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Supplemental Digital Content is available in the text, Objective: This study updates the mortality experience of over 25,000 workers in a large Canadian petroleum company through December 31, 2006. Methods: Standardized mortality ratios were generated for all-cause and specific cause mortality. Results: All cause and all cancer mortality were favorable compared with the general Canadian population. Cancers of previous interest were largely consistent with expectation. There is a continuing excess of mesothelioma, which is of similar magnitude as the previous update, although based on larger numbers. This excess is mostly attributable to men who died in their 50s and 60s and who worked in the refining sector. Conclusion: Most causes of death show mortality rates lower than the Canadian general population. Given the excess of mesothelioma observed, this study supports ongoing vigilance in asbestos exposure control programs, as refineries continue to remove asbestos from their facilities.

Occupational exposure to benzene at levels of 10 ppm or more has been associated with increased risk of acute myeloid leukaemia (AML). The mode of action (MOA) for AML development leading to mortality is anticipated to include multiple earlier key events, which can be observed in hematotoxicity and genetic toxicity in peripheral blood of exposed workers. Prevention of these early events would lead to prevention of the apical, adverse outcomes, the morbidity and mortality caused by the myelodysplastic syndrome (MDS) and AML.. Incorporation of key event information should modify the risk model, but few modification approaches have been suggested. To that end, two approaches to risk model modification are described that use sub-linear and segmented linear increases in risk below key events, while maintaining a linear increase in AML mortality risk beginning at 2 ppm, the lowest observed adverse effect concentration (LOAEC) identified for hemato- and geno- toxicity in high quality studies of human occupational exposure. Below 2 ppm two different modification approaches to quantitative risk models were applied: a continuously decreasing slope model and a segmented modification in slope. These two approaches provide greater flexibility to incorporate MOA information in risk model development and selection.

This paper derives an occupational exposure limit for benzene using quality assessed data. Seventy-seven genotoxicity and 36 haematotoxicity studies in workers were scored for study quality with an adapted tool based on that of Vlaanderen et al 2008 (Environ Health. Perspect. 116 1700-5). These endpoints were selected as they are the most sensitive and relevant to the proposed mode of action and protecting against these will protect against benzene carcinogenicity. Lowest and No- Adverse Effect Concentrations (LOAECs and NOAECs) were derived from the highest quality studies (i.e. those ranked in the top tertile or top half) and further assessed as being “more certain” or “less certain”. Several sensitivity analyses were conducted to assess whether alternative “high quality” constructs affected conclusions. The lowest haematotoxicity LOAECs showed effects near 2 ppm (8h TWA), and no effects at 0.59 ppm. For genotoxicity, studies also showed effects near 2 ppm and showed no effects at about 0.69 ppm. Several sensitivity analyses supported these observations. These data define a benzene LOAEC of 2 ppm (8h TWA) and a NOAEC of 0.5 ppm (8h TWA). Allowing for possible subclinical effects in bone marrow not apparent in studies of peripheral blood endpoints, an OEL of 0.25ppm (8h TWA) is proposed., Shorter and updated version of this article

Understanding the Mode of Action (MOA) for a chemical can help guide decisions in development of Occupational Exposure Limits (OELs). Where sufficient information exists, it can provide the OEL developer the basis for selecting either a health-based or risk-based approach. To support the development of an OEL for benzene, scientific information relevant to MOA assessment for risk-based and health-based OEL approaches was reviewed. Direct-acting mutagenicity was considered as a basis for a risk-based OEL, versus MOAs consistent with a health-based approach: indirect mutagenicity via topoisomerase II inhibition, indirect mutagenicity via reactive oxygen species generation, or an immune-based bone marrow dysfunction. Based on the evidence against direct DNA reactivity, threshold expectations for remaining MOAs, and evidence for dose rate affecting acute myeloid leukemia and myelodysplastic syndrome risk, the weight of evidence favors a health-based OEL approach. In the case of benzene, development of an OEL based on observations of earlier key events (i.e., hematologic changes and genetic toxicity) is anticipated to provide protection from later adverse outcomes such as leukemia.

We studied the risk of 11 cancers of a priori interest in petroleum refinery workers.Iterative searches identified 36 studies for the 11 cancer sites. Statistical heterogeneity and publication bias were assessed to enhance interpretation of meta-relative risks.Statistical heterogeneity was marked for mesothelioma, but was largely due to study quality. Higher quality studies showed a meta-relative risk (RR) of 3.22, (95% prediction interval 1.45 to 7.23). Melanoma (meta-RR = 1.23) and acute lymphoid leukemia (meta-RR = 1.51), showed results consistent with higher risk, but both were driven by one or two studies. Eight other cancer outcomes showed summary meta-RR's consistent with unity.Most cancer outcomes are consistent with background risk in refinery workers. This work has clarified an excess mesothelioma risk, conditional on study quality stratification. Continued surveillance is warranted for melanoma and ALL.

Two apparently contradictory findings in the literature on low-dose human metabolism of benzene are as follows. First, metabolism is approximately linear at low concentrations, e.g., below 10 ppm. This is consistent with decades of quantitative modeling of benzene pharmacokinetics and dose-dependent metabolism. Second, measured benzene exposure and metabolite concentrations for occupationally exposed benzene workers in Tianjin, China show that dose-specific metabolism (DSM) ratios of metabolite concentrations per ppm of benzene in air decrease steadily with benzene concentration, with the steepest decreases below 3 ppm. This has been interpreted as indicating that metabolism at low concentrations of benzene is highly nonlinear. We reexamine the data using non-parametric methods. Our main conclusion is that both findings are correct; they are not contradictory. Low-concentration metabolism can be linear, with metabolite concentrations proportional to benzene concentrations in air, and yet DSM ratios can still decrease with benzene concentrations. This is because a ratio of random variables can be negatively correlated with its own denominator even if the mean of the numerator is proportional to the denominator. Interpreting DSM ratios that decrease with air benzene concentrations as evidence of nonlinear metabolism is therefore unwarranted when plots of metabolite concentrations against benzene ppm in air show approximately straight-line relationships between them, as in the Tianjin data. Thus, an apparent contradiction that has fueled heated discussions in the recent literature can be resolved by recognizing that highly nonlinear, decreasing DSM ratios are consistent with linear metabolism.

Epidemiologic findings play an important role in benzene risk assessment, which is utilized to guide the selection of recommended benzene exposure levels to prevent adverse health effects. For decades, excess leukemia risk, especially that in the Pliofilm® cohort, has been the focus of benzene risk assessment. While more stringent benzene standards, often ≤1 ppm, have been promulgated to protect workers from developing leukemia, recent epidemiologic studies have reported elevated risk of myelodysplastic syndrome (MDS). This report aims to examine whether the use of new data on MDS is scientifically warranted in future benzene risk assessments. First, we reviewed current benzene guidelines, regulations, and underlying risk assessments in developed countries. Second, we examined current epidemiologic literature on benzene and MDS, which identified seven studies with simultaneous measures of MDS risk and benzene exposure and 17 studies on MDS in populations potentially exposed to benzene. Next, we examined the potential of the MDS data to serve as the basis of future benzene risk assessments, by comparing its quality and risk estimates with those used in current benzene standards. We conclude from the current literature that there is strong evidence that MDS can be caused by benzene, and the MDS data from the pooled petroleum study should be further examined in future benzene risk assessments. We recommend that future MDS-based benzene risk assessment use total MDS as the endpoint, take into consideration the full exposure period, and examine a range of benzene exposure metrics, including the role of peak, intermittent benzene exposures.