[en] Curium isotopes are major by-products in irradiated nuclear reactor fuel and comprise a significant fraction of the alpha-emitting radionuclide inventory. Although little use is currently being made of purified Cm sources, such usage is possible if reprocessing of spent fuel becomes feasible. Because little information is available on the biokinetics and dosimetry of inhaled Cm compounds, a study was conducted in which adult beagle dogs received a single inhalation exposure to either a monodisperse aerosol of 244Cm2O3 (1.4 micron activity median aerodynamic diameter [AMAD]; sigma g = 1.16) or a polydisperse aerosol of 244Cm (NO3)3 (1.1 micron AMAD; sigma g = 1.74). At times ranging from 4 h to 2 y after exposure, animals were sacrificed and their tissues analyzed for Cm content. The data describing the uptake and retention of 244Cm in the different organs and tissues and the measured rates of excretion of these dogs formed the basis on which a biokinetic model of Cm metabolism was constructed. This Cm model was based on a previously published model of the biokinetics of 241Am that was shown to be applicable to data from human cases of inhalation exposure to 241Am aerosols. This Cm model was found to be adequate to describe the biological distribution of Cm in dogs and was also applied to the sparse data from humans. Reasonable agreement was found between the model predictions for lung retention of Cm and for urinary excretion patterns in humans

[en] Chronic inhalation of insoluble particles of low toxicity that produce substantial lung burdens of particles, or inhalation of particles that are highly toxic to the lung, can impair clearance. This report describes model calculations of accumulations in lung of inhaled low-toxicity diesel exhaust soot and high-toxicity Ga2O3 particles. Lung burdens of diesel soot were measured periodically during a 24-mo exposure to inhaled diesel exhaust at soot concentrations of 0, 0.35, 3.5, and 7 mg m-3, 7 h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y after a 4-wk exposure to 23 mg Ga2O3 m-3, 2 h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y both studies using inhaled radiolabeled tracer particles. Simulation models fit the observed lung burdens of diesel soot in rats exposed to the 3.5- and 7-mg m-3 concentrations of soot only if it was assumed that clearance remained normal for several months, then virtually stopped. Impaired clearance from high-toxicity particles occurred early after accumulations of a low burden, but that from low-toxicity particles was evident only after months of exposure, when high burdens had accumulated in lung. The impairment in clearances of Ga2O3 particles and radiolabeled tracers was similar, but the impairment in clearance of diesel soot and radiolabeled tracers differed in magnitude. This might have been related to differences in particle size and composition between the tracers and diesel soot. Particle clearance impairment should be considered both in the design of chronic exposures of laboratory animals to inhaled particles and in extrapolating the results to people

[en] The subject matter for this 26th Annual Hanford Life Sciences Symposium evolved from the deliberations of a Task Group on Modeling for Scaling to Humans, which was established in January 1986 through the efforts of the Office of Health and Environmental Research of the Department of Energy (OHER/DOE). Several laboratories that utilize animals in radiobiological research sponsored by the OHER/DOE were extensively reviewed in the spring of 1985, and, as a result, OHER recommended establishment of eight task groups designed for selected purposes. The current membership of the Task Group on Modeling for Scaling to Humans is presented. Dr. James A. Mewhinney of the Lovelace Inhalation Toxicology Research Institute has been Chairman since these Task Groups were established. Ms. Judy Mahaffey of Battelle. Pacific Northwest Laboratories served as chairperson for this symposium, and the Task Group membership has served as the Program Committee. The OHER/DOE thanks all of them for their work as members of the Task Group as well as for their arranging such a potentially productive and informative meeting

[en] Data were obtained from the literature for gonad and body weights and for the Pu or Ce content of the gonads and body at death for several laboratory animal species, five human Pu injection cases, and 731 human adults exposed environmentally to Pu in fallout. Data for Pu concentration in gonads, liver, and bone samples of 59 male and five female occupational Pu cases (including four completely analyzed whole bodies) were obtained from the U.S. Transuranium Registry. A logarithmic function was used to relate fractional Pu or Ce concentration in testes and ovaries to body weight of the animals and to predict fractional Pu or Ce concentrations in human gonads, [Pu]G . PuB-1 = aBWb, where [Pu]G or [Ce]G is the nuclide concentration in gonads (Bq g-1 of wet weight), PuB or CeB is the nuclide content of the body at death, and BW is body weight (kg). The fractional Pu and Ce concentrations in both the testes and ovaries are inverse and nearly linear functions of body weight. The regression lines of fractional Pu or Ce concentration in testes and ovaries have similar slopes (b = -1.07 +/- 0.14); however, the nuclide concentrations (coefficient a) in ovaries are six times greater than in testes. Extrapolation of the animal data yielded fractional Pu concentrations in human testes and ovaries that agree with those calculated for the occupational cases and those recommended by the International Commission on Radiological Protection. The good agreement between the fractional concentrations of Pu and Ce in the testes and in the ovaries suggests that these data can be substituted in metabolic models of chemically similar elements for which gonadal data are scarce

[en] Concentrations and organ distribution patterns of alpha-emitting isotopes of U (238U and 234U), Th (232Th, 230Th, and 228Th), and Pu (239,240Pu) were determined for beagle dogs of our colony. The dogs were exposed to environmental levels of U and Th isotopes through ingestion (food and water) and inhalation to stimulate environmental exposures of the general human population. The organ distribution patterns of these radionuclides in beagles are compared to patterns in humans to determine if it is appropriate to extrapolate organ content data from beagles to humans. The results indicated that approximately 80% of the U and Th accumulated in bone in both species. The organ content percentages of these radionuclides in soft tissues such as liver, kidney, etc. of both species were comparable. The human lung contained higher percentages of U and Th than the beagle lung, perhaps because the longer life span of humans resulted in a longer exposure time. If the U and Th content of dog lung is normalized to an exposure time of 58 y and 63 y, median ages of the U and Th study populations, respectively, the lung content for both species is comparable. The organ content of 239,240Pu in humans and beagles differed slightly. In the beagle, the liver contained more than 60%, and the skeleton contained less than 40% of the Pu body content. In humans, the liver contained approximately 37%, and the skeleton contained approximately 58% of the body content. This difference may have been due to differences in the mode of intake of Pu in each species or to differences in the chemical form of Pu. In general, the results suggest that the beagle may be an appropriate experimental animal from which to extrapolate data to humans with reference to the percentage of U, Th, and Pu found in the organs

[en] Stochastic effects have been defined as those for which the probability increases with dose, without a threshold. Nonstochastic effects are those for which incidence and severity depends on dose, but for which there is a threshold dose. These definitions suggest that the two types of effects are not related. In this paper it will be shown that at least some of the nonstochastic effects are the consequence of accumulated stochastic effects and that both types of effect can be related to a common cellular damage. It is proposed that, at the cellular level, effects such as mutation induction and cell reproductive death are related to DNA double-strand breaks caused by radiation. Further, we propose that stochastic effects depend on a mutational event induced in a critical cell of a target organ. Nonstochastic effects are considered to arise because the function of a substantial proportion of critical cells is impaired. In some cases the predominant effect is comparable to cell reproductive death. Animal mortality, for instance, may occur because a substantial proportion of bone marrow cells is killed. Using this concept, mathematical formulas can be derived for the various effects. Modification of the irradiation conditions (e.g., low dose rate or density ionizing radiation) leads to changes in the initial molecular lesions and, consequently, to changes in the dose effect relationships of stochastic and nonstochastic effects. Experimental support will be discussed, using animal mortality as an endpoint. The implications of this approach will be discussed with emphasis on its application to radiological protection

[en] Reevaluation of neutron exposures to atomic bomb survivors has greatly reduced the significance of that data base for estimating the relative biological effectiveness of radiations with high linear energy transfer (LET). Consequently, greater emphasis is being given to animal data and mechanistic studies at the cellular and molecular level in assessing the role of radiation quality in the health effects of low-level radiation exposure. We are investigating the spatial patterns of energy deposited in DNA by ionizing radiation and their influence on cell killing and mutation induction. Our basic hypothesis is that high ionization density increases the probability that radiation-induced DNA damage will be unrepairable or misrepaired. This paper discusses the use of computer simulation to investigate damage induced in DNA by the decay of incorporated 125I

[en] The metabolic behavior of ²³⁹Pu and ²⁴¹Am present in three industrial dusts has been studied after their inhalation by the rat. A comparative experiment has also been carried out with a mixture of these actinides, inhaled as their nitrates. The aim of this work was to provide an experimental basis for assessing limits on intake and to establish whether the ²³⁹Pu content in the lungs could be interpolated from measurements of ²⁴¹Am. The results (1) demonstrate the wide differences in the lung retention kinetics of the actinides and in the absolute and relative amounts which translocate to the blood that can occur for industrially produced materials; (2) show that the annual limits on intake (ALI) for the different materials vary between those postulated for class W and Y compounds by the International Commission on Radiological Protection; (3) indicate that, depending on the nature of the dust, acute intakes of ²³⁹Pu equivalent to the ALI can be estimated from ²⁴¹Am chest-monitoring data at times from a few days up to about 3 y after exposure

[en] Values of an inaccessible biological parameter in man may be predicted from values measured in animals by correlating with a parameter accessible in both species, such as body weight, energy production, excretion rate, etc. Predicting toxic effects, from environmental chemicals, of therapeutic doses for drug administration and of radiation absorbed dose from medical and environmental radioactivity depends on the rationalization of relationships between concentration and time when scaling to humans from animal data. For example, the retention of ^99mTc, injected intravenously as pertechnetate, reaches 10% in the mouse at about 1 d, but this level occurs in humans at about 7 d. Making a simultaneous transformation between two species for the concentration and time variables by using a method of least-squares fitting, we have derived a series of transformation factors for several species. When correlated with a biological parameter such as body weight, these factors can be used to yield predicted values that are in good agreement with measured values. This system may be used with any related variables, making it useful for predicting other types of biological data

[en] In this paper, recent developments in the quantitative assessment of carcinogenic risks based on toxicological and epidemiological data are reviewed. In particular, model-free approaches to low-dose risk assessment which involve only the assumption of low-dose linearity are considered. Measures of carcinogenic potency which avoid the need to extrapolate to low doses are also described. The allometric bases for converting risk estimates between species are then discussed. Pharmacokinetic models for determining the dose delivered to the target tissue are examined, and the implications of using such models in extrapolating between doses, of exposure, and species are examined. The application of these concepts in chemical and radiation carcinogenesis is illustrated by means of brief case studies of methylene chloride and Rn. Biologically motivated cancer models based on the initiation-promotion-progression theory of carcinogenesis are discussed and compared with the classical multistage model. The estimation of risks with time-dependent exposure patterns is considered, and conditions under which the use of a time-weighted average dose is appropriate are identified. Finally, the estimation of carcinogenic risks posed by exposure to complex mixtures is explored. 92 references