Dose and Biological Indicators Levets of Biological Organization Pair B: Public Health populations Defined populations and subgroups Organisms System-element Pair A: Medicine-toxicology Organs are used extensively and with a high degree of precision. Late effects. particularly cancer where the approach becomes more problematical. will then be discussed. Molecules Fig. 1. Levels of biological organization, which are both interlocking and recursive. Thus any given level, e.g., Organ-organism can at once serve as a system, the vital elements of which are cells (system-element Pair A), and the elements of a larger system. a defined human population (system-element Pair B). that must be known for proper diagnosis and prognosis. In whatfollows, it is the intent to showthat this approach is the reverse of the historical and normal course of events in medicine, i.e., it is the severity of organ effect that is used ultimately for diagnosis and prognosis. This holds even if the dose of an offending agent has played a causal role in the abnormal condition requiring medical attention. and often even when therapy has been started with an initial dose of a medicinal agent. To elaborate, the fraction of organ cells killed or the number of chromosomeaberrations in cells can be indicators of the severity of biological effect in the organ. Under proper conditions, one can then use this information as an indicator of the likelihood that the biological system of interest will respond quantally. Even if a dose of a causative offending agent has been estimated, there is no need to go backto that dose for purposes of diagnosis or prognosis. However. the severity of effect has varying degrees of usefulness. depending upon howclosely the effect observed can be causally related to the probability of a quantal response of the organ system. Thus an effort will be made to specify the conditions under which a biological indicator can a be directly relevant f| 4 re it | a q= de & 3 2> a E 2 0 0.0 wo The Two Constituent Curves Celis Organelles OSE Wt re oa As an initial example. only early acute effects from and responses to radiation exposure will be used e.g.. early mortality in the mammal. Here biological indicators must be and 0.90 Toillustrate the normal role of severity of organ effect in diagnostic medicine, it is first shown that the usual acute dose mortality response curve. e.g.. for x- or gammarays delivered to the whole body. can be broken downinto two separate curves. For the usual curve (Fig. 2). acute mortality in, e.g.. the mouse. the fraction of animals responding quantally (dying). 1s plotted against the absorbed doseto obtain the usual threshold. sigmoid function. Thefirst derivative of this curve yields a gaussian-type distribution. that is often associated with the distribution of sensitivities of the individual animals [1]. It 1s nowwell accepted that the usual 30 day mortality is due to complications resulting from depletion of the stem cell population in the bone marrow of the animal, i.e.. with reference to Figure 1. the bone marrowis the system ofinterest. the relevant elements of which are the stem cells (system-element pair A.1in Fig. 1). 100 904 ao- % Mouse Mortality System-element Societal or other Bond Fig. tion (CFL dose. value may respec This cell McC repr cour Med man: phot How appe abou asso of b« rem: 704 left c the s arith 604 nate: ‘4 5 Dose (Gy) Fig. 2. A conventional dose-quantal response function. tor which the (fractional) number of animais responding lethallyis plotted against the dose of the agent. radiation energy {250 kVp x-rays). These data were derived from mice of the CBA/Ca (BNL) strain. curv rele\ tion low. thee is Se’ to di Tesp amo can