Biologic monitoring and surveillance results for the department of veterans affairs' depleted uranium cohort: Lessons learned from sustained exposure over two decades.

BACKGROUND: A small group of Gulf War I veterans wounded in depleted uranium (DU) friendly fire incidents have been monitored in a clinical surveillance program at the Veterans Affairs Medical Center, Baltimore since 1994. METHODS: An in-patient clinical surveillance protocol was performed on 35 members of the cohort, including exposure monitoring for total and isotopic uranium concentrations in urine and a comprehensive assessment of health outcomes. RESULTS: Although urine U concentrations continue to be elevated in this group, illustrating on-going in situ mobilization of U from embedded fragments, no consistent U-related health effects have been observed. CONCLUSIONS: Now more than 20 years since first exposure to DU, an aging cohort of military veterans continues to show no U-related health effects in known target organs of U toxicity. As tissue concentrations continue to accrue with exposure duration, critical tissue-specific U concentration thresholds may be reached, thus recommending on-going surveillance of this veteran cohort.

In vivo skin penetration and metabolic path of quantum dots.

The skin is the largest organ of the body and is a potential route of exposure to sunscreens and cosmetics containing nanoparticles; however, the permeability of the skin to these nanoparticles is currently unknown. In this paper, we studied the transdermal delivery capacity through mouse skin of water-soluble CdSeS quantum dots (QDs) and the deposition of these QDs in the body. QD solution was coated onto the dorsal hairless skin of male ICR mice. Fluorescence microscopy and transmission electron microscopy (TEM) were used to observe the distribution of QDs in the skin and organs, and inductively coupled plasma-mass spectrometry (ICP-MS) was used to measure the (111)Cd content to indicate the concentration of QDs in plasma and organs. Experimental results indicate that QDs can penetrate into the dermal layer and are limited to the uppermost stratum corneum layers and the hair follicles. Through blood circulation, QDs deposit mostly in liver and kidney and are difficult to clear. (111)Cd concentration was greater than 14 ng g(-1) in kidney after 120 h after 0.32 nmol QDs was applied to a mouse. These results suggest that QDs have in vivo transdermal delivery capacity through mouse skin and are harmful to the liver and kidney.

Identification of sources of lead exposure in French children by lead isotope analysis: a cross-sectional study.

BACKGROUND: The amount of lead in the environment has decreased significantly in recent years, and so did exposure. However, there is no known safe exposure level and, therefore, the exposure of children to lead, although low, remains a major public health issue. With the lower levels of exposure, it is becoming more difficult to identify lead sources and new approaches may be required for preventive action. This study assessed the usefulness of lead isotope ratios for identifying sources of lead using data from a nationwide sample of French children aged from six months to six years with blood lead levels ≥25 µg/L. METHODS: Blood samples were taken from 125 children, representing about 600,000 French children; environmental samples were taken from their homes and personal information was collected. Lead isotope ratios were determined using quadrupole ICP-MS (inductively coupled plasma - mass spectrometry) and the isotopic signatures of potential sources of exposure were matched with those of blood in order to identify the most likely sources. RESULTS: In addition to the interpretation of lead concentrations, lead isotope ratios were potentially of use for 57% of children aged from six months to six years with blood lead level ≥ 25 µg/L (7% of overall children in France, about 332,000 children), with at least one potential source of lead and sufficiently well discriminated lead isotope ratios. Lead isotope ratios revealed a single suspected source of exposure for 32% of the subjects and were able to eliminate at least one unlikely source of exposure for 30% of the children. CONCLUSIONS: In France, lead isotope ratios could provide valuable additional information in about a third of routine environmental investigations.

Differential uptake and oxidative stress response in zebrafish fed a single dose of the principal copper and zinc enriched sub-cellular fractions of Gammarus pulex.

The sub-cellular compartmentalisation of trace metals and its effect on trophic transfer and toxicity in the aquatic food chain has been a subject of growing interest. In the present study, the crustacean Gammarus pulex was exposed to either 11 microg Cu l(-1), added solely as the enriched stable isotope 65Cu, or 660 microg Zn l(-1), radiolabeled with 2MBq (65)Zn, for 16 days. Post-exposure the heat stable cytosol containing metallothionein-like proteins (MTLP) and a combined granular and exoskeletal (MRG+exo) fractions were isolated by differential centrifugation, incorporated into gelatin and fed to zebrafish as a single meal. Assimilation efficiency (AE) and intestinal lipid peroxidation, as malondialdehyde (MDA) were measured. There was a significant difference (p<0.05) between the retention of the MTLP-Zn (39.0+/-6.4%) and MRG+exo-Zn (17.2+/-3.7%) and of this zinc retained by the zebrafish a significantly greater proportion of the MTLP-Zn feed had been transported away from the site of uptake. For 65Cu, although the results pointed towards greater bioavailability of the MTLP fraction compared to MRG+exo during the slow elimination phase (24-72 h) these results were not significant (p=0.155). Neither zinc feed provoked a lipid peroxidation response in the intestinal tissue of zebrafish compared to control fish (gelatin fed), but both 65Cu labeled feeds did. The greater effect was exerted by the MRG+exo (2.96+/-0.29 nmol MDA mg protein(-1)) feed which three-fold greater than control (p<0.01) and almost twice the MDA concentration of the MTLP feed (1.76+/-0.21 nmol MDA mg protein(-1), p<0.05). The oxidative stress response produced by Zn and Cu is in keeping with their respective redox potentials; Zn being oxidatively inert and Cu being redox active. These results are similar, in terms of bioavailability and stress response of each feed, to those in our previous study in which 109Cd labeled G. pulex fractions were fed to zebrafish. Thus it appears that when a metal (Cu or Cd) has the potential to cause cytotoxicity via lipid peroxidation, a feed consisting of a largely unavailable fraction (MRG+exo) causes a greater intestinal stress response than the more bioavailable (MTLP) feed.

Progress in the use of gadolinium for NCT.

The evaluation of possible improvement in the use of Gd in cancer therapy, in reference to gadolinium in cancer therapy (GdNCT), has been analysed. At first the problem of the gadolinium compounds toxicity was reviewed identifying the Motexafin Gadolinium as the best. Afterwards, the spectrum of IC and Auger electrons was calculated using a special method. Afterwards, this electron source has been used as input of the PENELOPE code and the energy deposit in DNA was well defined. Taking into account that the electron yield and energy distribution are related to the neutron beam spectrum and intensity, the shaping assembly architecture was optimised through computational investigations. Finally the study of GdNCT was performed from two different points of view: macrodosimetry using MCNPX, with calculation of absorbed doses both in tumour and healthy tissues, and microdosimetry using PENELOPE, with the determination of electron RBE through the energy deposit. The equivalent doses were determined combining these two kinds of data, introducing specific figures of merit to be used in treatment planning system (TPS). According to these results, the GdNCT appears to be a fairly possible tumour therapy.

Lead/cadmium contamination and lead isotopic ratios in vegetables grown in peri-urban and mining/smelting contaminated sites in Nanjing, China.

Lead/cadmium contamination in vegetables grown in peri-urban area of Nanjing, China was assessed and the route for metals entering into plants was investigated through lead isotopic tracing. Results show that agricultural soils have been polluted with Cd. Contents of Pb (22.1-37.5 mg kg(-1 )dw) and Cd (2.53-4.19 mg kg(-1) dw) in vegetables' edible parts nearby a lead/zinc mining/smelting plant were beyond their maximum allowable limit prescribed in the (EC) No 1881/2006. Pb isotope ratios in plants differed from those in the corresponding soils, suggesting that soils were not the only contamination source of Pb and Cd in plants.

Evaluation of the genotoxic effects of the boron neutron capture reaction in human melanoma cells using the cytokinesis block micronucleus assay.

The present work reports on the genotoxicity of the boron neutron capture (BNC) reaction in human metastatic melanoma cells (A2058) assessed by the cytokinesis block micronucleus assay (CBMN) using p-borono-L-phenylalanine (BPA) as the boron delivery agent. Different concentrations of BPA (0.48, 1.2 and 2.4 mM) and different fluences of thermal neutrons were studied. Substantial genotoxic potential of alpha and lithium particles generated inside or near the malignant cell by the BNC reaction was observed in a dose-response manner as measured by the frequency of micronucleated binucleated melanoma cells and by the number of micronuclei (MN) per binucleated cell. The distribution of the number of MN per micronucleated binucleated cell was also studied. The BNC reaction clearly modifies this distribution, increasing the frequency of micronucleated cells with 2 and, especially, > or =3 MN and conversely decreasing the frequency of micronucleated cells with 1 MN. A decrease in cell proliferation was also observed which correlated with MN formation. A discrete genotoxic and anti-proliferative contribution from both thermal neutron irradiation and BPA was observed and should be considered secondary. Additionally, V79 Chinese hamster cells (chromosomal aberrations assay) and human lymphocytes (CBMN assay) incubated with different concentrations of BPA alone did not show any evidence of genotoxicity. The presented results reinforce the usefulness of the CBMN assay as an alternative method for assessment of the deleterious effects induced by high LET radiation produced by the BNC reaction in human melanoma cells.

Stable isotopes in pharmacology studies: present and future.

Stable-isotope techniques offer advantages over older methods in safety, sensitivity, specificity, and reduction in numbers of subjects required and analytic determinations for some types of pharmacology studies. In addition to their use as internal standards in gas chromatography-mass spectrometry analytic methods, stable isotopes have been successfully employed in studies of absorption, bioavailability, distribution, biotransformation, excretion, metabolite identification, time-dependent and dose-dependent pharmacokinetic changes, drug interactions, pharmacologic changes during pregnancy, mutagenicity, and teratogenicity.

Embryotoxicity of stable isotopes and use of stable isotopes in studies of teratogenetic mechanisms.

Experiments on teratogenic effects of stable isotopes from our own and other laboratories are evaluated. In the first series of investigations, the enrichment of the stable isotope 13C derived from U-13C-glucose was studied in mouse embryos at various stages of development, including limb buds in organ culture. Preimplantation mouse embryos incubated in vitro in 13C-enriched medium for 48 hours showed normal development during subsequent differentiation in vitro and also in vivo after embryo transfer to faster mothers. These embryos were 15% to 20% enriched in 13C. Administration of U-13-C-glucose to pregnant mice during organogenesis led to an increase of the absolute 13C content of the embryo for several days after the end of isotope administration, whereas the enrichment in maternal tissue decreased. No alterations of embryonic development were detected due to stable isotope enrichment. Development of cultured mouse limb buds was unaffected by incubation with 82 mol% U-13C-glucose as judged from morphologic and biochemical criteria. The second part of the article describes the value of deuterium-labeled drugs as probes into the mechanism of activation of teratogenic metabolites. A comparison of the pharmacokinetics as well as the teratogenicity between cyclophosphamide and some specific deuterium-labeled analogues showed that the isotope effect observed can be related to a particular metabolic pathway crucial for teratogenic activation by this drug.

The application of stable isotopes in biomedical research.

Many of the ways in which isotopes are used in biomedical research are reviewed. The use of stable isotopes in stable isotope dilution assays, for metabolite identification and in pharmacokinetic studies, is discussed and relevant examples are given to illustrate the various points made. Isotope effects and their implications for future drug design are considered. Some of the toxicity problems associated with the use of stable isotopes are also considered. Finally, a brief subjective view of possible future advances is made.