[en] The following studies were conducted: physical character of lead acetate and other toxic metal compounds as related to tissue distribution, toxicity, and therapeutic removal; interactions of monomeric plutonium with specific components of mouse liver and skeleton; metabolism and therapeutic decorporation of plutonium in mice and dogs; comparative studies of tissue distribution of plutonium isotopes; and microdistribution of monomeric and polymeric plutonium in beagle liver and bone

[en] The focus of the program is on late effects of neutron and gamma radiation and assessment of risk. Principal research activities are in two complementary areas: life-span experiments with large populations of laboratory mice to compare the effectiveness of single or protracted doses of neutron or gamma radiation for life shortening due to cancer and other debilitating noncancerous diseases; and basic research on cellular injury and recovery for the evaluation of potential contributions of latent injury in the mouse circulatory, immune, and hematopoietic systems to life shortening, and for the comparison of late radiation effects in proliferating tissues. The data are used to test existing models and to formulate new models for prediction of radiation hazards and the relative biological effectiveness (RBE) of fission neutrons, particularly at low radiation doses. The neutron dose-response curve is nonlinear, with the life shortening effect decreasing from 3-4 day/rad to 1 day/rad with increasing dose over the range of 20-240 rad. Clearly, linear extrapolations from high neutron doses to estimate life shortening at low doses would underestimate risk; the underestimation is even greater when the enhancement of life shortening produced by fractionated neutron exposure, described previously by us, is also considered. These results from single neutron doses deviate from predictions of total dose dependency based on the predictive model of Kellerer and Rossi. The shape of the gamma radiation dose-response curve is linear over the range of 90 to 788 rad; linear dose-response curves for gamma radiation have been described previously by others, but a quadratic function has been considered by some to be most applicable

[en] Three related, but separate, studies are in progress. In the first, young adult beagles of both sexes are placed in the γ-ray field, to be kept there for duration of life at one of a number of daily exposure rates. In the second, young adult beagles are exposed in a similar fashion until they have accumulated predetermined amounts of total exposure ranging up to 4000 R, delivered at various daily exposure rates. They are then removed from the radiation field and kept for the rest of their lives to allow development of late effects attributable to radiation exposure. In the third study, pregnant beagles are irradiated, at one of four daily exposure rates, for all or part of their gestation periods, to produce an evaluation of the effects of continuous irradiation in the developing fetus. All of these studies are done by arranging dogs at various distances from a calibrated ⁶⁰Co γ-ray source, where they are irradiated during 22 hours of each day. The remaining 2 hours are used for animal care, maintenance, and clinical evaluation of the dogs. The combined results demonstrate that the cellular and organ systems of the dog respond predictably, and in a differential manner, depending on exposure rate. Exposure rates in excess of 17 R/day destroy the blood-cell producing elements of bone marrow and cause death, therefore, within 1 to 2 months. Minimally sublethal exposure rates to bone marrow (5-17 R/day), however, produce a very high (50-75 percent) incidence of anemia or myeloid leukemia. Furthermore, at exposure rates of 5 R/day or below, bone marrow appears to function in an essentially normal fashion, and causes of death appear, from preliminary data, to be related to degenerative disease and malignancies of other tissues

[en] The contributions of the group consist of six reports. The first is concerned with recent developments in the isolation and characterization of subcellular components of mammalian cells: the inhibition by imipramine of digitonin-induced lysis of mitochondrial membranes; age-dependent changes in mitochondrial sedimentability; peroxisomal enzymes; and collaborative studies on near-uv effects on bacterial respiration, radiation effects on mouse heart mitochondria, and toxicity and distribution of liposome-encapsulated drugs. Plant physiology is the theme of the next two reports. The first describes progress in a NASA-supported program on the involvement of organelles, especially dictyosomes, in the georesponse of roots, and the second covers work principally supported by ERDA on the interaction of light and gravity on differential growth of corn roots. Progress in liposome encapsulation of drugs is presented in three contributions. The first deals with studies on the toxicity, distribution, therapeutic action, and mechanism of encapsulated cancer chemotherapeutic agents; the second with morphologic studies, based principally on electron microscopy; and the third with alteration of liposomal surface properties by varying the lipid composition, in order to modify tissue distribution

[en] The ultimate objective is to predict potential health costs tp man accruing from the effluents or by-products of any energy system or mix of systems, but the establishment of reliable prediction equations first requires a baseline analysis of those preexisting and essentially uncontrolled factors known to have significant influence on patterns of mortality. These factors are the cultural, social, economic, and demographic traits of a defined local or regional population. Thus, the immediate objective is the rigorous statistical definition of consistent relationships that may exist among the above traits and between them and selected causes of death, especially those causes that may have interpretive value for the detection of environmental pollutants

[en] Research is reported on magnetic resonance spectroscopy of biological molecules, development of clinical applications of stable isotopes, circadian cybernetics, and X-ray crystallography of immunoglobulins. Biological processes occur in fluid media, and ultimately our knowledge of their mechanisms requires detailed information for chemical and molecular structural properties in biological fluids. Magnetic resonance spectroscopy has unique advantages over other approaches in this area that are being exploited in studies currently underway in the group. The program continues to develop along three interrelated lines, measurement and analysis of high resolution spectra for biological molecules (especially nucleic acid constituents and drugs), synthesis of selectively labeled nucleic acid fragments essential for complete spectral assignments, and computation of conformational properties from NMR parameters. This coordinated approach enabled the first complete conformation analysis for a dinucleoside monophosphate, ApA, in aqueous solution. It was found that the conformation is actually a time-average of right helical, loop, and extended conformations, the interchange being extremely rapid on an NMR time scale. Spectral analyses were also completed for all possible ribonucleotide dimers, the assignments again relying heavily on synthesis of appropriate deuterated counterparts. Studies of conformational flexibility in nucleic acid fragments showed that changes in hydrogen ion concentration and temperature produce correlated conformational changes specific for each nucleotidyl unit. Studies were also initiated in three new projects dealing with the effect of hapten binding on antibody structure, counter ion influence on nucleic acid free radicals, and membrane differences between normal and sickled erythrocytes

[en] Progress is reported on the following research projects: genetic effects of high LET radiations; genetic regulation, alteration, and repair; chromosome replication and the division cycle of Escherichia coli; effects of radioisotope decay in the DNA of microorganisms; initiation and termination of DNA replication in Bacillus subtilis; mutagenesis in mouse myeloma cells; lethal and mutagenic effects of near-uv radiation; effect of 8-methoxypsoralen on photodynamic lethality and mutagenicity in Escherichia coli; DNA repair of the lethal effects of far-uv; and near uv irradiation of bacterial cells

[en] The long-term aims are concerned with various aspects of the natural history and biology of cancer, the mechanism of induction and of the advancement of time of appearance of tumors, the development of systems suitable for the assay of oncogenesis and cocarcinogenesis, and the elucidation of some of the factors important to the problem of extrapolation of estimates of risk made in experimental systems to the estimate of risk in man. It is necessary to have a number of test systems in order to study the various factors related to cocarcinogenesis; some of these are clearly tissue specific. The liver tumor system is clearly useful for certain compounds, and the liver is an excellent tissue for the study of the mechanisms of cocarcinogenesis. This year we report on the relatively rapid induction of what appears histologically to be carcinoma of the thyroid by aminotriazole. In a collaborative study with the Neutron and Gamma-Ray Toxicity Group, we have established a new example of synergism in carcinogenesis, namely between radiation and pituitary hormone(s) in the production of Harderian gland tumors. Not only does a synergistic effect on incidence occur, but also on the degree of malignancy of the tumor induced. We thus have three different model systems for the study of various aspects of cocarcinogenesis: various chemicals, including nononcogenic polycyclic hydrocarbons, in liver tumorigenesis; ionizing radiation and aminotriazole in thyroid tumorigenesis; and in conjunction with the JANUS Program, the interaction of radiation and hormones in the production of Harderian gland, mammary gland, and other tumors

[en] Progress is reported on the following research projects: the effects of N-ethyl-maleimide and hydroxyurea on hamster cells in culture; sensitization of synchronized human cells to x rays by N-ethylmaleimide; sensitization of hypoxic mammalian cells with a sulfhydryl inhibitor; damage interaction due to ionizing and nonionizing radiation in mammalian cells; DNA damage relative to radioinduced cell killing; spurious photolability of DNA labeled with methyl-¹⁴C-thymidine; radioinduced malignant transformation of cultured mouse cells; a comparison of properties of uv and near uv light relative to cell function and DNA damage; Monte Carlo simulation of DNA damage and repair mechanisms; and radiobiology of fast neutrons

[en] The program goal is to provide basic data for evaluating the hazard to man from radioactive materials deposited within the body. The original objective, to obtain dose-response information and to provide data from several species for extrapolating animal data to man, is receiving less attention at present as effort is being put into determining how radiation causes bone cancer and whether viruses play a role. The program began with the very early radiotoxicologic investigations of materials important in the development of the atomic bomb and the necessity to establish maximum permissible levels of exposure to these materials. With the demonstration that bone cancer is the most sensitive indicator of damage from transuranic elements and some of the fission products, bone pathology became the focus of attention. When it became evident that questions of human hazard cannot be answered unequivocally on the basis of dose-response relationships, different approaches were considered, and one based on knowledge of mechanisms of cancer induction seemed most likely to be successful. The detection of viruses in both radiation-induced and spontaneous bone cancer of mice, and the present evidence for a similar virus in bone cancer of man, support the hypothesis that radiation causes cancer by activating endogenous neoplastic information, which can also be expressed as oncornavirus. Present emphases therefore concern understanding the biological, biochemical, and physical attributes of the five murine oncornaviruses that have now been isolated in the course of the program; demonstrating the existence of a comparable human oncornavirus; and discovering how radiation and virus interact in the induction of bone cancer