Abstract
Objectives:
Although many studies have investigated the association between trichloroethylene (TCE) exposure and non-Hodgkin lymphoma (NHL), less is known about other chlorinated solvents. We extended our previous analysis of occupational TCE exposure in a multi-center population-based case-control study of NHL to investigate associations with five additional chlorinated solvents: 1,1,1,-trichloroethane, carbon tetrachloride, chloroform, methylene chloride, and perchloroethylene.
Methods:
Cases (n= 1189) and controls (n = 982) provided detailed information on their occupational histories and workplace exposure to chlorinated solvents for selected occupations using job-specific interview modules. An industrial hygienist used this information and a review of the literature to assess occupational exposure to chlorinated solvents. We computed odds ratios (ORs) and 95% confidence intervals (CIs) for different exposure metrics, with the unexposed group as the referent. We also computed ORs by NHL subtype.
Results:
High cumulative hours exposed to carbon tetrachloride was associated with NHL (>520 hours: OR 1.9; 95%CI 1.0–3.6; Ptrend = 0.04). This association remained after restricting to jobs with high-intensity exposure (2.0; 1.1–3.8; 0.03) and ≥90% exposure probability (2.1;1.0–4.3; 0.03), adjusting for TCE (2.1; 1.0–4.1; 0.04) and incorporating a 15-year lag (1.9; 1.0–3.6; 0.06). The other evaluated chlorinated solvents were not associated with NHL.
Conclusions:
This is the first study using high-quality quantitative exposure assessment methods to identify a statistically significant elevated association between occupational exposure to carbon tetrachloride and NHL. Our findings, though limited by a small number of exposed cases, offer evidence that carbon tetrachloride may be a lymphomagen.
INTRODUCTION
Chlorinated solvents are a family of chlorine-containing synthetic compounds that have been used in a wide variety of industrial applications, including vapor degreasing, dry cleaning, paint removers, glues, and other operations.1 2 The production and use of these solvents declined over the course of the 20th century due to concerns over their toxicity, including their carcinogenic potential.1 2 Trichlorethylene (TCE) is classified as a human carcinogen (Group 1) by the International Agency for Research on Cancer (IARC) based on sufficient epidemiologic evidence of an association with kidney cancer and suggestive evidence for non-Hodgkin lymphoma (NHL) and liver cancer,3 while other chlorinated solvents have been classified by IARC as probably carcinogenic to humans (Group 2A; perchloroethylene), possibly carcinogenic (Group 2B; carbon tetrachloride, chloroform, methylene chloride) or unclassifiable with regards to carcinogenicity (Group 3; 1,1,1-trichloroethane).3–5
Evidence that several chlorinated solvents can induce immunotoxic effects has motivated epidemiologic research to investigate associations with NHL, a malignancy linked to immune dysregulation.6 While the relationship between TCE exposure and NHL has frequently been the focus of investigation (reviewed by:7), fewer studies have evaluated NHL associations for other chlorinated solvents.8–15 Moreover, findings from several studies have been limited by use of relatively non-specific exposure assessment methods, such as job-exposure matrices or self-reported use of chlorinated solvents. In a previous analysis of occupational TCE exposure within a population-based case-control study of NHL using job-by-job expert review of occupational exposure, we found high TCE exposure to be associated with increased risk of NHL.16 To clarify the association between occupational exposure to other chlorinated solvents and risk of NHL, we have expanded our investigation within this study to assess exposure to 1,1,1,-trichloroethane, carbon tetrachloride, chloroform, methylene chloride, and perchloroethylene.
METHODS
Details of the study have been described.17 18 Briefly, the National Cancer Institute – Surveillance, Epidemiology, and End Results (NCI-SEER) Study is a large population-based multi-center case-control study of NHL designed to obtain detailed information regarding workplace exposure to solvents. Participants were enrolled from four US SEER registry areas: the State of Iowa; Los Angeles County, California; and the metropolitan areas of Seattle, Washington; and Detroit, Michigan. Eligible cases were individuals between ages 20–74, diagnosed with incident, histologically confirmed NHL (ICD-O-3 codes 967–972) between July 1998 and June 2000, without known HIV infection. Cases of multiple myeloma were not enrolled in this study, which predates the 2001 World Health Organization (WHO) classification that expanded the definition of NHL to include this malignancy.19 Eligible controls were identified from the general population in the four registry areas via random digit dialing (RDD; < 65 years of age) or from Medicare files (65–74 years of age), with stratification on age (5-year intervals), sex, race, and SEER area to match the distribution of the cases. The study was approved by the institutional review boards at the NCI and the participating institutions, and study participants provided informed consent.
We identified 2,248 potentially eligible cases. Of these 320 (14%) died before they could be interviewed, 127 (6%) could not be found, 16 (1%) had moved away, and 57 (3%) had physician refusals. Of the remaining 1,728 cases; 1,321 agreed to participate (participation rate of 76% and an overall response rate of 59%). Sixty-one percent of the cases were interviewed within 6 months after the diagnosis date, and 84% within 12 months after diagnosis.
Of the 2,409 potentially eligible controls identified from RDD and Medicare files, 28 (1%) died before they could be interviewed, 311 (13%) could not be located, and 24 (1%) had moved away. Of the remaining 2,046 potential controls, 1,057 participated, which yielded a participation rate of 52% and an overall response rate of 44%. We excluded 132 cases and 75 controls who were never employed or had unknown occupations, thus 1,189 cases and 982 controls were included in our analyses.
Exposure assessment
Participants were mailed an occupational history calendar prior to the home visit. During the home visit, a trained interviewer administered a computer-assisted personal interview that gathered information on a variety of topics including occupational history. The occupational history queried the name of the employer, dates of employment, job title, number of hours worked (full or part time), type of business or service, tasks performed, chemicals or materials handled, and tools and equipment used for each job a participant held for at least 12 months since the age of 16. All jobs were coded using the US Standard Industrial Classification (SIC) and US Standard Occupational Classification (SOC) systems.20 21 Additionally, for selected occupations, one of 32 job- or industry-specific interview modules was administered. Twenty-eight of the modules included questions related to exposure to solvents, collecting information on the solvent(s) used, average frequency of and length of time spent on a variety of solvent-related tasks, work practices, potential for dermal exposure, and use of personal protective equipment.22–24 To reduce participant burden, a maximum of five modules was administered in an interview; six cases and four controls who reached the five-module limit had at least one additional job that would have prompted a module.
Exposure metrics for the five newly assessed chlorinated solvents (chloroform, methylene chloride, perchloroethylene, carbon tetrachloride, and 1,1,1-trichloroethane) were developed using previously described methods.25 An expert industrial hygienist used information from systematic reviews of the industrial hygiene literature on the uses of perchloroethylene2 and similar unpublished reviews for the other substances to develop 38 job and task exposure matrices for each of the five newly assessed solvents. These matrices provided an initial estimate of probability and frequency of exposure to each of the five solvents for different combinations of occupation, industry, and decade of employment.
The industrial hygienist used the information gathered from the occupational histories, and the job modules, the literature review, and the exposure matrices, to assess the probability, frequency, and determinants of exposure intensity for each chlorinated solvent for each job. Probability, defined as the theoretical probability of exposure to the solvent, was assigned to one of five categories: 0%, <10%, 10–49%, 50–89%, or ≥90%. A probability of ≥90% was assigned when the participant specifically reported using a given solvent. Otherwise, the industrial hygienist assigned a probability that the specific solvent was used when the job was held within the context of the other available information.
Jobs with a probability ≥50% were assigned an exposure frequency and intensity. Exposure frequency was assigned to one of four categories: <2, 2–9, 10–19, or ≥20 hours per week. The assigned frequency was either the reported frequency of performing a solvent-related task or, if missing, the average frequency of all reports for that task. If frequency was not asked about in the occupational questionnaire, it was assigned based on the industrial hygienist’s knowledge of the job and workplace. Determinants of chlorinated solvent exposure intensity, defined as the solvent concentration in a participant’s breathing zone while exposed, were identified from previously developed predictive intensity models for three chlorinated solvents26 and estimated from the literature review and the industrial hygienist’s knowledge. These determinants of exposure intensity included job location (indoor, outdoors, both), local exhaust ventilation (effective, ineffective, absent), mechanism of solvent release (evaporation, aerosolized, other active), proximity (near, far, both), and process temperature (room temperature, elevated, both). An algorithm using these parameters was developed to assign a qualitative job exposure intensity of “high” or “low” (Supplemental Table 1). Levels of confidence ranging from 1 (lowest) to 4 were assigned to the values for probability, frequency, and intensity parameters. The exposure assessment was performed without knowledge of case/control status.
Job-specific estimates of probability, frequency, and intensity were combined to develop participant level metrics of exposure. The highest exposure probability across all jobs was assigned as a participant’s exposure probability. Participants with an exposure probability ≥50% for a given solvent were assigned the following exposure metrics: duration of exposure (years), the sum of the number of years worked in jobs with an exposure probability ≥50%; cumulative hours exposed (hours), the sum of the product of the job-specific frequency midpoint (1, 6, 15, or 30 hours/week) and the job duration in weeks across all jobs with an exposure probability ≥50%; and average weekly exposure (hours per week), the cumulative hours exposed divided by the duration of exposure in weeks. These exposure metrics were defined as zero for participants with an exposure probability of 0% (unexposed). Participants with an exposure probability between >0% and <50% for a given solvent were excluded from analyses of that solvent. We also calculated these metrics restricted to jobs with ≥90% exposure probability and with a high exposure intensity and incorporating a five or 15-year exposure lag.
Statistical analysis
Differences between cases and controls across exposure metrics were assessed using odds ratios (OR) and 95% confidence intervals (CI) computed from unconditional logistic regression models. These models were adjusted for age (<35, 35–44, 45–54, 55–64, ≥65), sex, study center, race (black, white, or other), and education (<12 years, 12–15 years, >16 years, or missing). Estimates of exposure duration for each solvent were dichotomized at the median value of exposed controls with unexposed participants as the referent category. Tests for trend were performed by modelling the intra-category median among controls as a continuous variable, with values for unexposed participants set to zero. We note that our results for tests of trend should not be interpreted as independent of the results of exposure categories.
We stratified analyses by sex and tested for interaction by including multiplicative terms for the sex and the solvent variables. We conducted analyses of specific histologic NHL subtypes, as defined by the WHO27 using polytomous logistic regression to compute ORs for the four most common NHL subtypes in our study [diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL)]. Tests for heterogeneity across these subtypes were conducted using the Wald test.
To assess the robustness of our findings we conducted certain analyses stratified by exposure probability, restricted to jobs with high exposure intensity, ≥90% exposure probability, restricting to exposed participants for whom the industrial hygienist assessed exposure with high confidence (≥3), incorporating a five- and 15-year lag, restricting to participants less than 65 years of age, and adjusting for cumulative hours exposed to TCE.
RESULTS
Characteristics of cases and controls in the NCI-SEER study are described in Table 1. Compared to controls, cases tended to be slightly younger and were less likely to be African American but otherwise were comparable with regards to sex, SEER site, and education level.
Table 1.
Selected characteristics of participants in the NCI-SEER study, 1998–2001.
| Characteristic | Cases (n = 1189) | Controls (n = 982) | |
|---|---|---|---|
| n (%) | Pa | ||
|
|
|||
| Age (years) | |||
| <35 | 68 (5.7) | 53 (5.4) | |
| 35–44 | 153 (12.9) | 98 (10.8) | |
| 45–54 | 261 (22.0) | 185 (18.8) | |
| 55–64 | 316 (26.6) | 230 (23.4) | |
| ≥65 | 391 (32.9) | 416 (42.4) | 0.0002 |
| Sex | |||
| Female | 523 (44.0) | 458 (46.6) | |
| Male | 666 (56.0) | 524 (53.4) | 0.22 |
| Study center | |||
| Detroit | 209 (17.6) | 144 (14.7) | |
| Iowa | 352 (29.6) | 273 (27.8) | |
| Los Angeles | 310 (26.1) | 273 (27.8) | |
| Seattle | 318 (26.8) | 292 (29.7) | 0.13 |
| Race | |||
| White | 1014 (85.3) | 787 (80.1) | |
| African American | 91 (7.7) | 132 (13.4) | |
| Other | 84 (7.1) | 63 (6.4) | <0.0001 |
| Years of education | |||
| <12 | 118 (9.9) | 97 (9.9) | |
| 12–15 | 734 (61.7) | 584 (59.5) | |
| ≥16 | 336 (28.3) | 301 (30.7) | |
| Missing | 1 | 0.47 | |
Category percentages may not sum to 100% because of rounding.
P-value from chi-square test of independence between cases and controls.
In analyses among controls, after excluding participants unexposed to any chlorinated solvent, solvent exposure probabilities were moderately correlated with one another (Supplemental Table 2), with Spearman coefficients ranging from 0.05 (TCE and 1,1,1-trichloroethane) to 0.67 (1,1,1-trichloroethane and methylene chloride).
Table 2 summarizes the association between exposure to the five newly assessed chlorinated solvents and risk of NHL. The prevalence of exposure to these solvents was low in this study population, with the proportion of controls with an exposure probability ≥50% ranging from 1.2% (1,1,1-trichloroethane) to 9.1% (methylene chloride). Degreasing was the most common exposure-related task among participants with exposure probability ≥50% to methylene chloride (45%), carbon tetrachloride (65%), and 1,1,1-trichloroethane (74%). The most common exposure-related tasks assessed for the remaining solvents were: for chloroform, surgery (28%), degreasing (15%), and dry cleaning (10%); for perchloroethylene, dry cleaning (42%) and degreasing (29%).
Table 2.
Associations between measures of exposure to individual chlorinated solvents (exposure probability, cumulative hours exposed) and non-Hodgkin’s lymphoma risk, the NCI-SEER study, 1998–2001.
| Solvent | Exposure probability | Cumulative hours | Cases | Controls | ORa (95% CI) |
|---|---|---|---|---|---|
| N (%) | N (%) | ||||
|
| |||||
| Chloroform | |||||
| Unexposed | 836 (70.6) | 711 (72.5) | 1.0 | ||
| <50% | 329 (27.8) | 255 (26.0) | 1.0 (0.8, 1.3) | ||
| ≥50% | 19 (1.6) | 15 (1.5) | 1.2 (0.6, 2.3) | ||
| ≤1560 | 12 (1.4) | 8 (1.1) | 1.3 (0.5, 3.2) | ||
| >1560 | 7 (0.8) | 7 (1.0) | 1.0 (0.3, 2.8) | ||
| Ptrend 0.98 | |||||
| Methylene chloride | |||||
| Unexposed | 602 (50.8) | 536 (54.6) | 1.0 | ||
| <50% | 468 (39.5) | 356 (36.3) | 1.1 (0.9, 1.3) | ||
| ≥50% | 115 (9.7) | 89 (9.1) | 1.0 (0.7, 1.3) | ||
| ≤1560 | 68 (9.5) | 44 (7.1) | 1.2 (0.8, 1.9) | ||
| >1560 | 44 (6.2) | 42 (6.8) | 0.8 (0.5, 1.3) | ||
| Ptrend 0.47 | |||||
| Perchloroethylene | |||||
| Unexposed | 693 (58.5) | 608 (62.0) | 1.0 | ||
| <50% | 468 (39.5) | 353 (36.0) | 1.1 (0.9, 1.3) | ||
| ≥50% | 24 (2.0) | 20 (2.0) | 1.0 (0.6, 1.9) | ||
| ≤2652 | 11 (1.5) | 10 (1.6) | 1.0 (0.4, 2.3) | ||
| >2652 | 11 (1.5) | 9 (1.4) | 1.1 (0.4, 2.7) | ||
| Ptrend 0.87 | |||||
| Carbon tetrachloride | |||||
| Unexposed | 829 (70.0) | 712 (72.6) | 1.0 | ||
| <50% | 301 (25.4) | 234 (23.9) | 1.0 (0.8, 1.3) | ||
| ≥50% | 54 (4.6) | 35 (3.6) | 1.3 (0.8, 2.0) | ||
| ≤520 | 17 (1.9) | 16 (2.2) | 0.9 (0.4, 1.8) | ||
| >520 | 34 (3.9) | 16 (2.2) | 1.9 (1.0, 3.6) | ||
| Ptrend 0.04 | |||||
| 1,1,1-trichloroethane | |||||
| Unexposed | 619 (52.3) | 555 (56.6) | 1.0 | ||
| <50% | 551 (46.5) | 414 (42.2) | 1.1 (0.9, 1.3) | ||
| ≥50% | 14 (1.2) | 12 (1.2) | 1.0 (0.4, 2.1) | ||
| ≤312 | 2 (0.3) | 6 (1.1) | 0.3 (0.1, 1.6) | ||
| >312 | 11 (1.7) | 6 (1.1) | 1.5 (0.6, 4.3) | ||
| Ptrend 0.47 | |||||
adjusted for age, study center, sex, race, and education. “Exposure probability” percentages may not sum to 100% due to rounding error. “Cumulative hours exposed” percentages may not sum to “≥50% probability” percentage due to rounding and subjects with missing data for this metric. Tests for trend were performed by modelling the intra-category median among controls as a continuous variable, with values for unexposed participants set to zero.
While we did not observe evidence of an association with NHL for most of the solvents, high cumulative hours exposed to carbon tetrachloride was associated with increased risk (Table 2; >520 exposure hours vs. unexposed: OR 1.9, 95% CI 1.0–3.6; Ptrend = 0.04). In analyses of other carbon tetrachloride exposure metrics, weak, non-significant associations between duration (>9 years vs. unexposed: OR 1.3, 95% CI 0.7–2.4; Ptrend= 0.36) and average weekly exposure (>1hour/week vs. unexposed: OR 1.4, 95% CI 0.7–3.0; Ptrend=0.28) and increased risk were observed. When we further stratified by exposure probability (Table 3), the association with >520 cumulative hours exposed to carbon tetrachloride was confined to subjects with ≥90% exposure probability (OR 2.1, 95% CI 1.0–4.3).
Table 3.
Associations between exposure probability and cumulative hours exposed to carbon tetrachloride and non-Hodgkin’s lymphoma risk, the NCI-SEER study, 1998–2001.
| Exposure probability | Cumulative hours | Cases N |
Controls N |
ORa (95% CI) |
|---|---|---|---|---|
| Unexposed | 829 | 712 | 1.0 | |
| <50% | 300 | 234 | 1.0 (0.8, 1.3) | |
| 50–89% | ≤520 | 6 | 4 | 1.2 (0.3, 4.4) |
| >520 | 7 | 5 | 1.2 (0.4, 3.9) | |
| ≥90% | ≤520 | 11 | 12 | 0.7 (0.3, 1.7) |
| >520 | 27 | 11 | 2.1 (1.0, 4.3) |
adjusted for age, study center, sex, race, and education.
Additional analyses of carbon tetrachloride by NHL subtype are presented in Table 4. The association with high cumulative hours exposed was observed for FL (>520 exposure hours vs. unexposed: OR 2.7, 95% CI 1.2–6.3; Ptrend = 0.02) and MCL (3.5, 1.0–11.5; Ptrend = 0.04), but not DLBCL (1.1, 0.4–2.9; Ptrend = 0.87) or CLL/SLL (0.9, 0.2–3.9; Ptrend = 0.91). However, tests for heterogeneity were not statistically significant. Subtype specific analyses for exposure to other solvents were null (results not shown).
Table 4.
Analysis of estimated occupational exposure to carbon tetrachloride and selected NHL histologic subtypes within the NCI-SEER study, 1998–2001.
| Exposure probability | Cumulative hours | Controls | DLBCL | FL | CLL/SLL | MCL | P heterogeneity | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||||
| n | n | ORa (95% CI) | n | ORa (95% CI) | n | ORa (95% CI) | n | ORa (95% CI) | |||
|
| |||||||||||
| Unexposed | 712 | 260 | 1.0 | 210 | 1.0 | 91 | 1.0 | 33 | 1.0 | ||
| <50% | 234 | 95 | 1.0 (0.7, 1.3) | 70 | 0.9 (0.7, 1.3) | 42 | 1.2 (0.8, 1.8) | 12 | 0.8 (0.4, 1.6) | 0.71 | |
| ≥50% | 35 | 10 | 0.7 (0.3, 1.5) | 12 | 1.2 (0.6, 2.4) | 8 | 1.4 (0.6, 3.3) | 4 | 1.9 (0.7, 5.4) | 0.31 | |
| ≤520 | 16 | 3 | 0.5 (0.1, 1.6) | 2 | 0.4 (0.1, 1.8) | 6 | 2.5 (0.9, 6.7) | 1 | 0.8 (0.1, 6.5) | 0.06 | |
| >520 | 16 | 6 | 1.1 (0.4, 2.9) | 10 | 2.7 (1.1, 6.0) | 2 | 0.9 (0.2, 3.9) | 4 | 3.5 (1.0, 11.5) | 0.17 | |
| Ptrend 0.87 | Ptrend 0.02 | Ptrend 0.91 | Ptrend 0.04 | 0.17 | |||||||
Abbreviations: NHL, non-Hodgkin’s lymphoma; DLBCL, diffuse large B-cell lymphoma; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; MCL, mantle cell lymphoma; OR, odds ratio; CI, confidence interval.
adjusted for age, study center, sex, race, and education. Tests for trend were conducted by modelling the intra-category median among controls as a continuous variable, with values for unexposed participants set to zero. Tests for heterogeneity were based on Wald test of beta coefficients across subtypes from polytomous logistic regression models.
We conducted several sensitivity analyses to assess the robustness of the association between >520 cumulative hours exposed to carbon tetrachloride and NHL. The association persisted in analyses restricted to high intensity exposure (OR 2.0, 95% CI 1.1–3.8; Ptrend = 0.03), restricted to participants the hygienist assessed with high confidence (2.1, 1.1–4.3; Ptrend = 0.04), incorporating a five- and fifteen-year exposure lags (2.0, 1.1–3.8; Ptrend = 0.03 and 1.9, 1.0–3.6; Ptrend = 0.06, respectively), restricting to participants less than 65 years of age (3.9, 1.1–13.9; Ptrend = 0.03), and adjusting for cumulative hours exposed to TCE (2.1, 1.0–4.1; Ptrend = 0.04).
DISCUSSION
In this expanded investigation of chlorinated solvents within the NCI-SEER case-control study of NHL, cumulative hours exposed to carbon tetrachloride was associated with NHL. We observed null findings for chloroform, methylene chloride, perchloroethylene, and 1,1,1-trichloroethane and other metrics of carbon tetrachloride exposure.
Carbon tetrachloride was widely used between the 1930’s and 1980’s in the US as a degreasing and cleaning agent, in the production of chlorinated refrigerants and propellants, as a fire extinguisher, and as a grain fumigant.28 Since it is an ozone-depleting chemical, dispersive use of carbon tetrachloride was eliminated in the US in 1996 and non-dispersive uses have been strictly regulated.29 The findings from previous epidemiologic studies of carbon tetrachloride (one cohort, three case-control) support an association with NHL. NHL mortality was non-significantly elevated in a study of aircraft maintenance workers exposed to carbon tetrachloride.30 Self-reported use of carbon tetrachloride as a fumigant was associated with NHL in a study of 517 male NHL cases and 1,506 controls (OR 2.4, 95% CI 1.2–5.1).11 Occupational exposure to carbon tetrachloride, estimated from a job-exposure matrix, was associated with NHL (OR 2.3, 95% CI 1.3– 4.0) in a study of only women.9 Another study that used an expert assessment of work histories reported a non-significant association with this chemical (OR 2.0, 95% CI 0.6–6.9).8 Although our study and the two previous studies that considered subtype of NHL were underpowered to detect associations with individual subtypes, our observed carbon tetrachloride association with FL and MCL, and absence of an association with DLBCL and CLL/SLL, is not consistent with the findings from the previous studies.8 31 However, TCE exposure has been more strongly associated with FL in our study16 and in a pooled analysis of 3788 NHL cases and 4279 controls that included participants from our study.32
The biologic basis for an association between carbon tetrachloride and NHL is unclear, as there have been no human studies investigating immunologic and other biologic effects among exposed workers. However, rodent studies have indicated that hepatotoxic doses of carbon tetrachloride (≥500 mg/kg) suppress T-cell activity, which could be due in part to the transforming growth factor beta (TGF-β) secreted by the liver during repair.33 34
To our knowledge, no prior studies of carbon tetrachloride and NHL attempted to control for possible confounding by exposure to TCE or other solvents. Use of specific chlorinated solvents for a given task has overlapped in various industries over time, and has complicated the interpretation of studies regarding the carcinogenicity of specific solvents.32 Our observed association between carbon tetrachloride and NHL remained upon adjustment for exposure to TCE, thus arguing against confounding from this solvent as an explanation for our findings.
We did not observe evidence of NHL associations for the other evaluated chlorinated solvents. We acknowledge, however, that we had limited power to detect modest associations with these chemicals, particularly for 1,1,1-trichloroethane, perchloroethylene, and chloroform, for which less than three percent of cases or controls were exposed. We thus cannot rule out the existence of subtle effects on NHL overall or on a certain subtype.
Inferences from our study should be made in the context of several limitations. Despite the relatively large sample size of this case-control study, we identified only small numbers of subjects with high exposure probabilities, which is not unexpected given the rarity of these occupational exposures in the general population. Sample size limitations were particularly severe in our analyses of NHL subtypes. We cannot rule out selection bias as an explanation for our finding, because the participation rate among controls was comparatively low, although we previously estimated demographic and socioeconomic differences between control participants and nonparticipants to be generally minor.35 As with all retrospective case-control studies, it is possible that cases may have ruminated more deeply on past exposures leading to recall bias. However, we did not observe an association between NHL and four out of the six solvents we assessed, which would be expected if cases were systematically overreporting occupational exposures. We made many comparisons in our analyses, thus the association between carbon tetrachloride could be due to chance, however prior epidemiologic studies have also observed an association with carbon tetrachloride and NHL risk, which provides some reassurance that chance alone is not an alternate explanation. Lastly, our occupational history only collected information on jobs held by participants for six months or longer, thus exposures from shorter-term jobs may not have been captured.
Our study has several important strengths. Importantly, we had detailed information on workplace tasks gathered from a general work history and job- and industry-specific modules designed to elicit information on solvent exposure. An extensive literature review informed the development of task-, job-, industry-, and decade-specific exposure matrices and assessment rules a priori. This rich dataset was used by an industrial hygienist to assign several parameters of exposure. These expected improvements in exposure assessment facilitated several sensitivity analyses, including the calculation of exposure metrics among participants who were rated as having a high probability of exposure to carbon tetrachloride. In addition to increasing the sensitivity of exposure estimates, our method likely increased the specificity of exposure assessment, which is essential to reduce the potential for bias from exposure misclassification in studies, such as ours, with a low exposure prevalence.36 Furthermore, we were able to adjust for a broad range of chlorinated solvents.
In conclusion, we observed a significantly elevated association between cumulative hours exposed to carbon tetrachloride exposure and NHL, which was not attenuated after adjustment for TCE. These findings offer further support that carbon tetrachloride may be a lymphomagen. While additional investigations of this relationship may not be feasible given the reduction of use of carbon tetrachloride, a meta-analysis or other quantitative summary of the epidemiologic literature may be informative.
Supplementary Material
KEY FINDINGS.
What is already known about this subject?
Trichloroethylene, a chlorinated solvent used to degrease metal parts, has been associated with non-Hodgkin lymphoma (NHL) in several studies. We extended our previous analyses of trichloroethylene within a case-control study to include expert assessment of occupational exposure to five additional solvents.
What are the new findings?
NHL cases were more likely than controls to have high cumulative hours exposed to carbon tetrachloride, a solvent previously used in several industrial applications. The association between carbon tetrachloride and NHL persisted after adjustment for co-exposure to trichloroethylene.
How might this impact on policy or clinical practice in the foreseeable future?
Carbon tetrachloride was classified in 1999 as a possible human carcinogen by the International Agency for Research on Cancer (IARC), our findings will inform any future evaluation of carcinogenicity for this chemical.
FUNDING
This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, with Public Health Service contracts N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, and N02-PC-71105.
Footnotes
COMPETING INTERESTS
P.S. is employed by Stewart Exposure Assessments, LLC (Arlington, VA, USA). The remaining authors declare they have no actual or potential competing financial interests.
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