This article distills from available data descriptions of typical human symptoms in reaction to prompt total-body ionizing radiation in the dose range 0.5 to 30 Gy midline body tissue. The symptoms are correlated with dose and time over the acute postexposure period of 6 wk. The purpose is to provide a symptomatology basis for assessing early functional impairment of individuals who may be involved in civil defense, emergency medical care and various military activities in the event of a nuclear attack. The dose range is divided into eight subranges associated with important pathophysiological events. For each subrange, signs and symptoms are designated including estimates of symptom onset, severity, duration and incidence.

We explore the relationship among experimental design, parameter estimation, and systematic error in sloppy models. We show that the approximate nature of mathematical models poses challenges for experimental design in sloppy models. In many models of complex biological processes it is unknown what are the relevant physical mechanisms that must be included to explain system behaviors. As a consequence, models are often overly complex, with many practically unidentifiable parameters. Furthermore, which mechanisms are relevant/irrelevant vary among experiments. By selecting complementary experiments, experimental design may inadvertently make details that were ommitted from the model become relevant. When this occurs, the model will have a large systematic error and fail to give a good fit to the data. We use a simple hyper-model of model error to quantify a model’s discrepancy and apply it to two models of complex biological processes (EGFR signaling and DNA repair) with optimally selected experiments. We find that although parameters may be accurately estimated, the discrepancy in the model renders it less predictive than it was in the sloppy regime where systematic error is small. We introduce the concept of a sloppy system–a sequence of models of increasing complexity that become sloppy in the limit of microscopic accuracy. We explore the limits of accurate parameter estimation in sloppy systems and argue that identifying underlying mechanisms controlling system behavior is better approached by considering a hierarchy of models of varying detail rather than focusing on parameter estimation in a single model.

No abstract

An assay for the survival of renal tubule cells was developed using mice. It is analogous to other in-situ clonogenic cell survival assays. One kidney was irradiated using a 137Cs irradiator and removed 60-68 weeks later for histological examination. In unirradiated animals there were about 370 tubules in contact with the capsule in a coronal cross section at the middle of the kidney. After irradiation, extensive tubular damage was the dominant lesion. The number of epithelialized tubules in contact with the capsule showed a dose-dependent logarithmic decline. The dose-survival relationship for the clonogenic cells responsible for the regeneration of tubule epithelium was described by a D0 value of 1.5 Gy over the dose range 11-16 Gy. This radiosensitivity resembles that of stem cells in acutely responding tissues. The lack of histological evidence of damage to the arterial vasculature at the time the tubules are initially denuded of epithelium, and the similarity of renal tubule cell radiosensitivity to that of other mammalian cells, support the hypothesis that "late" radiation injury results primarily from depletion of parenchymal cells, not indirectly from injury to blood vessels, as has been the prevailing belief.

WHEN mice were injected with urethane and the skin of the back subsequently painted once each seventb day for twenty weeks with croton oil as a promoting agent, the number of papiRomata produced was found to be increased if the mice were given a preliminary apphcation of croton ofl, dissolved in acetone, to the area at 18, 24 or 48 hours preceding the injection of urethane (Pound and Ben, 1962). This was due to local phenomena produced in the skin by the prehminary application of croton oil (Pound, 1963).Croton oil is one of the few materials that act as potent promoting agents after the apphcation of initiating agents such as the carcinogenic hydrocarbons is smaR single doses to the skin of mice (Gw-ynn and Salaman, 1953; Roe and Peirce, 1961). Local applications of many other substances that, like croton oil, produce inflammation or hyperplasia of the skin did not promote the development of tumours in this animal (Salaman, 1958).It was necessary, therefore, to consider whether the augmenting influence of a preliminary apphcation of croton oil was associated with croton oil specificauy, in particular with its action as a promoter, or was an effect that could be elicited by any other substance or means that produced inflammation or ceRular proliferation in the skin. Some authors consider that croton oil itself is a mild carcinogen (Roe, 1956 ; Boutwell, Bosch and Rusch, 1957) and, foRowing this line of thought, it is possible that the augmenting influence of croton oil, apphed before the administration of urethane, might be viewed as a simple additive effect or due to synergism. The time relationships reported by Pound and Bell (1962) disprove the first of these views and render the second improbable except in a general sense lacking scientific precision.Accordingly, the present experiments were carried out to determine the influence of scarification or preliminary treatment of the sldn with various chemicals that produce hyperplasia or inflammation (referred to collectively in this paper as " irritants ") on the initiation of tumours by urethane. Further, the augmenting influence of a solution of croton oil in acetone has been ascribed in previous work to the croton oil (Pound and Bell, 1962 ; Pound, 1963) so that data are now presented formaRy proving that the acetone solvent has an insignificant influence in this respect. MATERIALS AND METHODS MiceMice of the strain " Hall " bred in this department (Pound, 1962) were used. The animals weighed between 20 and 30 grams at the beginning of the experiments and were accommodated in stainless steel compartments each holding ten mice.