The results from this population-based case-control study suggest that occupational exposure to organic solvents may increase NHL risk for women. In this study, we observed significantly increased risks of NHL with exposure to any organic solvent at medium-high average intensity and/or average probability levels. Moreover, significantly increased risks of NHL were observed for high cumulative intensity or probability groups. The risk of NHL increased with level of average and cumulative intensity or probability. Significantly increased risks of NHL for those exposed to organic solvents have also been reported in previous studies (18
). Hardell et al. (34
) observed a 2-fold increased risk of NHL with exposure to organic solvents (OR
2.4, 95% CI: 1.4, 3.9); moreover, an odds ratio of 3.5 (95% CI: 1.7, 7.1) was found for those exposed to high-grade organic solvents (34
). Although Fritschi et al. (36
) observed a marginally increased risk of NHL for only those exposed to any solvent (OR
1.3, 95% CI: 1.0, 1.6), a significant dose-response effect by solvent exposure levels was also found. Olsson and Brandt (18
) reported a 3-fold increased risk of NHL (OR
3.3, 95% CI: 1.9, 5.8) for males exposed to organic solvents for at least 1 year. Dryver et al. (33
) found a 60% increased risk for Swedish workers exposed to solvents for more than 5 years (OR
1.6, 95% CI: 1.1, 2.3).
Our results also showed that the increased risk of NHL associated with exposure to solvents was seen mainly for those who reported exposure to chlorinated solvents. Chlorinated solvents have been widely used as extraction solvents, paint solvents, and coating solvents, as well as in cleaning and degreasing solvents. Seidler et al. (37
) reported a significant association between malignant lymphoma risk and high exposure to chlorinated hydrocarbons (OR
2.1, 95% CI: 1.1, 4.3). McDuffie et al. (38
) observed a 2.4-fold increased risk of NHL for male Canadian pesticide workers who may have been exposed to carbon tetrachloride (95% CI: 1.2, 5.1). The lymphatic system has been regarded as a target for trichloroethylene toxicity (39
). Results of 2 cohort studies of aircraft maintenance workers exposed to trichloroethylene or perchloroethylene suggested an increased NHL risk (40
). Note that only a relative small number of participants in our study were ever exposed to carbon tetrachloride; moreover, this exposure occurred for the most part at a low average probability exposure level. Thus, the significant finding between carbon tetrachloride and risk of NHL in this study might be due to chance.
A dose-dependent association between benzene exposure and risk of NHL was observed. A significantly increased risk of DLBCL for those exposed to benzene at a medium-high average probability level was found. A nonsignificantly but increased risk of NHL was also found for those who had an average medium-high intensity or probability level of exposure to benzene. Lymphocytes in peripheral blood are a hematologic cell type particularly sensitive to benzene toxicity (42
), and peripheral lymphatic cells are targeted by the genotoxic metabolites of benzene (44
). Furthermore, benzene exposure has been linked to chromosomal aberrations found in NHL in cultured peripheral lymphocytes of exposed workers (45
Thus, our results are consistent with an association between benzene exposure and risk of NHL. However, results regarding the association between benzene exposure and risk of NHL have been inconsistent in previous studies. A Chinese cohort study reported a 4-fold increased risk of NHL (risk ratio
4.1, 95% CI: 1.2, 14.4) for workers employed before 1972, and the risk was strongly associated with cumulative exposure that occurred more than 10 years prior to diagnosis (P
0.005). A case-control study from France also reported an almost 5-fold increased risk of NHL (OR
4.6, 95% CI: 1.1, 19.2) for those who reported being exposed to benzene for more than 810 days (46
). There are also studies that did not find any association between benzene exposure and risk of NHL among petroleum workers (47
), which may have been due to the healthy-worker effect (48
). As presented by Smith et al. (48
), after adjusting for the healthy-worker effect, the observed standardized mortality ratio of lymphoreticulosarcoma in male refinery workers increased from 1.1 (95% CI: 0.6, 1.7) to 1.5 (95% CI: 1.2, 1.8). However, a recent meta-analysis found evidence of a significant association between occupational benzene exposure and NHL risk, particularly when restricted to studies with a higher-quality exposure assessment (49
). Risk estimates for medium-high probability of exposure to benzene and NHL in the current study are consistent with the magnitude of effects reported in the meta-analysis.
Exposure to formaldehyde was found to be associated with an increased risk of NHL in our study, but the risk was mainly for those with a low exposure intensity or probability. Formaldehyde is used widely in manufacturing and chemical industries and also as a human tissue preservative. In experimental studies, formaldehyde is associated with increased frequencies of micronuclei, sister chromatid exchanges, chromosomal aberrations, and DNA-protein cross-links in peripheral lymphocytes of humans, as summarized by Hauptmann et al. (50
). Two cohort studies have linked formaldehyde exposure to an increased risk of leukemia (50
). One epidemiologic study suggested that exposure to formaldehyde may be responsible for the observed increased risk of lymphoma for woodwork-related exposures (52
); however, other studies have not found a positive association between formaldehyde exposure and NHL risk (13
Our results provide weak evidence that NHL risk may differ by subtypes. NHL comprises a heterogeneous group of lymphoid malignancies; it has been hypothesized that each subtype may have a distinct etiology (55
). We observed that the effect of chlorinated solvent exposure on risk of NHL varied with major NHL subtypes at only a high-medium average intensity level. In this study, the sample size of a certain histologic subtype was relatively small, which limited our ability to detect the effect of solvent exposure on the risk of a certain NHL subtype. Few studies so far have evaluated the association between organic solvent exposures and risk of subtypes of NHL. Tatham et al. (53
) found that exposure to solvents is associated with a significantly increased risk of small-cell diffuse lymphomas (OR
1.6, 95% CI: 1.1, 2.2). Rego et al. (20
) reported a 2-fold increased risk of diffuse NHL (OR
2.0, 95% CI: 1.1, 3.7) for those whose first exposure to solvents occurred 6–25 years preceding diagnosis or interview. Fritschi et al. (36
) reported an increased risk of B-cell NHL among workers ever exposed to solvents (OR
1.3, 95% CI: 1.0, 1.7). Kato et al. (56
) found an increased risk of B-cell NHL (OR
1.5, 95% CI: 1.1, 2.1) for those with paint thinners/turpentine exposure.
This study is one of the few that has applied a job-exposure matrix to evaluate the association between solvents exposure and the risk of NHL in the United States. Most of the early epidemiologic studies used occupational titles or industry as surrogates to evaluate the association between occupational exposures and NHL risk. As pointed out by others, exposure and exposure intensity may vary by industries included in the same occupation title. Thus, use of job titles or industries separately as surrogates to study the exposure and disease relation may result in serious misclassification of exposure and intensity of exposure, which could bias the estimated association between the exposure and disease of interest (57
). The advantages of using job-exposure matrixes to analyze occupational exposure and disease risk include that the job-exposure matrixes link information from both occupational titles and industry titles with specific exposures, therefore minimizing exposure misclassification, and allow for semiquantitative measurements of the occupational exposures and disease relation. Use of job-exposure matrixes in occupational epidemiologic studies could also significantly increase the statistical power compared with use of job or industrial titles (58
Several potential limitations should be considered in interpreting our study results. One concern is misclassification of exposure. We assessed occupational exposure to specific solvents by linking the job-exposure matrixes with self-reported occupational histories, and some degree of exposure misclassification was unavoidable. In general, misclassification of exposure is unlikely to be differential. For multilevel exposure, nondifferential misclassification may bias relative risks away from the null in some categories (59
); however, it can bias the relative risk toward the null in the highest exposure category only (60
). In this study, when exposure intensities and probabilities were categorized into more than 2 levels, significant associations were observed mainly at the highest exposure level.
Another potential limitation of the study is the relatively small sample size of certain subtypes and the low prevalence of occupational exposure to some organic solvents. A small sample size with low exposure prevalence not only reduces statistical power but also increases the possibility of false-positive associations. When we evaluated associations between occupational exposures and risks of major subtypes of NHL, significantly increased associations were observed for DLBCL patients only, the most common NHL subtypes in this study. Further studies with a larger sample size are needed to explore the associations between occupational solvents exposure and the risk of NHL by subtype.
In conclusion, in this population-based case-control study of Connecticut women, we found an increased risk of NHL from occupational exposure to any organic solvent, formaldehyde, chlorinated solvents, and carbon tetrachloride and some evidence of an association with benzene. These results support a potential association between occupational exposure to organic solvents and the risk of NHL among women. Future evaluation of the relation between solvent exposure and risk of NHL and its subtypes is warranted.