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Administrative data

Endpoint:
epidemiological data
Type of information:
other: : observational study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Human population study, published in peer-reviewed literature, minor restrictions in design but adequate for assessment.
Cross-reference
Reason / purpose:
reference to other study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Myelodysplastic syndrome and benzene exposure among petroleum workers: an international pooled analysis.
Author:
Schnatter, AR, Glass DC, Tang G, Irons RD and Rushton L
Year:
2012
Bibliographic source:
J Natl Cancer Inst, 104, 1724-37
Reference Type:
publication
Title:
Risk of myeloproliferative disease and chronic myeloid leukaemia following exposure to low-level benzene in a nested case-control study of petroleum workers.
Author:
Glass DC, Schnatter AR, Tang G, Irons RD, Rushton L.
Year:
2014
Bibliographic source:
Occup Environ Med, 71, 266-74.
Reference Type:
publication
Title:
Acute myeloid and chronic lymphoid leukaemias and exposure to low-level benzene among petroleum workers.
Author:
Rushton L, Schnatter AR, Tang G, Glass DC.
Year:
2014
Bibliographic source:
Br J Cancer, 110, 783-7.

Materials and methods

Study type:
case control study (retrospective)
Endpoint addressed:
carcinogenicity
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
The study updated three nested case–control studies based on cohorts of petroleum distribution workers in Canada (Schnatter et al., 1996) and the United Kingdom (Rushton and Romaniuk, 1997), and based on petroleum distribution, refining, and upstream workers in Australia (Glass et al., 2003) and pooled the resulting data. The study assessed the risk of five lymphohematopoietic cancers, including the three most common leukemia cell-types (acute myeloid leukemia, chronic myeloid leukemia, and chronic lymphoid leukemia) and two myeloid tumors (myelodysplastic syndrome and myeloproliferative disease) relative to benzene exposure.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
Common name: Benzene
No other data provided

Method

Type of population:
occupational
Ethical approval:
other: approved by relevant ethics committees in Australia, Canada and UK.
Details on study design:
HYPOTHESIS TESTED (if cohort or case-control study): To determine whether there is an increased risk of five lymphohematopoietic (LH) cancers at the lower levels of benzene exposure experienced by petroleum workers.

METHOD OF DATA COLLECTION
- Type: Record review/Work history/Interview
- Details: National mortality and cancer incidence registries in Canada, the United Kingdom, and Australia were used to update each nested case–control study to include new case subjects with LH cancers. For the Australian study, 3 self-reported LH cancers confirmed by medical documentation were included. Work histories consisting of job titles, locations, and effective dates were assembled from company records in the Canadian and UK studies for the entire follow-up period. For the Australian study, job history data was collected by trained interviewers for the entire cohort. These interviews were conducted in 1981-1983, 1986-1987, 1991-1993, and 1996-2000 and validated where possible against company records.

STUDY PERIOD
Canadian Study: January 1, 1964, through December 31, 1983 (original study) updated through December, 1994
UK Study: January 1, 1950, through December 31, 1992 (original study) updated through December, 2005
Australian Study: January 1, 1981, through December 31, 1999 (original study) updated through December, 2006

SETTING: Petroleum Workers (petroleum distribution, refining, and upstream workers in Australia; petroleum distribution workers in Canada and the UK)

STUDY POPULATION
- Total population (Total no. of persons in cohort from which the subjects were drawn): 46682 (Australia 16910; Canada 6672; UK 23300)
- Selection criteria: The Canadian and UK studies were nested in retrospective studies with a 1-year employment criterion for inclusion, and the Australian study was nested in a prospective study with a 5-year employment criterion for inclusion. The selection time periods for the 3 studies are not stated.
- Total number of subjects participating in study: 370 case subjects including 60 cases of acute myeloid leukemia (AML), 28 cases of chronic myeloid leukemia (CML), 80 cases of chronic lymphoid leukemia (CLL), 29 cases of myelodysplastic syndrome (MDS) and 30 cases of myeloproliferative disease (MPD), and 1587 control subjects. 143 case subjects (mixed myelodysplastic and myeloproliferative disease (including chronic myelomonocytic leukemia), acute leukemias of ambiguous lineage, acute lymphoid leukemia, and unspecified leukmias, as well as case subjects with non-Hodgkin lymphoma and multiple myeloma, which were not included in the original UK study) and their 626 control subjects were not included in analyses.
- Sex/age/race: All case subjects were male (because of the paucity of females in the parent cohorts)
- Smoker/nonsmoker: Smoking data were collected from interview and workplace records, although this information was missing for 936 of the 1957 subjects (49%), mainly from the UK study.
Matching criteria: Case subjects in the original studies were age and sex matched to either 4 control subjects (Canada and UK) or 5 control subjects (Australia). For each case subjects identified in the update, either 4 age- and company-matched (Canadian and UK studies)) or 5 age-matched (Australian study control subjects were selected from each cohort.

COMPARISON POPULATION- Type: Control or reference group:
Details: Control subjects were required to be LH cancer–free at the time of diagnosis in case subjects and selected with replacement from employees in the cohorts using incidence density based sampling.

HEALTH EFFECTS STUDIED- Disease(s): AML, CML, CLL, MDS, MPD

Exposure assessment:
estimated
Details on exposure:
Benzene exposure was assessed by investigators who were blind to case-control status. Work histories consisting of job titles, locations, and effective dates were assembled from company records in the Canadian and UK studies for the entire follow-up period. For the Australian study, job history data was collected by trained interviewers for the entire cohort. These interviews were conducted in 1981-1983, 1986-1987, 1991-1993, and 1996-2000 and validated where possible against company records.
For each job or task, the average benzene exposure (base estimate [BE] in parts per million [ppm]) was derived from over 5800 measurements collected at study facilities for specific exposed jobs and at both study and similar industrial facilities for jobs only exposed to background concentrations. Estimates of exposure intensity (workplace exposure estimates [WEs]) were calculated for work history entries by choosing the analogous BE or adjusting a BE for facility- or era-specific differences, including fuel transfer technology, benzene product content, and working environment variables such as temperature.
Six exposure metrics were derived to capture different aspects of benzene exposure: cumulative exposure (ppm-years); duration of employment (years); average exposure intensity (ppm); maximum exposure intensity (ppm) (ie, the highest job-specific full-shift WE); peak exposure (at least 1-year employment in jobs likely experiencing >3 ppm exposure for 15-60 minutes at least weekly); and
dermal exposure (the highest job-specific relative probability of skin contact for at least a year). Metrics were calculated over the entire work history as well as a 2-15-year exposure window for myeloid tumors, because recent exposures have been reported as more important in benzene-induced AML. Exposure estimates among the three studies were compared and refined to improve interstudy consistency.
Benzene exposure was relatively low. The lower and upper tertiles of cumulative exposure among control subjects were 0.348 and 2.93 ppm-years, while almost one third of control subjects in Figure 2C had maximum exposure below the background concentration level of 0.016 ppm.
Statistical methods:
Conditional logistic regression was performed to assess the relationship between LH cancers relative to benzene exposure. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated relative to a baseline category. For concentration measures (average and maximum) the cut-off for the baseline category was the background benzene concentration of 0.016 ppm. Concentrations greater than the background level were categorized into tertiles based upon exposure distributions among control subjects. Background categories were not utilized for metrics that were not based on concentrations (eg, cumulative exposure, duration of exposure) and the first tertile served as the baseline category. Global likelihood ratio χ2 tests were performed that assessed whether all ORs are consistent with a value of 1.0 (Pglobal) or whether ORs were consistent with a linear trend (Ptrend).
Conditional logistic regression models with penalized regression smoothing splines (P-splines) were also used to examine dose-response relationships. Models were fitted via the “coxph” function in R as well as S-plus software packages using matched risk sets (i.e., matched case and control subjects) as strata.
Subgroup analyses were conducted specific to study, facility type, and job (terminal workers and tanker drivers were of particular interest as they are the groups most likely to be exposed to higher benzene concentrations). Heterogeneity of results by study was evaluated by assessing interaction terms (viz, study × exposure metric) using χ2 tests (Phomogeneity).
Sensitivity analyses were performed for diagnostic certainty (using only high and medium certain cancers) and exposure certainty (using only subjects with medium or high certainty as a weighted career average score) to mitigate possible effects of disease and exposure misclassification.
All statistical tests were two-sided, and P-values were considered statistically significant if they were .05 or less. SAS, v 9.2.

Results and discussion

Results:
In categorical analyses of all subjects, cumulative benzene exposure showed a monotonic dose-response relationship with MDS (0.348–2.93 vs ≤ 0.348 ppm-years [referent], OR = 1.73 [95% CI = 0.55 to 5.47]; ≥ 2.93 vs ≤ 0.348 ppm-years [referent], OR = 4.33 [95% CI = 1.31 to 14.3]: Ptrend = 0.01). Dose–response trends were weaker in tertile analyses of other exposure metrics, but MDS was the only outcome that showed consistent increasing trends for all metrics.
Similar dose-response patterns were seen in P-spline analyses, and the relationship between MDS and benzene exposure strengthened (ie, a steeper slope and lower P-value) in dose-response analyses for all subjects vs subjects with more certain diagnoses: cumulative exposure, Pspline = .07 vs Pspline = .02; average exposure, Pspline = .07 vs Pspline = .03; and maximum exposure, Pspline = .03 vs Pspline = .02).
Peak exposures greater than 3 ppm showed an increased risk of MDS (ever peak exposure >3 ppm vs never peak exposure >3 ppm, OR = 2.48 [95% CI = 0.97 to 6.35]) and the association strengthened in high and medium certainty diagnoses (peak exposure vs no peak exposure, OR = 6.32 [95% CI = 1.32 to 30.2]) and in workers having the highest exposure certainty (peak exposure vs no peak exposure, OR = 5.74 [95% CI = 1.05 to 31.2]). Models of MDS risk that simultaneously included peak exposure and other exposure metrics suggested that peak exposure was the more robust metric. For highly certain case subjects, the P-values for the cumulative exposure term increased when including peak exposure in the model, yet the P-value for peak exposure remained statistically significant and unchanged when including cumulative exposure in the model.
There was little evidence of dose–response relationships for AML, CLL, CML, or MPD, although significantly elevated ORs were observed for CML among workers with cumulative benzene exposure between the lower and upper tertiles, and for CLL among those with duration of exposure between the lower and upper tertiles. ORs for AML rose with cumulative exposure, duration of exposure, peak exposure and dermal exposure increase, but there was no clear pattern for average or maximum intensity of exposure.
Confounding factors:
Smoking has been related to AML and MDS. Smoking data was unavailable for almost half of subjects, but the MDS-benzene relationship did not weaken among workers with known smoking histories. Other potential confounders (e.g., radiation exposure, genetic susceptibility) were not assessed.
Strengths and weaknesses:
STRENGTHS: Enhanced ascertainment of disease subtype diagnoses via assembly of source records and use of hematopathologic expertise. Extensive exposure validation to ensure comparability across the three studies. Sensitivity analyses based on more certain diagnostic and exposure assessments to limit disease and exposure misclassification. Study size, which allowed analysis of etiologically distinct LH cancer subgroups.

WEAKNESSES: The exposure assessment did not account for infrequent and individualized exposure events, such as spills, nonroutine maintenance activities, or compromised work practices and may have led to underestimation of exposure in individual study subjects. Exposures were low compared to measurement error and almost one third of subjects only ever experienced background levels of exposure. The MDS arm of the case control study has only 29 cases. Subjects who developed MDS before the 1980s were likely grouped with or misclassified as aplastic anemia, myeloproliferative diseases, or other leukemias. The record review employed in the study identified five such MDS cases which had been misclassified in the original studies.

Applicant's summary and conclusion

Conclusions:
The study provides evidence of an association between MDS and benzene exposure at lower levels than previously reported. In categorical analyses, associations were reported between MDS and cumulative benzene exposure and peak exposure to benzene (at least 1-year employment in jobs likely experiencing >3 ppm exposure for 15–60 minutes at least). In P-spline analyses, associations were observed with cumulative, average and maximum exposure. It was not possible to ascribe precise concentrations of benzene to MDS. No convincing association was identified between AML, CLL, CML, or MPD and low exposure to benzene.
Executive summary:

The study updated three nested case–control studies based on cohorts of petroleum distribution workers in Canada and the United Kingdom, and based on petroleum distribution, refining, and upstream workers in Australia and pooled the resulting data. The study assessed the risk of five lymphohematopoietic (LH) cancers, including the three most common leukemia cell-types (acute myeloid leukemia [AML], chronic myeloid leukemia [CML], and chronic lymphoid leukemia [CLL]) and two myeloid tumors (myelodysplastic syndrome [MDS] and myeloproliferative disease [MPD]) relative to benzene exposure. 370 potential case subjects including 60 cases of AML, 28 cases of CML, 80 cases of CLL, 29 cases of MDS and 30 cases of MPS and 1587 matched LH cancer-free control subjects were pooled together for the purpose of this study. Benzene exposure (parts per million [ppm]) was blindly reconstructed using historical monitoring data, and exposure certainty was scored as high, medium, or low. Two hematopathologists assigned diagnoses and scored the certainty of diagnosis as high, medium, or low. Dose-response relationships were subsequently determined for the five LH cancers using conditional logistic regression, controlling for age, sex, and time period.

In categorical analyses, cumulative benzene exposure showed a monotonic dose–response relationship with MDS (highest vs lowest tertile, >2.93 vs ≤ 0.348 ppm-years, OR = 4.33, 95% CI = 1.31 to 14.3: Ptrend= 0.01). For peak benzene exposures (>3 ppm), the risk of MDS was increased in high and medium certainty diagnoses (peak exposure vs no peak exposure, OR = 6.32, 95% CI = 1.32 to 30.2) and in workers having the highest exposure certainty (peak exposure vs no peak exposure, OR = 5.74, 95% CI = 1.05 to 31.2). In P-spline analyses, associations were observed with cumulative, average and maximum exposure. There was little evidence of dose–response relationships for AML, CLL, CML, or MPD. The study provides evidence of an association between MDS and benzene exposure at lower levels than previously reported, but it was not possible to ascribe precise concentrations of benzene to MDS. No convincing association was identified between AML, CLL, CML, or MPD and low exposure to benzene.