The Impact of Dose, Sex, and Age at Time of Acute Whole-body Radiation Exposure on Long-term Hematopoiesis in Rhesus Macaques (Macaca mulatta)

The hematopoietic system is highly sensitive to ionizing radiation exposure. Accumulating evidence from the Japanese A-bomb survivor cohort and animal studies suggests that radiation-induced damage to the hematopoietic system can persist long after exposure, and therefore has the potential of contributing to delayed effects of acute radiation exposure (DEARE). In this study, archival data from the non-human primate radiation late effects cohort was analyzed to evaluate long-term effects on the hemopoietic system. The dataset included white blood cell and leukocyte differential counts from two hundred sixteen rhesus macaques (Macaca mulatta) exposed to 1.14 to 8.5 Gy and 47 non-irradiated control animals; blood samples were collected approximately 1-year post-acute uniform whole-body exposure and continuously thereafter every 2–6 months. Linear mixed models were developed for total leukocyte and differential counts, which included neutrophil, lymphocyte, and monocyte counts and percentages. Longitudinal trends were estimated for three dose ranges (low dose <LD10/30, 1.14 to 5.5 Gy; mid dose LD10/30–LD50/30, 5.5 to 6.8 Gy; high dose >LD50/30, 6.8 to 8.5 Gy) and controls, and adjusted for sex and age at time of exposure. All models suggested that radiation dose was a statistically significant factor in the longitudinal trends of leukocyte and differential changes observed. Control and low-dose irradiated non-human primates (NHPs) presented a slight decrease in total leukocyte count and monocyte skewed differentiation, consistent with changes expected from natural aging of the hematopoietic system; longitudinal changes for the mid-dose <LD10ca animals were similar. In contrast, estimates for the neutrophil-to-lymphocyte ratio (NLR) showed a statistically significant increase in the LD10/30–LD50/30 group. Additionally, the increase in monocyte counts over time was larger for the LD10/30–LD50/30 and >LD50/30 NHPs than for the controls and <LD10/30 animals. Elevated neutrophil and monocyte counts are indicative of persistent inflammation and/or long-term impairment of the immune system, which can contribute to DEARE diseases, including cancer and cardiovascular disease. Extended analyses, including development of machine learning models to improve accuracy of predictions utilizing a variety of relevant radiation biomarkers and actual health outcomes, will be key future steps toward improved understanding and risk assessment of DEARE.