Mutagenicity monitoring in humans: Global versus specific origin of mutations

An underappreciated aspect of human mutagenicity biomonitoring is tissue specificity reflected in different assays, especially those that measure events that can only occur in developing bone marrow (BM) cells. Reviewed here are 9 currently-employed human mutagenicity biomonitoring assays. Several assays measure chromosome-level events in circulating T-lymphocytes (T-cells), i.e., traditional analyses of aberrations, translocation studies involving chromosome painting and fluorescence in situ hybridization (FISH) and determinations of micronuclei (MN). Other T-cell assays measure gene mutations. i.e., hypoxanthine-guanine phosphoriboslytransferase (HPRT) and phosphoribosylinositol glycan class A (PIGA). In addition to the T-cell assays, also reviewed are those assays that measure events in peripheral blood cells that necessarily arose in BM cells, i.e., MN in reticulocytes; glycophorin A (GPA) gene mutations in red blood cells (RBCs), and PIGA gene mutations in RBC or granulocytes. This review considers only cell culture- or cytometry-based assays to describe endpoints measured, methods, optimal sampling times, and sample summaries of typical quantitative and qualitative results. However, to achieve its intended focus on the target cells where events occur, kinetics of the cells of peripheral blood that derive at some point from precursor cells are reviewed to identify body sites and tissues where the genotoxic events originate. Kinetics indicate that in normal adults, measured events in T-cells afford global assessments of in vivo mutagenicity but are not specific for BM effects. Therefore, an agent's capacity for inducing mutations in BM cells cannot be reliably inferred from T-cell assays as the magnitude of effect in BM, if any, is unknown. By contrast, chromosome or gene level mutations measured in RBCs/reticulocytes or granulocytes must originate in BM cells, i.e. in RBC or granulocyte precursors, thereby making them specific indicators for effects in BM. Assays of mutations arising directly in BM cells may quantitatively reflect the mutagenicity of potential leukemogenic agents.