David B Warheit

The Chemours Company, Wilmington, Delaware, United States

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Publications (131)457.97 Total impact

  • David B. Warheit · Christie M. Sayes ·
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    ABSTRACT: The basic principles for evaluating the health risks posed by nanoparticles (NPs) require an identification and recognition of potential exposures;—in addition to the associated hazards that may occur. Accordingly, this brief chapter has been developed to describe the range and types of potential human exposures that may result from interactions with NPs—either in the occupational/workplace environment, in consumer products (including food materials), or in a diagnostic/therapeutic medical setting. Very little is known about the ecological consequences to flora and fauna from environmental exposures to NPs—thus this particular issue will not be discussed further. In addition, following a brief description of the possible NP exposures that may stem from applications and portal routes such as inhalation, dermal, oral, etc., a Nano Risk Framework is presented and its components defined. This brief summary takes into account the various routes of exposure during the lifecycle of an NP-containing product, and seeks to develop a risk framework/management tool for screening potential hazards.
    Nanoengineering, 12/2015: pages 41-54; , ISBN: 9780444627476
  • D.B. Warheit · R Boatman · S.C. Brown ·
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    ABSTRACT: Six different commercial forms and sizes of titanium dioxide particles were tested in separate developmental toxicity assays. The three pigment-grade (pg) or 3 ultrafine (uf)/nanoscale (anatase and/or rutile) titanium dioxide (TiO2) particle-types were evaluated for potential maternal and developmental toxicity in pregnant rats by two different laboratories. All studies were conducted according to OECD Guideline 414 (Prenatal Developmental Toxicity Study). In addition, all test materials were robustly characterized. The BET surface areas of the pg and uf samples ranged from 7 - 17 m(2)/g and 50 - 82 m(2)/g respectively (see Table 1). The test substances were formulated in sterile water. In all of the studies, the formulations were administered by oral gavage to time-mated rats daily beginning around the time of implantation and continuing until the day prior to expected parturition. In 3 of the studies (uf-1, uf-3, & pg-1), the formulations were administered to Crl:CD(SD) rats beginning on gestation day (GD) 6 through GD 20. In 3 additional studies (uf-2, and pg-2, pg-3 TiO2 particles), the formulations were administered to Wistar rats beginning on GD 5 through 19. The dose levels used in all studies were 0, 100, 300, or 1000 mg/kg/day; control group animals were administered the vehicle. During the in-life portions of the studies, body weights, food consumption, and clinical observations before and after dosing were collected on a daily basis. All dams were euthanized just prior to expected parturition (GD 21 for Crl:CD(SD) rats and GD 20 for Wistar rats). The gross necropsies included an examination and description of uterine contents including counts of corpora lutea, implantation sites, resorptions, and live and dead fetuses. All live fetuses were sexed, weighed, and examined externally and euthanized. Following euthanasia, fresh visceral and head examinations were performed on selected fetuses. The fetal carcasses were then processed and examined for skeletal alterations. There was no evidence of maternal or developmental toxicity at any dose level tested in any of the six studies. Based on these results, the no-observed-adverse-effect level (NOAEL) for titanium dioxide was 1000 mg/kg/day, the highest administered dose, in both the Sprague-Dawley (Crl:CD(SD) and Wistar rat strains.
    Regulatory Toxicology and Pharmacology 10/2015; DOI:10.1016/j.yrtph.2015.09.032 · 2.03 Impact Factor
  • D B Warheit · T R Webb · K L Reed ·
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    ABSTRACT: Allergic asthma is a pulmonary disease characterized by antigen-induced pulmonary eosinophilia, airway hyperresponsiveness, antigen-specific IgE antibody responses, and broncho-constriction. In attempting to elucidate mechanisms associated with the pathogenesis of this disease, a number of animal models have been developed. The current studies were undertaken to develop a model of allergic asthma model in Brown Norway rats. Unlike the neutrophilic inflammatory response to inhaled particles in most strains of rats, inhalation of antigens in sensitized Brown Norway rats results in a complex cellular response which is characterized by a variety of inflammatory cell types, and is dependent on the time course of inflammatory cell recruitment. In characterizing this ovalbumin-challenge model of allergic asthma, it was important to assess the time course of pulmonary inflammation, cell proliferation, and apoptosis. Male Brown Norway rats were sensitized and boosted with intraperitoneal injections of ovalbumin in aluminum hydroxide on experimental days 1 and 8. On days 15-17, rats were challenged by an inhalation exposure to 5% ovalbumin and were evaluated by bronchoalveolar lavage (BAL) at 24 or 48 h postexposure (PE). Control rats were similarly treated to ovalbumin aerosol exposures; however, these animals had been sensitized and boosted with aluminum hydroxide (minus the ovalbumin). Cell differential evaluations demonstrated that the rats exposed for 3 days/24 h postexposure and for 2 days/ 48 h postexposure produced the greatest numbers of BAL eosinophils and corresponding indicators of pulmonary toxicity. It was interesting to note that earlier exposure time periods (i.e., 1 day/24 h PE) generated a predominantly neutrophilic inflammatory response, while longer exposure/postexposure time periods (i.e., 3 days/48 h) produced a predominant mononuclear inflammatory response. Subsequent studies demonstrated that the 2-day/ 48-h protocol produced the optimum eosinophilic, cytotoxic, cell proliferative, and apoptotic response. Histopathological evaluations demonstrated a chronically active alveolitis and bronchiolitis, characterized by epithelial cell proliferation in the airways and inflammatory cell proliferation in the alveoli. Studies are ongoing to assess the cell types undergoing apoptosis in both the airway and parenchymal regions to fully characterize this model in order to assess its relevance and utility for studying asthma in humans.
    Inhalation Toxicology 09/2015; 12 Suppl 3:381-8. DOI:10.1080/08958378.2000.11463249 · 2.26 Impact Factor
  • 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: The exponential growth in the employment of nanomaterials (NMs) has given rise to the field of nanotoxicology; which evaluates the safety of engineered NMs. Initial nanotoxicological studies were limited by a lack of both available materials and accurate biodispersion characterization tools. However, the years that followed were marked by the development of enhanced synthesis techniques and characterization technologies; which are now standard practice for nanotoxicological evaluation. Paralleling advances in characterization, significant progress was made in correlating specific physical parameters, such as size, morphology, or coating, to resultant physiological responses. Although great strides have been made to advance the field, nanotoxicology is currently at a crossroads and faces a number of obstacles and technical limitations not associated with traditional toxicology. Some of the most pressing and influential challenges include establishing full characterization requirements, standardization of dosimetry, evaluating kinetic rates of ionic dissolution, improving in vitro to in vivo predictive efficiencies, and establishing safety exposure limits. This Review will discuss both the progress and future directions of nanotoxicology: highlighting key previous research successes and exploring challenges plaguing the field today. Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.
    Toxicological Sciences 09/2015; 147(1):5-16. DOI:10.1093/toxsci/kfv106 · 3.85 Impact Factor
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  • 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
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    ABSTRACT: The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) ‘Nano Task Force’ proposes a Decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping) that consists of 3 tiers to assign nanomaterials to 4 main groups, to perform sub-grouping within the main groups and to determine and refine specific information needs. The DF4nanoGrouping covers all relevant aspects of a nanomaterial’s life cycle and biological pathways, i.e. intrinsic material and system-dependent properties, biopersistence, uptake and biodistribution, cellular and apical toxic effects. Use (including manufacture), release and route of exposure are applied as ‘qualifiers’ within the DF4nanoGrouping to determine if, e.g. nanomaterials cannot be released from a product matrix, which may justify the waiving of testing. The four main groups encompass (1) soluble nanomaterials, (2) biopersistent high aspect ratio nanomaterials, (3) passive nanomaterials, and (4) active nanomaterials. The DF4nanoGrouping aims to group nanomaterials by their specific mode-of-action that results in an apical toxic effect. This is eventually directed by a nanomaterial’s intrinsic properties. However, since the exact correlation of intrinsic material properties and apical toxic effect is not yet established, the DF4nanoGrouping uses the ‘functionality’ of nanomaterials for grouping rather than relying on intrinsic material properties alone. Such functionalities include system-dependent material properties (such as dissolution rate in biologically relevant media), bio-physical interactions, in vitro effects and release and exposure. The DF4nanoGrouping is a hazard and risk assessment tool that applies modern toxicology and contributes to the sustainable development of nanotechnological products. It ensures that no studies are performed that do not provide crucial data and therefore saves animals and resources.
    Regulatory Toxicology and Pharmacology 03/2015; 8(2). DOI:10.1016/j.yrtph.2015.03.007 · 2.03 Impact Factor
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    ABSTRACT: a b s t r a c t The grouping of substances serves to streamline testing for regulatory purposes. General grouping approaches for chemicals have been implemented in, e.g., the EU chemicals regulation. While specific regulatory frameworks for the grouping of nanomaterials are unavailable, this topic is addressed in dif-ferent publications, and preliminary guidance is provided in the context of substance-related legislation or the occupational setting. The European Centre for Ecotoxicology and Toxicology of Chemicals Task Force on the Grouping of Nanomaterials reviewed available concepts for the grouping of nanomaterials for human health risk assessment. In their broad conceptual design, the evaluated approaches are consis-tent or complement each other. All go beyond the determination of mere structure–activity relationships and are founded on different aspects of the nanomaterial life cycle. These include the NM's material prop-erties and biophysical interactions, specific types of use and exposure, uptake and kinetics, and possible early and apical biological effects. None of the evaluated grouping concepts fully take into account all of these aspects. Subsequent work of the Task Force will aim at combining the available concepts into a comprehensive 'multiple perspective' framework for the grouping of nanomaterials that will address all of the mentioned aspects of their life cycles.
    Regulatory Toxicology and Pharmacology 09/2014; 70(2):492. DOI:10.1016/j.yrtph.2014.07.025 · 2.03 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
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    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

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9k Citations
457.97 Total Impact Points


  • 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