Feasibility of Thorium-227/Radium-223 Gamma-Camera Imaging During Radionuclide Therapy.

Thorium-227 (227Th) is a long-lived (T1/2 = 18.7 d) α-emitter that has emerged as candidate for radioimmunotherapy. Imaging of patients treated with thorium-227 conjugates is challenging due to the low activity administered and to photon emissions with low yields. In addition, the radioactive daughter radium-223 (223Ra) have photon emissions in the same energy range as 227Th. The long half-life of 223Ra (T1/2 = 11.4 d) and the possibility of redistribution motivates efforts to separate 227Th and 223Ra. The aim of this study was to investigate the feasibility of imaging of patients treated with 227Th-labeled-monoclonal antibody (mAb) and to determine acquisition and image processing parameters to enable discrimination between 227Th and 223Ra. Imaging was performed with a GE Discovery 670 NM/CT γ-camera. Radionuclide separation with different energy windows (EW) and collimators was studied in images of vials with either 227Th or 223Ra. Phantom acquisitions with clinically relevant activities were performed to assess image quality and the usefulness of background subtraction and spatial filtering. Two patients treated with 227Th-labeled-mAb were imaged. Imaging of vials showed that 223Ra can be distinguished from 227Th using multiple energy windows. Medium- and high-energy collimators showed similar performance of sensitivity and spatial resolution, whereas the low-energy collimator had higher sensitivity but poor resolution due to collimator penetration. Visually, the image quality was improved with background subtraction and spatial filtering. The patient images exhibited the expected image quality and a possibility to separate 227Th and 223Ra. γ-Camera imaging of patients treated with 227Th-mAb is feasible and 223Ra can be distinguished from 227Th. Image quality is substantially improved using background subtraction and a spatial smoothing filter. Acquisition settings recommended for planar images are: high-energy general purpose or medium-energy general purpose collimator, 40 min acquisition time and energy windows: (1) 70-100 keV (227Th and 223Ra); (2) 215-260 keV (227Th); (3) 260-290 keV (223Ra); (4) 350-420 keV (223Ra).

Administration of lower doses of radium-224 to ankylosing spondylitis patients results in no evidence of significant overall detriment.

The use of low doses of radium-224 (224Ra) chloride for the treatment of ankylosing spondylitis was stopped following the discovery that patients treated with it had a higher than control incidence of leukaemia and other cancers. This was so even though the treatment resulted in decreased pain and increased mobility-both of which are associated with decreased mortality. It was decided to re-analyze the epidemiological data looking at all causes of death. The risk of leukaemia, solid cancer, death from non-cancer causes and from all causes in a study populations of men that received either the typical dose of 5.6 to 11.1 MBq of 224Ra, any dose of 224Ra or no radium were compared using the Cox proportional hazard model. For patients that received the typical dose of 224Ra agreed with the excess cancer was similar to that reported in previous studies. In contrast, these patients were less likely to die from non-cancer diseases and from all causes of death than the control patients. No excess mortality was also found in the population of all males that received the radionuclide. It is concluded that 224Ra treatment administered at low doses to patients with ankylosing spondylitis did not impact mortality from all causes. The study demonstrates the need to consider all causes of death and longevity when assessing health impacts following irradiation.

Alpha-Particle Therapy for Multifocal Osteosarcoma: A Hypothesis.

Osteosarcoma (OST) is the most common bone tumor in children and adolescents with a second peak of incidence in elderly adults usually diagnosed as secondary tumors in Paget's disease or irradiated bone. Subjects with metastatic disease or whose disease relapses after the initial therapy have a poor prognosis. Moreover, multifocal OST contains tumor-initiating cells that are resistant to chemotherapy. The use of aggressive therapies in an attempt to eradicate these cells can have long-term negative consequences in these vulnerable patient populations. 227Th-labeled molecular probes based on ligands to OST-associated receptors such as IGF-1R (insulin-like growth factor receptor 1), HER2 (human epidermal growth factor receptor 2), and PSMA (prostate-specific membrane antigen) are expected to detect and treat osseous and nonosseous sites of multifocal OST. Published reports indicate that 227Th has limited myelotoxicity, can be stably chelated to its carriers and, as it decays at targeted sites, 227Th produces 223Ra that is subsequently incorporated into the areas of increased osteoblastic activity, that is, osseous metastatic lesions. Linear energy transfer of α particles emitted by 227Th and its daughter 223Ra is within the range of the optimum relative biological effectiveness. The radiotoxicity of α particles is virtually independent of the phase in the cell cycle, oxygenation, and the dose rate. For these reasons, even resistant OST cells remain susceptible to killing by high-energy α particles, which can also kill adjacent quiescent OST cells or cells with low expression of targeted receptors. Systemic side effects are minimized by the limited range of these intense radiations. Quantitative single-photon emission computed tomography of 227Th and 223Ra is feasible. Additionally, the availability of radionuclide pairs, for example, 89Zr for positron emission tomography and 227Th for therapy, establish a strong basis for the theranostic use of 227Th in the individualized treatment of multifocal OST.

Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers.

PURPOSE: Targeted thorium-227 conjugates (TTC) represent a new class of molecules for targeted alpha therapy (TAT). Covalent attachment of a 3,2-HOPO chelator to an antibody enables specific complexation and delivery of the alpha particle emitter thorium-227 to tumor cells. Because of the high energy and short penetration range, TAT efficiently induces double-strand DNA breaks (DSB) preferentially in the tumor cell with limited damage to the surrounding tissue. We present herein the preclinical evaluation of a mesothelin (MSLN)-targeted thorium-227 conjugate, BAY 2287411. MSLN is a GPI-anchored membrane glycoprotein overexpressed in mesothelioma, ovarian, pancreatic, lung, and breast cancers with limited expression in healthy tissue. EXPERIMENTAL DESIGN: The binding activity and radiostability of BAY 2287411 were confirmed bioanalytically. The mode-of-action and antitumor potency of BAY 2287411 were investigated in vitro and in vivo in cell line and patient-derived xenograft models of breast, colorectal, lung, ovarian, and pancreatic cancer. RESULTS: BAY 2287411 induced DSBs, apoptotic markers, and oxidative stress, leading to reduced cellular viability. Furthermore, upregulation of immunogenic cell death markers was observed. BAY 2287411 was well-tolerated and demonstrated significant antitumor efficacy when administered via single or multiple dosing regimens in vivo. In addition, significant survival benefit was observed in a disseminated lung cancer model. Biodistribution studies showed specific uptake and retention of BAY 2287411 in tumors and enabled the development of a mechanistic pharmacokinetic/pharmacodynamic model to describe the preclinical data. CONCLUSIONS: These promising preclinical results supported the transition of BAY 2287411 into a clinical phase I program in mesothelioma and ovarian cancer patients (NCT03507452).

Antitumor Activity of Novel Bone-seeking, α-emitting 224Ra-solution in a Breast Cancer Skeletal Metastases Model.

BACKGROUND/AIM: Bone metastases are associated with increased morbidity and poor prognosis in a variety of cancers. The present study investigated the effects of targeted radionuclide therapy with α-emitting, bone-seeking radium-224 (224Ra) on osteolytic bone metastasis of MDA-MB-231(SA)-GFP human breast cancer cells injected intracardially into nude mice. MATERIALS AND METHODS: Vehicle, ethylenediamine tetra (methylene phosphonic acid) (EDTMP) and 224Ra-solution (45, 91 or 179 kBq/kg) with EDTMP were intravenously administered to mice two days after cell injection. The bone-seeking EDTMP was added to the 224Ra-solution to improve bone targeting of 212Pb, which is a progeny of 224Ra. RESULTS: Radium-224 solution treatment decreased in a dose-dependent manner the areas of osteolytic lesions in the hind limbs and the number of tumor foci in the whole skeleton, and extended survival. Paraplegia was not observed in 179 kBq/kg 224Ra-solution group. CONCLUSION: Radium-224-solution containing chelated 212Pb is a promising candidate for the treatment of breast cancer patients with bone metastases.

Ra-224 labeling of calcium carbonate microparticles for internal α-therapy: Preparation, stability, and biodistribution in mice.

Internal therapy with α-emitters should be well suited for micrometastatic disease. Radium-224 emits multiple α-particles through its decay and has a convenient 3.6 days of half-life. Despite its attractive properties, the use of 224 Ra has been limited to bone-seeking applications because it cannot be stably bound to a targeting molecule. Alternative delivery systems for 224 Ra are therefore of considerable interest. In this study, calcium carbonate microparticles are proposed as carriers for 224 Ra, designed for local therapy of disseminated cancers in cavitary regions, such as peritoneal carcinomatosis. Calcium carbonate microparticles were radiolabeled by precipitation of 224 Ra on the particle surface, resulting in high labeling efficiencies for both 224 Ra and daughter 212 Pb and retention of more than 95% of these nuclides for up to 1 week in vitro. The biodistribution after intraperitoneal administration of the 224 Ra-labeled CaCO3 microparticles in immunodeficient mice revealed that the radioactivity mainly remained in the peritoneal cavity. In addition, the systemic distribution of 224 Ra was found to be strongly dependent on the amount of administered microparticles, with a reduced skeletal uptake of 224 Ra with increasing dose. The results altogether suggest that the 224 Ra-labeled CaCO3 microparticles have promising properties for use as a localized internal α-therapy of cavitary cancers.

Use of pectin-thorium (IV) tungstomolybdate nanocomposite for photocatalytic degradation of methylene blue.

Pectin-thorium (IV) tungstomolybdate (Pc/TWM) nanocomposite was prepared by mixing biopolymer pectin with its inorganic counterpart thorium (IV) tungstomolybdate (TWM) using the sol-gel method. The nanocomposite was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR). Distribution coefficient, thermal stability, pH titrations, elution and concentration behaviour were investigated to explore the ion exchange behaviour of nanocomposite material. Pc/TWM exhibited higher ion exchange capacity (1.10 mequiv/g) than its inorganic counterpart (0.62 mequiv/g). The Pc/TWM nanocomposite ion exchanger was thermally stable as it retained 59% of its ion exchange capacity upto 400°C. The pH titrations study revealed the bifunctional nature of Pc/TWM. In order to explore the environmental applicability of the Pc/TWM nanocomposite material, its antibacterial and photocatalytic activities was investigated. 76% of methylene blue dye was photocatalytically degraded after five hours exposure. It also totally inhibited Escherichia coli at 400 µg/ml concentration of Pc/TWM nanocomposite.

Thorium-induced neurobehavioural and neurochemical alterations in Swiss mice.

PURPOSE: Thorium ((232)Th), a heavy metal radionuclide that targets the liver and skeleton, has been shown to accumulate in the central nervous system at low levels. The present study was aimed to investigate neurobehavioural and neurochemical changes in mice treated with (232)Th at sub-lethal doses. MATERIALS AND METHODS: Swiss albino mice were administered intraperitoneally with thorium nitrate. The chelation-based therapeutic effect of calcium diethylenetriamine pentaacetate (Ca-DTPA) was tested on the (232)Th-treated mice. (232)Th localisation was determined in brain regions by the Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES) method. Achetylcholine esterase (AChE) activity in different brain regions was evaluated to assess the cholinergic function of mice CNS. Oxidative damage was evaluated by assessing the activities of antioxidant enzymes (i.e., superoxide dismutase and catalase) and the level of lipid peroxidation. The neurobehavioural alteration in the treated mice was studied by the shuttle box method. RESULTS: (232)Th accumulation found in different brain regions followed the order: Cerebellum (Cbl) > cortex (Ctx) > hippocampus (Hp) > striatum (Str). However, removal of (232)Th by Ca-DTPA was significant from brain regions like Cbl, Ctx and Str but not from Hp. A significant increase in lipid peroxidation and acetylcholine esterase (AChE) activity was observed in the treated mice but activities of superoxide dismutase and catalase was found substantially decreased. (232)Th treatment impaired the learning and memory-based neurobehaviour of the mice. Furthermore, our data suggest that Ca-DTPA injection in (232)Th-treated animals failed to improve the neurobehaviour of the treated mice, perhaps because Ca-DTPA could not decorporate (232)Th or mitigate (232)Th-mediated neurochemical changes effectively from/in hippocampus, a brain region implicated in learning and memory response. CONCLUSION: Administration of (232)Th in mice caused neurobehavioural alteration and impairment of cholinergic function, which might be the consequence(s) of oxidative stress induction in different brain regions.

Biokinetic modelling of natural thorium in humans by ingestion.

The retention of naturally occurring thorium (228Th, 230Th, 232Th) in model compartments and its daily urinary and faecal excretion after acute and chronic injections and ingestions were calculated for male and female subjects of six age groups based on the current age-dependent biokinetic model for thorium (Th) recommended by the International Commission on Radiological Protection (ICRP). The results are tabulated in a database. The calculated contents of 228,230,232Th in organs or tissues using their reference concentrations in foodstuffs for the European population are compared with autopsy data. The model prediction of 232Th in whole body for a 50-year-old unexposed person is 22 mBq, 86% of that in skeleton, 9.7% in other soft tissues, 3.4% in liver, 0.7% in kidneys and 0.01% in blood. The modelling predicts lower contents of the natural Th isotopes in whole body, especially in blood compared with measured data for the unexposed public. Modelled 232Th daily urinary excretions are 5 to 10 times less than bio-assay data from the authors' own laboratory.

Radiological impact of dietary intakes of naturally occurring radionuclides on Pakistani adults.

Daily dietary intakes of three naturally occurring long-lived radionuclides (232)Th, (238)U and (40)K were estimated for the adult population of Pakistan using neutron activation analysis (NAA), inductively coupled plasma mass spectrometry (ICP-MS) and atomic absorption spectrometry (AAS), respectively. The daily intakes of (232)Th ranged from 4 to 29 mBq, (238)U ranged from 17 to 82 mBq and (40)K ranged from 51 to 128 Bq. The geometric means of these intakes were 10 mBqd(-1) for (232)Th, 33 mBqd(-1) for (238)U and 78.5 Bqd(-1) for (40)K. The measured values give annual committed effective doses of 0.80, 0.53 and 178.75 microSvyr(-1) for (232)Th, (238)U and (40)K, respectively to Pakistani population. The net radiological impact of these radionuclides is 180.08 microSvyr(-1). This value gives cancer risk factor of 4.5 x 10(-4) and loss of life expectancy of 0.87 days only. Whereas ICRP cancer risk factor for general public is 2.5 x 10(-3) and total risk involve from the all natural radiation sources based on global average annual radiation dose of 2.4 mSvyr(-1) is 6.0 x 10(-3). The estimated cancer risk shows that probability of increase of cancer risk from daily Pakistani diet is only a minor fraction of ICRP values. Therefore, the diet does not pose any significant health hazard and is considered radiologically safe for human consumption.

Dosimetric assessment from 212Pb inhalation at a thorium purification plant.

At the Instituto de Pesquisas Energeticas e Nucleares (IPEN), Sao Paulo, Brazil, there is a facility (thorium purification plant) where materials with high thorium concentrations are manipulated. In order to estimate afterwards the lung cancer risk for the workers, the thoron daughter (212Pb) levels were assessed and the committed effective and lung committed equivalent doses for workers in place. A total of 28 air filter samples were measured by total alpha counting through the modified Kusnetz method, to determine the 212Pb concentraion. The committed effective dose and lung committed equivalent dose due to 212Pb inhalation were derived from compartmental analysis following the ICRP 66 lung compartmental model, and ICRP 67 lead metabolic model.

Dose effect for Japanese due to 232Th and 238U in imported drinking water.

The consumption rate of bottled mineral water in Japan has increased due to changes in eating habits and contamination of water sources. Radioactivity levels of 238U and 232Th in imported mineral water were checked from the viewpoint of internal radiation for Japanese subjects. Concentration ranges of 238U and 232Th in imported bottled mineral water, domestic bottled mineral water, domestic tap water, and domestic soft drinks were as follows: for U, N.D to 7.48 x 10(3), 1.07 to 344, 0.66 to 104, and 3.04 to 46.2 ng dm (ppt); for Th, 0.60 to 5.12, 0.65 to 22.4, 0.64 to 22.1, and 11.0 to 48.5 ng dm, respectively. In some brands of imported bottled mineral water, U concentration was sometimes much higher than domestic bottled mineral water and domestic tap water. The annual effective dose (1.5 x 10(-3) mSv y(-1) estimated from intake of 238U was approximately 7 times higher than that through dietary intake in Japanese. However, the internal dose added by drinking the imported portable water is negligible compared with total annual internal dose. Concentrations of non-radioactive elements were also compared between imported and domestic bottled water. Geometric means of cobalt, arsenic, strontium, cesium, phosphorous, and calcium in imported bottled water were higher compared with those of domestic bottled mineral water and domestic tap water. Maximum values of 11 elements (arsenic, rubidium, strontium, cesium, barium, sodium, magnesium, potassium, calcium, and manganese) were also found in imported bottled water.

NORM workers: a challenge for internal dosimetry programmes.

The mining, milling and processing of uranium and thorium bearing minerals may result in radiation doses to workers. The control of occupational exposures from these natural sources of radiation imposes a challenge to regulators and radiation protection advisers. A survey pilot programme, which included six mines in Brazil and a monazite plant, was established, consisting of the collection and analysis of concentrations of uranium, thorium and polonium in urine, faeces and air samples. Results from workers were compared to background data from their families living in the same area and from residents from the population of Rio de Janeiro. Positive exposure results were identified among the coal miners, the niobium miners and the monazite sand workers. Difficulties in the application of internal dosimetry programmes are discussed in relation to the control of NORM workers.

Improved chelation therapy of intramuscularly deposited thorium by CaDTPA in the rat.

Comparative studies on the translocation and retention of intramuscularly (i.m.) injected thorium nitrate (234Th 46 ng + 232Th 5 microg per rat) in solutions of citrate, CaDTPA or citrate + CaDTPA in rats have been conducted. Results showed that only thorium in mixed-ligand solution was entirely translocated from the muscle, with the greatest part being excreted from the body. In this case, the whole-body retention of thorium decreased to 16% of the injected radioactivity within 2 d, 13% being retained in the skeleton. Studies on the decorporation of 234Th + 232Th nitrates from a rat wound simulated with i.m. injection have also been carried out. The greatest translocation of thorium and its excretion was achieved with a single local injection of the mixed-ligand (citrate + CaDTPA) solution when compared with those of citrate or CaDTPA alone. The efficiency of mixed-ligand treatment decreased with its delay. On day 2 post-therapy, the whole-body content of thorium decreased to 30, 37 and 55% of injected radioactivity when the local treatment started immediately, postponed to 1 h or 24 h, after i.m. injection of thorium, respectively. In control rats without treatment, there was only a slight decrease in the content of thorium in the whole body.

Estimation of dietary 232Th, 238U, cesium, and strontium intakes in Vietnamese people from different geographical regions.

Diet samples were collected to estimate dietary intakes of 232Th, 238U, cesium, and strontium for Vietnamese adults using duplicate portion studies and market basket studies. Average concentrations of 232Th, 238U, cesium, and strontium in diet samples were 4.0 ng/g-dry, 2.5 ng/g-dry, 41 ng/g-dry, and 4.5 ng/g-dry, respectively. Daily intakes per person for 232Th, 238U, cesium, and strontium were estimated to be 0.99 microg, 0.66 microg, 10 microg, and 1.2 mg, respectively. Daily intakes of 232Th, 238U, and cesium differed statistically between northern and southern of Vietnam, depending on geological conditions and food habits. However, intakes of the four nuclides were similar to the global averages.

Does body size contribute to sensitivity of bone tumor induction by radionuclide exposure?

Investigation of a possible increase in sensitivity to occurrence of radionuclide-induced skeletal malignancy with increasing body size was analyzed among 358 beagles injected as young adults with either 226Ra or monomeric 239Pu and maintained for their lifespans. Corresponding analyses were performed for about 240 other beagles injected as young adults with 90Sr, 228Ra, or 228Th. Body masses at the time of injection ranged between about 5.6 and 16 kg. Logistic regression analysis using body mass and cumulative skeletal radiation dose as the independent variables indicated that there could not be established a dependency of tumor occurrence upon body mass, although skeletal dose was found to be significantly correlated with occurrence of bone cancer. Regression analysis indicated that for any dosage group there could not be established a correlation between body mass and skeletal dose. Each dosage group having similar injected kBq kg(-1) for each nuclide was divided into 2 subgroups of equal size, one containing the less massive dogs and the other containing the more massive dogs. These subgroups within a roughly uniform value of skeletal dose-rate were compared by Fisher's Exact Test, and the less massive subgroups were combined within each nuclide for an additional, separate analysis against the combined more massive subgroups using the same method. In only one instance (the dosage group given 3607 kBq 90Sr kg(-1)) was there indicated a substantially greater tumor occurrence among dogs in the more massive subgroup (p = 0.061). However, for the group given 0.382 kBq 239Pu kg(-1) there was indicated a significant difference between subgroups, but the effect was exactly opposite to that found for the highest level 90Sr dogs in that the less massive subgroup had a higher relative tumor occurrence than the most massive (p = 0.042). For all groups with a p-value < 0.10, a possible correlation was investigated between survival and body mass at injection (since bone tumor occurrence might be a function of longevity), but a significant relationship could not be determined. No significant differences could be established between the combined more massive and the combined less massive subgroups for any radionuclide. We conclude that, for the conditions in our experiment, relative size within a species does not contribute importantly to the sensitivity (lifetime occurrence) for induction of skeletal malignancy.

Is the beagle dog an appropriate experimental animal for extrapolating data to humans on organ distribution patterns of U, Th, and Pu?

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.

The beagle: an appropriate experimental animal for extrapolating the organ distribution pattern of Th in humans.

The concentrations and the organ distribution patterns of 228Th, 230Th and 232Th in two 9-y-old dogs of our beagle colony were determined. The dogs were exposed only to background environmental levels of Th isotopes through ingestion (food and water) and inhalation as are humans. The organ distribution patterns of the isotopes in the beagles were compared to the organ distribution patterns in humans to determine if it is appropriate to extrapolate the beagle organ burden data to humans. Among soft tissues, only the lungs, lymph nodes, kidney and liver, and skeleton contained measurable amounts of Th isotopes. The organ distribution pattern of Th isotopes in humans and dog are similar, the majority of Th being in the skeleton of both species. The average skeletal concentrations of 228Th in dogs were 30 to 40 times higher than the average skeletal concentrations of the parent 232Th, whereas the concentration of 228Th in human skeleton was only four to five times higher than 232Th. This suggests that dogs have a higher intake of 228Ra through food than humans. There is a similar trend in the accumulations of 232Th, 230Th and 228Th in the lungs of dog and humans. The percentages of 232Th, 230Th and 228Th in human lungs are 26, 9.7 and 4.8, respectively, compared to 4.2, 2.6 and 0.48, respectively, in dog lungs. The larger percentages of Th isotopes in human lungs may be due simply to the longer life span of humans. If the burdens of Th isotopes in human lungs are normalized to an exposure time of 9.2 y (mean age of dogs at the time of sacrifice), the percent burden of 232Th, 230Th and 228Th in human lungs are estimated to be 3.6, 1.3 and 0.66, respectively. These results suggest that the beagle may be an appropriate experimental animal for extrapolating the organ distribution pattern of Th in humans.