Holthusen (1921) first quantified the oxygen effect finding 2.5 to 3.0-fold less hatching eggs of the nematode Ascaris in oxygenated compared to anoxic conditions, which was incorrectly assigned to changes in cell division. However, two years later, Petry (1923) first attributed oxygen tension as affecting ionizing radiation effects on vegetable seeds. Later, the implications of the effects of oxygen on radiotherapy were discussed by Mottram (1936).
A key observation limiting hypotheses to explain the biological mechanisms of the oxygen effect is that the gas nitric oxide is a radiosensitizer with similar effects to oxygen observed in tumour cells. Another important observation is that oxygen must be present at irradiation or within milliseconds afterward for the oxygen effect to take place.
The best known explanation of the oxygen effect is the oxygen fixation hypothesis developed by Alexander in 1962, which posited that radiation-induced non-restorable or "fixed" nuclear DNA lesions are lethal to cells in the presence of diatomic oxygen. Recent hypotheses include one based on oxygen-enhanced damage from first principles. Another hypothesis posits that ionizing radiation provokes mitochondria to produce reactive oxygen (and nitrogen species), which are leakage during oxidative phosphorylation that varies with a hyperbolic saturation relationship observed with both the oxygen and nitric oxide effects.