Preclinical Evaluation of 203/212Pb-Labeled Low-Molecular-Weight Compounds for Targeted Radiopharmaceutical Therapy of Prostate Cancer.

Targeted radiopharmaceutical therapy (TRT) using α-particle radiation is a promising approach for treating both large and micrometastatic lesions. We developed prostate-specific membrane antigen (PSMA)-targeted low-molecular-weight agents for 212Pb-based TRT of patients with prostate cancer (PC) by evaluating the matching γ-emitting surrogate, 203Pb. Methods: Five rationally designed low-molecular-weight ligands (L1-L5) were synthesized using the lysine-urea-glutamate scaffold, and PSMA inhibition constants were determined. Tissue biodistribution and SPECT/CT imaging of 203Pb-L1-203Pb-L5 were performed on mice bearing PSMA(+) PC3 PIP and PSMA(-) PC3 flu flank xenografts. The absorbed radiation dose of the corresponding 212Pb-labeled analogs was determined using the biodistribution data. Antitumor efficacy of 212Pb-L2 was evaluated in PSMA(+) PC3 PIP and PSMA(-) PC3 flu tumor models and in the PSMA(+) luciferase-expressing micrometastatic model. 212Pb-L2 was also evaluated for dose-escalated, long-term toxicity. Results: All new ligands were obtained in high yield and purity. PSMA inhibitory activities ranged from 0.10 to 17 nM. 203Pb-L1-203Pb-L5 were synthesized in high radiochemical yield and specific activity. Whole-body clearance of 203Pb-L1-203Pb-L5 was fast. The absorbed dose coefficients (mGy/kBq) of the tumor and kidneys were highest for 203Pb-L5 (31.0, 15.2) and lowest for 203Pb-L2 (8.0, 4.2). The tumor-to-kidney absorbed dose ratio was higher for 203Pb-L3 (3.2) and 203Pb-L4 (3.6) than for the other agents, but with lower tumor-to-blood ratios. PSMA(+) tumor lesions were visualized through SPECT/CT as early as 0.5 h after injection. A proof-of-concept therapy study with a single administration of 212Pb-L2 demonstrated dose-dependent inhibition of tumor growth in the PSMA(+) flank tumor model. 212Pb-L2 also demonstrated an increased survival benefit in the micrometastatic model compared with 177Lu-PSMA-617. Long-term toxicity studies in healthy, immunocompetent CD-1 mice revealed kidney as the dose-limiting organ. Conclusion:203Pb-L1-203Pb-L5 demonstrated favorable pharmacokinetics for 212Pb-based TRT. The antitumor efficacy of 212Pb-L2 supports the corresponding 203Pb/212Pb theranostic pair for PSMA-based α-particle TRT in advanced PC.

Bioaccessibility and radioisotopes of lead in soils around a fertilizer industry in Lebanon.

The use of phosphate ore by fertilizer industries is considered a major source of soil contamination by trace metals and radionuclides. Despite its low mobility and bioavailability, lead (Pb) is among soil contaminants that pose a serious risk to human health. This study evaluates the potential impact of a fertilizer factory in North Lebanon on the total content of Pb and the activity concentration of its radioisotopes in residential, non-agricultural lands around the industry, as well as its mobility and bioaccessibility in soil samples collected at different depths. Chemical extractions by EDTA and in vitro physiologically based extraction test were used to estimate, respectively, the available and bioaccessible fractions of Pb in soils. Radioisotopes 214Pb, 212Pb and 210Pb have been analyzed by gamma spectrometry. Different physicochemical soil parameters, such as pH, carbonate content, electrical conductivity, cation exchange capacity, clay, total nitrogen and redox potential, were studied. The pseudo-total Pb varied between 12.8 and 68.5 mg kg-1, while the extractable fractions were more variable, between 12 and 72% of total Pb concentration for the EDTA extracted fraction and up to 28.5% for the bioaccessible fractions. The processing of the data shows the decreases with depth in most sites of the total and available Pb and of the activity concentration of 210Pb and their positive correlations with total nitrogen. These variations and relationships with the location of studied sites show the influence of emissions from the factory or the transport of ore and by-products. The correlations between available and bioaccessible Pb on one hand, between available Pb and 210Pb on another hand, raise the question of health risk assessments taking into account the bioaccessibility of Pb and its radioisotopes.

Automated cassette-based production of high specific activity [203/212Pb]peptide-based theranostic radiopharmaceuticals for image-guided radionuclide therapy for cancer.

A method for preparation of Pb-212 and Pb-203 labeled chelator-modified peptide-based radiopharmaceuticals for cancer imaging and radionuclide therapy has been developed and adapted for automated clinical production. Pre-concentration and isolation of radioactive Pb2+ from interfering metals in dilute hydrochloric acid was optimized using a commercially-available Pb-specific chromatography resin packed in disposable plastic columns. The pre-concentrated radioactive Pb2+ is eluted in NaOAc buffer directly to the reaction vessel containing chelator-modified peptides. Radiolabeling was found to proceed efficiently at 85°C (45min; pH 5.5). The specific activity of radiolabeled conjugates was optimized by separation of radiolabeled conjugates from unlabeled peptide via HPLC. Preservation of bioactivity was confirmed by in vivo biodistribution of Pb-203 and Pb-212 labeled peptides in melanoma-tumor-bearing mice. The approach has been found to be robustly adaptable to automation and a cassette-based fluid-handling system (Modular Lab Pharm Tracer) has been customized for clinical radiopharmaceutical production. Our findings demonstrate that the Pb-203/Pb-212 combination is a promising elementally-matched radionuclide pair for image-guided radionuclide therapy for melanoma, neuroendocrine tumors, and potentially other cancers.

Production and in vivo imaging of (203)Pb as a surrogate isotope for in vivo (212)Pb internal absorbed dose studies.

(212)Pb is a clinically relevant therapeutic alpha emitter isotope. A surrogate, (203)Pb, if prepared with sufficiently high specific activity could be used to estimate (212)Pb in vivo absorbed doses. An improved production procedure of (203)Pb with a simple, new separation method and high specific radioactivity for imaging is reported. We determined the in-vivo biodistribution of (203)Pb in mice by SPECT/CT. This highlights application possibilities of (203)Pb for further in vivo and clinical uses (radiolabeled (212)Pb-peptide co-injection, dosimetry calculation).

Influence of submarine groundwater discharge on (210)Po and (210)Pb bioaccumulation in fish tissues.

This study presents the results of the accumulation of (210)Po and (210)Pb in fish tissues and organs in a brackish-water marshland that is characterized by high concentrations of (222)Rn and (226)Ra supplied by submarine groundwater discharge (SGD). Tissues and organs from Cyprinus carpio, Chelon labrosus and Carassius auratus in the wetland were significantly enriched by both (210)Pb and (210)Po (up to 55 and 66 times, respectively) compared to blanks. The major input route of (210)Pb and (210)Po into the fish body seems to be through ingestion, due to the high levels of (210)Pb and (210)Po found in the gut content as well as in organs involved in digestion and metabolism (i.e. gut, kidney and hepatopancreas). Results showed that (210)Po was more accumulated in all fish tissues and organs except for the spine, which showed a higher affinity for (210)Pb, due to its capacity to replace Ca from apatite in bones. Over all the variables analyzed, fish tissues/organs and, secondarily, fish species were the most important factors explaining the concentration of radionuclides, whereas fish length and the sampling location played a minor role. The relationship of the two radionuclides varied markedly among tissues and their concentration levels were only correlated in gills, gut and, marginally, in spines. In general, the highest values of (210)Pb and (210)Po concentrations in tissues were found on C. labrosus tissues rather C. auratus and C. carpio. This study demonstrates that inputs of natural radionuclides supplied by SGD to coastal semi-enclosed areas (such as marshlands, lagoons or ponds) may significantly increase the contents of (210)Pb and (210)Po in fish tissues/organs. Thus, this study represents one of the first evidences of direct ecological effects derived from SGD.

PET and SPECT Imaging for the Acceleration of Anti-Cancer Drug Development.

Lead-compound optimization is an iterative process in the cancer drug development pipeline, in which small molecule inhibitors or biological compounds that are selected for their ability to bind specific targets are synthesised, tested and optimised. This process can be accelerated significantly using molecular imaging with nuclear medicine techniques, which aim to monitor the biodistribution and pharmacokinetics of radiolabelled versions of compounds. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can be used to quantify fourdimensional (temporal and spatial) clinically relevant information, to demonstrate tumor uptake of, and monitor the response to treatment with lead-compounds. This review discusses the pre-clinical and clinical value of the information provided by nuclear medicine imaging compared to the histological analysis of biopsied tissue samples. Also, the role of nuclear medicine imaging is discussed with regard to the assessment of the treatment response, radiotracer biodistribution, tumor accumulation, toxicity, and pharmacokinetic parameters, with mention of microdosing studies, pre-targeting strategies, and pharmacokinetic modelling.

Pharmacokinetics and imaging of 212Pb-TCMC-trastuzumab after intraperitoneal administration in ovarian cancer patients.

PURPOSE: Study distribution, pharmacokinetics, and safety of intraperitoneal (IP) 212Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy. EXPERIMENTAL DESIGN: IP 212Pb-TCMC-trastuzumab was delivered, after 4 mg/kg intravenous (IV) trastuzumab, to 3 patients with HER-2-expressing cancer who had failed standard therapies. Patients were monitored for toxicity and pharmacokinetics/dosimetry parameters. RESULTS: Imaging studies after 0.2 mCi/m2 (7.4 MBq/m2) show little redistribution out of the peritoneal cavity and no significant uptake in major organs. Peak blood level of the radiolabeled antibody, determined by decay corrected counts, was <23% injected dose at 63 hours; maximum blood radioactivity concentration was 6.3nCi/mL at 18 hours. Cumulative urinary excretion was ≤6% in 2.3 half-lives. The maximum external exposure rate immediately post-infusion at skin contact over the abdomen averaged 7.67 mR/h and dropped to 0.67 mR/h by 24 hours. The exposure rates at the other positions monitored (axilla, chest, and femur) decreased as a function of distance from the abdomen. The data points correlate closely with 212Pb physical decay (T1/2=10.6 hours). Follow-up >6 months showed no evidence of agent-related toxicity. CONCLUSIONS: Pharmacokinetics and imaging after 0.2 mCi/m2 IP 212Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy showed minimal distribution outside the peritoneal cavity, ≤6% urinary excretion, and good tolerance.

Using tobacco plants as biomonitors of contaminated norm areas.

One of the largest biomonitoring tasks is the assessing and environment monitoring of radiological wastes produced by mining. Po-210 and Pb-210 are easy to mobilise even in a weak acidic medium and as we know the biological behaviour and accumulation capacity of tobacco, this could be a suitable option for biomonitoring. During our work the Pb-210 and Po-210 concentration values of tobacco parts and soil samples originating from a Hungarian remediated uranium mine site were determined. The source preparation was spontaneous deposition following combined acidic leaching with a Po-209 tracer; the detection was carried out with a semiconductor ('PIPS') detector alpha-spectrometer. According to the results for the tobacco plant parts and soil samples, secular equilibrium could be found between the Pb-210 and Po-210 isotopes, and the isotope content of the lower leaves of the tobacco plants was in correlation with the isotope concentration of the soil; therefore, the measurement of the activity concentration is suitable for tracing smaller levels of washing out. The Po-210 activity concentration values of tobacco (average: 15.5 ± 3.6 Bq kg(-1)) and soil (average: 60.1 ± 15.2 Bq kg(-1)) samples originating from the area investigated compared with samples from another part of Hungary, Balatonalmádi (tobacco: 12.5 ± 1.0 Bq kg(-1), soil: 57.0 ± 4.7 Bq kg(-1)), do not show significant radionuclide migration.

Radionuclides in marine mammals off the Portuguese coast.

Radionuclide analyses were performed in tissue samples including muscle, gonad, liver, mammary gland, and bone of marine mammals stranded on the Portuguese west coast during January-July 2006. Tissues were collected from seven dolphins (Delphinus delphis and Stenella coeruleoalba) and one pilot whale (Globicephala sp.). Samples were analyzed for (210)Po and (210)Pb by alpha spectrometry and for (137)Cs and (40)K by gamma spectrometry. Po-210 concentrations in common dolphin's muscle (D. delphis) averaged 56 ± 32 Bq kg(-1) wet weight (w.w.), while (210)Pb averaged 0.17 ± 0.07 Bq kg(-1) w.w., (137)Cs averaged 0.29 ± 0.28 Bq kg(-1) w.w., and (40)K 129 ± 48 Bq kg(-1) w.w. Absorbed radiation doses due to these radionuclides for the internal organs of common dolphins were computed and attained a 1.50 µGy h(-1) on a whole body basis. (210)Po was the main contributor to the weighted absorbed dose, accounting for 97% of the dose from internally accumulated radionuclides. These computed radiation doses in dolphins are compared to radiation doses from (210)Po and other radionuclides reported for human tissues. Due to the high (210)Po activity concentration in dolphins, the internal radiation dose in these marine mammals is about three orders of magnitude higher than in man.

Factors affecting 210Po and 210Pb activity concentrations in mussels and implications for environmental bio-monitoring programmes.

The activity of (210)Po and (210)Pb was determined in mussels of the same size (3.5-4.0 cm shell length) sampled monthly over a 17-month period at the Atlantic coast of Portugal. Average radionuclide concentration values in mussels were 759±277 Bq kg(-1) for (210)Po (range 460-1470 Bq kg(-1) dry weight), and 45±19 Bq kg(-1) for (210)Pb (range 23-96 Bq kg(-1) dry weight). Environmental parameters and mussel biometric parameters were monitored during the same period. Although there was no seasonal variation of radionuclide concentrations in sea water during the study period, the concentration of radionuclide activity in mussels varied seasonally displaying peaks of high concentrations in winter and low concentrations in summer. Analysis of radionuclide data in relation to the physiological Condition Index of mussels revealed that (210)Po and (210)Pb activities in the mussel (average activity per individual) remained nearly constant during the investigation period, while mussel body weight fluctuated due to fat storage/expenditure in the soft tissues. Similar variation of radionuclide concentrations was observed in mussels transplanted from the sea coast into the Tejo Estuary. However, under estuarine environmental conditions and with higher food availability throughout the year, transplanted mussel Condition Index was higher than in coastal mussels and average radionuclide concentrations were 210±75 Bq kg(-1) (dry weight) for (210)Po and 10±4 Bq kg(-1) (dry weight) for (210)Pb, therefore lower than in coastal mussels with similar shell length. It is concluded that the apparent seasonal fluctuation and inter-site difference of radionuclide concentrations were mostly caused by mussel body weight fluctuation and not by radionuclide body burden fluctuation. This interpretation can be extended to the apparent seasonal fluctuation in concentrations of lipophilic and lipophobic contaminants in mussels, and provides an explanation for occasional high concentrations of (210)Po and man-made contaminants measured in mussels far from pollution sources.

Levels and transfer of 210Po and 210Pb in Nordic terrestrial ecosystems.

Recent developments regarding environmental impact assessment methodologies for radioactivity have precipitated the need for information on levels of naturally occurring radionuclides within and transfer to wild flora and fauna. The objectives of this study were therefore to determine activity concentrations of the main dose forming radionuclides (210)Po and (210)Pb in biota from terrestrial ecosystems thus providing insight into the behaviour of these radioisotopes. Samples of soil, plants and animals were collected at Dovrefjell, Central Norway and Olkiluoto, Finland. Soil profiles from Dovrefjell exhibited an approximately exponential fall in (210)Pb activity concentrations from elevated levels in humus/surface soils to "supported" levels at depth. Activity concentrations of (210)Po in fauna (invertebrates, mammals, birds) ranged between 2 and 123 Bq kg(-1)d.w. and in plants and lichens between 20 and 138 Bq kg(-1)d.w. The results showed that soil humus is an important reservoir for (210)Po and (210)Pb and that fauna in close contact with this media may also exhibit elevated levels of (210)Po. Concentration ratios appear to have limited applicability with regards to prediction of activity concentrations of (210)Po in invertebrates and vertebrates. Biokinetic models may provide a tool to explore in a more mechanistic way the behaviour of (210)Po in this system.

Distribution and biokinetic analysis of 210Pb and 210Po in poultry due to ingestion of dicalcium phosphate.

Dicalcium phosphate (DCP) is used as a calcium supplement for food producing animals (i.e., cattle, poultry and pig). When DCP is produced via wet acid digestion of the phosphate rock and depending on the acid used in the industrial process, the final product can result in enhanced (210)Pb and (210)Po specific activities (approximately 2000 Bq.kg(-1)). Both (210)Pb and (210)Po are of great interest because their contribution to the dose received by ingestion is potentially large. The aims of this work are to examine the accumulation of (210)Pb and (210)Po in chicken tissues during the first 42 days of life and to build a suitable single-compartment biokinetic model to understand the behavior of both radionuclides within the entire animal using the experimental results. Three commercial corn-soybean-based diets containing different amounts and sources of DCP were fed to broilers during a period of 42 days. The results show that diets containing enhanced concentrations of (210)Pb and (210)Po lead to larger specific accumulation in broiler tissues compared to the blank diet. Radionuclides do not accumulate homogeneously within the animal body: (210)Pb follows the calcium pathways to some extent and accumulates largely in bones, while (210)Po accumulates to a large extent in liver and kidneys. However, the total amount of radionuclide accumulation in tissues is small compared to the amounts excreted in feces. The single-compartment non-linear biokinetic model proposed here for (210)Pb and (210)Po in the whole animal takes into account the size evolution and is self-consistent in that no fitting parameterization of intake and excretions rates is required.

Biokinetics of Hg and Pb accumulation in the encapsulated egg of the common cuttlefish Sepia officinalis: radiotracer experiments.

Uptake and depuration kinetics of dissolved (203)Hg and (210)Pb were determined during the entire embryonic development of the eggs of the cuttlefish, Sepia officinalis (50d at 17 degrees C). (203)Hg and (210)Pb were accumulated continuously by the eggs all along the development time reaching load/concentration ratio (LCR) of 467+/-43 and 1301+/-126g, respectively. During the first month, most of the (203)Hg and (210)Pb remained associated with the eggshell indicating that the latter acted as an efficient shield against metal penetration. From this time onwards, (203)Hg accumulated in the embryo, indicating that it passed through the eggshell, whereas (210)Pb did not cross the chorion during the whole exposure time. It also demonstrated that translocation of Hg associated with the inner layers of the eggshell is a significant source of exposure for the embryo. This study highlighted that the maturing embryo could be subjected to the toxic effects of Hg in the coastal waters where the embryonic development is taking place.

Local control of lung derived tumors by diffusing alpha-emitting atoms released from intratumoral wires loaded with radium-224.

PURPOSE: Diffusing alpha-emitters radiation therapy (DART) is a new form of brachytherapy enabling the treatment of solid tumors with alpha radiation. The present study examines the antitumoral effects resulting from the release of alpha emitting radioisotopes into solid lung carcinoma (LL2, A427, and NCI-H520). METHODS AND MATERIALS: An in vitro setup tested the dose-dependent killing of tumor cells exposed to alpha particles. In in vivo studies, radioactive wires (0.3 mm diameter, 5 mm long) with (224)Ra activities in the range of 21-38 kBq were inserted into LL/2 tumors in C57BL/6 mice and into human-derived A427 or NCI-H520 tumors in athymic mice. The efficacy of the short-lived daughters of (224)Ra to produce tumor growth retardation and prolong life was assessed, and the spread of radioisotopes inside tumors was measured using autoradiography. RESULTS: The insertion of a single DART wire into the center of 6- to 7-mm tumors had a pronounced retardation effect on tumor growth, leading to a significant inhibition of 49% (LL2) and 93% (A427) in tumor development and prolongations of 48% (LL2) in life expectancy. In the human model, more than 80% of the treated tumors disappeared or shrunk. Autoradiographic analysis of the treated sectioned tissue revealed the intratumoral distribution of the radioisotopes, and histological analysis showed corresponding areas of necrosis. In vitro experiments demonstrated a dose-dependent killing of tumors cells exposed to alpha particles. CONCLUSIONS: Short-lived diffusing alpha-emitters produced tumor growth retardation and increased survival in mice bearing lung tumor implants. These results justify further investigations with improved dose distributions.

(212)Pb@C(60) and its water-soluble derivatives: synthesis, stability, and suitability for radioimmunotherapy.

Fullerenes could potentially play a valuable role in radioimmunotherapy by more stably encapsulating radionuclides, especially where conventional chelation chemistry is inadequate due to the physical and/or chemical properties of the radionuclide. One of the therapeutically useful radionuclides that requires improved containment in vivo is 212Pb (tau1/2 = 10.6 h), the beta-emitting parent to alpha-emitting 212Bi (tau1/2 = 60.6 min). Myelotoxicity resulting from the accumulation of 212Pb in the bone marrow has limited the use of this radionuclide despite its favorable decay characteristics. In this work, 212Pb@C60 and its malonic ester derivatives were prepared for the first time by allowing the 212Pb to recoil into C60 following alpha-decay from its parent, 0.15-s 216Po, generated in situ from the decay of 224Ra (tau1/2 = 15 days). Repeated washing of the organic phase containing the 212Pb@C60 malonic esters with challenge solutions containing cold Pb2+ ions demonstrated that some of the 212Pb could not be exchanged and was apparently inside of the fullerenes. Malonic esters of endohedral alpha-emitting 213Bi (tau1/2 = 45 min) fullerenes were prepared by an analogous procedure. Following acidification of the esters, a preliminary biodistribution study in mice was performed with the untargeted water-soluble radiofullerenes. It was found that 212Pb did not accumulate in bone after being administered as an endohedral fullerene, in contrast to results with polyhydroxylated radiofullerenes and conventional polyaminocarboxylate chelators for 212Pb. The results indicate that 212Pb is held more tightly in the fullerene than in other methods and suggest that fullerenes may have an important role in the targeted delivery of 212Pb.

Pretargeted radioimmunotherapy in tumored mice using an in vivo 212Pb/212Bi generator.

OBJECTIVE: Pretargeting is the concept that combines optimal delivery of the antibody and rapid capture and elimination of the radioactivity. In this study, we evaluated the potential of antibody pretargeting to enable the tumor-targeting (212)Pb for in vivo generation of (212)Bi for alpha particle radiotherapy. METHODS: The (212)Pb/(212)Bi chelate of DOTA-biotin, as well as their gamma-emitting analogues, (203)Pb and (205)Bi, was prepared and characterized. The radiolabeled compounds were injected in animals for evaluation of tumor targeting and normal tissue uptake and retention. In the pretargeting protocol, injection of 400 microg of NR-LU-10 antibody-streptavidin conjugate was given at t = 0 h, then 100 microg of N-acetyl-galatosamine-biotin clearing agent was injected at t = 20-24 h; finally, 1 microg of (212)Pb/(212)Bi-DOTA-biotin was injected 6 h later. RESULTS: Both (203)Pb and (205)Bi-DOTA-biotin were stable for at least 4 days in the different challenging solutions including PBS, 10 mM DTPA and serum. Contrary to its gamma-emitting analogues, radiolabeled (212)Pb-DOTA-biotin was not stable. There was greater than 30% of free (212)Bi released 4 h after (212)Pb-labeled DOTA-biotin. The results of pretargeting protocol of (203)Pb and (205)Bi-DOTA-biotin showed that the tumor target reached 20% injected dose (ID)/g at 4 h postinjection and remained high for 5 days. The %ID/g in the whole blood and other nontarget organs was low after administration of labeled (203)Pb and (205)Bi-DOTA-biotin similar to the biodistribution of labeled DOTA-biotin alone. In the animals administered (212)Pb-DOTA-biotin, radioactivity in nontarget organs was low except the kidneys. The %ID/g in the kidney for (212)Bi was 14.5 at 2 h, higher than (212)Pb, but dropped to about 6% ID/g by 4 h. However, tumor uptake for (212)Pb and (212)Bi was >25% ID/g at 1 h postinjection and remained so through 24 h. CONCLUSIONS: Antibody pretargeting system with Mab-streptavidin, clearing agent and DOTA-biotin provides the potential of (212)Bi for solid tumor radiotherapy despite the release of (212)Bi after (212)Pb decay. Dosimetry calculations resulted in tumor dose at 93 rad/muCi and ratios of tumor to marrow and kidney at 386:1 and 12:1, respectively.

Purification of cyclotron-produced 203Pb for labeling Herceptin.

A simple and rapid procedure was developed for the purification of cyclotron-produced 203Pb via the 203Tl(d,2n) 203Pb reaction. A Pb(II) selective ion-exchange resin, with commercial name Pb Resin from Eichrom Technologies, Inc., was used to purify 203Pb from the cyclotron-irradiated Tl target with excellent recovery of the enriched Tl target material. The purified 203Pb was used to radiolabel the monoclonal antibody Herceptin. The in vitro and in vivo properties of the 203Pb radioimmunoconjugate were evaluated.

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.

Estimation of human exposure to natural radionuclides using in vivo skull measurements.

In a preliminary study, in vivo skull measurements and in vitro urine measurements of 210Pb and nulU have been performed to find out the individual, chronic exposure to waterborne natural radionuclides of a small group of Finnish people. For their domestic water, the studied individuals use water from drilled wells containing elevated concentrations of natural uranium and its daughter nuclides ((234,235,238)U, 222Rn, (226,228)Ra, 210Po, 210Pb). Enhanced 210Pb and 235U activities were observed in several people. A positive correlation is observed between the U concentration in urine (microg d(-1)) and the number of counts (cpm) in the gamma ray energy peaks originating from the decay of 235U and 234Th respectively. Calibration of the detector set-up and the determination of background sources are in progress.

Historical changes in lead concentrations in tree-rings of sycamore, oak and Scots pine in north-west England.

Lead concentrations in tree rings of sycamore (Acer pseudoplatanus L.), oak (Quercus robur L.) and Scots pine (Pinus sylvestris L.) sampled at a parkland in north-west England were measured in wood formed since the mid-1800s. Concentrations of Pb in Scots pine and oak peaked in wood formed between 1900 and 1940, most likely because of Pb accumulation in heartwood, indicating that oak and Scots pine are unsuitable for monitoring temporal changes in Pb deposition at the study site. In contrast, Pb concentrations in sycamore, a species that has similar heartwood and sapwood chemistry, were relatively constant in wood formed between the mid-1800s and 1950. Lead concentrations decreased steadily in sycamore tree rings formed after the 1950s, and decreased more abruptly in wood formed after 1985. This sharp decrease in wood Pb cannot be due to decreases in soil Pb concentration. Stable Pb isotope analysis was used to further investigate Pb patterns in sycamore wood. Excess 206Pb/207Pb ratios in tree-rings of sycamore were relatively constant, approximately 1.17, in wood formed prior to the 1930s, but decreased steadily thereafter reaching a minimum value of approximately 1.16 in wood formed between 1975 and 1985 after which time 206Pb/207Pb ratios increased. This pattern is consistent with changes in Pb isotope ratios measured in peat, sediment and aerosol samples in the UK. However, the magnitude of the decrease in 206Pb/207Pb (largely due to gasoline Pb) is considerably lower than in other studies and our estimates indicate that less than 20% of the total Pb in sycamore wood measured since the mid-1800s is derived from gasoline emissions. A more likely explanation for the pattern of Pb observed in sycamore tree rings is that soil Pb accumulates within rings of the diffuse porous wood over a number of years. Such uptake patterns would result in lower Pb concentrations in the outer (more recently formed) tree rings, which coincide with recent reductions in Pb deposition in the UK. Overall, this study indicates that tree ring chemistry is unsuitable for monitoring historical changes in Pb deposition at the study site.