Parental, In Utero, and Early-life Exposure to Benzene and the Risk of Childhood Leukemia: A Meta-analysis

Frolayne M. Carlos-Wallace; Luoping Zhang; Martyn T. Smith; Gabriella Rader; Craig Steinmaus


Am J Epidemiol. 2016;183(1):1-14. 

In This Article

Abstract and Introduction


Benzene is an established cause of adult leukemia, but whether it is associated with childhood leukemia remains unclear. We conducted a meta-analysis in which we reviewed the epidemiologic literature on this topic and explored causal inference, bias, and heterogeneity. The exposure metrics that we evaluated included occupational and household use of benzenes and solvents, traffic density, and traffic-related air pollution. For studies of occupational and household product exposure published from 1987 to 2014, the summary relative risk for childhood leukemia was 1.96 (95% confidence interval (CI): 1.53, 2.52; n = 20). In these studies, the summary relative risk was higher for acute myeloid leukemia (summary relative risk (sRR) = 2.34, 95% CI: 1.72, 3.18; n = 6) than for acute lymphoblastic leukemia (sRR = 1.57; 95% CI: 1.21, 2.05; n = 14). The summary relative risk was higher for maternal versus paternal exposure, in studies that assessed benzene versus all solvents, and in studies of gestational exposure. In studies of traffic density or traffic-related air pollution published from 1999 to 2014, the summary relative risk was 1.48 (95% CI: 1.10, 1.99; n = 12); it was higher for acute myeloid leukemia (sRR = 2.07; 95% CI: 1.34, 3.20) than for acute lymphoblastic leukemia (sRR = 1.49; 95% CI: 1.07, 2.08) and in studies that involved detailed models of traffic pollution (sRR = 1.70; 95% CI: 1.16, 2.49). Overall, we identified evidence of associations between childhood leukemia and several different potential metrics of benzene exposure.


Millions of people in the United States and worldwide are exposed to benzene, either in occupational settings or environmentally.[1,2] The International Agency for Research on Cancer has classified benzene as a human carcinogen based primarily on research that linked occupationally exposed workers to elevated risks of acute myeloid leukemia (AML).[3] Children and fetuses might also be exposed to benzene either through air pollution, exposure sources near residences (such as gas stations or automotive repair facilities), maternal workplace exposure during pregnancy, or home use of products that contain benzene. Despite the sufficient evidence linking benzene to leukemia in adults, it is less clear whether there is an association in exposed children.

Childhood cancer is one of the leading causes of death by disease in children,[4] and acute leukemia accounts for 30% of childhood malignancies.[5] The most common form is acute lymphoblastic leukemia (ALL), with AML being less common but more fatal.[6] Risk factors include genetic conditions such as Li-Fraumeni syndrome or Down syndrome, radiation therapy, chemotherapy, and possibly tobacco smoke.[5,7] To date however, the causes of most childhood leukemias are unknown, and no single chemical agent has been conclusively linked to this cancer.

Although the links between benzene and childhood leukemia have been evaluated in several studies,[8–12] the results have been mixed. The reasons for this are not well defined but could be attributed to differences in study design, exposure levels, leukemia subtypes, and the methods used to assess benzene exposure. Another possible reason is that exposures in children might be much lower than occupational exposures in adults. Studies of low exposures are likely to have relative risks closer to 1.0, and inadequate sample sizes, bias, or confounding can be especially important when increases in relative risks are small.[13]

We examined current epidemiologic studies of parental or childhood exposure to benzene and childhood leukemia. Our goals were to perform a systematic literature review, evaluate each study for the basic tenets of epidemiologic validity, and summarize this literature using meta-analysis. Another goal was to evaluate sources of heterogeneity, including heterogeneity based on study design, confounding, leukemia subtype, and methods and timing of exposure assessment.