David B Warheit

The Chemours Company, Wilmington, Delaware, United States

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Publications (122)445.76 Total impact

  • D.B. Warheit · S.C. Brown · E.M. Donner
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    ABSTRACT: Data generated using standardized testing protocols for toxicity studies generally provide reproducible and reliable results for establishing safe levels and formulating risk assessments. The findings of three OECD guideline-type oral toxicity studies of different duration in rats are summarized in this publication; each study evaluated different titanium dioxide (TiO2) particles of varying sizes and surface coatings. Moreover, each study finding demonstrated an absence of any TiO2 -related hazards. To briefly summarize the findings: 1) In a subchronic 90-day study (OECD TG 408), groups of young adult male and female rats were dosed with rutile-type, surface-coated pigment-grade TiO2 test particles (d50 = 145 nm - 21% nanoparticles by particle number criteria) by oral gavage for 90 days. The no-adverse-effect level (NOAEL) for both male and female rats in this study was 1000 mg/kg bw/day, the highest dose tested. The NOAEL was determined based on a lack of TiO2 particle-related adverse effects on any in-life, clinical pathology, or anatomic/microscopic pathology parameters; 2) In a 28-day repeated-dose oral toxicity study (OECD TG 407), groups of young adult male rats were administered daily doses of two rutile-type, uncoated, pigment-grade TiO2 test particles (d50 = 173 nm by number) by daily oral gavage at a dose of 24,000 mg/kg bw/day. There were no adverse effects measured during or following the end of the exposure period; and the NOAEL was determined to be 24,000 mg/kg bw/day; 3) In an acute oral toxicity study (OECD TG 425), female rats were administered a single oral exposure of surface-treated rutile/anatase nanoscale TiO2 particles (d50 = 73 nm by number) with doses up to 5,000 mg/kg and evaluated over a 14-day post-exposure period. Under the conditions of this study, the oral LD50 for the test substance was > 5000 mg/kg bw. In summary, the results from these three toxicity studies - each with different TiO2 particulate-types, demonstrated an absence of adverse toxicological effects. Apart from reporting the findings of these three studies, this publication also focuses on additional critical issues associated with particle and nanotoxicology studies. First, describing the detailed methodology requirements and rigor upon which the standardized OECD 408 guideline subchronic oral toxicity studies are conducted. Moreover, an attempt is made to reconcile the complex issue of particle size distribution as it relates to measurements of nanoscale and pigment-grade TiO2 particles. Clearly this has been a confusing issue and often misrepresented in the media and the scientific literature. It is clear that the particle-size distribution for pigment-grade TiO2, contains a small ("tail") component of nanoscale particles (i.e., 21% by particle number and < 1% by weight in the test material used in the 90-day study). However, this robust particle characterization finding should not be confused with mislabeling the test materials as exclusively in the nanoscale range. Moreover, based upon the findings presented herein, there appears to be no significant oral toxicity impact contributed by the nanoscale component of the TiO2 Test Material sample in the 90-day study. Finally, it seems reasonable to conclude that the study findings should be considered for read-across purposes to food-grade TiO2 particles (e.g., E-171), as the physicochemical characteristics are quite similar. Copyright © 2015. Published by Elsevier Ltd.
    Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 09/2015; DOI:10.1016/j.fct.2015.08.026 · 2.90 Impact Factor
  • David B Warheit · E Maria Donner
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    ABSTRACT: A recent review article critically assessed the effectiveness of published research articles in nanotoxicology to meaningfully address health and safety issues for workers and consumers. The main conclusions were that, based on a number of flaws in study designs, the potential risk from exposures to nanomaterials is highly exaggerated, and that no ‘nano-specific’ adverse effects, different from exposures to bulk particles, have been convincingly demonstrated. In this brief editorial we focus on a related tangential issue which potentially compromises the integrity of basic risk science. We note that some single investigation studies report specious toxicity findings, which make the conclusions more alarming and attractive and publication worthy. In contrast, the standardized, carefully conducted, ‘guideline study results’ are often ignored because they can frequently report no adverse effects; and as a consequence are not considered as novel findings for publication purposes, and therefore they are never considered as newsworthy in the popular press. Yet it is the Organization for Economic Cooperation and Development (OECD) type test guideline studies that are the most reliable for conducting risk assessments. To contrast these styles and approaches, we present the results of a single study which reports high toxicological effects in rats following low-dose, short-term oral exposures to nanoscale titanium dioxide particles concomitant with selective investigative analyses. Alternatively, the findings of OECD test guideline 408, standardized guideline oral toxicity studies conducted for 90 days at much higher doses (1000 mg kg−1) in male and female rats demonstrated no adverse effects following a very thorough and complete clinical chemical, as well as histopathological evaluation of all of the relevant organs in the body. This discrepancy in study findings is not reconciled by the fact that several biokinetic studies in rats and humans demonstrate little or no uptake of nanoscale or pigment-grade TiO2 particles following oral exposures. We conclude that to develop a competent risk assessment profile, results derived from standardized, guideline-type studies, and even ‘no effect’ study findings provide critically useful input for assessing safe levels of exposure; and should, in principle, be readily acceptable for publication in peer-reviewed toxicology journals. This is a necessary prerequisite for developing a complete dataset for risk assessment determinations.
    Science and Technology of Advanced Materials 06/2015; 16(3). DOI:10.1088/1468-6996/16/3/034603 · 3.51 Impact Factor
  • David B. Warheit · Kenneth L. Reed · Michael P. DeLorme
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    ABSTRACT: Pulmonary exposures to air pollution-derived particulate matter (PM) may result in both activation of lung responses and adverse cardiovascular (CV) effects. This suggests a cross-talk relationship between local and systemic responses potentially leading to CV disease in humans. To test this hypothesis in a normal animal model, rats were exposed to aerosols of carbon nanofibers (CNF) for 13 weeks. The highest CNF concentration (25 mg/m(3)) produced persistent respiratory tract (RT) inflammation/cytotoxicity throughout the exposure and 3-month recovery period, concomitant with translocation of inhaled CNF from airspace to extrapulmonary sites. The finding provided a basis for postulating that local RT effects could translocate to the systemic circulation, thereby producing CV alterations such as inflammation and/or coagulation changes. Therefore, assessments of cardiovascular endpoints such as cardiomyocyte cell proliferation (CP)/histopathology, C-reactive protein (CRP) levels, and 4 different diagnostic coagulation parameters, were investigated. No significant differences were measured between air or CNF-exposed rats when measuring fibrinogen levels, platelet counts, PT and aPTT bleeding times, and CRP levels. In addition, CP and histopathology evaluations were not different in CNF-exposed rats. Cardiac physiology and telemetry responses were not measured in this study. It was concluded that no apparent cross-talk was evident between local respiratory and systemic/cardiovascular compartments. (c) 2013 Elsevier Ltd. All rights reserved.
    Carbon 10/2013; 62:165-176. DOI:10.1016/j.carbon.2013.06.008 · 6.20 Impact Factor
  • 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; 220(2). DOI:10.1016/j.toxlet.2013.04.002 · 3.26 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; 41(2). DOI:10.1177/0192623312467401 · 2.14 Impact Factor
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    ABSTRACT: The widespread and increasing use of carbon nanotubes in scientific and engineering research and their incorporation into manufactured goods has urged an assessment of the risks and hazards associated with exposure to them. The field of nanotoxicology studies the toxicology of nanoparticles such as carbon nanotubes and has become a major growth area aimed towards risk assessment of nanoparticles. Compiled by a team of leading experts at the forefront of research, this is the first book dedicated to the toxicology of carbon nanotubes. It provides state-of-the-science information on how and why they are so potentially dangerous if breathed in, including their similarities to asbestos. The book examines various aspects of carbon nanotubes, from their manufacture and aerodynamic behaviour to their effects at molecular level in the lungs. It is invaluable to the many groups involved with research in this area, as well as to regulators and risk assessors.
    Edited by Ken Donaldson, 06/2012; Cambridge University Press., ISBN: 9781107008373
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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. DOI:10.1093/toxsci/kfs172 · 3.85 Impact Factor
  • Ken Donaldson · David B. Warheit
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    ABSTRACT: This chapter contains sections titled: IntroductionUFs in Particulate Matter (PM), the Road to Concern Over Manufactured NPs, and the Rise of NanotoxicologyNPs at the Cellular LevelNanoparticokinetics: Translocation from the Lungs and New TargetsExemplar New Manufactured NPs and their NanotoxicologyThe Bed For NPs-Surface Area, Surface Reactivity, Soluble Ions, and BiopersistenceHazard Assessment and Predictive TestingConclusion on the Cardiovascular System and Manufactured NPsReferences
    Cardiovascular Effects of Inhaled Ultrafine and Nanosized Particles, 03/2011: pages 525-543; , ISBN: 9780470433539
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    Andrew D Maynard · David B Warheit · Martin A Philbert
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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(Suppl 1):S109-29. DOI:10.1093/toxsci/kfq372 · 3.85 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. DOI:10.1007/978-1-61779-052-2_20 · 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(4):409-13. DOI:10.3109/17435390.2010.485704 · 6.41 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; 10(12). DOI:10.1021/nl103432w · 13.59 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. DOI:10.1007/s00216-010-4000-5 · 3.44 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. DOI:10.3109/08958370903359992 · 2.26 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. Copyright © 2009 John Wiley & Sons, Inc. For further resources related to this article, please visit the WIREs website.
    Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology 11/2009; 1(6):660-70. DOI:10.1002/wnan.58 · 4.49 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. DOI:10.1016/j.toxlet.2009.11.006 · 3.26 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. DOI:10.1021/es901453p · 5.33 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. DOI:10.1080/17435390902725930 · 6.41 Impact Factor
  • David B Warheit
    Toxicological Sciences 09/2009; 112(2):273-5. DOI:10.1093/toxsci/kfp237 · 3.85 Impact Factor
  • Christie M. Sayes · David B. Warheit
    Nanotoxicity, 08/2009: pages 29 - 39; , ISBN: 9780470747803

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8k Citations
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  • 2015
    • The Chemours Company
      Wilmington, Delaware, United States
  • 2009
    • Texas A&M University
      • Department of Veterinary Physiology & Pharmacology
      College Station, TX, United States
  • 2006–2007
    • Rice University
      • Department of Chemistry
      Houston, Texas, United States
    • Woodrow Wilson International Center for Scholars
      Washington, Washington, D.C., United States
  • 1989–2007
    • Dupont
      • Central Research and Development
      Delaware, Ohio, United States
  • 1995
    • University of Rochester
      Rochester, New York, United States
  • 1984–1988
    • National Institute of Environmental Health Sciences
      Durham, North Carolina, United States