The comet assay as a tool in human biomonitoring exposure to antineoplastic drugs – A systematic review and meta-analysis

Antineoplastic agents are toxic compounds, generally used in the treatment of cancers, which are recognized as carrying a cancer development risk. In this systematic review and meta-analysis of human biomonitoring studies, we have assessed the effects of exposure to antineoplastic drugs on levels of DNA strand breaks in leukocytes, measured by the comet assay. Focusing on the application of the comet assay in human biomonitoring of occupational exposure to antineoplastic agents, we have analyzed 458 original research studies which used this assay, following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA-ScR). The systematic review led to 23 studies, of which 20 studies met the criteria for inclusion in the meta-analysis. Using standardized mean difference and 95% confidence interval (CI), the meta-analyses show increased levels of DNA strand breaks in subjects exposed to antineoplastic drugs (1.26, 95% CI: 0.78, 1.73). Results originate mainly from studies on healthcare workers, with only one study in an industrial setting. Subgroup analysis indicates that all studies combined from middle-income countries have a higher effect size (1.77, 95% CI: 1.00, 2.55) than studies from high-income countries (0.49, 95% CI: 0.09, 0.90). This difference between middle- and high-income countries may be attributable in part to differences in exposure levels or exposure assessment. Additionally, sensitivity analysis indicates that studies with moderate/high risk of comet assay measurement bias have higher effect size (2.07, 95% CI: 0.82, 3.31) than studies with low risk of bias (0.73, 95% CI: 0.34, 1.13); and that studies with high risk of exposure misclassification have higher effect size (1.47, 95% CI: 0.89, 2.06) than studies with low/moderate risk (0.13, 955 CI: -0.08, 0.33). Most studies have low/moderate risk of bias related to the comet assay procedure (15 out of 20 studies), absence of reporting the use of assay controls (1 out of 20 studies), blinded analysis of samples (7 out 20 studies); exposure assessment (16 out of 20 studies). In conclusion, this systematic review and meta-analysis shows that exposure to antineoplastic drugs is associated with increased levels of DNA strand breaks in human leukocytes.