Serial iron kinetics studies and radiophosphorus determinations of total red cell volume were performed in three groups of beagles exposed to hypoxia (${\rm pO}_{2}=72$ mm Hg), sublethal whole-body proton irradiation (200 rads midline absorbed dose in tissue), or a combination of these two stresses. Hypoxia alone resulted in an increase, within 1 day, in plasma iron turnover rate (PITR), an increase in fractional incorporation of radioiron in red cells, and a corresponding elevation in total red cell volume. Sublethal whole-body proton irradiation alone resulted in diminution in PITR within 1 day, and a corresponding marked depression of fractional incorporation of radioiron in red cells. Dogs receiving a combination of whole-body proton irradiation followed by hypoxic hypoxia demonstrated an initial increase in plasma iron turnover rate (PITR) for the first 7 days approximating the response seen with hypoxia alone. At 14 days the PITR and the fractional radioiron incorporation into red cells rapidly decreased, approaching, but not reaching, that seen in the dogs receiving radiation alone. Thereafter, the increase in the PITR in these dogs was greater than that seen following irradiation alone and by 29 days again approximated that seen in dogs subjected to hypoxia alone. At all times total red cell volume in dogs subjected to combined whole-body irradiation and hypoxia was maintained at a level intermediate between that seen in dogs subjected to whole-body irradiation alone or to hypoxia alone. We conclude that, following sublethal whole-body proton irradiation, cells responsible for synthesis of hemoglobin are capable of normal or increased rates of hemoglobin synthesis in response to hypoxic stimulation despite severe radiation damage. Red cells produced under such hypoxic stress following whole-body irradiation are not extremely short lived and are functionally significant as evidenced by normally shaped red cell iron-59 incorporation curves and red cell volumes which are greater than that noted in dogs receiving radiation alone. Those cells present in the bone marrow at the time of irradiation which were "responsible" for hemoglobin synthesis during the ensuing 7 days are little affected by 200 rads of whole-body proton irradiation, with regard to their capability of synthesizing hemoglobin in response to hypoxia. Additionally, although those cells present in the bone marrow at the time of irradiation which are "responsible" for hemoglobin synthesis beyond 7 days following irradiation are more affected by 200 rads of whole-body proton irradiation than are those cells "responsible" for hemoglobin synthesis during the initial 7 days, even these cells are capable of being stimulated by hypoxic hypoxia.

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