B. B. Boecker

Predicted and observed early effects of combined alpha and beta lung irradiation

The nonstochastic radiobiological effects of combined alpha and beta irradiation of the lungs of rats from inhaled radionuclides were studied. Both respiratory functional morbidity at 18 mo and mortality from radiation pneumonitis within 18 mo after exposure were examined for rats exposed to the beta-emitter 147Pm, the alpha-emitter 238Pu, or both combined. The results were used to validate hazard-function models that were developed (1) for respiratory functional morbidity at 18 mo and (2) for lethality from radiation pneumonitis within 18 mo. Both models were found to adequately predict the experimental observations for chronic alpha plus beta irradiation of the lung. Based on this 18-mo study, a relative biological effectiveness of approximately seven was obtained for 238Pu alpha radiation compared to 147Pm beta radiation for both respiratory functional morbidity and lethality from radiation pneumonitis. However, the relative biological effectiveness for the alpha radiation is likely to increase with longer follow-up.

THORIUM DISTRIBUTION AND EXCRETION STUDIES. II. GENERAL PATTERNS FOLLOWING INHALATION AND THE EFFECT OF THE SIZE OF THE INHALED DOSE

A series of single, short-term inhalation exposures of rats to thorium chloride aerosols was conducted to study thorium distribution and excretion patterns and the effect of the size of the initial lung thorium burden on these patterns. Soon after exposure, a fraction of the thorium in the lungs was absorbed into the body and the largest portion of this absorbed fraction was deposited in the skeleton. Following this initiai uptake, the organ thorium burdens remained approximately constant while the lung burden decreased with time after exposure accompanied by excretion of thorium predominantly in the feces. The fraction of the lung thorium burden that was absorbed and the fractions excreted in the urine and feces did not appear to be affected by a variation in the size of the initial lung burden by a factor of 1.1 x 10/sup 5/. Calculations of the (MPC)/sub a/ values based on these data yielded a value of 1 x 10/sup -11/ mu c/cm/sup 3/ for both soluble and insoluble natural thorium and soluble Th/sup 232/ compounds. The corresponding value for insoluble Th/sup 232/ compounds was found to be 2.5 x 10/sup -11/ mu c/cm/sup 3/. (auth)

Skeletal malignancies among beagles injected with 241Am.

Seventy skeletal malignancies in 44 dogs were identified among 117 beagles injected as young adults with graded dosages of approximately 0.07 to 104 kBq 241Am kg-1 and maintained for lifetime observation. All of these tumors were osteosarcomas except four fibrosarcomas of bone and four chondrosarcomas of bone. Of these 117 animals, 114 survived beyond the minimum age (of 2.79 y) for radiation-induced bone cancer, and all are now dead. An expression was derived that described the dependence of percent occurrence of bone sarcoma on skeletal radiation dose of A = 0.76 + 30D, where A = percent of dogs with skeletal malignancy within any dosage group, D = average skeletal dose (< 3 Gy) at 1 y before death (average skeletal dose was calculated to the presumed start of tumor growth, which we have taken to be 1 y before death), and 0.76 represents the lifetime percent malignant bone tumor response among 132 suitable control dogs in our colony not given any radioactivity. All dosage groups with skeletal doses of > 3 Gy at 1 y before death exhibited close to 100% occurrence and appeared to be beyond the region of linearity. Therefore, they were excluded from the derivation of this expression. Similar analysis of corresponding data for beagles given 226Ra as young adults, excluding the two highest dosage groups in which the bone tumor response was approximately 100%, yielded the expression, A = 0.76 + 4.7D, (D < 20 Gy). A ratio of the coefficients in these two expressions indicates the effectiveness at low radiation doses for bone-cancer induction of 241Am relative to 226Ra, or (30 +/- 2.6)(4.7 +/- 0.47)-1 = 6 +/- 0.8. This compares to the relative effectiveness at low radiation doses that was obtained earlier for a 239Pu:226Ra toxicity ratio of about 16 +/- 5.

Application of an informatics-based decision-making framework and process to the assessment of radiation safety in nanotechnology.

AbstractThe National Council on Radiation Protection and Measurements (NCRP) established NCRP Scientific Committee 2‐6 to develop a report on the current state of knowledge and guidance for radiation safety programs involved with nanotechnology. Nanotechnology is the understanding and control of matter at the nanoscale, at dimensions between ∼1 and 100 nm, where unique phenomena enable novel applications. While the full report is in preparation, this paper presents and applies an informatics-based decision-making framework and process through which the radiation protection community can anticipate that nano-enabled applications, processes, nanomaterials, and nanoparticles are likely to become present or are already present in radiation-related activities; recognize specific situations where environmental and worker safety, health, well-being, and productivity may be affected by nano-related activities; evaluate how radiation protection practices may need to be altered to improve protection; control information, interpretations, assumptions, and conclusions to implement scientifically sound decisions and actions; and confirm that desired protection outcomes have been achieved. This generally applicable framework and supporting process can be continuously applied to achieve health and safety at the convergence of nanotechnology and radiation-related activities.

Bioassay model for estimating body burdens of 241Am from excretion analyses.

A simple bioassay model for predicting the organ burdens of 241Am from excretion rates is presented for inhalation exposures. The model uses three compartments representing lung, liver and skeleton. The model was developed using data from studies in laboratory animals of inhaled or injected 241Am and was validated for people by comparison to cases of accidental inhalation exposures to 241Am. The data for people have a large amount of variability but indicate that the retention half-time of 241Am in liver is approximately 2 yr and in skeleton is approximately 30 yr. These parameters can be used in the model to estimate body and organ burdens from excretion rates after inhalation of 241Am or the model can be fitted to an individuals measured excretion rates.

Dose-response Relationships for Bone Cancers from Plutonium in Dogs and People

The risk of bone cancers developing from internally deposited plutonium must be estimated from studies in laboratory animals because no plutonium-induced cancers have been observed in people. Studies of the effects of 226Ra and 239Pu injected into beagle dogs at the University of Utah and 238PuO2 inhaled by beagle dogs at the Inhalation Toxicology Research Institute provide a key link to understanding the longterm effects of inhaled alpha-emitting radionuclides in people. Injected radium and plutonium are rapidly deposited in bone whereas plutonium deposited in lung by inhalation is translocated to bone more slowly, depending on its chemical form. The development of bone cancers is a late occurring effect seen after either injection of plutonium or radium or inhalation of plutonium. The incidence of bone cancers from alpha radiation to the skeletons of dogs was compared to bone cancer incidences in radium dial painters to estimate bone cancer risk from inhaled plutonium in people. A risk factor of 1200 bone cancers/10(6) rad to skeleton (average dose) was estimated.

Pulmonary Carcinogenesis and Chronic Beta Irradiation of Lung

Light water nuclear power reactor fuel cycles at various stages contain substantial quantities of β-emitting radionuclides. Thus, in the event of an accident, there is potential for inhalation exposure of man to various types and forms of β-emitting radionuclides. In order to study the biological effects of such potential exposures, a series of life span studies have been initiated in which beagle dogs have been exposed to inhalation to achieve graded lung burdens of a relatively insoluble fused clay form of β-emitting radionuclides. The specific radionuclides, 90Y, 91Y, 144Ce, or 90Sr, were selected on the basis of physical half-life to produce a variety of radiationdose patterns to the lung. Early effects have been the development of radiation pneumonitis and progressive pulmonary fibrosis. In general, dogs which receive high- and rapidly-declining dose-rate exposure from 90Y or 91Y die earlier and at lower cumulative doses than dogs exposed to 144Ce or 90Sr. By contrast, the incidence of later-occurring malignant lung tumors and the degree of inflammatory response is greater in dogs which received protracted low dose-rate exposure associated with 144Ce and 90Sr. Of particular note is the nature of the lung tumors thus far observed. These have been of endothelial origin — hemangiosarcomas rather than the epithelial carcinomas that are seen in uranium miners or dogs exposed to 239PuO2. This association between β-radiation exposure and vascular neoplasms will be discussed further.

Future development of biological understanding of radiation protection: implications of nonstochastic effects

Radiation-protection standards are based on minimizing or preventing biological effects in exposed populations. Radiation-induced biological effects can be classified as stochastic--malignant and hereditary diseases for which the probability of an effect occurring is a function of dose without threshold--and nonstochastic--inflammatory and degenerative diseases for which the severity and frequency of the effect varies with the dose and for which a threshold is present. The current International Commission on Radiation Protection (ICRP) approach for setting limits for intakes of radionuclides by workers, which accounts for doses to significantly exposed organs of the body, is based on limitation of stochastic effects in most situations. When setting exposure limits, nonstochastic effects are generally considered to be unlikely at the limits for stochastic effects. In some situations, limits based on prevention of nonstochastic effects are lower than for stochastic effects. This review considers the threshold radiation doses for thyroid, bone, liver and lung and their relationship to the limits recommended by the ICRP and the cancer risks at the limits. This review indicates that the threshold dose for nonstochastic effects in thyroid and lung is much above the dose limit as advocated by ICRP. The threshold dose for nonstochastic effects in bone and liver is much closer to the dose limit, but protection from nonstochastic effects should still be afforded by the dose limits.

144Ce in tissues of beagle dogs after inhalation of CeCl3 with special emphasis on endocrine glands and reproductive organs.

Beagle dogs inhaled aerosols containing 144CeC1,. Deposition of la4Ce in tissues was determined in serially sacrificed dogs to characterize radiation dose patterns at early times after exposure. Uptakes of 144Ce in endocrine glands and reproductive organs were also measured; radiation doses were calculated and those doses were compared with the doses to the major organs of deposition-lung, liver and skeleton. Integrated radiation doses in pituitary and adrenal glands, pancreas, ovaries, testes, prostate and uterus were less than 2 % of those in lung and liver, while the thyroid dose was about 30 % of the dose in liver. These findings were consistent with previously reported biological responses in beagle dogs exposed to high levels of 144CeC1, wherein no radiation effects related to endocrine glands or the reproductive system have been observed. Use of these results in predicting the dosimetry of 144Ce in exposed humans re-emphasized the importance of radiation damage to lung, liver, skeleton and gastrointestinal tract compared to other organ systems. INTRODUCTION TISSUE distribution and retention patterns of internally deposited lanthanide elements [also called the rare earth group, atomic numbers 58 (Ce) through 71 (Lu)] are of interest, because many of their radioactive isotopes are abundant by-products of nuclear fission. Discussions of the metabolism and health considerations of the lanthanide fission products usually include two other chemically similar elements [57 (La) and 39 (Y)]. As discussed by MAGNUSSON (1963), ianthanide elements and especially 144Ce dominate aged fission products from 70 days to 6 yr after fission of 238U. Lanthanides generally form trivalent ions, but bivalent and tetravalent forms also occur. Reviews of metabolic characteristics of the lanthanide elements have been published by DURBIN et al. (1956), DURBIN (1960) and MAGNUSSON (1963). When absorbed into the circulation, lanthanides are bound to piasma proteins and transported predominately to liver and skeleton. Their tendency to form insoluble * Research performed under US. Energy Research and Development Administration Contract No. E(29-2)-1013 and conducted in facilities fully accredited by the American Association for Accreditation of Laboratory Animal Care. colloids and hydroxides, phosphates and carbonates has often confused interpretation of tissue distribution studies following injection or inhalation of poorly characterized lanthanide compounds. In discussions of possible relationships between cancer mortality and fission product fallout patterns after weapons testing, STERNGLASS (1 973) suggested that lanthanide elements may be concentrated by glands having endocrine functions. He also suggested that there were direct relationships between human cervical, prostatic, pancreatic and lung cancer incidence and fallout lanthanides and yttrium. Previous work of SPODE (1958), reported high concentrations of 9lY in pancreas, spleen, kidney and liver following intraperitoneal injection of DIYCla into guinea pigs. Following intracardial or subcutaneous injection, however, concentrations in kidney, liver, femur and spleen were higher than in other organs. Spode discussed those findings in relation to the specific methods used for isotope administration and the possibility that radiocolloid formation influenced subsequent isotope distribution patterns and uptake by abdominal organs or organs of the reticuloendothelial system. GRAUL and HUNDESHAGEN 53 54 144Ce IN TISSUES OF BEAGLE DOGS AFTER INHALATION OF CeCl, (1958) reported results in guinea pigs similar to those of SPODE (1958) ; concentrations were high in pancreas, liver, spleen and kidneys and low in femur after intraperitoneal injection; OOY concentrations were high in femur, spleen and liver and low in pancreas after intracardial injection. They reported unusually high concentrations of QOY in the pituitary gland after either oral or intracardial administration. I t has been suggested (P. W. DURBIN, private communication) that the high concentrations in the pituitary gland were most likely the result of technical errors. However, it is possible that collodial was accumulated in the abundant reticuloendothelial cells of the lining of the pituitary sinusoids (GREEP, 1954). There were measurable QOY concentrations in other endocrine glands that have significant complements of reticuloendothlial cells (thyroid, pancreas, adrenals, testes) , but they were lower than those in liver, skeleton, spleen or kidney. BOECKER and CUDDIHY (1974) reported tissue concentrations of 14*Ce in beagle dogs following inhalation of 144CeC1, aerosols. Tissue concentrations were expressed as fractions of liver concentration at 8, 16 and 32 days after inhalation exposure. Only nasal turbinate and lung tissues had higher concentrations than liver a t these early times. Smaller tissues such as tracheobronchial lymph nodes, adrenals, thyroid and ovaries may have had significant concentrations of 144Ce which were undetected because of the small masses and low radioactivity. Pituitary was not sampled. Additional studies of la4Ce tissue concentrations in beagle dogs are reported here and the endocrine glands and reproductive organs are particularly emphasized. Inhalation of 144CeC13 aerosols was used to avoid difficulties associated with injection of uncertain chemical forms. In addition, radiochemical techniques were used to increase the sensitivity of 144Ce detection in small tissue samples. EXPERIMENTAL METHODS Adult beagle dogs, six males and six females between 25 and 50 months of age, were exposed by inhalation to aerosols containing 144CeC1,. Aerosols were generated by nebulizing solutions containing 0.3 mg CeCl,/ml, 9.7 mg CsCl/ml and 3 mCi 144Ce/ml in equilibrium with its daughter 144Pr. Air concentrations of 144Ce in the exposure chambers averaged 7.5 ,uCi/ml during the 10to 30-min exposure periods. The aerosol particle sizes were distributed lognormally with an activity median aerodynamic diameter of 2.5 ,urn and a geometric standard deviation of 1.6 as determined with cascade impactors (MERCER et al., 1970). Dogs inhaled the aerosols in an apparatus which provides for a nose-onIy exposure previously described by BOECKER et al. (1964). Total body deposition averaged 70% of the estimated inhaled radioactivity and resulted in initial body burdens of about 220pCi Ce. Following exposure, dogs were maintained in metabolism cages for excreta collections, and total body measurements of 144Ce-144Pr were made frequently until sacrifice. Pairs of dogs, one male and one female, were sacrificed 2 hr, and 2, 4, 8 and 32 days after exposure. Animals were killed by maximum blood withdrawal under sodium pentobarbital anesthesia. Assuming that the total blood volume represented 10% of total body weight (WOODWARD et al., 1968), it was estimated that 69 & 5 % of the blood volume was withdrawn. Necropsies were performed immediately to obtain well-trimmed whole organs and defleshed skeletons for radioactivity analyses. Scintillation detectors with minimum detection levels for 144Ce-144Pr of less than 1 nCi were used for large tissue samples. Small tissues-adrenal glands, pituitary, thyroid, ovaries, testes, prostate, uterus and salivary glands-were wet ashed, plated and the beta particles were counted in a gas proportional counter. Thus, levels of activity greater than 0.5 pCi were detectable. Tissue concentrations were calculated using data from radioactivity analyses and standardized tissue weights for beagle dogs normalized to 10 kg total body weight. Standardized organ weights, which include the normal complement of blood as given in Table 3, were used in place of weights obtained at necropsy because sacrifice by blood withdrawal can markedly change tissue weights (CUDDIHY et al., in preparation) particularly such vascular organs as liver, lung, spleen and kidney. When standardized weights were not available, weights were obtained from tissues collected in this study. Integral radiation doses to various tissues were R. G. CUDDIHY, B. B. BQECKER, R. 0. McCLELLAN and G. M. KANAPILLY 55 Table I . Beta and gamma emissions from 144Ce-144Pr considered in iissua radtation dose calculalions. Values for radiation yield are giuen in terms of emirsionldisintegration of 144Ce through la4Nd _-l___^ _. Energy (MeV) Type o f Radiation Em,, EaVg .Yield Source Beta 0.31 0.09 0.17 0.045 Gamna 0.134 Beta 2.99 1.23