58.

Kreuzer M, Schnelzer M, Tschense A, Grosche B. 2004. Risk of lung cancer and other cancers in the German uranium miners cohort study. 11th IRPA-Congress. Available: http://irpa11.irpa.net/pdfs/1b16.pdf [accessed 8 March 2007].

Kulich M, Lin DY. 2004. Improving the efficiency of relative risk estimation in case-cohort studies. J Am Stat Assoc 99:832–844.

Möhner M, Lindtner M, Otten H, Gille HG. 2006. Leukemia and exposure to ionizing radiation among German uranium miners. Am J Ind Med 49:238–248.

Rericha V, Kulich M, Rericha R, Shore DL, Sandler DP. 2006. Incidence of leukemia, lymphoma, and multiple myeloma in Czech uranium miners: a case–cohort study. Environ Health Perspect 114: 818–822.