Adverse outcome pathways of ionizing radiation investigated with multi-omics and benchmark dose modeling
Background/Issue and Objectives: Health risks from chronic low dose radiation exposures encountered in environmental and occupational settings are uncertain. A key aspect to understanding health risks is precise and accurate modelling of the dose-response relationship. Benchmark dose (BMD) modeling is an approach used in chemical hazard assessments to identify the dose at which a pre-defined (e.g., 10%) change relative to background occurs. Herein, this method is being explored for radiation hazard assessments along with Adverse Outcome Pathways (AOPs), a knowledge framework of causally linked chains of key events (KEs) from a molecular initiating event to an adverse outcome (AO). Design/Method/Description: Blood was drawn from human participants (6 females and 8 males), and lymphocytes were isolated, cultured and X-irradiated at a lower dose-rate (LDR: 0.05 Gy/minute) and higher dose-rate (HDR: 1 Gy/minute) across nine different doses (0, 0.05, 0.10 0.25, 0.5, 1, 2, 4 and 6 Gy).  Transcriptomic and proteomic changes were then assessed 24 hours post-exposure. Concurrently, cell membrane integrity and cellular ATP level were also measured, which are markers of radiation injuries. BMD values were then derived for each endpoint and pathways enriched in omics data were compared with Kes in an existing AOP to leukemia (www.aopwiki.org/aop/432). Conclusions/Impacts/Outcomes/Implications/Next Steps: By using AOPs as an organizational framework and BMD modeling for dose-response analysis, it provides a pragmatic platform to analyse complex data for radiation hazard assessment. Future work will entail in-depth analysis of the responses specific to LDR and HDR and effects of confounding factors on BMD values. Overall design: Blood was drawn from human participants (6 females and 8 males), and lymphocytes were isolated, cultured and X-irradiated at 1 Gy/minute across nine different doses (0, 0.05, 0.10 0.25, 0.5, 1, 2, 4 and 6 Gy).  Transcriptomic and proteomic changes were then assessed 24 hours post-exposure. Concurrently, cell membrane integrity and cellular ATP level were also measured, as phenotypic indicators. BMD values were then derived for each endpoint and pathways enriched in omics data including the associated BMDs were aligned with KEs in an AOP to leukemia (www.aopwiki.org/aop/432)