Carcinogenic Dose-Rate Effects in Humans

Although much is known about the carcinogenic effects of radiationexposure, the precise role of dose-rate effects in humans is stillunclear. Radiation risk estimates are based mainly on populationsexposed to intermediate or high doses delivered at high dose rates.However, low-dose, low dose-rate exposures are most relevant for themajority of human exposures. Notwithstanding the fairly largenumber of experimental studies that have documented variations inthe effects of dose with dose rate, conclusions are still uncertain.Findings from animal studies differ depending on species, strain,type of malignancy, and total dose, making it difficult toextrapolate results to humans. Based on experimental data, it isthought that for low-LET radiation, there is a sparing effect asdose rate decreases. It has been suggested that the tumorigeniceffects are mitigated at low dose rates because there is anopportunity for cellular repair of sublethal damage, cellsredistribute during the mitotic cycle, and enhanced cellproliferation compensates for lethal damage. But for high~LETradiation, the influence of dose rate is more variable. Following areduction in dose rate, tumor induction can decrease, remain thesame, or increase. This may be due to the combination of the highpotential for molecular damage, the minimal chance for repair andredistribution, and the potential for compensatory cellproliferation to provide more targets for cell damage. High-LETradiation delivered at low dose rates may also allow exposure to agreater number of cells during the hypersensitive interval of thecell cycle.Despite the limited data in humans, regulatory and scientificcommittees feel the need to incorporate some dose-rate effect factor(DREF) in estimating radiation risks. To date, most committees haveassumed that high dose rates will be between two and ten times aseffective as low dose rates. However, the BEIR v committee decidednot to use a DREF in estimating solid cancer risks, although theythought that a DREF of 2 was reasonable. This decision was partlyresponsible for the high BEIR v risk estimates compared to BEIR III.The effect of dose rate may be modified py several factors, manyof which are highly correlated and time dependent. These factors,e.g. total dose, organ dose, number of fractions, interval betweenfractions, protraction, duration, LET, radiation type, cell killing,age at exposure, time since last exposure, organ sensitivity,concomitant exposures, and reason for radiation exposure all mayplay important roles, individually and jointly, in determining thedose rate effect. unfortunately, the data from most studies are toosparse to disentangle these complex relationships.There are few human studies on high-LET radiation and fewer stillinclude significant numbers of children. Most of our understandingis based on patients treated with injected radium for spondylitis orTB, patients exposed to thorotrast as a contrast medium, radium dialpainters and uranium miners. Only thorotrast seems to beleukemogenic. However, thorotrast was administered in a colloidsolution which in itself may be carcinogenic. Based on singlestudies with few exposed cases, significant excesses of thyroid andbreast cancer are observed among radium dial painters and radiumtreated spondylitic patients, respectively. An excess of lungcancer is seen among uranium miners who receive highly protractedradon exposure and some thorotrast patients. Consistent with some