To the Editor:
In their recent nested case-control study of benzene exposure and lymphohematopoietic cancer, Glass et al.1 concluded that an excess leukemia risk was found at lower benzene exposures than previously reported, with no evidence of an exposure threshold. I want to offer additional comments on these data, developed while working with the authors as a study advisor.
The authors acknowledge that the reported relative risks are higher than those in similar case-control studies.2,3 These results are also higher than those found in more highly exposed cohorts4–6 used in risk assessments. For example, 11- and 98-fold risks are reported for >8 and >16 ppm-years, respectively. More perplexing are the reported 4- to 6-fold risks at >1 ppm-year (ie, 0.02 ppm over a working career). These results imply that either the study has detected high risks from exposures below existing standards or that risks have been overestimated.
Table 3 of the Glass paper1 shows that the baseline exposure category (≤1 ppm-year) contains 35% of controls and 33% of non-Hodgkin lymphoma/multiple myeloma (NHL/MM) cases, but only 9% of leukemia cases. A critical question is whether 9% (3 cases) represents a valid baseline, because, aside from matching factors, odds ratios (ORs) depend on the case/control ratio in the baseline group. Aside from chance (which cannot be excluded), at least 3 issues are germane to this question: the consistency of these data with the parent cohort study and the wider literature, recall bias, and cutpoint bias.
This study's parent cohort7 can be used as one way to estimate the number of leukemia cases expected in the baseline exposure group. Gun et al.7 report 19.5 expected leukemias and 42.3 expected NHL/MM cases, for a ratio of 0.46. A similar ratio would be expected in the case-control study's baseline category, because the matching factor (age) is similar in the 2 groups (see Table 1). Instead, the 3 leukemias and 15 NHL/MM cases yield a ratio of 0.20. The cohort leukemia/(NHL/MM) ratio of 0.46 would predict that 7 cases of leukemia should occur in the baseline group in the case-control study. The cohort also experienced 27 leukemias, an absolute excess of 7.5 cases, further arguing against an unprecedented effect of benzene in these workers.
If leukemia cases or their surrogates preferentially recall benzene exposure, migration of cases from the baseline to higher-exposure groups could result. Glass and colleagues1 suggest that the effect of recall bias should be small and could not account for the reported benzene/leukemia associations, but this bias could have exaggerated the exposure–risk relationship and hidden an exposure threshold. Although I agree with this observation to some extent, it is important to note that use of narrow cell boundaries could magnify the potential for recall bias and could explain moderately elevated ORs, especially in the lower-exposure categories.
There is also some evidence of “cutpoint bias,” ie, different categorical boundaries yielding disparate trends. For example, category boundaries in Table 2 produce unadjusted ORs of 1.0, 4.9, 5.5, 2.2, 5.2, and 18.9, similar to the adjusted ORs depicted in Figure 1. Yet, the boundaries used in Table 6 produce unadjusted ORs of 1.0, 0.7, and 2.9, which conveys a different interpretation of risks at low concentrations.
In summary, although Glass et al.1 present evidence of a relationship between benzene and leukemia, particularly at higher-exposure categories, the low occurrence of leukemia in the baseline group hinders a stronger interpretation of the study. The feasibility of conducting a collective analysis of similar studies of petroleum workers might be a means of providing further insight on the risk of lower benzene concentrations.
A. Robert Schnatter
ExxonMobil Biomedical Sciences, Inc. Division of Occupational and Public Health Annandale, NJ email@example.com
1. Glass DC, Gray CN, Jolley DJ, et al. Leukemia risk associated with low-level benzene exposure. Epidemiology
2. Rushton L, Romaniuk H. A case-control study to investigate the risk of leukemia associated with exposure to benzene in petroleum marketing and distribution workers in the United Kingdom. Occup Environ Med
3. Schnatter AR, Armstrong TW, Nicolich MJ, et al. Lymphohematopoietic malignancies and quantitative estimates of exposure to benzene in Canadian petroleum distribution workers. Occup Environ Med
4. Rinsky RA, Hornung RW, Silver SR, et al. Benzene exposure and hematopoietic mortality: A long-term epidemiologic risk assessment. Am J Ind Med
5. Collins JJ, Ireland B, Buckley CF, et al. Lymphohaematopoietic cancer mortality among workers with benzene exposure. Occup Environ Med
6. Bond GG, McLaren EA, Baldwin CL, et al. An update of mortality among chemical workers exposed to benzene. Br J Ind Med
7. Gun RT, Pratt NL, Griffith EC, et al. Update of a prospective study of mortality and cancer incidence in the Australian petroleum industry. Occup Environ Med
. 2004; in press.