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. 2012 Nov 21;104(22):1724-37.
doi: 10.1093/jnci/djs411. Epub 2012 Oct 30.

Myelodysplastic syndrome and benzene exposure among petroleum workers: an international pooled analysis

A Robert Schnatter  1 , Deborah C Glass, Gong Tang, Richard D Irons, Lesley Rushton
Affiliations

Myelodysplastic syndrome and benzene exposure among petroleum workers: an international pooled analysis

A Robert Schnatter et al. J Natl Cancer Inst. .

Abstract

Background: Benzene at high concentrations is known to cause acute myeloid leukemia (AML), but its relationship with other lymphohematopoietic (LH) cancers remains uncertain, particularly at low concentrations. In this pooled analysis, we examined the risk of five LH cancers relative to lower levels of benzene exposure in petroleum workers.

Methods: We updated three nested case-control studies from Australia, Canada, and the United Kingdom with new incident LH cancers among petroleum distribution workers through December 31, 2006, and pooled 370 potential case subjects and 1587 matched LH cancer-free control subjects. Quantitative benzene exposure in 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 examined for five LH cancers, including the three most common leukemia cell-types (AML, chronic myeloid leukemia [CML], and chronic lymphoid leukemia [CLL]) and two myeloid tumors (myelodysplastic syndrome [MDS] and myeloproliferative disease [MPD]). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression, controlling for age, sex, and time period.

Results: 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). For peak benezene 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). There was little evidence of dose-response relationships for AML, CLL, CML, or MPD.

Conclusions: Relatively low-level exposure to benzene experienced by petroleum distribution workers was associated with an increased risk of MDS, but not AML, suggesting that MDS may be the more relevant health risk for lower exposures.

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Figures

Figure 1.
Figure 1.
Process for pooling and updating three nested case–control studies in petroleum workers and resulting median cumulative exposure estimates for five lymphohematopoietic cancer subtypes. *These include diagnoses with too few case subjects for statistical analysis, plus non-Hodgkin lymphoma and multiple myeloma. AML = acute myeloid leukemia; MDS = myelodysplastic syndrome; CLL = chronic lymphoid leukemia; CML = chronic myeloid leukemia; MPD = myeloproliferative disease; IQR = interquartile range.
Figure 2.
Figure 2.
Funnel plots of dose–response relationships between five lymphohematopoietic (LH) cancer subtypes and six discrete benzene exposure metrics. Metrics were calculated over the entire work history as well as a 2–15-year exposure window for myeloid tumors AML, CML, MDS, and MPD. A) Association of cumulative exposure (ppm-years) with LH cancer subtype. B) Association of average exposure intensity (ppm) with LH cancer subtype. C) Association of maximum exposure intensity (ppm) with LH cancer subtype. D) Association of duration of employment (years) with LH cancer subtype. E) Association of peak exposure (at least weekly exposure to >3 ppm for 15–60 minutes) with LH cancer subtype. F) Association of dermal exposure (relative probability) with LH cancer subtype. AML = acute myeloid leukemia; MDS = myelodysplastic syndrome; CLL = chronic lymphoid leukemia; CML = chronic myeloid leukemia; MPD = myeloproliferative disease.
Figure 2.
Figure 2.
Funnel plots of dose–response relationships between five lymphohematopoietic (LH) cancer subtypes and six discrete benzene exposure metrics. Metrics were calculated over the entire work history as well as a 2–15-year exposure window for myeloid tumors AML, CML, MDS, and MPD. A) Association of cumulative exposure (ppm-years) with LH cancer subtype. B) Association of average exposure intensity (ppm) with LH cancer subtype. C) Association of maximum exposure intensity (ppm) with LH cancer subtype. D) Association of duration of employment (years) with LH cancer subtype. E) Association of peak exposure (at least weekly exposure to >3 ppm for 15–60 minutes) with LH cancer subtype. F) Association of dermal exposure (relative probability) with LH cancer subtype. AML = acute myeloid leukemia; MDS = myelodysplastic syndrome; CLL = chronic lymphoid leukemia; CML = chronic myeloid leukemia; MPD = myeloproliferative disease.
Figure 2.
Figure 2.
Funnel plots of dose–response relationships between five lymphohematopoietic (LH) cancer subtypes and six discrete benzene exposure metrics. Metrics were calculated over the entire work history as well as a 2–15-year exposure window for myeloid tumors AML, CML, MDS, and MPD. A) Association of cumulative exposure (ppm-years) with LH cancer subtype. B) Association of average exposure intensity (ppm) with LH cancer subtype. C) Association of maximum exposure intensity (ppm) with LH cancer subtype. D) Association of duration of employment (years) with LH cancer subtype. E) Association of peak exposure (at least weekly exposure to >3 ppm for 15–60 minutes) with LH cancer subtype. F) Association of dermal exposure (relative probability) with LH cancer subtype. AML = acute myeloid leukemia; MDS = myelodysplastic syndrome; CLL = chronic lymphoid leukemia; CML = chronic myeloid leukemia; MPD = myeloproliferative disease.
Figure 2.
Figure 2.
Funnel plots of dose–response relationships between five lymphohematopoietic (LH) cancer subtypes and six discrete benzene exposure metrics. Metrics were calculated over the entire work history as well as a 2–15-year exposure window for myeloid tumors AML, CML, MDS, and MPD. A) Association of cumulative exposure (ppm-years) with LH cancer subtype. B) Association of average exposure intensity (ppm) with LH cancer subtype. C) Association of maximum exposure intensity (ppm) with LH cancer subtype. D) Association of duration of employment (years) with LH cancer subtype. E) Association of peak exposure (at least weekly exposure to >3 ppm for 15–60 minutes) with LH cancer subtype. F) Association of dermal exposure (relative probability) with LH cancer subtype. AML = acute myeloid leukemia; MDS = myelodysplastic syndrome; CLL = chronic lymphoid leukemia; CML = chronic myeloid leukemia; MPD = myeloproliferative disease.
Figure 2.
Figure 2.
Funnel plots of dose–response relationships between five lymphohematopoietic (LH) cancer subtypes and six discrete benzene exposure metrics. Metrics were calculated over the entire work history as well as a 2–15-year exposure window for myeloid tumors AML, CML, MDS, and MPD. A) Association of cumulative exposure (ppm-years) with LH cancer subtype. B) Association of average exposure intensity (ppm) with LH cancer subtype. C) Association of maximum exposure intensity (ppm) with LH cancer subtype. D) Association of duration of employment (years) with LH cancer subtype. E) Association of peak exposure (at least weekly exposure to >3 ppm for 15–60 minutes) with LH cancer subtype. F) Association of dermal exposure (relative probability) with LH cancer subtype. AML = acute myeloid leukemia; MDS = myelodysplastic syndrome; CLL = chronic lymphoid leukemia; CML = chronic myeloid leukemia; MPD = myeloproliferative disease.
Figure 2.
Figure 2.
Funnel plots of dose–response relationships between five lymphohematopoietic (LH) cancer subtypes and six discrete benzene exposure metrics. Metrics were calculated over the entire work history as well as a 2–15-year exposure window for myeloid tumors AML, CML, MDS, and MPD. A) Association of cumulative exposure (ppm-years) with LH cancer subtype. B) Association of average exposure intensity (ppm) with LH cancer subtype. C) Association of maximum exposure intensity (ppm) with LH cancer subtype. D) Association of duration of employment (years) with LH cancer subtype. E) Association of peak exposure (at least weekly exposure to >3 ppm for 15–60 minutes) with LH cancer subtype. F) Association of dermal exposure (relative probability) with LH cancer subtype. AML = acute myeloid leukemia; MDS = myelodysplastic syndrome; CLL = chronic lymphoid leukemia; CML = chronic myeloid leukemia; MPD = myeloproliferative disease.
Figure 3.
Figure 3.
Penalized regression smoothing spline (P-spline) functions showing log odds ratio of risk of lymphohematopoietic (LH) cancer subtypes and specific benzene exposure metrics. We used conditional logistic regression models with P-splines to examine dose–response relationships. P spline P-values (testing whether there was any dose–response relationship) were calculated using two-sided likelihood ratio tests. A) Association of cumulative exposure (ppm-years) with LH cancer subtype. B) Association of average exposure intensity (ppm) with LH cancer subtype. C) Association of maximum exposure intensity (ppm) with LH cancer subtype. D) Association of duration of employment (years) with LH cancer subtype.
Figure 4.
Figure 4.
Penalized regression smoothing spline (P-spline) functions showing log odds ratio of risk of myelodysplastic syndrome (MDS) and specific benzene exposure metrics for more certain cases and more certain exposure history. We defined more certain case subjects as those with diagnostic certainty scores of 2 or higher, and more certain exposure history as subjects whose weighted career certainty score was 2 or higher. Here 95% confidence intervals around P-spline functions are displayed for all case and control subjects. A) Association of cumulative exposure (ppm-years) with MDS. B) Association of average exposure intensity (ppm) with MDS. C) Association of maximum exposure intensity (ppm) with MDS. D) Association of duration of employment (years) with MDS.
Figure 5.
Figure 5.
Plot of MDS case subjects and control subjects by maximum exposure intensity (ppm) and duration of employment (years).
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