Occupational and Environmental Benzene Exposure and Risk of Adult Acute Myeloid Leukemia

Abstract

That benzene causes acute myeloid leukaemia is settled. What is not settled is the shape of the curve at low exposure, and that shape determines every occupational limit set from it. Applying two different historical exposure reconstructions to the same cohort of workers produces a linear relationship under one and a quadratic one under the other. Objectives: To review the published evidence on benzene exposure and adult acute myeloid leukaemia: what risk is reported at high and low cumulative exposure, how the dose-response relationship has been modelled, why estimates differ between cohorts, and what follows for exposure limits.
Material and Methods: Narrative review of occupational cohort studies, case-cohort analyses, meta-analyses, risk assessments and agency evaluations indexed in PubMed and the major occupational health and epidemiology journals. Studies were eligible if they reported the association between quantified benzene exposure and myeloid malignancy in a defined adult population. No new patient data were generated and no participants were recruited; every estimate quoted is one published by the original investigators.
Results: In a case-cohort analysis following 110,631 Chinese workers between 1972 and 1999, risk of myelodysplastic syndrome or acute myeloid leukaemia rose with cumulative exposure, with an excess relative risk per 100 parts per million-years of 0.30 (95% CI −0.02 to 1.09, trend p = 0.08), corresponding to a rate ratio of 1.30. Pooled analysis gave an odds ratio of 1.94 (95% CI 0.95 to 3.95) for cumulative exposure below 40 parts per million-years. Among petroleum distribution workers, myelodysplastic syndrome risk was elevated above 2.93 against below 0.348 parts per million-years, at an odds ratio of 4.33 (95% CI 1.31 to 14.3), an exposure range more than ten times lower than the pooled analysis low category. Significant dose-response for acute myeloid leukaemia has been reported from cumulative exposures just below 1 part per million-year. In the historically pivotal cohort, one exposure reconstruction predicted a linear dose-response and another a quadratic one, with the departure from linearity borderline at p = 0.08. Conclusion: The causal relationship is not in question and the quantitative basis for regulation is weaker than its use implies. Effects are being detected at
exposures well below limits derived from cohorts whose lowest category exceeds them by an order of magnitude. Abbreviations: AML – Acute Myeloid Leukaemia, MDS – Myelodysplastic Syndrome, AMML – Acute Myelomonocytic Leukaemia, ANLL – Acute Non-Lymphocytic Leukaemia, ppm – Parts Per Million, ERR – Excess Relative Risk, RR – Rate Ratio, OR – Odds Ratio, OEL – Occupational Exposure Limit, TWA – Time-Weighted Average, TLV – Threshold Limit Value, LMS – Linearized Multistage, IARC – International Agency for Research on Cancer.