Principal findings
The present large-scale umbrella review explored the strength and validity of evidence in 509 meta-analyses of environmental exposures and risk of developing 10 different types of childhood cancer. None of the 509 meta-analyses were supported by strong evidence, whereas only 2.4% of the associations were considered to have highly suggestive evidence inferred by strongly statistically significant results. These associations were mainly confined to increased risk of overall leukemia, especially ALL, in relation to high birthweight, paternal smoking and exposure to pesticides, particularly insecticides, as well as decreased risk of ALL related to maternal vitamin supplementation and breastfeeding (>6 months). There was also highly suggestive evidence for increased risk of CNS tumors, and especially astrocytoma in relation to high birthweight, as well as increased risk of testicular cancer in relation to testicular microlithiasis and isolated cryptorchidism.
Despite the abundance of published evidence on environmental exposures and childhood cancer risk, 40% of the included meta-analyses reported a nominally statistically significant summary effect estimate. Moreover, though the reported associations seem biologically plausible, our study showed that inherent biases might overestimate the suggested associations, which is consistent with the results of previous umbrella reviews on cancer epidemiology . When decreasing the threshold atp <10-6, only 4% of the summary random effects estimates remained statistically significant. Considerable or substantial heterogeneity (>50%) was reported in 26% of meta-analyses, albeit the 95% prediction intervals which further account for heterogeneity included the null value in most associations (76%). There was indication for small study effects in 13% of the meta-analyses, while 7% of the associations had evidence of excess significance bias. Lastly, most of the included meta-analyses had a moderate- and high-quality rating based on the AMSTAR quality assessment tool.