Dose and Biological Indicators 24 are most affected. and the severity of damage. It C57BL/6 MORTALITY vs. CFU-~S MORTALITY AFTER X—IRRADIATION 100 £ 9G e ee 89 t Ez 60 = 70 §3 40 = 30 4 Again. dose plays norole at al]. unti} the severity ® f e ‘ E59 ° e / 20 “ e 19 0 99.80 > en raralitlivd ~ 99.85 99.90 ' 99.95 , 100.00 wide Sg am 1" ae ae SEVERITY OF EFFECT (UNITS OF PERCENT KILLED STEM CELLS) Fig. 6. The same data shownin Figure 5, but plotted on an expanded scale to show that the steepness of the curve in Figure 5 is due only to scaling and nota decrease in the variance. measure of the severity of a relevant. causal effect on the population of elements, the fate of the entire organ-organism system can be described and predicted: dose need play noroleat all. The above separation of the usual mortality response Curve into two constituent curves serves to illustrate several points. Although the dose response curve in Figure 1 is frequently used in medicine and veterinary medicine, and in their subdisciplines of pharmacology and toxicology. it is in a therapeutic mode only, and not for diagnosis. For example. in medicine, when a patientis first seen medically, the cause of the patient’s complaint, or indeed what the offending agent may be, is usually unknown or poorly known. Thus no dose is involved. This is true even in the case of accidental poisonings. Here the physician may ask for an estimate of the amount of offending agent that was received by the patient; however any estimates given are taken as being extremely unreliable, and thus of little aid in assessing the gravity of the situation. Thustheyare largely or entirely ignored. The physician immediately begins with a history, physical examination and laboratory pro- cedures to determine what offending agent, if any, is involved, which organ or organs is most likely damaged, and the severity of effect on those organs. It is on the basis of these findings alone, i.e., the severity of the effect. that the physician comesto a tentative, and then increasingly firm decision as to which organ or organs KA) AWLAG is upon this basis that diagnosis. prognosis. and the type and extent of therapy is determined. of effect is determined and medications or other corrective measures are under consideration. As a specific example. one may take coronary heart disease and the degree to which a given segment of a coronary vessel has been occluded. Here the severity of effect is measured on a scale of 0 to | to indicate the fractional (percent) amountof narrowing of the lumen. A second example may be morerelevant. In 1954, following the detonation of a large atomic weapon, a number of Marshall Islanders were exposed to large doses of external penetrating gamma rays, as well as internal emitters, principally radioactive isotopes of iodine [2}. A team of principally naval physicians. including Drs. E. P. Cronkite, V. P. Bond, and R. A. Conard, was assembled to determine the medical condition of those dosed and to take actions necessary relative to these exposures. It wasrealized by the medical team that there might well be estimates of dose provided on arrival in the Marshall Islands. Considerable discussion took place in the aircraft on the way out to the Marshall Islands, with respect to what, if any, use should be made of these estimates. The agreement was unanimous that, although such estimates would be welcome, they would play a minimal if any role in definitive action taken with respectto the care of the patients. Instead.al! medical and Jaboratory studies thoughtto berelevant and possible would be done. Any definitive action with respect to prognosis and care would be made on the basis of the severity of the effect found in any organ, whetherthe severity was that expected from the dose estimates. It then becomes obvious what the criteria for a biological indicator must be, for it to be of maximum use in diagnosis and prognosis. Clearly the indicator must be largelyif not entirely causative of whatever degree of organ failure is present. Also, the function for the severity of effect versus quantal response of the system must be monotonic (usually S-shaped). and it must saturate at 1.0 (i.e. 100% severity means total failure of the organ, and thus. if the organ is vital, death of the patient). To the degree that the indicator of biological effects strays from these criteria, the less useful it is for prognosis and therapy.