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T R Webb

Publications and source records attributed to T R Webb.

At least 19 recordsLinked to original sources
PubMed2006

Pulmonary toxicity screening studies in male rats with TiO2 particulates substantially encapsulated with pyrogenically deposited, amorphous silica.

The aim of this study was to evaluate the acute lung toxicity in rats of intratracheally instilled TiO2 particles that have been substantially encapsulated with pyrogenically deposited, amorphous silica. Groups of rats were intratracheally instilled either with doses of 1 or 5 mg/kg of hydrophilic Pigment A TiO2 particles or doses of 1 or 5 mg/kg of the following control or particle-types: 1) R-100 TiO2 particles (hydrophilic in nature); 2) quartz particles, 3) carbonyl iron particles. Phosphate-buffered saline (PBS) instilled rats served as additional controls. Following exposures, the lungs of PBS and particle-exposed rats were evaluated for bronchoalveolar lavage (BAL) fluid inflammatory markers, cell proliferation, and by histopathology at post-instillation time points of 24 hrs, 1 week, 1 month and 3 months. The bronchoalveolar lavage results demonstrated that lung exposures to quartz particles, at both concentrations but particularly at the higher dose, produced significant increases vs. controls in pulmonary inflammation and cytotoxicity indices. Exposures to Pigment A or R-100 TiO2 particles produced transient inflammatory and cell injury effects at 24 hours postexposure (pe), but these effects were not sustained when compared to quartz-related effects. Exposures to carbonyl iron particles or PBS resulted only in minor, short-term and reversible lung inflammation, likely related to the effects of the instillation procedure. Histopathological analyses of lung tissues revealed that pulmonary exposures to Pigment A TiO2 particles produced minor inflammation at 24 hours postexposure and these effects were not significantly different from exposures to R-100 or carbonyl iron particles. Pigment A-exposed lung tissue sections appeared normal at 1 and 3 months postexposure. In contrast, pulmonary exposures to quartz particles in rats produced a dose-dependent lung inflammatory response characterized by neutrophils and foamy (lipid-containing) alveolar macrophage accumulation as well as evidence of early lung tissue thickening consistent with the development of pulmonary fibrosis. Based on our results, we conclude the following: 1) Pulmonary instillation exposures to Pigment A TiO2 particles at 5 mg/kg produced a transient lung inflammatory response which was not different from the lung response to R-100 TiO2 particles or carbonyl iron particles; 2) the response to Pigment A was substantially less active in terms of inflammation, cytotoxicity, and fibrogenic effects than the positive control particle-type, quartz particles. Thus, based on the findings of this study, we would expect that inhaled Pigment A TiO2 particles would have a low risk potential for producing adverse pulmonary health effects.

Journal Article↗
PubMed2005

Biodegradability of para-aramid respirable-sized fiber-shaped particulates (RFP) in human lung cells.

Using both in vivo (inhalation) and in vitro (cell culture) studies, we previously reported that p-aramid respirable fibers (RFP--defined as respirable-sized fiber-shaped particulates) are biodegraded in lungs and lung cells of rats following exposures. The current studies were undertaken to determine whether shortening mechanisms of p-aramid RFP biodegradability are also operative in human lung cells. Cultures of human A549 lung epithelial cells (A549), primary alveolar macrophages (HBAL) (collected via bronchoalveolar lavage [BAL]) from volunteers), and co-cultures (Co) of the A549 and HBAL were incubated with p-aramid RFP for either 1 h, 1 day, or 1 week to assess RFP shortening. Lengths of RFP were measured using scanning electron microscopy (SEM) following fixation, digestion of culture tissue components, and processing. Similar to findings using rat lung cells, only slight RFP shortening was measured in A549 cultures at 1-day and 1-week post-incubation. More importantly, in HBAL and Co groups, greater transverse cleavage of p-aramid RFP was measured at 1-day and 1-week postexposure compared to 1-h HBAL or Co groups, or in any A549 groups. In contrast, cellulose RFP, a biopersistent reference control fiber, were not measurably shortened under similar circumstances. Second, p-aramid RFP were incubated either with phosphate-buffered saline (PBS), or acellular BAL fluids from human volunteers or rats and processed for SEM analysis of RFP lengths. Mean lengths of p-aramid RFP incubated with human or rat BAL fluids were substantially decreased compared to PBS. Similar to our findings with rat lung cells, components of human lung fluids coat the p-aramid RFP as a prerequisite for subsequent enzymatic cleavage by human phagocytic lung cells and this finding reinforces the concept that inhaled p-aramid RFP are likely to be biodegradable in the lungs of humans.

Administration, Inhalation↗
PubMed2005

Comparative pulmonary toxicity inhalation and instillation studies with different TiO2 particle formulations: impact of surface treatments on particle toxicity.

Most pigment-grade titanium dioxide (TiO(2)) samples that have been tested in pulmonary toxicity tests have been of a generic variety-i.e., generally either uncoated particles or TiO(2) particles containing slightly hydrophilic surface treatments/coatings (i.e., base TiO(2)). The objectives of these studies were to assess in rats, the pulmonary toxicity of inhaled or intratracheally instilled TiO(2) particle formulations with various surface treatments, ranging from 0-6% alumina (Al(2)O(3)) or alumina and 0-11% amorphous silica (SiO(2)). The pulmonary effects induced by TiO(2) particles with different surface treatments were compared to reference base TiO(2) particles and controls. In the first study, groups of rats were exposed to high exposure (dose) concentrations of TiO(2) particle formulations for 4 weeks at aerosol concentrations ranging from 1130-1300 mg/m(3) and lung tissues were evaluated by histopathology immediately after exposure, as well as at 2 weeks and 3, 6, and 12 months postexposure. In the second study, groups of rats were intratracheally instilled with nearly identical TiO(2) particle formulations (when compared to the inhalation study) at doses of 2 and 10 mg/kg. Subsequently, the lungs of saline-instilled and TiO(2)-exposed rats were assessed using both bronchoalveolar (BAL) biomarkers and by histopathology/cell proliferation assessment of lung tissues at 24 h, 1 week, 1 and 3 months postexposure. The results from these studies demonstrated that for both inhalation and instillation, only the TiO(2) particle formulations with the largest components of both alumina and amorphous silica surface treatments produced mildly adverse pulmonary effects when compared to the base reference control particles. In summary, two major conclusions can be drawn from these studies: (1) surface treatments can influence the toxicity of TiO(2) particles in the lung; and (2) the intratracheal instillation-derived, pulmonary bioassay studies represent an effective preliminary screening tool for inhalation studies with the identical particle-types used in this study.

Administration, Inhalation↗
PubMed2003

Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats.

The aim of this study was to evaluate the acute lung toxicity of intratracheally instilled single-wall carbon nanotubes (SWCNT) in rats. The lungs of rats were instilled either with 1 or 5 mg/kg of the following control or particle types: (1) SWCNT, (2) quartz particles (positive control), (3) carbonyl iron particles (negative control), (4) phosphate-buffered saline (PBS) + 1% Tween 80, or (5) graphite particles (lung tissue studies only). Following exposures, the lungs of PBS and particle-exposed rats were assessed using bronchoalveolar lavage (BAL) fluid biomarkers and cell proliferation methods, and by histopathological evaluation of lung tissue at 24 h, 1 week, 1 month, and 3 months postinstillation. Exposures to high-dose (5 mg/kg) SWCNT produced mortality in ~15% of the SWCNT-instilled rats within 24 h postinstillation. This mortality resulted from mechanical blockage of the upper airways by the instillate and was not due to inherent pulmonary toxicity of the instilled SWCNT particulate. Exposures to quartz particles produced significant increases versus controls in pulmonary inflammation, cytotoxicity, and lung cell parenchymal cell proliferation indices. Exposures to SWCNT produced transient inflammatory and cell injury effects. Results from the lung histopathology component of the study indicated that pulmonary exposures to quartz particles (5 mg/kg) produced dose-dependent inflammatory responses, concomitant with foamy alveolar macrophage accumulation and lung tissue thickening at the sites of normal particle deposition. Pulmonary exposures to carbonyl iron or graphite particles produced no significant adverse effects. Pulmonary exposures to SWCNT in rats produced a non-dose-dependent series of multifocal granulomas, which were evidence of a foreign tissue body reaction and were nonuniform in distribution and not progressive beyond 1 month postexposure (pe). The observation of SWCNT-induced multifocal granulomas is inconsistent with the following: (1) lack of lung toxicity by assessing lavage parameters, (2) lack of lung toxicity by measuring cell proliferation parameters, (3) an apparent lack of a dose response relationship, (4) nonuniform distribution of lesions, (5) the paradigm of dust-related lung toxicity effects, (6) possible regression of effects over time. In addition, the results of two recent exposure assessment studies indicate very low aerosol SWCNT exposures at the workplace. Thus, the physiological relevance of these findings should ultimately be determined by conducting an inhalation toxicity study.

Alkaline Phosphatase↗
PubMed2003

Pulmonary toxicity studies in rats with triethoxyoctylsilane (OTES)-coated, pigment-grade titanium dioxide particles: bridging studies to predict inhalation hazard.

The aim of this study was to assess and compare the acute lung toxicities of intratracheally instilled hydrophobic relative to hydrophilic surface-coated titanium dioxide (TiO(2)) particles using a pulmonary bridging methodology. In addition, the results of these instillation studies were bridged with data previously generated from inhalation studies with hydrophilic, pigment-grade (base) TiO(2) particles, using the base, pigment-grade TiO(2) particles as the inhalation/instillation bridge material. To conduct toxicity comparisons, the surface coatings of base pigment-grade TiO(2) particles were made hydrophobic by application of triethoxyoctylsilane (OTES), a commercial product used in plastics applications. For the bioassay experimental design, rats were intratracheally instilled with 2 or 10 mg/kg of the following TiO(2) particle-types: (1) base (hydrophilic) TiO(2) particles; (2) TiO(2) with OTES surface coating; (3) base TiO(2) with Tween 80; or (4) OTES TiO(2) with Tween 80. Saline instilled rats served as controls. Following exposures, the lungs of sham- and TiO(2)-exposed rats were assessed both using bronchoalveolar lavage (BAL) biomarkers and by histopathology of lung tissue at 24 hours, 1 week, 1 month, and 3 months post exposure. The results demonstrated that only the base, high-dose (10 mg/kg) pigment-grade TiO(2) particles and those with particle-types containing Tween 80 produced a transient pulmonary inflammatory response, and this was reversible within 1 week postexposure. The authors conclude that the OTES hydrophobic coating on the pigment-grade TiO(2) particle does not cause significant pulmonary toxicity.

Animals↗
PubMed2002

Coordination chemistry of silver(I) with the nitrogen-bridged ligands (C(6)H(5))(2)PN(H)P(C(6)H(5))(2) and (C(6)H(5))(2)PN(CH(3))P(C(6)H(5))(2): the effect of alkylating the nitrogen bridge on ligand bridging versus chelating behavior.

The coordination chemistry of silver(I) with the nitrogen-bridged ligands (C(6)H(5))(2)PN(R)P(C(6)H(5))(2) [R = H (dppa); R = CH(3) (dppma)] has been investigated by (31)P NMR and electrospray mass spectrometry (ESMS). Species observed by (31)P NMR include Ag(2)(mu-dppa)(2+), Ag(2)(mu-dppa)(2)(2+), Ag(2)(mu-dppa)(3)(2+), Ag(2)(mu-dppma)(2+), Ag(2)(mu-dppma)(2)(2+), and Ag(eta(2)-dppma)(2)(+). Species observed by ESMS at low cone voltages were Ag(2)(dppa)(2)(2+), Ag(2)(dppa)(3)(2+), Ag(2)(dppma)(2)(2+), and Ag(dppma)(2)(+). (C(6)H(5))(2)PN(CH(3))P(C(6)H(5))(2) showed a strong tendency to chelate, while (C(6)H(5))(2)PN(H)P(C(6)H(5))(2) preferred to bridge. Differences in the bridging versus chelating behavior of the ligands are assigned to the Thorpe-Ingold effect, where the methyl group on nitrogen sterically interacts with the phenyl groups on phosphorus. The crystal structure of the three-coordinate dinuclear silver(I) complex (Ag(2)[(C(6)H(5))(2)PN(H)P(C(6)H(5))(2)](3))(BF(4))(2) has been determined. Bond distances include Ag-Ag = 2.812(1) A, Ag(1)-P(av) = 2.492(3) A, and Ag(2)-P(av) = 2.509(3) A. The compound crystallizes in the monoclinic space group Cc at 294 K, with a = 18.102(4)(o), Z = 4, V = 7261(3) A(3), R = 0.0503, and R(W) = 0.0670.

Journal Article↗
PubMed2002

Biodegradability of inhaled p-aramid respirable fiber-shaped particulates (RFP): mechanisms of RFP shortening and evidence of reversibility of pulmonary lesions.

These studies elucidated mechanisms of inhaled p-aramid respirable fiber-shaped particulates (RFP) biodegradation in the lungs of exposed rats and hamsters. We postulate that lung fluids coat/activate inhaled p-aramid RFP which deposits in the lung and promote enzymatic attack and consequent shortening. p-Aramid or cellulose (biopersistent control) RFP were instilled into the lungs of rats and the lungs digested 24 h later using two different (KOH or enzymatic) digestion techniques. In vivo, the enzyme but not the KOH solution produced shortening of p-aramid but not cellulose RFP recovered from the lungs. For in vitro studies, the two RFP-types were incubated with BAL fluids and underwent simulated digestions; also rat lung epithelial cells, macrophages or co-cultures were incubated with p-aramid and digested at 1, 24, or 168 h postexposure. The results of in vitro acellular studies demonstrated that only p-aramid RFP incubated in BAL fluids and digested by the enzyme method were shortened. In vitro cellular studies demonstrated a shortening of p-aramid RFP in macrophages and co-cultures but not in lung epithelial cells at 24 h and 1 week postexposure. These results demonstrate that lung fluids coat and catalyze the p-aramid RFP as a prelude for shortening and describe a likely mechanism for the biodegradability of inhaled p-aramid RFP in the lungs of exposed animals.

Administration, Inhalation↗
PubMed2001

Biodegradability of inhaled para-aramid respirable-sized fiber-shaped particulates: mechanistic in vivo and in vitro studies.

Biopersistence represents an important health-related issue in fiber toxicology. These studies were undertaken to elucidate the mechanism(s) through which inhaled p-aramid respirable-sized fiber-shaped particulates (RFP) are biodegraded in the lungs of exposed rats and hamsters. Previously, we and others have reported that, following deposition in the lung, long p-aramid RFPs are cleaved into shorter fibrous fragments. To investigate the mechanisms of RFP biodegradation, we have postulated that lung fluids coat/activate p-aramid RFP following deposition in the alveolar regions of the lung, thus predisposing the RFP to enzymatic attack and consequent shortening. This process enhances the rate of clearance of the inhaled RFP. To test this hypothesis, we have conducted both in vivo and in vitro cellular and noncellular investigations. First, p-aramid or cellulose RFP were instilled into the lungs of rats and the lungs were digested 24 h postexposure using two different digestion techniques: (1) a conventional ethanolic KOH method and (2) an enzymatic method that simulates the action of lung enzymes. Cellulose RFP were utilized as a control organic fiber-type that is known to be biopersistent. The results demonstrated that the enzymatic but not the KOH method resulted in transverse cleavage of the p-aramid RFP; the lengths of cellulose RFP recovered from rat lungs were not reduced by either method. Next, standardized preparations of p-aramid RFP or cellulose RFP were incubated with saline or lung fluids and then processed by one of two tissue digestion techniques. Mean lengths of p-aramid RFP incubated with saline and processed with KOH or the enzyme method were not found to be altered. Indeed, only the preparation of p-aramid RFP that had been incubated with bronchoalveolar lavage (BAL) fluids and processed with the enzyme solution resulted in cleavage of p-aramid RFP. Moreover, when the BAL fluids were autoclaved to denature proteins, the length dimensions of p-aramid RFP were intermediate between saline controls and RFP incubated with normal BAL fluids and processed via the enzymatic technique. In contrast to the in vitro noncellular studies with p-aramid RFP, the combination of BAL fluid incubation and enzyme digestion method had no measurable effect on shortening of cellulose RFP, indicating that the results with p-aramid were specific to that fiber-type. In a final set of in vitro cellular studies, cultures of rat lung epithelial cells, alveolar macrophages, or co-cultures of epithelial cells and macrophages were treated with p-aramid RFP for 1 h, 1 day, or 1 week to determine whether RFP shortening occurs directly in the phagocytic cells. The lengths of fibrils were measured using scanning electron microscopy techniques. The results demonstrated that (1) no shortening occurred in the epithelial cell cultures at any time point; however, (2) in the macrophage and cocultures, cleavage of p-aramid RFP was observed at 1 day and 1 week postexposure. Our data suggest that components of lung fluids coat and catalyze the p-aramid RFP as a prerequisite for enzymatic cleavage. This process could play a significant role in facilitating the transverse cleavage or shortening of inhaled p-aramid RFP in the lungs of exposed rats and hamsters.

Administration, Inhalation↗
PubMed2001

Man-made respirable-sized organic fibers: what do we know about their toxicological profiles?

Man-made organic fibers (MMOFs) have been manufactured for over 50 years. Until recently, there have been few concerns raised regarding the safety of organic fiber dusts. This is due, in large part, to the perception that the dimensions of most, if not all, of these products were too large to be inhaled into the distal lungs of workers, i.e., were considered to be nonrespirable. A brief review of some of the issues related to organic fiber toxicology is presented herein. Some of the organic fiber-types used in commerce are identified and some fundamental tenets of fiber toxicology are discussed. In addition, the European Union, in their recent consideration for banning chrysotile asbestos fibers, evaluated some organic fiber substitutes and compared them to the hazards of asbestos. A brief review of their conclusions is described below. Finally, the results of some recent studies assessing the mechanisms of biodegradability of para-aramid respirable-sized, fiber-shaped particulates (RFP) are presented. Para-aramid (p-aramid) RFP are the most extensively-studied respirable organic fiber-type and RFP is the new term which describes respirable-sized organic fibers (ECETOC, 1996) (1). The results of these studies provide clues regarding the mechanism(s) of p-aramid RFP shortening in the lungs of exposed animals, and may be relevant for humans.

Administration, Inhalation↗
PubMed2000

The utilization of a unified pharmacophore query in the discovery of new antagonists of the adenosine receptor family.

Pharmacophore queries from previously known potent selective A3 antagonists were generated by Chem-X. These queries were used to search a pharmacophore database of diverse compounds (CNS-Set). In vitro assays of 186 'hits' yielded over 30 active compounds, for four adenosine receptor subtypes. This search strategy may also be applicable to the discovery of new ligands via receptor homology data.

Adenosine-5'-(N-ethylcarboxamide)↗
PubMed2000

Biodegradability of inhaled p-aramid respirable fibre-shaped particulates: representative of other synthetic organic fibre-types?

OBJECTIVES: Biopersistence, or alternatively, biodegradability (i.e., low biopersistence) represents an important concept in fibre toxicology. The studies described below were undertaken to investigate the mechanisms through which inhaled para-aramid (p-aramid) respirable, fibre-shaped particulates (RFP) are biodegraded in the lungs of exposed rats and hamsters; in contrast, cellulose fibres, another organic fibre-type, are known to be biopersistent. To investigate the mechanisms of RFP biodegradation, we have hypothesized that lung fluids activate p-aramid RFP following deposition, and the RFP are then vulnerable to enzymatic attack in the lungs. METHODS: To test the hypothesis, p-aramid RFP or cellulose RFP were instilled into the lungs of rats and the lungs digested 24 h post-exposure using two different digestion techniques: (1) a conventional ethanolic KOH method, and (2) an enzymatic method which simulates lung enzymes. RESULTS: The enzymatic but not the KOH method artificially cleaved the p-aramid RFP recovered from rat lungs. Next, p-aramid RFP or cellulose RFP were incubated with saline or lung fluids and then processed by one of the two digestion techniques. Mean lengths of p-aramid RFP processed with KOH and evaluated by SEM were 13.4 microm; in contrast, mean lengths of p-aramid RFP samples, incubated in lung fluids and treated with the enzymatic method were 8.8 microm. The enzymatic digestion method had no discernible effect on shortening of cellulose RFP, indicating that the results with p-aramid were specific. CONCLUSIONS: Our data indicate that components of lung fluids coat and catalyze the p-aramid, thereby predisposing the RFP to enzymatic cleavage. This could play a significant mechanistic role in facilitating the transverse cleavage or shortening of inhaled p-aramid RFP in the lungs of exposed rats and hamsters.

Air Pollutants, Occupational↗
PubMed1993

Reversal of copper(II)-induced methemoglobin formation by thiols.

Oxyhemoglobin is oxidized to methemoglobin by copper(II) in a two-stage reaction that results in conversion of Fe(II) to Fe(III) in heme of the beta subunits, but not the alpha subunits. Glutathione and other thiols, which are slowly oxidized by Cu(II), protect oxyhemoglobin from Cu(II)-induced oxidation. In the present studies, when oxyhemoglobin was first oxidized to methemoglobin by Cu(II) and thiols such as glutathione added to the sample, methemoglobin was reduced to oxyhemoglobin. Once reduction of methemoglobin stopped, as the thiol was oxidized, the oxyhemoglobin formed was reoxidized by Cu(II). The addition of the same thiols to methemoglobin formed by autoxidation did not reduce it to oxyhemoglobin. The addition of thiols such as cysteine, which are rapidly oxidized by Cu(II), to methemoglobin formed by incubation with Cu(II) also resulted in reduction of methemoglobin, but the period of reversal was much shorter than that seen with glutathione and other less reactive thiols. When cysteine and glutathione were added together to Cu(II)-induced methemoglobin, the rate of reduction and reoxidation was intermediate to that seen when either was added separately. When EDTA was added to a system in which oxyhemoglobin was undergoing Cu(II)-induced oxidation, oxidation of oxyhemoglobin ceased and there was no reduction of the methemoglobin to oxyhemoglobin. When both glutathione and EDTA were added to this system, the response was the same as with EDTA alone, suggesting that Cu(I) or (II) may be required for the reduction of copper-induced methemoglobin by thiols. These studies show that thiols that are slowly oxidized by Cu(II) both protect oxyhemoglobin from Cu(II)-induced oxidation, and reduce the methemoglobin formed to oxyhemoglobin.

Copper↗
PubMed1988

1-(2,3-Anhydro-beta-D-lyxofuranosyl)cytosine derivatives as potential inhibitors of the human immunodeficiency virus.

We report here that 1-(2,3-anhydro-beta-D-lyxofuranosyl)cytosine has activity against the human immunodeficiency virus in vitro. A number of 2',3'-anhydro-beta-D-lyxofuranosyl nucleoside derivatives were prepared, but none had the activity of the title compound. New efficient procedures were developed for the synthesis of 3'-deoxy-3'-alkyl- and 3'-deoxy-beta-D-arabinosylpyrimidine derivatives.

Ancitabine↗
PubMed1987

Template-primer analogs as substrates for DNA polymerase.

In order to gain more understanding about the mode of action of DNA polymerase, eight related partially self-complementary "hairpin" shaped oligodeoxynucleotides were prepared. Four of the oligomers contained either 1-beta-D-arabinofuranosyluracil (ara-U) or 1-beta-D-2'deoxyxylofuranosylthymine (dxT) nucleoside analogs at their 3' termini. We investigated the ability of the oligomers to prime DNA synthesis in relationship to the stability of the hybridized region, the nature of the sugar terminus and the DNA polymerase used (reverse transcriptase, or polymerase alpha). The results are discussed in relation to the mode of action of some nucleoside analog inhibitors of DNA polymerase. An understanding of the mechanism of DNA polymerase action was used to design template-primer analogs as polymerase inhibitors. Two of the oligodeoxynucleotide analogs prepared were found to be potent inhibitors of polymerase alpha.

DNA Polymerase II↗