D B Warheit

Dupont, Delaware, Ohio, United States

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Publications (107)386.42 Total impact

  • David B Warheit
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    ABSTRACT: Due to its multifunctional applications, titanium dioxide particles have widespread use in commerce. The particle-types function as sources of pigment color, in food products, anti-bacterial components, ultraviolet radiation scavengers, catalysts, as well as in cosmetics. Because of its inherent properties in a diverse number of products, exposures may occur via any of the major point-of-entry routes, i.e., inhalation, oral or dermal. Although the majority of TiO2 applications are known to exist in the pigment-grade form, nanoscale forms of TiO2 are also common components in several products. This brief review is designed to identify relevant toxicology and risk-related issues which inform health effects assessments on the various forms of titanium dioxide particles. While there has been an abundance of hazard data generated on titanium dioxide particulates, many of the published reports have limited informational value for assessing health effects due, in large part, to shortcomings in experimental design issues, such as: 1) inadequate material characterization of test samples; 2) questionable relevance of experimental systems employed to simulate human exposures; 3) applications of generally high doses, exclusive focus on acute toxicity endpoints, and a lack of reference benchmark control materials, to afford interpretation of measured results; and/or 4) failure to recognize fundamental differences between hazard and risk concepts. Accordingly, a number of important toxicology issues are identified and integrated herein to provide a more comprehensive assessment of the health risks of different forms of pigment-grade and nanoscale titanium dioxide particles. It is important to note that particle-types of different TiO2 compositions may have variable toxicity potencies, depending upon crystal structure, particle size, particle surface characteristics and surface coatings. In order to develop a more robust health risk evaluation of TiO2 particle exposures, this review focuses on the following issues: 1) Introduction to TiO2 particle chemistry/functionality and importance of robust material characterization of test samples; 2) Implementation of meaningful hazard studies for gauging EHS safety issues- pulmonary bioassay data and development of the Nano risk framework for developmental nano TiO2 compounds; 3) Epidemiological study findings on titanium dioxide workers- the most heavily-exposed populations; 4) Methodologies for setting occupational exposure limits including benchmarking or bridging comparisons; and 5) The importance of particle overload data in the lungs of rats as it relates to gauging the relevance of health effects for humans. A comprehensive evaluation of the existing animal and human health data is a necessary prerequisite for facilitating accurate assessments of human health risks to TiO2 exposures.
    Toxicology Letters 04/2013; · 3.15 Impact Factor
  • David B Warheit, Kenneth L Reed, Michael P Delorme
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    ABSTRACT: The goal of this article is to evaluate a recently published subchronic inhalation study with carbon nanofibers in rats and discuss the importance of a weight-of-evidence (WOE) framework for determining no adverse effect levels (NOAELs). In this Organization for Economic Cooperation and Development (OECD) 413 guideline inhalation study with VGCF™-H carbon nanofibers (CNFs), rats were exposed to 0, 0.54, 2.5 or 25 mg/m(3) CNF for 13 weeks. The standard toxicology experimental design was supplemented with bronchoalveolar lavage (BAL) and respiratory cell proliferation (CP) endpoints. BAL fluid (BALF) recovery of inflammatory cells and mediators (i.e., BALF- lactate dehydrogenase [LDH], microprotein [MTP], and alkaline phosphatase [ALKP] levels) were increased only at 25 mg/m(3), 1 day after exposure. No differences versus control values in were measured at 0.54 or 2.5 mg/m(3) exposure concentrations for any BAL fluid endpoints. Approximately 90% (2.5 and 25 mg/m(3)) of the BAL-recovered macrophages contained CNF. CP indices at 25 mg/m(3) were increased in the airways, lung parenchyma, and subpleural regions, but no increases in CP versus controls were measured at 0.54 or 2.5 mg/m(3). Based upon histopathology criteria, the NOAEL was set at 0.54 mg/m(3), because at 2.5 mg/m(3), "minimal cellular inflammation" of the airways/lung parenchyma was noted by the study pathologist; while the 25 mg/m(3) exposure concentration produced slight inflammation and occasional interstitial thickening. In contrast, none of the more sensitive pulmonary biomarkers such as BAL fluid inflammation/cytotoxicity biomarkers or CP turnover results at 2.5 mg/m(3) were different from air-exposed controls. Given the absence of convergence of the histopathological observations versus more quantitative measures at 2.5 mg/m(3), it is recommended that more comprehensive guidance measures be implemented for setting adverse effect levels in (nano)particulate, subchronic inhalation studies including a WOE approach for establishing no adverse effect levels; and a suggestion that some findings should be viewed as normal physiological adaptations (e.g., normal macrophage phagocytic responses-minimal inflammation) to long-term particulate inhalation exposures.
    Toxicologic Pathology 12/2012; · 2.06 Impact Factor
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    ABSTRACT: A subchronic inhalation toxicity study of inhaled vapor grown carbon nanofibers (CNF) (VGCF-H) was conducted in male and female Sprague Dawley rats. The CNF test sample was composed of > 99.5% carbon with virtually no catalyst metals; Brunauer, Emmett, and Teller (BET) surface area measurements of 13.8 m2/g; and mean lengths and diameters of 5.8 µm and 158 nm, respectively.Four groups of rats per sex were exposed nose-only, 6 h/day, for 5 days/week to target concentrations of 0, 0.50, 2.5, or 25 mg/m3 VGCF-H over a 90-day period and evaluated 1 day later. Assessments included conventional clinical and histopathological methods, bronchoalveolar lavage fluid (BALF) analysis, and cell proliferation (CP) studies of the terminal bronchiole (TB), alveolar duct (AD), and subpleural regions of the respiratory tract. In addition, groups of 0 and 25 mg/m3 exposed rats were evaluated at 3 months postexposure (PE). Aerosol exposures of rats to 0.54 (4.9 f/cc), 2.5 (56 f/cc), and 25 (252 f/cc) mg/m(3) of VGCF-H CNFs produced concentration-related small, detectable accumulation of extrapulmonary fibers with no adverse tissue effects. At the two highest concentrations, inflammation of the TB and AD regions of the respiratory tract was noted wherein fiber-laden alveolar macrophages had accumulated. This finding was characterized by minimal infiltrates of inflammatory cells in rats exposed to 2.5mg/m(3) CNF, inflammation along with some thickening of interstitial walls, and hypertrophy/hyperplasia of type II epithelial cells, graded as slight for the 25mg/m(3) concentration. At 3 months PE, the inflammation in the high dose was reduced. No adverse effects were observed at 0.54mg/m(3). BALF and CP endpoint increases versus controls were noted at 25mg/m(3) VGCF-H but not different from control values at 0.54 or 2.5mg/m(3). After 90 days PE, BALF biomarkers were still increased at 25mg/m(3), indicating that the inflammatory response was not fully resolved. Greater than 90% of CNF-exposed, BALF-recovered alveolar macrophages from the 25 and 2.5mg/m(3) exposure groups contained nanofibers (> 60% for 0.5mg/m(3)). A nonspecific inflammatory response was also noted in the nasal passages. The no-observed-adverse-effect level for VGCF-H nanofibers was considered to be 0.54mg/m(3) (4.9 fibers/cc) for male and female rats, based on the minimal inflammation in the terminal bronchiole and alveolar duct areas of the lungs at 2.5mg/m(3) exposures. It is noteworthy that the histopathology observations at the 2.5mg/m(3) exposure level did not correlate with the CP or BALF data at that exposure concentration. In addition, the results with CNF are compared with published findings of 90-day inhalation studies in rats with carbon nanotubes, and hypotheses are presented for potency differences based on CNT physicochemical characteristics. Finally, the (lack of) relevance of CNF for the high aspect ratio nanomaterials/fiber paradigm is discussed.
    Toxicological Sciences 05/2012; 128(2):449-60. · 4.33 Impact Factor
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    ABSTRACT: It has long been recognized that the physical form of materials can mediate their toxicity--the health impacts of asbestiform materials, industrial aerosols, and ambient particulate matter are prime examples. Yet over the past 20 years, toxicology research has suggested complex and previously unrecognized associations between material physicochemistry at the nanoscale and biological interactions. With the rapid rise of the field of nanotechnology and the design and production of increasingly complex nanoscale materials, it has become ever more important to understand how the physical form and chemical composition of these materials interact synergistically to determine toxicity. As a result, a new field of research has emerged--nanotoxicology. Research within this field is highlighting the importance of material physicochemical properties in how dose is understood, how materials are characterized in a manner that enables quantitative data interpretation and comparison, and how materials move within, interact with, and are transformed by biological systems. Yet many of the substances that are the focus of current nanotoxicology studies are relatively simple materials that are at the vanguard of a new era of complex materials. Over the next 50 years, there will be a need to understand the toxicology of increasingly sophisticated materials that exhibit novel, dynamic and multifaceted functionality. If the toxicology community is to meet the challenge of ensuring the safe use of this new generation of substances, it will need to move beyond "nano" toxicology and toward a new toxicology of sophisticated materials. Here, we present a brief overview of the current state of the science on the toxicology of nanoscale materials and focus on three emerging toxicology-based challenges presented by sophisticated materials that will become increasingly important over the next 50 years: identifying relevant materials for study, physicochemical characterization, and biointeractions.
    Toxicological Sciences 03/2011; 120 Suppl 1:S109-29. · 4.33 Impact Factor
  • Christie M Sayes, Kenneth L Reed, David B Warheit
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    ABSTRACT: Health risks following exposures to nanoparticle types are dependent upon two primary factors, namely, hazard and exposure potential. This chapter describes a pulmonary bioassay methodology for assessing the hazardous effects of nanoparticulates in rats following intratracheal instillation exposures; these pulmonary exposures are utilized as surrogates for the more physiologically relevant inhalation route of exposure. The fundamental features of this pulmonary bioassay are dose-response evaluations and time-course assessments to determine the sustainability of any observed effect. Thus, the major endpoints of this assay are the following: (1) time course and dose-response intensity of pulmonary inflammation and cytotoxicity, (2) airway and lung parenchymal cell proliferation, and (3) histopathological evaluation of lung tissue. This assay can be performed using particles in the fine (pigmentary) or ultrafine (nano) size regimes.In this assay, rats are exposed to selected concentrations of particle solutions or suspensions and lung effects are evaluated at 24 h, 1 week, 1 month, and 3 months postinstillation exposure. Cells and fluids from groups of particle-exposed animals and control animals are recovered by bronchoalveolar lavage (BAL) and evaluated for inflammatory and cytotoxic endpoints. This protocol also describes the lung tissue preparation and histopathological analysis of the lung tissue of particle-instilled rats. This assay demonstrates that instillation exposures of particles produce effects similar to those previously measured in inhalation studies of the same particulates.
    Methods in molecular biology (Clifton, N.J.) 01/2011; 726:313-24. · 1.29 Impact Factor
  • David B Warheit, E Maria Donner
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    ABSTRACT: The development of an environmental health and safety risk management system for nanoscale particle-types requires a base set of hazard data. Accurate determination of health and environmental risks of nanomaterials is a function of the integration of hazard and exposure datasets. Recently, a nanoparticle risk assessment strategy was promulgated and the components are described in a document entitled “Nanorisk framework” (www.nanoriskframework.com). A major component of the hazard evaluation includes a proposed minimum base set of toxicity studies. Included in the suggested studies were substantial particle characterization, a variety of acute hazard and environmental tests, concomitant with screening-type genotoxicity studies. The implementation of well-accepted genotoxicity assays for testing nanomaterials remains a controversial issue. This is because many of these genotoxicity tests were designed for screening general macroparticle chemicals and might not be suitable for the screening of nanomaterials (even of the same compositional material). Furthermore, no nanoparticle-type positive controls have been established or universally accepted for these tests. Although it is the comparative results of the test material vs. the negative or vehicle control that forms the basis for interpreting the results and potency of test materials in genetic toxicology assays, the lack of a nanoparticle-type positive control questions the suitability of the tests to identify nanomaterials with genotoxic properties. It is also not possible to establish historical positive control ranges that would confirm the sensitivity of the tests. Although several genetic toxicology tests have been validated for chemicals according to the Organisation for Economic Co-operation and Development (OECD) test guidelines, the relevance of these assays for nanoparticulate materials remains to be determined. In an attempt to remedy this issue, the OECD has established current projects designed to evaluate the relevance and reproducibility of safety hazard tests for representative nanomaterials, including genotoxicity assays (i.e., Steering Group 3 – Safety Testing of Representative Nanomaterials). In this article, we discuss our past approaches and experience in conducting genotoxicity assays (1) for a newly developed ultrafine TiO₂ particle-type; and (2) in a recent inhalation study, evaluating micronucleus formation in rat erythrocytes following exposures to engineered amorphous nanosilica particles. It seems clear that the development of standardized approaches will be necessary in order to determine whether exposures to specific nanoparticle-types are associated with genotoxic events. The appropriateness of available genotoxicity test systems for nanomaterials requires confirmation and standardization. Accordingly, it seems reasonable to conclude that any specific regulatory testing requirements for nanoparticles would be premature at this time.
    Nanotoxicology 12/2010; 4:409-13. · 7.84 Impact Factor
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    David B Warheit
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    ABSTRACT: Nanotechnology is currently undergoing an impressive expansion in material science research and development of systems that have novel properties due to their small size. Most of the research efforts have been focused on applications, while the implications efforts (i.e., environmental health and safety) have lagged behind. As a consequence, the success of nanotechnology will require assurances that the products being developed are safe from an environmental, health, and safety standpoint. These concerns have led to a debate among governmental agencies and advocacy groups on whether implementation of special regulations should be required for commercialization of products containing nanomaterials. Therefore the assessments of nanomaterial-related health risks must be accurate and verifiable. A mechanism for conducting well-designed toxicology studies includes rigorous attention to nanoparticle physicochemical characterization, as well as consideration of potential routes of exposure, justification of nanoparticle doses, and inclusion of benchmark controls. Unfortunately, some results obtained from earlier studies have fostered general perceptions and fears about nanoparticle health hazards-based mainly upon simple metrics such as particle size, surface area, and particle dose. In addition, there are currently held views that results of screening in silico or in vitro cell culture assays can serve as adequate screening substitutes for identifying health hazards. Some of these "misconceptions" should be challenged or confirmed by the implementation of thorough and accurately detailed nanotoxicology studies. In this article, the author briefly discusses some of the generalized "misconceptions" regarding nanomaterial toxicity and presents alternative views on these issues.
    Nano Letters 10/2010; · 13.03 Impact Factor
  • David B Warheit
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    ABSTRACT: This brief discussion provides an overview of current concepts and perceptions regarding the pulmonary toxicity of ultrafine or nanoparticles. These aspects include, but are not limited to comparisons of fine particle vs. ultrafine particle effects and the unique response of pulmonary effects in rats vs. other rodent species, particularly at particle overload concentrations. In the final section, two studies are described which demonstrate that particle size is not the most significant particulate factor in producing exposure-related pulmonary effects.
    Analytical and Bioanalytical Chemistry 09/2010; 398(2):607-12. · 3.66 Impact Factor
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    ABSTRACT: Inhalation toxicity and exposure assessment studies for nonfibrous particulates have traditionally been conducted using particle mass measurements as the preferred dose metric (i.e., mg or microg/m(3)). However, currently there is a debate regarding the appropriate dose metric for nanoparticle exposure assessment studies in the workplace. The objectives of this study were to characterize aerosol exposures and toxicity in rats of freshly generated amorphous silica (AS) nanoparticles using particle number dose metrics (3.7 x 10(7) or 1.8 x 10(8) particles/cm(3)) for 1- or 3-day exposures. In addition, the role of particle size (d(50) = 37 or 83 nm) on pulmonary toxicity and genotoxicity endpoints was assessed at several postexposure time points. A nanoparticle reactor capable of producing, de novo synthesized, aerosolized amorphous silica nanoparticles for inhalation toxicity studies was developed for this study. SiO(2) aerosol nanoparticle synthesis occurred via thermal decomposition of tetraethylorthosilicate (TEOS). The reactor was designed to produce aerosolized nanoparticles at two different particle size ranges, namely d(50) = approximately 30 nm and d(50) = approximately 80 nm; at particle concentrations ranging from 10(7) to 10(8) particles/cm(3). AS particle aerosol concentrations were consistently generated by the reactor. One- or 3-day aerosol exposures produced no significant pulmonary inflammatory, genotoxic, or adverse lung histopathological effects in rats exposed to very high particle numbers corresponding to a range of mass concentrations (1.8 or 86 mg/m(3)). Although the present study was a short-term effort, the methodology described herein can be utilized for longer-term inhalation toxicity studies in rats such as 28-day or 90-day studies. The expansion of the concept to subchronic studies is practical, due, in part, to the consistency of the nanoparticle generation method.
    Inhalation Toxicology 12/2009; 22(4):348-54. · 1.89 Impact Factor
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    ABSTRACT: Sepiolite is a magnesium silicate-containing nanoclay mineral and is utilized as a nanofiller for nanocomposite applications. We postulated that lung exposures to Sepiolite clay samples could produce sustained effects. Accordingly, the pulmonary and extrapulmonary systemic impacts in rats of intratracheally instilled Sepiolite nanoclay samples were compared with quartz or ultrafine (uf) titanium dioxide particle-types at doses of 1mg/kg or 5mg/kg. All particulates were well characterized, and dedicated groups were evaluated by bronchoalveolar lavage, lung cell proliferation, macrophage functional assays and full body histopathology at selected times postexposure (pe). Bronchoalveolar lavage results demonstrated that quartz particles produced persistent, dose-dependent lung inflammatory responses measured from 24h through 3 months pe. Exposures to uf TiO(2) particles or Sepiolite samples produced transient neutrophilic responses at 24-h pe; however, unlike the other particle-types, Sepiolite exposures produced macrophage-agglomerates or multinucleate giant cells at 1 week, 5 weeks and 3 months pe. In vitro alveolar macrophage functional studies demonstrated that mononuclear cells recovered from quartz but not Sepiolite or uf TiO(2)-exposed rats were deficient in their chemotactic capacities. Moreover, lung parenchymal cell proliferation rates were increased in rats exposed to quartz but not Sepiolite or uf TiO(2) particles. Histopathological evaluation of lung tissues revealed that pulmonary exposures to Sepiolite nanoclay or quartz samples produced inflammation in centriacinar regions at 24-h pe but the effects decreased in severity over time for Sepiolite and increased for quartz-exposed rats. The quartz-induced lesions were progressive and were characterized at 3 months by acinar foamy alveolar macrophage accumulation and septal thickening due to inflammation, alveolar Type II cell hyperplasia and collagen deposition. In the Sepiolite nanoclay group, the finding of multinucleated giant cell accumulation associated with minor collagen deposition in acinar regions was rarely observed. Exposures to ultrafine TiO(2) produced minimal effects characterized by the occurrence of phagocytic macrophages in alveolar ducts. Full body histopathology studies were conducted at 24h and 3 months post particle exposures. Histopathological evaluations revealed minor particle accumulations in some mediastinal or thoracic lymph nodes. However, it is noteworthy that no extrapulmonary target organ effects were observed in any of the particle-exposed groups at 3 months postexposure.
    Toxicology Letters 11/2009; 192(3):286-93. · 3.15 Impact Factor
  • Christie M Sayes, David B Warheit
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    ABSTRACT: A key element of any nanomaterial toxicity screening strategy is a detailed and comprehensive physicochemical characterization of the test material being studied. This is a critical factor for correlating the nanoparticle surface characteristics with any measured biological/toxicological responses, as well as to provide an adequate reference point for comparing toxicity results with the hazard-based findings of other investigators. Moreover, when hazard or risk-based evaluations are made on a particular nanomaterial (based on a variety of studies), it is important to ensure that the nanoparticle-types are identical or very similar in composition. This can only be accomplished if rigorous characterization is conducted. In the absence of an adequate assessment of the physical characteristics, it is easy to draw general conclusions on nanoparticle-types which may have similar chemical compositions but, in fact, have different sizes, shapes, crystal structures, surface coatings, and surface reactivity characteristics. The determination of nanomaterial physicochemical properties is vitally important to nanomedicinal applications in that the fate, accumulation, and transport of nanomaterials through the body over time may be predicted based on specific surface characteristics.
    Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology 11/2009; 1(6):660-70. · 5.68 Impact Factor
  • D B Warheit, C M Sayes, K L Reed
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    ABSTRACT: The development of accurate in vitro screening assays to assess lung hazard potential of nanomaterials is a highly desirable goal. However, some studies have noted little correlation between in vitro and in vivo results. Moreover, a recent National Academy of Sciences report predicts that future hazard testing will be conducted primarily using cell culture assays. The three major objectives of this study were to compare lung toxicity impacts of nanoscale (NZnO) vs fine zinc oxide (FZnO) particulates, assess predictability of in vitro cell culture systems, and compare effects of instillation vs inhalation exposures in rats. Physicochemical aspects of ZnO particle types were rigorously characterized and did not agree with specifications provided by the supplier; i.e., the ZnO particle types were closer in size than advertised. Rats were exposed in vivo either by intratracheal instillation to 1 or 5 mg/kg of nanoscale or fine size zinc oxide particle types or by inhalation to aerosols of 25 or 50 mg/m3 for 1 or 3 h. Lung inflammation, cytotoxicity, and histopathological endpoints were assessed at several time points postexposure. Three different in vitro culture conditions were utilized. Cultures of (1) rat lung epithelial cells, (2) primary alveolar macrophages, and (3) alveolar macrophages-L2 lung epithelial cell cocultures were incubated with fine or nano ZnO particles and evaluated for cytotoxicity biomarkers (LDH) and proinflammatory cytokines (MIP-2 and TNF-alpha). In vivo exposures to instilled or inhaled fine or nanoscale ZnO produced "metal fume fever" responses, characterized by transient short-term lung inflammatory or cytotoxic responses. Alternatively, in vitro exposures to fine or nanoscale ZnO particles produced minor cytotoxic responses at 4 and 24 h, only in cocultures and at the highest (particle overload) dose with little detectable proinflammatory cytokine generation (MIP-2, and TNF-alpha). To summarize, the comparisons of in vivo and in vitro toxicity measurements following nano or fine ZnO particle exposures demonstrated little convergence and few differences in potency.
    Environmental Science and Technology 10/2009; 43(20):7939-45. · 5.48 Impact Factor
  • David B. Warheit, Kenneth L. Reed, Christie M. Sayes
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    ABSTRACT: A variety of pulmonary hazard studies in rats have demonstrated that exposures to ultrafine or nanoparticles (generally defined as particles in the size range < 100 nm) produce more intensive inflammatory responses when compared with bulk-sized particle-types of similar chemical composition. However, this common perception of greater nanoparticle toxicity is based on a limited number of studies, conducted primarily with titanium dioxide and carbon black particle-types. Apart from variables such as particle size and surface area, it is conceivable that several additional physicochemical particle characteristics could play more significant roles in facilitating the development of nanoparticle-related toxicity; particularly when considering particle surface-cell interactions. These include but are not limited to: (i) Surface reactivity of particle-types; (ii) surface coatings; (iii) aggregation/disaggregation potential; and (iv) the method of nanoparticle synthesis. We present results of pulmonary bioassay hazard/safety studies with quartz particles of varying sizes/surface areas. These demonstrated that intratracheal instillation exposures to fine-sized, Min-U-Sil quartz particles (0.5 µm [particle size] – 5 m2/g [surface area]) produced (persistent) enhanced pulmonary toxicity (inflammation, cytotoxicity, cell proliferation and/or histopathology) in rats when compared to nanoscale quartz particles (50 nm–31 m2/g), but not when compared to smaller nanoscale quartz sizes (e.g., 12 nm–91 m2/g). The toxicity results correlated with red blood cell hemolytic potency as a measure of particle surface reactivity. In a second pulmonary bioassay study in rats, pulmonary hazard effects were measured following exposures to three different ultrafine (nano) TiO2 particle-types, each with similar particle size distributions. The various TiO2 particles differed in their crystal structures and surface reactivity endpoints as measured by the Vitamin C yellowing assay. Moreover, the surface activity characteristics correlated with potency of hazard biomarkers as described above, in these dose/response, time-course studies. It is concluded that particle surface reactivity, rather than particle size/surface area endpoints correlated best with lung inflammatory potency following exposures to particles.
    Nanotoxicology 09/2009; 3(3):181-187. · 7.84 Impact Factor
  • Christie M. Sayes, David B. Warheit
    Nanotoxicity, 08/2009: pages 29 - 39; , ISBN: 9780470747803
  • David B Warheit, Kenneth L Reed, Christie M Sayes
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    ABSTRACT: Results of some lung toxicology studies in rats indicate that pulmonary exposures to ultrafine or nanoparticles produce enhanced inflammatory responses compared to fine-sized particles. Apart from particle size and corresponding surface area considerations, several additional factors may influence the lung toxicity of nanoparticles. These include surface reactivity or surface treatments/coatings of particles, and aggregation potential of aerosolized particles. Conclusions from three pulmonary bioassay hazard/safety studies are summarized herein and demonstrate that particle surface characteristics such as chemical reactivity often correlate better with pulmonary toxicity than particle size or surface area considerations. In the first study, fine-sized quartz particle exposures in rats (500 nm) produced similar effects (inflammation, cytotoxicity, cell proliferation, and/or histopathology) compared to smaller 12-nm nanoscale quartz particles. In another study, no measurable differences in lung toxicity indices were quantified when comparing exposure effects in rats to (1) fine-sized TiO(2) particles (300 nm, 6 m(2)/g [surface area]); (2) TiO(2) nanodots (6-10 nm, 169 m(2)/g); or (3) TiO(2) nanorods (27 m(2)/g). In a third study, exposures to ultrafine TiO(2) particles of similar sizes and different surface areas produced differential degrees of toxicity--based in large part upon surface reactivity endpoints--rather than particle size or surface area indices. Finally, in a related issue for nanotechnology implications, a concept for developing a risk assessment system for the development of new nanomaterials is presented. Embodied in a Nanorisk framework process, implementation of a base set of toxicity tests for evaluating the health and environmental hazards related to nanoparticle exposures is discussed.
    Inhalation Toxicology 08/2009; 21 Suppl 1:61-7. · 1.89 Impact Factor
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    ABSTRACT: Risk evaluations for nanomaterials require the generation of hazard data as well as exposure assessments. Most of the validated nanotoxicity studies have been conducted using invivo experimental designs. It would be highly desirable to develop invitro pulmonary hazard tests to assess the toxicity of fine and nanoscale particle-types. However, invitro evaluations for pulmonary hazards are known to have limited predictive value for identifying invivo lung toxicity effects. Accordingly, this study investigated the capacity of invitro screening studies to predict invivo pulmonary toxicity of several fine or nanoparticle-types following exposures in rats. Initially, complete physicochemical characterization of particulates was conducted, both in the dry and wet states. Second, rats were exposed by intratracheal instillation to 1 or 5mg/kg of the following particle-types: carbonyl iron, crystalline silica, amorphous silica, nanoscale zinc oxide, or fine zinc oxide. Inflammation and cytotoxicity endpoints were measured at 24h, 1 week, 1month and 3months post-instillation exposure. In addition, histopathological analyses of lung tissues were conducted at 3months post-exposure. Pulmonary cell invitro studies consisted of three different culture conditions at 4 different time periods. These included (1) rat L2 lung epithelial cells, (2) primary rat alveolar macrophages, and (3) alveolar macrophage—L2 lung epithelial cell co-cultures which were incubated with the same particles as tested in the invivo study for 1, 4, 24, or 48h. Cell culture fluids were evaluated for cytotoxicity endpoints and inflammatory cytokines at the different time periods in an attempt to match the biomarkers assessed in the invivo study. Results of invivo pulmonary toxicity studies demonstrated that instilled carbonyl iron particles produced little toxicity. Crystalline silica and amorphous silica particle exposures produced substantial inflammatory and cytotoxic effects initially, but only the crystalline silica variety produced sustained and progressive inflammatory and cytotoxic responses, leading to the development of pulmonary fibrosis. Exposures to nanoscale or fine-sized zinc oxide particles produced potent but typical “metal fume fever”-like reversible inflammation/cytotoxic effects which were resolved by 1-month postinstillation exposure. In contrast to the invivo results, using cytotoxicity and inflammation endpoints, invitro effects to the various particle-types were difficult to gauge, owing to the number of variables that were studied (i.e., cell-types, time-course, dose response (including particle overload doses)), and various endpoints (e.g., cytotoxicity=LDH, MTT; inflammation/cytokines=MIP-2). For instance, none of the invitro endpoints could mimic a transient inflammatory/cytotoxic response—as was measured following exposures to amorphous silica, or fine or nanoscale zinc oxide particles. We conclude that current invitro cell culture systems do not accurately forecast the pulmonary hazard responses of instilled particle-types. It seems clear that invitro cellular systems will need to be further developed, standardized, and validated (relative to invivo effects) in order to provide useful screening data on the relative toxicity of inhaled particles.
    Journal of Nanoparticle Research 01/2009; 11(2):421-431. · 2.18 Impact Factor
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    ABSTRACT: Abstract Hydrochlorofluorocarbon (HCFC) 122 (1,1-difluoro-1,2,2-trichloroethane) is an intermediate in the synthesis of HCFC-123, a principal potential replacement candidate for chlorofluorocarbon (CFC) compounds in blowing agent and chiller applications. Because the possibility exists for inhalation exposure of HCFC-722 for workers, this study was conducted to assess the toxicity of repeated inhalation of sublethal concentrations of HCFC-722. Four groups of 10 male Cr1:CD BR rats were exposed 6 h/day, 5 days/wk for 2 wk to concentrations of 0, 700, 540, and 2200 ppm HCFC-122 in air. No deaths occurred that could be related to exposure to HCFC-122. Male rats exposed to 2200 ppm HCFC-122 had significantly decreased body weights at various time periods during the exposure but not during the recovery periods. In addition, rats exposed to 170 and 2200 but not 540 ppm had significantly decreased body weight gains during the exposure phase of the study. Functional observational battery (FOB) assessments of exposed and control male rats were conducted before and after exposures on exposure days 1 and 8. On the basis of these evaluations, HCFC-722 was not considered to be neurotoxic. Clinical pathological examinations revealed exposure-related decreases in mean serum concentrations of triglycerides, cholesterol, and globulin, and increases in urine fluoride for all treated groups. Rats in the 540 and 2200 ppm groups also had decreased serum concentrations of total protein and increased alanine aminotransferase (ALV activities. All clinical chemical changes were reversible following a 2-wk recovery period except urine fluoride concentrations, which remained increased in all treatment groups. Pathological examinations revealed significant decreases in mean final body weights in the 540 and 2200 groups, and increased mean relative liver weights in all treated groups relative to controls. These effects were reversible following a 2-wk recovery period. Microscopically, hepatocellular hypertrophy correlated with liver weight changes. Hypertrophy was minimal and occurred in all treated groups without a definitive dose-reesponse relationship with respect to incidence or severity All pathological changes were reversible following the 14-day recovery period. Under the conditions of this study and based on the clinical chemical and pathological parameters measured, a no-observable-effect level for male rats could not be established. The findings of treatment-related clinical chemical and pathological changes in the liver reflect the target organ toxicity.
    09/2008; 4(2):81-93.
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    ABSTRACT: Abstract The pulmonary toxicities of 5 different ethylene oxide/propylene oxide (EO/PO) copolymer commercial lubricant candidates were assessed by exposing groups of rats for 3 consecutive days (6 hlday) to aerosols of the different EO/PO test materials and evaluating pulmonary parameters at selected postexposure time periods. Because all 5 compounds could not be evaluated simultaneously, these studies were conducted over a period of 2 wk. During wk 1 of the study, rats were exposed either to 22 mg/m3 (mean value for the 3 days) of UCON 50-HB-5100 (50-HB-5100), to 110 mg/m3 of Pluronic L31 (131), or to 99.4 mg/m3 of Pluronic L64 (L64). The mass median aerodynamic diameters (MMADs) for all 3 compounds were < 2.6 μm. In the second group of studies, rats were exposed to 42 mg/m3 of UCON 50-HB-2000 (50-HB-2000), or to 111 mg/m3 of UCON 75-H-1400 (75-H-1400), with MMADs < 1.8 μm. Sham controls were exposed to room air. One rat in the UCON 50-HB-5W0 group died within 7 days postexposure. Similarly, 1 rat in the UCON 50-HB-2000 group died within 8 days postexposure. Within 48 h after exposure, the lungs of rats exposed to UCON 50-HB-5W0 and 50-HB-2000 were edematous. The lungs of rats were lavaged at 0 h (i.e., immediately after), 2 days, 1 wk, 1 and 3 mo postexposure. Cellular and biochemical data on samples recovered from bronchoalveolar lavage (BAD demonstrated a substantial pulmonary inflammatory response concomitant with increases in BAL fluid levels of lactate dehydrogenase (LDH), protein, alkaline phosphatase, and N-acetylglucosaminidase in the lungs of rats exposed to UCON 50-HB-5100. Similarly, the BAL biochemical and pulmonary cell differential data for 50-HB-2000-exposed rats were similar but less severe to that previously measured in 50-HB-5100-exposed rats. In contrast, the lungs of rats exposed to Pluronic 131 and L64 and UCON 75 H-1400 demonstrated only slight and reversible pulmonary inflammatory effects. The results from this study validate this inhalation bioassay technique for predicting the pulmonary toxicity of inhaled aerosols by confirming the effects measured in a previous 2-wk inhalation toxicity study with these same compounds. In the earlier study, UCON 50-HB-5W0 and UCON 50-HB-2000 produced severe pulmonary toxicity in rats. The cellular and biochemical results presented here confirm the earlier findings of significant pulmonary toxicity produced by inhalation of the UCON 50-HB-5W0 and UCON 50-HB-2000 compounds. In contrast, the three other compounds (Pluronic L31, Pluronic L64, UCON 75-H-1400) produced only weak pulmonary inflammatory effects following 3-day exposures at high aerosol concentrations.
    09/2008; 7(3):377-392.
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    ABSTRACT: The field of nanotechnology currently is undergoing a dramatic expansion in material science research and development. Most of the research efforts have been focused on applications; the implications (i.e., health and environmental effects) research has lagged behind. The success of nanotechnology will require assurances that the products being developed are safe from an environmental, health, and safety (EHS) standpoint. In this regard, it has been previously reported in pulmonary toxicity studies that lung exposures to ultrafine or nanoparticles (defined herein as particle size <100 nm in one dimension) produce enhanced adverse inflammatory responses when compared to larger particles of similar composition. Surface properties (particularly particle surface area) and free radical generation, resulting from the interactions of particles with cells may play important roles in nanoparticle toxicity. This brief review identifies some of the key factors for studying EHS risks and hazard effects related to nanoparticle exposures. Health and environmental risk evaluations are products of hazard and exposure assessments. The key factors for discussion herein include the importance of particle characterization studies; development of a nanomaterial risk framework; as well as corresponding hypothesis-driven, mechanistically-oriented investigations, concomitant with base set hazard studies which clearly demonstrate that particle size is only a single (and perhaps minor) factor in influencing the safety of nanomaterials.
    Pharmacology [?] Therapeutics 08/2008; 120(1):35-42. · 7.79 Impact Factor
  • David B Warheit
    Toxicological Sciences 03/2008; 101(2):183-5. · 4.33 Impact Factor

Publication Stats

5k Citations
386.42 Total Impact Points

Institutions

  • 1989–2010
    • Dupont
      Delaware, Ohio, United States
  • 2009
    • University of Arkansas at Little Rock
      • Department of Applied Sciences
      Little Rock, AR, United States
    • Texas A&M University
      • Department of Veterinary Physiology & Pharmacology
      College Station, TX, United States
  • 2007
    • Rice University
      • Department of Chemistry
      Houston, Texas, United States
  • 1988
    • National Institute of Environmental Health Sciences
      Durham, North Carolina, United States