Investigation of Cytotoxicity, Oxidative Stress, and Inflammatory Responses of Tantalum Nanoparticles in THP-1-Derived Macrophages.

Tantalum (Ta) is gaining attention as a biomaterial in bone tissue engineering. Although the clinical advantage of Ta-based implants for primary and revision total joint replacement (TJA) has been well documented, few studies investigated the effect of wear products of Ta implants on peri-implant cells, and their potential contribution to aseptic implant loosening. This study is aimed at examining the cytotoxicity, oxidative stress, and proinflammatory potential of Ta and TiO2 nanoparticles (NPs) on macrophages in vitro. NPs were characterized using scanning electron microscopy, dynamic light scattering, and energy-dispersive X-ray. To test the NP-mediated cellular response in macrophages, THP-1-derived macrophages were challenged with both NPs, and cytotoxicity was analyzed using CCK-8 and LDH assays. Flow cytometry was used to investigate particle uptake and their internalization routes. NP-mediated oxidative stress was investigated by measuring the production of reactive oxygen species, and their proinflammatory potential was determined by quantifying the production of TNFα and IL-1ß in cell culture supernatants using ELISA. We found that both Ta and TiO2 NPs were taken up through actin-dependent phagocytosis, although TiO2 NPs did also show some involvement of macropinocytosis and clathrin-mediated endocytosis. Ta NPs caused no apparent toxicity, while TiO2 NPs demonstrated significant cytotoxicity at a concentration of over 100µg/mL at 24 h. Ta NPs induced negligible ROS generation and proinflammatory cytokines (TNFα, IL-1ß) in macrophages. In contrast, TiO2 NPs markedly induced these effects in a dose-dependent manner. Our findings indicate that Ta NPs are inert, nontoxic, and noninflammatory. Therefore, Ta could be considered an excellent biomaterial in primary and revision joint arthroplasty implants.

Nanolamellar Tantalum Interfaces in the Osteoblast Adhesion.

The design of topographically patterned surfaces is considered to be a preferable approach for influencing cellular behavior in a controllable manner, in particular to improve the osteogenic ability of bone regeneration. In this study, we fabricated nanolamellar tantalum (Ta) surfaces with lamellar wall thicknesses of 40 and 70 nm. The cells attached to nanolamellar Ta surfaces exhibited higher protein adsorption and expression of ß1 integrin, as compared to the nonstructured bulk Ta, which facilitated the initial cell attachment and spreading. We thus, as expected, observed significantly enhanced osteoblast adhesion, growth, and alkaline phosphatase activity on nanolamellar Ta surfaces. However, the beneficial effects of nanolamellar structures on osteogenesis became weaker as the lamellar wall thickness increased. The interaction between cells and Ta surfaces was examined through adhesion forces using atomic force microscopy. Our findings indicated that the Ta surface with a lamellar wall thickness of 40 nm exhibited the strongest stimulatory effect. The observed strongest adhesion force between the cell-attached tip and the Ta surface with a 40 nm thick lamellar wall encouraged the much stronger binding of cells with the surface and thus well-attached, -stretched, and -grown cells. We attributed this to the increase in the available contact area of cells with the thinner nanolamellar Ta surface. The increased contact area allowed the enhancement of the cell surface interaction strength and, thus, improved osteoblast adhesion. This study suggests that the thin nanolamellar topography shows immense potential in improving the clinical performance of dental and orthopedic implants.

Drug-Loaded Mesoporous Tantalum Oxide Nanoparticles for Enhanced Synergetic Chemoradiotherapy with Reduced Systemic Toxicity.

Combining chemotherapy and radiotherapy (chemoradiotherapy) has been widely applied in many clinical practices, showing promises in enhancing therapeutic outcomes. Nontoxic nanocarriers that not only are able to deliver chemotherapeutics into tumors, but could also act as radiosensitizers to enhance radiotherapy would thus be of great interest in the development of chemoradiotherapies. To achieve this aim, herein mesoporous tantalum oxide (mTa2 O5 ) nanoparticles with polyethylene glycol (PEG) modification are fabricated. Those mTa2 O5 -PEG nanoparticles could serve as a drug delivery vehicle to allow efficient loading of chemotherapeutics such as doxorubicin (DOX), whose release appears to be pH responsive. Meanwhile, owing to the interaction of Ta with X-ray, mTa2 O5 -PEG nanoparticles could offer an intrinsic radiosensitization effect to increase X-ray-induced DNA damages during radiotherapy. As a result, DOX-loaded mTa2 O5 -PEG (mTa2 O5 -PEG/DOX) nanoparticles can offer a strong synergistic therapeutic effect during the combined chemoradiotherapy. Furthermore, in chemoradiotherapy, such mTa2 O5 -PEG/DOX shows remarkably reduced side effects compared to free DOX, which at the same dose appears to be lethal to animals. This work thus presents a new type of mesoporous nanocarrier particularly useful for the delivery of safe and effective chemoradiotherapy.

Quaternary Ti-20Nb-10Zr-5Ta alloy during immersion in simulated physiological solutions: formation of layers, dissolution and biocompatibility.

Samples of the quaternary Ti-20Nb-10Zr-5Ta alloy were immersed in Hanks' simulated physiological solution and in minimum essential medium (MEM) for 25 days. Samples of Ti metal served as controls. During immersion, the concentration of ions dissolved in MEM was measured by inductively coupled plasma mass spectrometry, while at the end of the experiment the composition of the surface layers was analyzed by X-ray photoelectron spectroscopy, and their morphology by scanning electron microscopy equipped for chemical analysis. The surface layer formed during immersion was comprised primarily of TiO2 but contained oxides of alloying elements as well. The degree of oxidation differed for different metal cations; while titanium achieved the highest valency, tantalum remained as the metal or is oxidized to its sub-oxides. Calcium phosphate was formed in both solutions, while formation of organic-related species was observed only in MEM. Dissolution of titanium ions was similar for metal and alloy. Among alloying elements, zirconium dissolved in the largest quantity. The long-term effects of alloy implanted in the recipient's body were investigated in MEM, using two types of human cells-an osteoblast-like cell line and immortalized pulmonary fibroblasts. The in vitro biocompatibility of the quaternary alloy was similar to that of titanium, since no detrimental effects on cell survival, induction of apoptosis, delay of growth, or change in alkaline phosphatase activity were observed on incubation in MEM.

Large-scale synthesis of bioinert tantalum oxide nanoparticles for X-ray computed tomography imaging and bimodal image-guided sentinel lymph node mapping.

Ever since Au nanoparticles were developed as X-ray contrast agents, researchers have actively sought alternative nanoparticle-based imaging probes that are not only inexpensive but also safe for clinical use. Herein, we demonstrate that bioinert tantalum oxide nanoparticles are suitable nanoprobes for high-performance X-ray computed tomography (CT) imaging while simultaneously being cost-effective and meeting the criteria as a biomedical platform. Uniformly sized tantalum oxide nanoparticles were prepared using a microemulsion method, and their surfaces were readily modified using various silane derivatives through simple in situ sol-gel reaction. The silane-modified surface enabled facile immobilization of functional moieties such as polyethylene glycol (PEG) and fluorescent dye. PEG was introduced to endow the nanoparticles with biocompatibility and antifouling activity, whereas immobilized fluorescent dye molecules enabled simultaneous fluorescence imaging as well as X-ray CT imaging. The resulting nanoparticles exhibited remarkable performances in the in vivo X-ray CT angiography and bimodal image-guided lymph node mapping. We also performed an extensive study on in vivo toxicity of tantalum oxide nanoparticles, revealing that the nanoparticles did not affect normal functioning of organs.

Cytotoxicity, Oxidative Stress, and Autophagy Effects of Tantalum Nanoparticles on MC3T3-E1 Mouse Osteoblasts.

As a bone implant material, porous tantalum (Ta) has better corrosion resistance and more suitable elastic modulus than titanium. Surface nanomodification can accelerate the integration of Ta implants with bone tissue, which has broad application prospects in the field of dental implantology. Due to mechanical stress and load wear, nanoscale Ta fragments are inevitably exfoliated from the implant surface and brought into direct contact with osteoblasts surrounding the implant. These wear fragments may affect the biological characteristics of osteoblasts and thus the stability of implants. To date, the interaction of nanoscale Ta fragments with osteoblasts has not been clearly investigated. In the current study, we used the mouse osteoblast cell line MC3T3-E1 to explore the effects of Ta nanoparticles (Ta-NPs) on the cytotoxicity, oxidative stress and autophagy of osteoblasts. We found that a low concentration (12.5 µg/mL) of Ta-NPs can promote the proliferation of osteoblasts, while the Ta-NPs began to induce a decrease in cell viability at concentrations ≥25 µg/mL. Increased cell mortality, reactive oxygen species (ROS) production and decreased mitochondrial membrane potential (MMP) occurred in a dose-dependent manner after Ta-NP treatment. Moreover, with Ta-NP stimulation, the ratio of LC3-II/LC3-I increased, and the level of p62 protein was reduced. However, the degradation of p62 was not continuously increased when the concentration of Ta-NPs was ≥25 µg/mL. These results indicate that Ta-NPs induced osteoblast damage via oxidative stress. Autophagy activation may be a key factor in the cellular response to Ta-NP toxicity and could have an important impact on determining the survival or death of osteoblasts.

Surfactant-free tantalum oxide nanoparticles: synthesis, colloidal properties, and application as a contrast agent for computed tomography.

With the growing interest of the medical industry in biocompatible nanoparticles (NPs), the current synthetic methods should be adapted to appropriate demands (toxicity, scalability, etc.). Most applications require colloidal systems to be stable not only in water but also in vivo, which represents a major challenge. In this study, biocompatible Ta2O5 NPs were synthesized by a solvothermal method avoiding toxic reagents, and surfactant-free stable hydrosols were obtained and used for computed tomography (CT) imaging. The small hydrodynamic size (2 nm) and colloidal stability of primary NPs were studied by dynamic light scattering (DLS). The particles were characterized by X-ray diffraction, transmission electron microscopy, energy-dispersive X-ray spectroscopy, and Brunauer-Emmett-Teller analysis to confirm their structure and purity. To develop a stable hydrosol preparation protocol, the influence of pH and ultrasonication duration on the stability of Ta2O5 sols was analyzed by DLS and microelectrophoresis. To enhance the understanding of NP behavior in vivo, sol stability in conditions close to physiological (NaCl solutions) was studied in a pH range of 3-9. Hydrosols prepared by the proposed protocol were stable for at least 6 months and exhibited negligible cytotoxicity. Ta2O5 NPs also showed high CT contrast both in theoretical calculations and in vivo (rat gastrointestinal tract).

Cytotoxicity analysis of a novel titanium alloy in vitro: adhesion, spreading, and proliferation of human gingival fibroblasts.

A recently developed novel Ti-29Nb-13Ta-4.6Zr alloy (Ti-Ta) was investigated physically and chemically, and the results suggested it to be a possibly suitable dental material. In this study we analyzed the effects of the alloy, in comparison with those of other dental metals, on the adhesion, spreading, and proliferation of human gingival fibroblasts (Gin-1 cells) in vitro. The Gin-1 cells adhered and spread well on the Ti-Ta as well as on commercially pure titanium (Ti) and commercial Ti-6Al-7Nb alloy (Ti-Al), forming long processes showing a typical fibroblastic morphology that was close to that on glass. The proliferation of Gin-1 cells was significantly suppressed on Au-Pd-Ag alloy (Au-Pd) and commercially pure copper (Cu); however, the cells proliferated as well on Ti-Ta as they did on Ti, Ti-Al, and glass. Though most of the Gin-1 cells on Cu and about half of them on Au-Pd died after 1 day and 5 days of culture, respectively, the cells on Ti-Ta, Ti, Ti-Al and glass showed 100% viability even after 5 days of culture. These results suggest that the newly developed Ti-Ta alloy has biocompatibility as good as that of Ti and Ti-Al with respect to morphology and proliferation of Gin-1 cells in vitro.

Fatigue performance and cyto-toxicity of low rigidity titanium alloy, Ti-29Nb-13Ta-4.6Zr.

A beta type titanium alloy, Ti-29Nb-13Ta-4.6Zr, was newly designed and developed for biomedical applications. The new alloy contains non-toxic elements such as Nb, Ta, and Zr. In the present study, phases that appeared in the new alloy through various aging treatments were characterized by hardness tests and microstructural observations in order to identify the phase transformation. Fatigue properties of the new alloy were investigated. Young's modulus and cyto-toxicity of the new alloy were also evaluated. Precipitated phases distribute homogeneously over the whole specimen, and they are alpha phase, a small amount of omega phase, and beta phase when the new alloys are subjected to aging treatment at 673K for 259.2ks after solution treatment at 1063K for 3.6ks. The fatigue strength of the new alloy subjected to aging at 673K for 259.2ks after solution treatment at 1063K for 3.6ks is much better than when subjected to other aging treatments. In this case, the fatigue limit is around 700MPa. Young's modulus of the new alloy is much smaller than that of Ti-6Al-4V ELI. The cyto-toxicity of the new alloy is equivalent to that of pure Ti. Therefore, it is proposed that the new alloy, Ti-29Nb-13Ta-4.6Zr, will be of considerable use in biomedical applications.

Effects of six particulate metals on osteoblast-like MG-63 and HOS cells in vitro.

The effects of six particulate metals (Al, Ti, Zr, Nb, Ta and Cr) on cell viability and alkaline phosphatase (ALP) activity were studied in vitro using two types of osteoblast-like cells, MG-63 and HOS cells. The cell viability in the presence of Al, Ti and Zr was depressed at lower concentrations than in the presence of Nb, Ta and Cr. The average sizes of the Al, Ti, Zr, Nb, Ta and Cr particulates were 6.48 microm, 16.99 microm, 5.07 microm, 14.18 microm, 8.32 microm and 23.27 microm respectively. The interaction of HOS cells with the particulates was more sensitive than that of MG-63 cells. ALP activity increased at higher concentrations only with the Al particulates; other experimental conditions did not exert an influence on ALP activity. These findings suggest that the cell viability of osteoblast-like cells might be influenced by particulate size and metal type, but ALP activity was not influenced by these factors.

Cytotoxicity comparison of three current direct pulp-capping agents with a new bioceramic root repair putty.

INTRODUCTION: The purpose of this in vitro study was to compare the cytotoxicity of white mineral trioxide aggregate cement (AMTA, MTA-Angelus), Brasseler Endosequence Root Repair Putty (ERRM), Dycal, and Ultra-blend Plus (UBP) by using human dermal fibroblasts and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. METHODS: Cultured adult human dermal fibroblasts were exposed to multiple concentrations of material elutes. The test material samples were immersed and incubated in the culture medium for 2, 5, or 8 days at 37°C. The cytotoxic effects were recorded by using an MTT-based colorimetric assay. Positive and negative controls were used. The results were statistically examined by one-way analysis of variance and Tukey post tests. RESULTS: The cell viability of cultures exposed to all dilutions of AMTA, ERRM, and UBP was statistically similar to the negative control at 2 and 5 days. Only the Dycal-exposed specimens exhibited a statistically significant increase in cytotoxicity at the 2 initial evaluation periods. After exposure to the 8-day elutes, the respective percentage of cell survivability was 91% (Brasseler), 88% (MTA-Angelus), 76% (Ultra-blend Plus), and 37% (Dycal). CONCLUSIONS: From the data in this in vitro study, AMTA, ERRM, and UBP had statistically similar adult human dermal fibroblast cytotoxicity levels. Relative to the negative control, only Dycal was shown to have a statistically significant cytotoxic effect to adult human dermal fibroblasts at all tested intervals.

A comparison of the cytotoxicity and proinflammatory cytokine production of EndoSequence root repair material and ProRoot mineral trioxide aggregate in human osteoblast cell culture using reverse-transcriptase polymerase chain reaction.

INTRODUCTION: The purpose of this study was to compare the cytotoxicity and cytokine expression profiles of EndoSequence Root Repair Material (ERRM; Brasseler, Savannah, GA) putty, ERRM flowable, and ProRoot mineral trioxide aggregate (MTA; Dentsply Tulsa Dental, Johnson City, TN) using osteoblast cells (MG-63). METHODS: Four millimeters in diameter of each material was placed in the center of a 6-well culture plate, and a 2-mL suspension (10(5) cells/mL) of human osteoblasts was seeded in each well. Photomicrograph images were used to evaluate cytotoxicity as evidenced by the lack of osteoblast cell growth in relation to the materials with AH-26 (Dentsply Tulsa Dental) as the positive control. In addition, reverse-transcriptase polymerase chain reaction (RT-PCR) was used to evaluate the expression of interleukin (IL)-1ß, IL-6, IL-8, and tumor necrosis factor-α (TNF-α). Cytokine expression of MG-63 cells upon lipopolysaccharide treatment was used as controls. RT-PCR results were normalized by the expression of the housekeeping gene ß-actin and were used to measure cytokine expression. Statistical analysis was performed using analysis of variance. RESULTS: Results showed that ERRM putty and MTA exhibited minimal levels of cytotoxicity; however, ERRM was slightly more cytotoxic although not statistically significant. The expression of IL-1ß, IL-6, and IL-8 was detected in all samples with minimal TNF-α expression. CONCLUSIONS: We concluded that ERRM and MTA showed similar cytotoxicity and cytokine expressions.

Cytotoxicity and alkaline phosphatase activity evaluation of endosequence root repair material.

INTRODUCTION: The purpose of this in vitro study was to evaluate the cytotoxicity and alkaline phosphatase (ALP) activity of a new bioceramic root repair material, EndoSequence Root Repair Material (ESRRM; Brasseler USA, Savannah, GA), and to compare these characteristics with those of ProRoot MTA (Dentsply Tulsa Dental, Tulsa, OK) and Geristore (GR; Den-Mat LLC, Santa Maria, CA). METHODS: Human Saos-2 osteoblast-like cells were exposed to 1-, 3-, and 7-day elutes of the materials (100% and 50% strength) for 24 hours after which the bioactivity and ALP activity of the cells were evaluated using a methylthiazol sulfophenyl (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay and para-Nitrophenylphosphate colorimetric assay, respectively. In the positive control group, Triton X-100 (Boehringer Mannheim Corp, Indianapolis, IN) was used to lyse the cells, representing 100% cytotoxicity, and in the negative control group cells received fresh culture medium only. Data were statistically analyzed using the unpaired t test and 1-way analysis of variance. RESULTS: The results revealed that the bioactivity of the cells as well as ALP activity were significantly decreased after exposure to ESRRM elutes in almost all time periods, both in 100% and 50% concentrations, with the exception of ALP activity of day 1 elutes of ESRRM at 50% concentration. MTA did not change the bioactivity or ALP activity of the cells. GR elutes of 100% concentration reduced the bioactivity on days 1 and 3, whereas GR elutes of 50% concentration affected the cells only on day 1. None of the GR elutes had any effect on ALP activity of the cells. CONCLUSIONS: It was concluded that ESRRM elutes of all time periods in general reduced the bioactivity and ALP activity of osteoblast-like cells. GR reduced bioactivity only, whereas MTA had no effect on the cells.

Cytotoxicity comparison of mineral trioxide aggregates and EndoSequence bioceramic root repair materials.

INTRODUCTION: The purpose of this bench top evidence level 5 in vitro study was to compare the cytotoxic effect of 2 brands of white mineral trioxide aggregate cement (ProRoot MTA and MTA-Angelus), Brasseler EndoSequence Root Repair Material, and Brasseler EndoSequence Root Repair Putty by using human dermal fibroblasts. METHODS: The cells were cultured in recommended culture conditions and exposed to the tested materials. The cytotoxic effects were recorded at an observation period of 24 hours by using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-based colorimetric assay. Results were analyzed by using one-way analysis of variance with significance of p < .05. RESULTS: All materials tested demonstrated cell viability ≥ 91.8%. Overall, there was no statistically significant difference in cell viability of ProRoot MTA, MTA-Angelus, and Brasseler EndoSequence Root Repair Material. However, there was a statistically significant difference negatively associated with the cell viability of human dermal fibroblasts in association with the Brasseler EndoSequence Root Repair Putty. CONCLUSIONS: The Brasseler EndoSequence Root Repair Materials were shown to have similar cytotoxicity levels to those of ProRoot MTA and MTA-Angelus.

Biocompatibility of two novel root repair materials.

INTRODUCTION: The purpose of the present study was to evaluate the biocompatibility of 2 root-end filling materials, Endosequence Root Repair Material Putty (ERRM Putty) and Paste (ERRM Paste) and compare them with gray mineral trioxide aggregate (MTA). METHODS: ERRM Putty, ERRM Paste, MTA, intermediate restorative material (IRM), and Cavit G were tested. For cytotoxicity assay, human gingival fibroblasts were incubated for 1, 3, and 7 days with extracts of varying concentrations from materials set for 2 days or 7 days. Cell viability was evaluated by methyl-thiazol-tetrazolium (MTT) assay. For cell adhesion assay, materials set for 7 days were examined under scanning electron microscope directly after setting, after incubation in cell culture medium for 7 days, and after incubation in gingival fibroblast suspension at a density of 5 × 10(4) cells/well for 2 and 7 days. The constituents of crystals formed on surface of materials were determined by energy dispersive analysis by x-ray. RESULTS: Cell viability was significantly correlated with the type of material, setting time, and incubation time (P < .001 for all parameters). ERRM Putty and ERRM Paste displayed similar cell viabilities to MTA at all experimental conditions, except that fresh samples of ERRM Paste showed slightly lower cell viabilities than MTA. Cell viabilities with IRM and Cavit G were significantly lower than with the other 3 materials (P < .001). Similar surface crystallographic features and cell adhesion were observed on ERRM Paste, ERRM Putty, and MTA. CONCLUSIONS: ERRM Putty and ERRM Paste displayed similar in vitro biocompatibility to MTA.

Cytotoxicity of titanium and titanium alloying elements.

It is commonly accepted that titanium and the titanium alloying elements of tantalum, niobium, zirconium, molybdenum, tin, and silicon are biocompatible. However, our research in the development of new titanium alloys for biomedical applications indicated that some titanium alloys containing molybdenum, niobium, and silicon produced by powder metallurgy show a certain degree of cytotoxicity. We hypothesized that the cytotoxicity is linked to the ion release from the metals. To prove this hypothesis, we assessed the cytotoxicity of titanium and titanium alloying elements in both forms of powder and bulk, using osteoblast-like SaOS(2) cells. Results indicated that the metal powders of titanium, niobium, molybdenum, and silicon are cytotoxic, and the bulk metals of silicon and molybdenum also showed cytotoxicity. Meanwhile, we established that the safe ion concentrations (below which the ion concentration is non-toxic) are 8.5, 15.5, 172.0, and 37,000.0 microg/L for molybdenum, titanium, niobium, and silicon, respectively.

[Biological evaluation of In-Ceram-ceramics compared to cobalt-base-alloys and the metals titanium, tantalum and niobium in animal experiments]. / Biologische Prüfung der In-Ceram-Keramik im Vergleich mit Kobaltbasis-Legierungen und den Metallen Titan, Tantal und Niob im Tierexperiment.

The aim of the study was to evaluate the biocompatibility of the in-cream-ceramic-system in several technological phases by animal experiments. The comparative materials were the Co-Cr-alloys Remanium CD and Wirobond and the implant materials Titanium, Tantalum and Columbium and the high biocompatible material Teflon. The experiments were carried out in accordance with the DIN-standard 13,930 using subcutaneous implantation to verify the toxicity of the materials. 20 cylindrical test pieces were implanted into the subcutaneous connective tissue of the neck in rats. After 12 weeks the animals were sacrificed and the implants were removed with the surrounding tissues. The thickness of the fibrous capsule and the number of cells within the capsule were measured microscopically. The in-ceram-ceramic-system showed the same results like approved Co-Cr-alloys. The results of the implant materials were not attained.

Urinary and serum mutagenicity studies with rats implanted with depleted uranium or tantalum pellets.

During the 1991 Persian Gulf War several US military personnel were wounded by shrapnel fragments consisting of depleted uranium. These fragments were treated as conventional shrapnel and were not surgically removed to spare excessive tissue damage. Uranium bioassays conducted over a year after the initial uranium injury indicated a significant increase in urine uranium levels above natural background levels. The potential mutagenic effects of depleted uranium are unknown. To assess the potential mutagenic effects of long-term exposure to internalized depleted uranium, Sprague-Dawley rats were implanted with depleted uranium and their urine and serum were evaluated for mutagenic potential at various times after pellet implantation using the Ames Salmonella reversion assay. Tantalum, an inert metal widely used in prosthetic devices was used for comparison. Enhancement of mutagenic activity in Salmonella typhimurium strain TA98 and the Ames II mixed strains (TA7001-7006) was observed in urine samples from animals implanted with depleted uranium pellets. In contrast, urine samples from animals implanted with tantalum did not show a significant enhancement of mutagenic activity in these strains. In depleted uranium-implanted animals, urine mutagenicity increased in a dose- and time-dependent manner demonstrating a strong positive correlation with urine uranium levels (r = 0.995, P < 0.001). There was no mutagenic enhancement of any bacterial strain detected in the sera of animals implanted with either depleted uranium or tantalum pellets. The results suggest that uranium content in the urine is correlated with urine mutagenicity and that urinary mutagenicity might be used as a biomarker to detect exposure to internalized uranium.