Terry Gordon, Ph.D.

WTC Dust Induces Gm-Csf In Serum Of Fdny Rescue Workers With Accelerated Decline Of Lung Function And In Cultured Alveolar Macrophages
Naveed B; Comfort AL; Ferrier N; Segal LN; Kasturiarachchi KJ; Kwon S; Chen LC; Gordon T; Cohen MD; Prophete C; Rom WN; Prezant DJ; Nolan A; Weiden M
2011 ;183:?-? #A4770, American journal of respiratory & critical care medicine
— id: 137901, year: 2011, vol: 183, page: ?, stat: Journal Article,

Concentration dependent effects of tobacco particulates from different types of cigarettes on expression of drug metabolizing proteins, and benzo(a)pyrene metabolism in primary normal human oral epithelial cells
Sacks, Peter G; Zhao, Zhong-Lin; Kosinska, Wieslawa; Fleisher, Kenneth E; Gordon, Terry; Guttenplan, Joseph B
2011 Sep;49(9):2348-2355, Food & chemical toxicology
The ability of tobacco smoke (TS) to modulate phase I and II enzymes and affect metabolism of tobacco carcinogens is likely an important factor in its carcinogenicity. For the first time several types of TS particulates (TSP) were compared in different primary cultured human oral epithelial cells (NOE) for their abilities to affect metabolism of the tobacco carcinogen, (BaP) to genotoxic products, and expression of drug metabolizing enzymes. TSP from, reference filtered (2RF4), mentholated (MS), reference unfiltered, (IR3), ultra low tar (UL), and cigarettes that primarily heat tobacco (ECL) were tested. Cells pretreated with TSP concentrations of 0.2-10 mug/ml generally showed increased rates of BaP metabolism; those treated with TSP concentrations above 10 mug/ml showed decreased rates. Effects of TSPs were similar when expressed on a weight basis. Weights of TSP/cigarette varied in the order: MS approximately IR3>2RF4>ECL>UL. All TSPs induced the phase I proteins, cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1), phase II proteins, NAD(P)H dehydrogenase quinone 1 (NQO1), and microsomal glutathione S-transferase 1 (MGST1), and additionally, hydroxysteroid (17-beta) dehydrogenase 2 (HSD17B2), as assessed by qRT-PCR. The pattern of gene induction at probable physiological levels favored activation over detoxification
— id: 138495, year: 2011, vol: 49, page: 2348, stat: Journal Article,

Diesel exhaust particle-treated human bronchial epithelial cells upregulate Jagged-1 and OX40 ligand in myeloid dendritic cells via thymic stromal lymphopoietin
Bleck, Bertram; Tse, Doris B; Gordon, Terry; Ahsan, Mohammad R; Reibman, Joan
2010 Dec 1;185(11):6636-6645, Journal of immunology
Ambient particulate matter, including diesel exhaust particles (DEP), promotes the development of allergic disorders. DEP increase oxidative stress and influence human bronchial epithelial cell (HBEC)-dendritic cell interactions via cytokines, including thymic stromal lymphopoietin (TSLP). Upregulation of TSLP results in Th2 responses. Using primary culture HBEC and human myeloid dendritic cell (mDC) cocultures, we show in this study that DEP upregulation of Th2 responses occurred via HBEC-dependent mechanisms that resulted from oxidative stress. Moreover, DEP-treated HBEC and ambient particulate matter-treated HBEC upregulated OX40 ligand (OX40L) and the Notch ligand Jagged-1 mRNA and expression on mDC. Upregulation of OX40L as well as Jagged-1 on mDC required HBEC and did not occur in the presence of N-acetylcysteine. Furthermore, OX40L and Jagged-1 upregulation was inhibited when HBEC expression of TSLP was silenced. Thus, DEP treatment of HBEC targeted two distinct pathways in mDC that were downstream of TSLP expression. Upregulation of OX40L and Jagged-1 by mDC resulted in mDC-driven Th2 responses. These studies expand our understanding of the mechanism by which ambient pollutants alter mucosal immunity and promote disorders such as asthma
— id: 114828, year: 2010, vol: 185, page: 6636, stat: Journal Article,

Pulmonary response after exposure to inhaled nickel hydroxide nanoparticles: short and long-term studies in mice
Gillespie PA; Kang GS; Elder A; Gelein R; Chen L; Moreira AL; Koberstein J; Tchou-Wong KM; Gordon T; Chen LC
2010 Mar 1;4(1):106-119, Nanotoxicology
Short and long-term pulmonary response to inhaled nickel hydroxide nanoparticles (nano-Ni(OH)(2), CMD = 40 nm) in C57BL/6 mice was assessed using a whole body exposure system. For short-term studies mice were exposed for 4 h to nominal concentrations of 100, 500, and 1000 mg/m(3). For long-term studies mice were exposed for 5 h/d, 5 d/w, for up to 5 months (m) to a nominal concentration of 100 mg/m(3). Particle morphology, size distribution, chemical composition, solubility, and intrinsic oxidative capacity were determined. Markers of lung injury and inflammation in bronchoalveolar lavage fluid (BALF); histopathology; and lung tissue elemental nickel content and mRNA changes in macrophage inflammatory protein-2 (Mip-2), chemokine ligand 2 (Ccl2), interleukin 1-alpha (Il-1alpha), and tumor necrosis factor-alpha (Tnf-alpha) were assessed. Dose-related changes in BALF analyses were observed 24 h after short-term studies while significant changes were noted after 3 m and/or 5 m of exposure (24 h). Nickel content was detected in lung tissue, Ccl2 was most pronouncedly expressed, and histological changes were noted after 5 m of exposure. Collectively, data illustrates nano-Ni(OH)(2) can induce inflammatory responses in C57BL/6 mice
— id: 138224, year: 2010, vol: 4, page: 106, stat: Journal Article,

Prenatal and Postnatal Cigarette Smoke Exposures Increase Susceptibility to Adult Disease
Lyon, J. L.; Gordon, T.
2010 AUG ;51(7):705-705, Environmental & molecular mutagenesis
— id: 113775, year: 2010, vol: 51, page: 705, stat: Journal Article,

WTC PM2.5 stimulates a more intense inflammatory response in human BAL cells than other ambient PM2.5 from NYC and surrounding environs
Naveed B.; Weiden M.D.; Rom W.N.; Prezant D.J.; Comfort A.; Chen L.; Kwon S.; Chen Y.; Gordon T.; Nolan A.
2010 ;3(2):S48-S48, Clinical & Translational Science
OBJECTIVES: Particulate matter (PM) exposure causes adverse health effects. The WTC collapse led to significant PM exposure and lung injury (Weiden et al. Chest 2009). The mechanism by which WTC PM causes pulmonary morbidity is not understood. We are investigating the differential cytokine effects on human alveolar cells, comparing ambient PM of WTC to ambient PM from NYC, South Bronx (SB) and Sterling Forest (SF), a rural area northwest of NYC. METHODS AND POPULATION: AM were obtained from Bronchoalveolar lavage (BAL) by adherence overnight. AM were exposed to 50mug/mL suspensions of WTC, SB, and SF PM2.5. Media alone was the negative control and 40 ng/mL of LPS was the positive control. After 24hrs, supernatants were collected and analyzed in duplicate using Human Cytokine Panel I (Millipore) on a Luminex-200. RESULTS: Fold induction of mediators was expressed as ratios of PM exposure/media alone. Exposure to WTC PM was markedly more inflammatory than SB and SF. The most significant inductions were of the leukocyte growth factors (GM-CSF, G-CSF), a promoter of angiogenesis (VEGF), the chemokine (RANTES) and the potent multifunctional cytokine IL-6. LPS caused a greater induction for all of the analytes when compared to WTC PM except for IL-1ra. SIGNIFICANCE OF STUDY: WTC PM2.5 produces a marked inflammatory effect in comparison to PM2.5 from both NYC, SB and rural sites. The large number of cytokines induced by WTC PM may drive airway injury and may be biomarkers for lung injury. WTC PM has been observed in induced sputum obtained 9 months after 9/11/2001 and so the elaboration of cytokines may underlie the severe and long lasting health effects produced by exposure to WTC PM
— id: 111408, year: 2010, vol: 3, page: S48, stat: Journal Article,

WTC PM2.5 Stimulates A More Intense Inflammatory Response In Human BAL Cells Than Other Ambient PM2.5 From NYC And Surrounding Environs
Naveed, Bushra; Weiden, Michael D; Rom, William N; Prezant, David J; Comfort, Ashley L; Chen, Yingdi; Kwon, Sophia; Chen, Lung Chi; Gordon, Terry; Nolan, Anna
2010 ;181:- #A1158, American journal of respiratory & critical care medicine
— id: 113678, year: 2010, vol: 181, page: , stat: Journal Article,

Strain-dependent differences in susceptibility to lung cancer in inbred mice exposed to mainstream cigarette smoke
Gordon, Terry; Bosland, Maarten
2009 Mar 18;275(2):213-220, Cancer letters
It is becoming increasingly clear that genetic susceptibility is an important host factor determining the effects of exposure to a number of airborne particles and gases. Although numerous studies have identified a genetic component for spontaneous pulmonary tumor development and for chemically induced lung cancer (e.g., urethane) in mice, a systematic examination of murine inter-strain differences in response to cigarette smoke inhalation has not been conducted. We addressed this research gap by examining the strain distribution pattern of lung cancer in nine inbred strains of mice exposed to 258 mg/m(3) mainstream cigarette smoke for 5 months followed by 4 months of rest. Lung tumors were enumerated on fixed lungs visualized at low magnification and on serial step sections examined microscopically. With the low magnification examination, we observed statistically significant increases in the number of lung tumors in cigarette smoke-exposed A/J and the genetically-related A/HeJ mice (p<0.05). While fewer tumors were identified by the microscopic enumeration method, it confirmed that significant increases in lung tumors occurred only in A/J and A/HeJ mice exposed to cigarette smoke (p<0.05). Thus, as predicted by epidemiologic studies and animal experiments using chemically induced lung cancer models, these findings suggest that genetic host factors play a significant role in the pulmonary tumorigenic response of mice to mainstream cigarette smoke
— id: 93226, year: 2009, vol: 275, page: 213, stat: Journal Article,

Patient relations "road show" at university health network
Gordon, Terry; Sedge, Erika; Bakas, Vasiliki
2009 ;12(4):92-95, Healthcare quarterly
COMPLAINTS, COMPLAINTS, COMPLAINTS! Where are my results? Why do I have to wait so long? Is anybody listening? Does anybody care? I'm a taxpayer; I am entitled! Sound familiar? These are the kinds of things we hear on a daily basis from patients and family members
— id: 138498, year: 2009, vol: 12, page: 92, stat: Journal Article,

Enhancement of oxidative stability of polyfluorenes for direct thermal lithography
Han, Xu; Chen, Xiwen; Gordon, Terry; Holdcroft, Steven
2009 Dec 16;30(24):2089-2095, Macromolecular rapid communications
A homopolymer of 9,9'-bis[4-(2-(2-tetrahydropyranyloxy)ethoxy)phenyl]fluorene and its copolymers with 3,4-benzothiadiazole and 4,7-di(3(4-n-octylphenyl)-2-thienyl)-2,1,3-benzothiadiazole were synthesized to produce a series of thermally reactive blue, green, and red luminescent polymers. Thermolytic removal of the tetrahydropyran (THP) group from polymer films, rendered the films insoluble due to the formation of hydroxyl groups on the termini of side chains. Thermal removal of the THP was lowered by up to 200 degrees C, when acid is present in the films. These polymers were found applicable to patterning by NIR direct thermal lithography, in conjunction with a NIR dye and thermal acid generator. The presence of the phenyl groups at the 9-site carbon was found necessary to eliminate fluorenone formation, and enhance the colour purity of the material
— id: 138497, year: 2009, vol: 30, page: 2089, stat: Journal Article,

Genetic determinants of sensitivity to beryllium in mice
Tarantino-Hutchison, Lauren M; Sorrentino, Claudio; Nadas, Arthur; Zhu, Yiwen; Rubin, Edward M; Tinkle, Sally S; Weston, Ainsley; Gordon, Terry
2009 Jun;6(2):130-135, Journal of immunotoxicology
Chronic beryllium disease (CBD), an irreversible, debilitating granulomatous lung disease is caused by exposure to beryllium. This occupational hazard occurs in primary production and machining of Be-metal, BeO, beryllium - containing alloys, and other beryllium products. CBD begins as an MHC Class II-restricted, T(H)1 hypersensitivity, and the Human Leukocyte Antigen, HLA-DPB1E(69), is associated with risk of developing CBD. Because inbred strains of mice have not provided good models of CBD to date, three strains of HLA-DPB1 transgenic mice in an FVB/N background were developed; each contains a single allele of HLA-DPB1 that confers a different magnitude of risk for chronic beryllium disease: HLA-DPB1*0401 (OR approximately 0.2), HLA-DPB1*0201 (OR approximately 3), and HLA-DPB1*1701 (OR approximately 46). The mouse ear swelling test (MEST) was employed to determine if these different alleles would support a hypersensitivity response to beryllium. Mice were first sensitized on the back and subsequently challenged on the ear. In separate experiments, mice were placed into one of three groups (sensitization/challenge): C/C, C/Be, and Be/Be. In the HLA-DPB1*1701 mice, the strain with the highest risk transgene, the Be/Be group was the only group that displayed significant maximum increased ear thickness of 19.6% +/- 3.0% over the baseline measurement (p < 0.05). No significant changes were observed in the other transgenic strains for any treatment condition. In addition, inter-strain differences in response to beryllium in seven inbred strains were investigated through use of the MEST, these included: FVB/N, AKR, Balb/c, C3H/HeJ, C57/BL6, DBA/2, and SJL/J. The FVB/N strain was least responsive, while the SJL/J and C57/BL6 strains were the highest responders. Our results suggest that the HLA-DPB1*1701 transgene product is an important risk factor for induction of the beryllium-sensitive phenotype. This model should be a useful tool for investigating beryllium sensitization
— id: 100670, year: 2009, vol: 6, page: 130, stat: Journal Article,

Age, strain, and gender as factors for increased sensitivity of the mouse lung to inhaled ozone
Vancza, Elizabeth M; Galdanes, Karen; Gunnison, Al; Hatch, Gary; Gordon, Terry
2009 Feb;107(2):535-543, Toxicological sciences
Ozone (O(3)) is a respiratory irritant that leads to airway inflammation and pulmonary dysfunction. Animal studies show that neonates are more sensitive to O(3) inhalation than adults, and children represent a potentially susceptible population. This latter notion is not well established, and biological mechanisms underlying a predisposition to pollution-induced pulmonary effects are unknown. We examined age and strain as interactive factors affecting differential pulmonary responses to inhaled O(3). Male and female adult mice (15 weeks old) and neonates (15-16 days old) from eight genetically diverse inbred strains were exposed to 0.8 ppm O(3) for 5 h. Pulmonary injury and lung inflammation were quantified as total protein concentration and total polymorphonuclear neutrophil (PMN) number in lavage fluid recovered 24-h postexposure. Dose-response and time-course curves were generated using SJL/J pups, and (18)O lung burden dose was assessed in additional mice. Interstrain differences in response to O(3) were seen in neonatal mice: Balb/cJ and SJL/J being most sensitive and A/J and 129x1/SvJ most resistant. The PMN response to O(3) was greater in neonates than in adults, specifically for SJL/J and C3H/HeJ strains, independent of dose. Small gender differences were also observed in adult mice. Variation in protein concentrations and PMN counts between adults and pups were strain dependent, suggesting that genetic determinants do play a role in age-related sensitivity to O(3). Further research will help to determine what genetic factors contribute to these heightened responses, and to quantify the relative contribution of genes vs. environment in O(3)-induced health effects
— id: 97452, year: 2009, vol: 107, page: 535, stat: Journal Article,

Source apportionment of particulate matter in the U.S. and associations with lung inflammatory markers
Duvall, Rachelle M; Norris, Gary A; Dailey, Lisa A; Burke, Janet M; McGee, John K; Gilmour, M Ian; Gordon, Terry; Devlin, Robert B
2008 May;20(7):671-683, Inhalation toxicology
Size-fractionated particulate matter (PM) samples were collected from six U.S. cities and chemically analyzed as part of the Multiple Air Pollutant Study. Particles were administered to cultured lung cells and the production of three different proinflammatory markers was measured to explore the association between the health effect markers and PM. Ultrafine, fine, and coarse PM samples were collected between December 2003 and May 2004 over a 4-wk period in each city. Filters were pooled for each city and the PM samples were extracted then analyzed for trace metals, ions, and elemental carbon. Particle extracts were applied to cultured human primary airway epithelial cells, and the secreted levels of interleukin-8 (IL-8), heme oxygenase-1, and cyclooxygenase-2 were measured 1 and 24 h following exposure. Fine PM sources were quantified by the chemical mass balance (CMB) model. The relationship between toxicological measures, PM sources, and individual species were evaluated using linear regression. Ultrafine and fine PM mass were associated with increases in IL-8 (r(2) = .80 for ultrafine and r(2) = .52 for fine). Sources of fine PM and their relative contributions varied across the sampling sites and a strong linear association was observed between IL-8 and secondary sulfate from coal combustion (r(2) = .79). Ultrafine vanadium, lead, copper, and sulfate were also associated with increases in IL-8. Increases in inflammatory markers were not observed for coarse PM mass and source markers. These findings suggest that certain PM size fractions and sources are associated with markers of lung injury or inflammation
— id: 96270, year: 2008, vol: 20, page: 671, stat: Journal Article,

Particulate matter inhibits DNA repair and enhances mutagenesis
Mehta, Manju; Chen, Lung-Chi; Gordon, Terry; Rom, William; Tang, Moon-Shong
2008 Dec 8;657(2):116-121, Mutation research
Exposure to ambient air pollution has been associated with adverse health effects including lung cancer. A recent epidemiology study has established that each 10mug/m(3) elevation in long-term exposure to average PM(2.5) ambient concentration was associated with approximately 8% of lung cancer mortality. The underlying mechanisms of how PM contributes to lung carcinogenesis, however, remain to be elucidated. We have recently found that transition metals such as nickel and chromium and oxidative stress induced lipid peroxidation metabolites such as aldehydes can greatly inhibit nucleotide excision repair (NER) and enhance carcinogen-induced mutations. Because PM is rich in metal and aldehyde content and can induce oxidative stress, we tested the effect of PM on DNA repair capacity in cultured human lung cells using in vitro DNA repair synthesis and host cell reactivation assays. We found that PM greatly inhibits NER for ultraviolet (UV) light and benzo(a)pyrene diol epoxide (BPDE) induced DNA damage in human lung cells. We further demonstrated that PM exposure can significantly increase both spontaneous and UV-induced mutagenesis. These results together suggest that the carcinogenicity of PM may act through its combined effect on suppression of DNA repair and enhancement of DNA replication errors
— id: 90028, year: 2008, vol: 657, page: 116, stat: Journal Article,

Ambient air particulate matter exposure and tissue factor expression in atherosclerosis
Sun, Qinghua; Yue, Peibin; Kirk, Rita I; Wang, Aixia; Moatti, Didier; Jin, Ximei; Lu, Bo; Schecter, Alison D; Lippmann, Morton; Gordon, Terry; Chen, Lung Chi; Rajagopalan, Sanjay
2008 Jan;20(2):127-137, Inhalation toxicology
Recent studies have suggested a link between inhaled particulate matter (PM) exposure and atherogenesis. We investigated tissue factor (TF) expression with ambient fine particulate matter (diameter < 2.5 microm, PM(2.5)) exposure and in response to in vitro exposure to fine and ultrafine PM in cultured human bronchial epithelial cells, vascular smooth muscle cells (hSMCs), and monocytes. ApoE-/- mice, fed with normal chow (NC) or high-fat chow (HFC), were exposed to concentrated PM(2.5) or filtered air (FA) for 6 mo (6 h/day, 5 day/wk, n = 28). Following in vivo ultrasound bio-microscopy (UBM) assessment of plaque area, macrophage infiltration (CD68) and TF expression in the aorta were quantified. Cultured cells were incubated with size-fractionated PM from cascade impactors, or with standard reference PM material (SRM, number 1649a) and assayed for TF protein, mRNA, and activity. UBM-derived plaque areas were 7 +/- 1% larger in the PM(2.5)-HFC than the FA-HFC group (p = .04), but not significantly different between the PM(2.5)-NC and FA-NC groups (p = .07). Immunohistochemistry revealed increased TF (15 +/- 3% vs. 8 +/- 2%, p < .01) and macrophage infiltration (19 +/- 2% vs. 14 +/- 3%, p < .01) in the plaques of PM(2.5)-HFC compared with FA-HFC groups. Impactor-collected PM(2.5) and ultrafine particles consistently increased TF protein in bronchial epithelial cells, monocytes, and hSMCs. TF mRNA expression increased rapidly (within 1 h) in response to SRM PM. We conclude that in vivo and in vitro exposure to ambient air PM(2.5) induces TF expression
— id: 78627, year: 2008, vol: 20, page: 127, stat: Journal Article,

Panel discussion review: session four--assessing biological plausibility of epidemiological findings in air pollution research
Brown, James S; Graham, Judith A; Chen, Lung Chi; Postlethwait, Edward M; Ghio, Andrew J; Foster, W Michael; Gordon, Terry
2007 Dec;17 Suppl 2:S97-105, Journal of exposure science & environmental epidemiology
In December 2006, the U.S. Environmental Protection Agency (EPA) sponsored a 2-day workshop on 'Interpretation of Epidemiologic Studies of Multipollutant Exposure and Health Effects' in Chapel Hill, NC. The final session at this workshop was devoted to assessing the biological plausibility of epidemiological findings with regard to criteria air pollutants. The presentations and the panel contributions of this last session primarily focused on controlled exposure studies and led to wide-ranging discussions, some of which were provocative. The panel summary provides some guidance to future evaluations of the biological plausibility of the epidemiological reports on criteria pollutants and is intended to stimulate thinking, without drawing any definitive conclusions. This paper does not approach, nor was it intended to approach, the more formal analytical approach such as that used in EPA's development of its Science Assessment Document for the criteria pollutants
— id: 78626, year: 2007, vol: 17 Suppl 2, page: S97, stat: Journal Article,

Comparative toxicity of size-fractionated airborne particulate matter obtained from different cities in the United States
Gilmour, M Ian; McGee, John; Duvall, Rachelle M; Dailey, Lisa; Daniels, Mary; Boykin, Elizabeth; Cho, Seung-Hyun; Doerfler, Donald; Gordon, Terry; Devlin, Robert B
2007 ;19 Suppl 1:7-16, Inhalation toxicology
Hundreds of epidemiological studies have shown that exposure to ambient particulate matter (PM) is associated with dose-dependent increases in morbidity and mortality. While early reports focused on PM less than 10 microm (PM10), numerous studies have since shown that the effects can occur with PM stratified into ultrafine (UF), fine (FI), and coarse (CO) size modes despite the fact that these materials differ significantly in both evolution and chemistry. Furthermore the chemical makeup of these different size fractions can vary tremendously depending on location, meteorology, and source profile. For this reason, high-volume three-stage particle impactors with the capacity to collect UF, FI, and CO particles were deployed to four different locations in the United States (Seattle, WA; Salt Lake City, UT; Sterling Forest and South Bronx, NY), and weekly samples were collected for 1 mo in each place. The particles were extracted, assayed for a standardized battery of chemical components, and instilled into mouse lungs (female BALB/c) at doses of 25 and 100 microg. Eighteen hours later animals were euthanized and parameters of injury and inflammation were monitored in the bronchoalveolar lavage fluid and plasma. Of the four locations, the South Bronx coarse fraction was the most potent sample in both pulmonary and systemic biomarkers, with a strong increase in lung inflammatory cells as well as elevated levels of creatine kinase in the plasma. These effects did not correlate with lipopolysaccharide (LPS) or total zinc or sulfate content, but were associated with total iron. Receptor source modeling on the PM2.5 samples showed that the South Bronx sample was heavily influenced by emissions from coal fired power plants (31%) and mobile sources (22%). Further studies will assess how source profiles correlate with the observed effects for all locations and size fractions
— id: 138501, year: 2007, vol: 19 Suppl 1, page: 7, stat: Journal Article,

Air pollution : toxicological studies
Gordon, Terry
Environmental and occupational medicine Philadelphia : Wolters Kluwer/Lippincott Williams & Wilkins, 2007,
— id: 5376, year: 2007, vol: , page: ?, stat: Chapter,

Linking health effects to PM components, size, and sources
Gordon, Terry
2007 ;19 Suppl 1:3-6, Inhalation toxicology
A number of physicochemical factors contribute to the adverse cardiopulmonary effects associated with exposure to ambient PM. It has become increasingly clear that mass concentration alone may not be the best indices for associating health effects with exposure to PM. Recent epidemiology and animal toxicology data have examined the role of particle size and components on cardiopulmonary effects. In addition, collaborative efforts in North America and Europe have examined the in vitro and in vivo toxicity of size-fractionated particles collected in a variety of urban and rural sites. The ability of these latter studies and other investigations to develop source apportionment findings will become increasingly important for policy makers and regulators in their deliberations
— id: 75379, year: 2007, vol: 19 Suppl 1, page: 3, stat: Journal Article,

The complexities of air pollution regulation: the need for an integrated research and regulatory perspective
Nadadur, Srikanth S; Miller, C Andrew; Hopke, Philip K; Gordon, Terry; Vedal, Sverre; Vandenberg, John J; Costa, Daniel L
2007 Dec;100(2):318-327, Toxicological sciences
The Clean Air Act mandates the U.S. Environmental Protection Agency to periodically reassess existing and new science that underlie the regulation of major ambient pollutants -- particulate matter (PM) and tropospheric ozone being most notable. While toxic effects have been ascribed individually to these and other pollutants in the air, it is clear that mixtures of these contaminants have the potential to interact and thereby influence their overall toxic outcomes. It follows that a more comprehensive assessment of the potential health effects of the air pollution complex might better protect human health; however, traditional regulatory drivers and funding constraints have impeded progress to such a goal. Despite difficulties in empirically conducting studies of complex mixtures of air pollutants and acquiring relevant exposure data, there remains a need to develop integrated, interdisciplinary research and analytical strategies to provide more comprehensive (and relevant) assessments of associated health outcomes and risks. The research and assessment communities are endeavoring to dissect this complexity using varied approaches Here we present five interdisciplinary perspectives of this evolving line of thought among researchers and those who use such data in assessment: (1) analyses that coordinate air quality-health analyses utilizing representative polluted U.S. air sheds to apportion source and component-specific health risks; (2) novel approaches to characterize air quality in terms of emission sources and how emission reduction strategies might effectively impact pollutant levels; (3) insights from present-day studies of effects of single ambient pollutants in animal and controlled clinical toxicology studies and how these are evolving to address air pollution; (4) refinements in epidemiologic health assessments that take advantage of the complexities of existent air quality conditions; and (5) new approaches to integrative analyses to establish the criteria for regulation of PM and other criteria pollutants. As these examples illustrate, implementing multidisciplined and integrative strategies offer the promise of more realistic and relevant science, greater reductions in uncertainty, and improved overall air pollution assessment. The regulatory mandate may lag behind the science, but real gains both in public health benefit and the science to dissect complex problems will result
— id: 138499, year: 2007, vol: 100, page: 318, stat: Journal Article,

Susceptibility to pulmonary hypertension in inbred strains of mice exposed to cigarette smoke
Nadziejko, Christine; Fang, Kaije; Bravo, Antonio; Gordon, Terry
2007 May;102(5):1780-1785, Journal of applied physiology (Bethesda)
Cor pulmonale is a significant cause of morbidity and mortality in patients with emphysema, but it is not known whether alveolar destruction is directly involved in the disease pathogenesis. The purpose of this study was to examine the relationship between susceptibility to smoking-induced cor pulmonale and alveolar destruction in eight inbred strains of mice: 129XI/SvJ, A/J, A/HeJ, BALB/cJ, C3H/HeJ, C57BL/6J, DBA/2J, and SWR/J. The mice were exposed to filtered air or mainstream cigarette smoke at a concentration of 250 mg/m(3) for 5.5 h/day, 5 days/wk for 5 mo, housed for 4 more months, and killed. The ratio of the weight of the right ventricle/left ventricle plus septum [RV/(LV + S)] was used to assess right ventricular hypertrophy. Alveolar mean linear intercept was used to quantify severity of alveolar destruction. Morphometric determination of blood vessel muscularization was done on sections from four mouse strains. Smoke exposure resulted in significant increases in RV/(LV + S) in the A/J and A/HeJ strains compared with air-exposed controls. The magnitude of the smoking-induced increase in RV/(LV + S) decreased as a function of the genetic distance of the other strains from the A/J and A/HeJ strains. Pulmonary vascular muscularization was significantly increased in smoke-exposed A/J and BALB/cJ mice but not in C3H/HeJ and C57BL/6 mice. Also, mouse strain susceptibility to smoking-induced pulmonary vascular muscularization did not correlate with changes in mean linear intercept. The data from this study suggest that alveolar destruction by itself is not sufficient to cause smoking-induced cor pulmonale in inbred mice
— id: 72153, year: 2007, vol: 102, page: 1780, stat: Journal Article,

Workshop summary: phosgene-induced pulmonary toxicity revisited: appraisal of early and late markers of pulmonary injury from animal models with emphasis on human significance
Pauluhn, J; Carson, A; Costa, D L; Gordon, T; Kodavanti, U; Last, J A; Matthay, M A; Pinkerton, K E; Sciuto, A M
2007 Aug;19(10):789-810, Inhalation toxicology
A workshop was held February 14, 2007, in Arlington, VA, under the auspices of the Phosgene Panel of the American Chemistry Council. The objective of this workshop was to convene inhalation toxicologists and medical experts from academia, industry and regulatory authorities to critically discuss past and recent inhalation studies of phosgene in controlled animal models. This included presentations addressing the benefits and limitations of rodent (mice, rats) and nonrodent (dogs) species to study concentration x time (C x t) relationships of acute and chronic types of pulmonary changes. Toxicological endpoints focused on the primary pulmonary effects associated with the acute inhalation exposure to phosgene gas and responses secondary to injury. A consensus was reached that the phosgene-induced increased pulmonary extravasation of fluid and protein can suitably be probed by bronchoalveolar lavage (BAL) techniques. BAL fluid analyses rank among the most sensitive methods to detect phosgene-induced noncardiogenic, pulmonary high-permeability edema following acute inhalation exposure. Maximum protein concentrations in BAL fluid occurred within 1 day after exposure, typically followed by a latency period up to about 15 h, which is reciprocal to the C x t exposure relationship. The C x t relationship was constant over a wide range of concentrations and single exposure durations. Following intermittent, repeated exposures of fixed duration, increased tolerance to recurrent exposures occurred. For such exposure regimens, chronic effects appear to be clearly dependent on the concentration rather than the cumulative concentration x time relationship. The threshold C x t product based on an increased BAL fluid protein following single exposure was essentially identical to the respective C x t product following subchronic exposure of rats based on increased pulmonary collagen and influx of inflammatory cells. Thus, the chronic outcome appears to be contingent upon the acute pulmonary threshold dose. Exposure concentrations high enough to elicit an increased acute extravasation of plasma constituents into the alveolus may also be associated with surfactant dysfunction, intra-alveolar accumulation of fibrin and collagen, and increased recruitment and activation of inflammatory cells. Although the exact mechanisms of toxicity have not yet been completely elucidated, consensus was reached that the acute pulmonary toxicity of phosgene gas is consistent with a simple, irritant mode of action at the site of its initial deposition/retention. The acute concentration x time mortality relationship of phosgene gas in rats is extremely steep, which is typical for a local, directly acting pulmonary irritant gas. Due to the high lipophilicity of phosgene gas, it efficiently penetrates the lower respiratory tract. Indeed, more recent published evidence from animals or humans has not revealed appreciable irritant responses in central and upper airways, unless exposure was to almost lethal concentrations. The comparison of acute inhalation studies in rats and dogs with focus on changes in BAL fluid constituents demonstrates that dogs are approximately three to four times less susceptible to phosgene than rats under methodologically similar conditions. There are data to suggest that the dog may be useful particularly for the study of mechanisms associated with the acute extravasation of plasma constituents because of its size and general morphology and physiology of the lung as well as its oronasal breathing patterns. However, the study of the long-term sequelae of acute effects is experimentally markedly more demanding in dogs as compared to rats, precluding the dog model to be applied on a routine base. The striking similarity of threshold concentrations from single exposure (increased protein in BAL fluid) and repeated-exposure 3-mo inhalation studies (increased pulmonary collagen deposition) in rats supports the notion that chronic changes depend on acute threshold mechanisms
— id: 73880, year: 2007, vol: 19, page: 789, stat: Journal Article,

Enhanced lung tumor development in tobacco smoke-exposed p53 transgenic and Kras2 heterozygous deficient mice
Yan, Ying; Tan, Qing; Wang, Yian; Wang, Daolong; Jin, Mike; Gordon, Terry; Lubet, Ronald A; You, Ming
2007 ;19 Suppl 1:183-187, Inhalation toxicology
A/J mice bearing either a mutation in the p53 gene or a Kras2 heterozygous deficiency were investigated for their susceptibility to tobacco smoke-induced lung tumorigenesis. Transgenic mice and their wild-type littermates were exposed to mainstream tobacco smoke (MS) for 5 mo, followed by 4 mo of recovery in filtered air. In sham (filtered air) groups, p53 transgenic mice did not exhibit a higher tumor multiplicity but did exhibit larger tumors, with tumor load increased 3.6-fold, when compared with wild-type mice. With exposure to MS, tumor multiplicity was increased 60% but there was a strikingly increased tumor load (15.9-fold) in p53 transgenic mice. Increased tumor load (5.3-fold) but not tumor multiplicity was seen in MS-exposed Kras2 heterozygous deficient mice. Interestingly, MS exposure did not increase benzo[a]pyrene-induced lung tumorigenesis when MS exposure was initiated after BaP treatment. These results indicate that a p53 mutation or loss of a Kras2 allele increases susceptibility to MS-induced lung tumor development
— id: 138500, year: 2007, vol: 19 Suppl 1, page: 183, stat: Journal Article,

History and results of the two inter-laboratory round robin endotoxin assay studies on cotton dust
Chun, David T W; Bartlett, Karen; Gordon, Terry; Jacobs, Robert R; Larsson, Britt-Marie; Larsson, Lennart; Lewis, Daniel M; Liesivuori, Jyrki; Michel, Olivier; Milton, Donald K; Rylander, Ragnar; Thorne, Peter S; White, Eugene M; Brown, Mary E; Gunn, Varina S; Wurtz, Helle
2006 Apr;49(4):301-306, American journal of industrial medicine
BACKGROUND: In the US cotton industry, airborne cotton dust levels are regulated, and other countries are moving to specify safety limits for airborne endotoxins. There is concern about potential respiratory health hazards associated with agricultural and other organic dusts. In laboratories, ranking which samples have high and low levels of endotoxin is usually in good agreement between laboratories. When different laboratories assay identical samples, the levels differ. The objective of this research was to evaluate the intra- and inter-laboratory variability for 13 laboratories measuring endotoxin in cotton dust. METHOD: Two inter-laboratory round robin endotoxin assay studies were conducted using cotton dust. In the first round robin, each laboratory used their normal in-house assay method and then used a common extraction protocol. In the second round robin, a common extraction protocol and endotoxin assay kit was used. RESULTS: The intra-laboratory results had small variations but inter-laboratory results had very high variations. The inter-laboratory results using a common extraction protocol showed reduced differences. Using the same extraction protocol and endotoxin assay kit, the intra-laboratory variation was small and inter-laboratory variation was reduced but not enough for inter-laboratory agreement. Most of the laboratories were able to discern between the high and low endotoxin concentration dusts. CONCLUSIONS: Standardization has reduced the differences in results between laboratories and possibly further standardization may bring closer inter-laboratory agreement
— id: 72154, year: 2006, vol: 49, page: 301, stat: Journal Article,

Mycobacterium immunogenum causes hypersensitivity pneumonitis-like pathology in mice
Gordon, Terry; Nadziejko, Christine; Galdanes, Karen; Lewis, Dan; Donnelly, Kevin
2006 May;18(6):449-456, Inhalation toxicology
A surprising number of cases of hypersensitivity pneumonitis have been observed at work sites employing automotive machinists. Because hypersensitivity pneumonitis is not typically associated with exposure to metalworking fluid aerosols, this study examined whether Mycobacterium immunogenum (M. immunogenum), a rapidly growing mycobacterium isolated from several affected work sites, could induce hypersensitivity pneumonitis in mice. Hypersensitivity pneumonitis-like histologic changes occurred in mice treated with heat-killed and lysed M. immunogenum. These lung lesions were characterized by peribronchial and perivascular lymphohistiocytic inflammation and noncaseating granulomas in the parenchyma. The pathologic changes observed in mice instilled with M. immunogenum-contaminated used metalworking fluid were indistinguishable from those observed with M. immunogenum alone. The role of genetic factors in M. immunogenum-induced lung lesions was examined by comparison of the response of eight inbred strains of mice. The observed immunologic changes in the lung were significantly greater in C57Bl/6, 129, and BALB/c mice than in the other strains, suggesting that genetic factor(s) contribute to the susceptibility of workers exposed to M. immunogenum-contaminated metalworking fluid aerosols. Thus, these studies provide indirect evidence that M. immunogenum is an unrecognized class of microorganisms capable of causing hypersensitivity pneumonitis and plays a role in the outbreaks of hypersensitivity pneumonitis in automotive plants
— id: 64652, year: 2006, vol: 18, page: 449, stat: Journal Article,

Interaction of iron and calcium minerals in coals and their roles in coal dust-induced health and environmental problems
Huang, X; Gordon, T; Rom, WN; Finkelman, RB
2006 NOV-DEC ;64(6):153-178, Reviews in mineralogy & geochemistry
Epidemiological studies using pollutant gases (e.g., SO2) and particle characteristics (e.g., elemental carbon) indicate that products of fossil fuel combustion are important contributors to particulate matter (PM)-associated hospital admissions and mortality. Coal is one of the world's most important fossil fuels, providing 40% of electricity worldwide. Besides individuals exposed to PM in ambient air, coal mining can cause adverse health effects in workers exposed to coal dusts at the workplace. Among the respiratory diseases, coal workers' pneumoconiosis (CWP) has received the most attention because of its clear occupational association. The field of CWP research is one of the few areas in occupational health in which considerable epidemiological data are available. This offers a good opportunity to focus on the relationship between epidemiological data and physico-chemical and/or biological characteristics of coals. The objective of this review is to assess whether some physico-chemical parameters play a role in the observed regional differences in the prevalence of CWP among various coalmine regions. We mainly concentrate on the chemical interaction of two minerals, pyrite (FeS2) and calcite (CaCO3) in the coals and their role in causing occupational lung diseases (e.g., pneumoconiosis) and other environmental problems (e.g., acid mine drainage). Therefore, understanding the chemical interaction of the two minerals in the coal may lead to the identification of the causal components in coal dusts as well as in PM. Examples from U.S.A. coals are used to illustrate the chemical interaction and geological distribution of iron and calcium minerals in various coalmine regions and how the differences in levels of these types of minerals contribute to the observed regional differences in the prevalence of CWP. Molecular mechanisms leading to the CWP development are also discussed, particular in the aspects of oxidative stress and inflammation
— id: 70749, year: 2006, vol: 64, page: 153, stat: Journal Article,

The parity-related protection against breast cancer is compromised by cigarette smoke during rat pregnancy: observations on tumorigenesis and immunological defenses of the neonate
Steinetz, Bernard G; Gordon, Terry; Lasano, Salamia; Horton, Lori; Ng, Sheung Pui; Zelikoff, Judith T; Nadas, Arthur; Bosland, Maarten C
2006 Jun;27(6):1146-1152, Carcinogenesis
Early pregnancy is a powerful negative risk factor for breast cancer (BCa) in women. Pregnancy also protects rats against induction of BCa by carcinogens such as N-methyl-N-nitrosourea (MNU), making the parous rat a useful model for studying this phenomenon. Smoking during early pregnancy may lead to an increased risk of BCa in later life, possibly attributable to carcinogens in cigarette smoke (CS), or to reversal of the parity-related protection against BCa. To investigate these possibilities, 50-day-old timed first-pregnancy rats were exposed to standardized mainstream CS (particle concentration = 50 mg/m3) or to filtered air (FA) 4 h/day, Day 2-20 of gestation. Age-matched virgin rats were similarly exposed to CS or FA. At age 100 days, the CS or FA-exposed, parous and virgin rats were injected s.c. with MNU (50 mg/kg body wt), or with MNU vehicle. Mammary tumors (MTs) first appeared in virgin rats 9 weeks post-MNU injection. While no MTs were detected in FA-exposed parous rats until 18 weeks post-MNU, MTs appeared in the CS-exposed parous rats as early as 10 wks (P < 0.02). As no MTs developed in CS-exposed rats not injected with MNU, CS did not act as a direct mammary carcinogen. Serum prolactin concentration on Day 19 of pregnancy in CS-exposed dams was reduced by 50% compared with FA-exposed dams (P < 0.005). CS exposure during a pregnancy may thus 'deprotect' rats, enhancing their vulnerability to MNU-induced BCa. Prenatal CS exposure had no detectable effect on the immune responses of the pups examined at 3, 8 or 19 weeks of age. However, prolactin concentration in stomach contents (milk) of 3-day-old pups suckled by CS-exposed dams was decreased when compared with that of FA-exposed dams (P < 0.032). As milk-borne prolactin modulates development of the central nervous and immune systems of neonatal rats, CS exposure of the dams could adversely affect later maturation of these systems by reducing milk prolactin
— id: 66151, year: 2006, vol: 27, page: 1146, stat: Journal Article,

International Workshop on the Design and Analysis of Experimental Studies using PM Concentrator Technologies, Boston, May 5, 2004
Lippmann, Morton; Cassee, Flemming R; Costa, Daniel L; Costantini, Maria; van Erp, Annemoon M; Gordon, Terry
2005 Dec 15;17(14):839-850, Inhalation toxicology
A workshop that brought together representatives of most of the laboratories that have conducted animal and/or human inhalation exposure studies with concentrated ambient air particles (CAPs) was convened by the Health Effects Institute in Boston on May 5, 2004. Participants agreed that CAPs researchers need to make serious efforts to harmonize their experimental and analytical protocols to permit the sharing of lessons learned, questions raised, and opportunities for more definitive studies. Standardized outcome measures based on spirometry and response markers in lung bronchoalveolar lavage (BAL) cells and fluids exist, including the appropriate times after exposure to collect samples and measurements. However, for the emerging focus on cardiac system responses, there are many different electrocardiographic (ECG) endpoints being examined, and little standardization on markers that are most informative about adverse effects; on when the measurements need to be made; and on how to make comparable measurements. The workshop focused on two aspects of dealing with these complexities: sorting out influential particulate matter (PM) components responsible for observed effects, and searching for time-varying responses in continuous outcome data. The need for more complete analyses of PM samples from the CAPs studies was also emphasized, as was obtaining a consistent set of parameters characterizing exposure atmospheres and the ambient PM from which the CAPs are sampled. CAPs studies have already had a significant impact within the air pollution health effects community, especially in regard to cardiovascular system effects, and a follow-up meeting with a greater focus on means to harmonize data collection and analysis is needed
— id: 62395, year: 2005, vol: 17, page: 839, stat: Journal Article,

Quantitative trait analysis of the development of pulmonary tolerance to inhaled zinc oxide in mice
Wesselkamper, Scott C; Chen, Lung Chi; Gordon, Terry
2005 ;6:73-73, Respiratory research
BACKGROUND: Individuals may develop tolerance to the induction of adverse pulmonary effects following repeated exposures to inhaled toxicants. Previously, we demonstrated that genetic background plays an important role in the development of pulmonary tolerance to inhaled zinc oxide (ZnO) in inbred mouse strains, as assessed by polymorphonuclear leukocytes (PMNs), macrophages, and total protein in bronchoalveolar lavage (BAL) phenotypes. The BALB/cByJ (CBy) and DBA/2J (D2) strains were identified as tolerant and non-tolerant, respectively. The present study was designed to identify candidate genes that control the development of pulmonary tolerance to inhaled ZnO. METHODS: Genome-wide linkage analyses were performed on a CByD2F2 mouse cohort phenotyped for BAL protein, PMNs, and macrophages following 5 consecutive days of exposure to 1.0 mg/m3 inhaled ZnO for 3 hours/day. A haplotype analysis was carried out to determine the contribution of each quantitative trait locus (QTL) and QTL combination to the overall BAL protein phenotype. Candidate genes were identified within each QTL interval using the positional candidate gene approach. RESULTS: A significant quantitative trait locus (QTL) on chromosome 1, as well as suggestive QTLs on chromosomes 4 and 5, for the BAL protein phenotype, was established. Suggestive QTLs for the BAL PMN and macrophage phenotypes were also identified on chromosomes 1 and 5, respectively. Analysis of specific haplotypes supports the combined effect of three QTLs in the overall protein phenotype. Toll-like receptor 5 (Tlr5) was identified as an interesting candidate gene within the significant QTL for BAL protein on chromosome 1. Wild-derived Tlr5-mutant MOLF/Ei mice were tolerant to BAL protein following repeated ZnO exposure. CONCLUSION: Genetic background is an important influence in the acquisition of pulmonary tolerance to BAL protein, PMNs, and macrophages following ZnO exposure. Promising candidate genes exist within the identified QTL intervals that would be good targets for additional studies, including Tlr5. The implications of tolerance to health risks in humans are numerous, and this study furthers the understanding of gene-environment interactions that are likely to be important factors from person-to-person in regulating the development of pulmonary tolerance to inhaled toxicants
— id: 66663, year: 2005, vol: 6, page: 73, stat: Journal Article,

The Collaborative Cross, a community resource for the genetic analysis of complex traits
Churchill, Gary A; Airey, David C; Allayee, Hooman; Angel, Joe M; Attie, Alan D; Beatty, Jackson; Beavis, William D; Belknap, John K; Bennett, Beth; Berrettini, Wade; Bleich, Andre; Bogue, Molly; Broman, Karl W; Buck, Kari J; Buckler, Ed; Burmeister, Margit; Chesler, Elissa J; Cheverud, James M; Clapcote, Steven; Cook, Melloni N; Cox, Roger D; Crabbe, John C; Crusio, Wim E; Darvasi, Ariel; Deschepper, Christian F; Doerge, R W; Farber, Charles R; Forejt, Jiri; Gaile, Daniel; Garlow, Steven J; Geiger, Hartmut; Gershenfeld, Howard; Gordon, Terry; Gu, Jing; Gu, Weikuan; de Haan, Gerald; Hayes, Nancy L; Heller, Craig; Himmelbauer, Heinz; Hitzemann, Robert; Hunter, Kent; Hsu, Hui-Chen; Iraqi, Fuad A; Ivandic, Boris; Jacob, Howard J; Jansen, Ritsert C; Jepsen, Karl J; Johnson, Dabney K; Johnson, Thomas E; Kempermann, Gerd; Kendziorski, Christina; Kotb, Malak; Kooy, R Frank; Llamas, Bastien; Lammert, Frank; Lassalle, Jean-Michel; Lowenstein, Pedro R; Lu, Lu; Lusis, Aldons; Manly, Kenneth F; Marcucio, Ralph; Matthews, Doug; Medrano, Juan F; Miller, Darla R; Mittleman, Guy; Mock, Beverly A; Mogil, Jeffrey S; Montagutelli, Xavier; Morahan, Grant; Morris, David G; Mott, Richard; Nadeau, Joseph H; Nagase, Hiroki; Nowakowski, Richard S; O'Hara, Bruce F; Osadchuk, Alexander V; Page, Grier P; Paigen, Beverly; Paigen, Kenneth; Palmer, Abraham A; Pan, Huei-Ju; Peltonen-Palotie, Leena; Peirce, Jeremy; Pomp, Daniel; Pravenec, Michal; Prows, Daniel R; Qi, Zhonghua; Reeves, Roger H; Roder, John; Rosen, Glenn D; Schadt, Eric E; Schalkwyk, Leonard C; Seltzer, Ze'ev; Shimomura, Kazuhiro; Shou, Siming; Sillanpaa, Mikko J; Siracusa, Linda D; Snoeck, Hans-Willem; Spearow, Jimmy L; Svenson, Karen; Tarantino, Lisa M; Threadgill, David; Toth, Linda A; Valdar, William; de Villena, Fernando Pardo-Manuel; Warden, Craig; Whatley, Steve; Williams, Robert W; Wiltshire, Tim; Yi, Nengjun; Zhang, Dabao; Zhang, Min; Zou, Fei
2004 Nov;36(11):1133-1137, Nature genetics
The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease
— id: 72155, year: 2004, vol: 36, page: 1133, stat: Journal Article,

Metalworking fluid--the toxicity of a complex mixture
Gordon, Terry
2004 Feb 13;67(3):209-219, Journal of toxicology & environmental health. Pt. A
Various chemicals are used in the manufacture of cooling and lubricating fluids and fall into the classes of straight, soluble, semisynthetic, and synthetic metalworking fluids. The diversity of chemicals and in-use contaminants makes the risk assessment of metalworking fluids quite difficult. Toxicologists have used a number of methods to evaluate the component(s) responsible for the adverse pulmonary effects of metal working fluid aerosols encountered in the workplace. Although investigators have studied the adverse effects of metalworking fluid chemicals alone and in combination, the majority of evidence strongly suggests that the microbial changes that occur in fluid composition, during use and storage in the workplace, are responsible for the pulmonary effects reported for workers exposed to metalworking fluid aerosols. This review discusses the methodologies used to examine the toxicity of the complex nature of modern metalworking fluids and the findings that point toward bacterial endotoxin as a major contributor to their adverse effects
— id: 42634, year: 2004, vol: 67, page: 209, stat: Journal Article,

Effect of particulate and gaseous pollutants on spontaneous arrhythmias in aged rats
Nadziejko, Christine; Fang, Kaijie; Narciso, Sandy; Zhong, Minhua; Su, Wei Cheng; Gordon, Terry; Nadas, Arthur; Chen, Lung Chi
2004 Jun;16(6-7):373-380, Inhalation toxicology
Epidemiology studies suggest that exposure to air pollution increases the frequency of cardiac arrhythmias. A limitation of these studies is that it is difficult to link an increased risk of arrhythmias to a specific air pollutant. Animal exposure studies offer the opportunity to examine the effects of concentrated ambient fine particulate matter (PM), ultrafine PM, and copollutant gases separately. Male Fischer 344 rats, aged 18 mo, with implanted electrocardiograph (ECG) transmitters were used to determine the effects of PM on the frequency of arrhythmias. We found that old F344 rats had many spontaneous arrhythmias. An arrhythmia classification system was developed to quantify arrhythmia frequency. Arrhythmias were broadly grouped into two categories: premature beats and delayed beats. The rats were exposed to concentrated ambient PM (CAPS) or air for 4 h. The rats were exposed twice with a crossover design so each rat could serve as its own control. The CAPS concentrations were 160 microg/m(3) and 200 microg/m(3) for the first and second exposures, respectively. There was a significant increase in the frequency of irregular and delayed beats after exposure to CAPS. The same rats were subsequently exposed to laboratory-generated ultrafine carbon particles, to SO(2), or to air with a repeated crossover design. In these experiments there was no significant change in the frequency of any category of spontaneous arrhythmia following exposure to ultrafine carbon or SO(2). Thus, this study adds supporting evidence that acute exposure to elevated levels of ambient PM increases the frequency of cardiac arrhythmias
— id: 43213, year: 2004, vol: 16, page: 373, stat: Journal Article,

Six month tracking of microbial growth in a metalworking fluid after system cleaning and recharging
Veillette, Marc; Thorne, Peter S; Gordon, Terry; Duchaine, Caroline
2004 Aug;48(6):541-546, Annals of occupational hygiene
Large volumes of metalworking fluids (MWFs) are used in manufacturing industries for cooling and lubrication of metal pieces and tools during machining. MWFs accumulate microbial growth through continuous recirculation and reuse. We studied the progression of microbial contamination for 6 months after dumping, cleaning and recharging (DCR) of a large semi-synthetic MWF system managed with several biocides. Fresh, uncontaminated fluid was added to the system after extensive cleaning. The following samples were collected and analyzed: pre-DCR fluid (before system cleaning); neat fluid diluted to 6% with water; in use MWF 12 h and 1, 3 and 6 months post-DCR. Samples were analyzed for total microorganism concentrations by direct counting using fluorescence microscopy and by plate counting on various media (R2A, BHI, Middlebrooks and rose bengal under aerobic conditions). In addition, PCR was performed for the detection of mycobacteria. There was a rapid progression in the total bacterial counts as determined by fluorescence microscopy: 5.7 x 10(7) cells/ml in the pre-DCR used fluid, no measurable bacteria in the neat fluid, 6.9 x 10(6) cells/ml after 12 h and 2.2 x 10(6), 3.6 x 10(8) and 6.1 x 10(8) cells/ml after 1, 3 and 6 months, respectively. On average, only 0.2% of the direct count organisms were quantified on R2A cultures. PCR showed the presence of mycobacteria in the used MWF at 3 and 6 months. Mycobacteria were also identified from cultures on Middlebrooks and R2A. This study demonstrates that standard methods for cleaning MWF systems are inadequate since residual bacteria in the system can rapidly repopulate the newly charged MWF
— id: 93835, year: 2004, vol: 48, page: 541, stat: Journal Article,

Metalworking fluids as complex mixtures
Gordon, T
2003 MAR ;72(1):226-227, Toxicological sciences
— id: 38498, year: 2003, vol: 72, page: 226, stat: Journal Article,

Beryllium: genotoxicity and carcinogenicity
Gordon, Terry; Bowser, Darlene
2003 Dec;533(1-2):99-105, Mutation research
Beryllium (Be) has physical-chemical properties, including low density and high tensile strength, which make it useful in the manufacture of products ranging from space shuttles to golf clubs. Despite its utility, a number of standard setting agencies have determined that beryllium is a carcinogen. Only a limited number of studies, however, have addressed the underlying mechanisms of the carcinogenicity and mutagenicity of beryllium. Importantly, mutation and chromosomal aberration assays have yielded somewhat contradictory results for beryllium compounds and whereas bacterial tests were largely negative, mammalian test systems showed evidence of beryllium-induced mutations, chromosomal aberrations, and cell transformation. Although inter-laboratory differences may play a role in the variability observed in genotoxicity assays, it is more likely that the different chemical forms of beryllium have a significant effect on mutagenicity and carcinogenicity. Because workers are predominantly exposed to airborne particles which are generated during the machining of beryllium metal, ceramics, or alloys, testing of the mechanisms of the mutagenic and carcinogenic activity of beryllium should be performed with relevant chemical forms of beryllium
— id: 46070, year: 2003, vol: 533, page: 99, stat: Journal Article,

Adaptation to stress induced by restraining rats and mice in nose-only inhalation holders
Narciso, Sandy P; Nadziejko, Elizabeth; Chen, Lung Chi; Gordon, Terry; Nadziejko, Christine
2003 Sep 15;15(11):1133-1143, Inhalation toxicology
There are limited data on the efficacy of procedures for adapting rodents to restraint in nose-only holders. We examined: (1) What effect does restraint in nose-only holders have on heart rate and body temperature? (2) Does a gradual increase in the duration of restraint facilitate adaptation? (3) How long does it take for rodents to become fully adapted to nose-only holders? (4) Do rats and mice respond and adapt similarly to restraint in nose only holders? Heart rate and body temperature were monitored as measures of stress using electrocardiograph (ECG) transmitters in male C57Bl/6J mice and Sprague-Dawley rats. In naive animals during the first hour of restraint, heart rate increased by 58 beats per minute (BPM) (18.6%) in rats and by 174 BPM (32.3%) in mice as compared to cage controls. Temperature increased by 2 degrees C in mice and was unchanged in rats compared to cage controls. Heart rate and temperature values remained within normal physiologic values during restraint. In rats, the response to restraint in nose-only holders was the same after 4 days regardless of whether the duration of restraint was increased gradually to 4 h/day or kept constant at 4 h/day. In mice, the group that was gradually adapted had a statistically significant higher heart rate and temperature after 4 days than the fixed-duration adapted group. Rats and mice restrained for 4 h/day every day showed a gradual decrease in heart rate and temperature over time. Full adaptation to restraint required 14 days of fixed-duration daily restraint
— id: 39091, year: 2003, vol: 15, page: 1133, stat: Journal Article,

Airway epithelial cells release MIP-3alpha/CCL20 in response to cytokines and ambient particulate matter
Reibman, Joan; Hsu, Yanshen; Chen, Lung Chi; Bleck, Bertram; Gordon, Terry
2003 Jun;28(6):648-654, American journal of respiratory cell & molecular biology
The initiation and maintenance of airway immune responses in Th2 type allergic diseases such as asthma are dependent on the specific activation of local airway dendritic cells (DCs). The cytokine microenvironment, produced by local cells, influences the recruitment of specific subsets of immature DCs and their subsequent maturation. In the airway, DCs reside in close proximity to airway epithelial cells (AECs). We examined the ability of primary culture human bronchial epithelial cells (HBECs) to synthesize and secrete the recently described CC-chemokine, MIP-3alpha/CCL20. MIP-3alpha/CCL20 is the unique chemokine ligand for CCR6, a receptor with a restricted distribution. MIP-3alpha/CCL20 induces selective migration of DCs because CCR6 is expressed on some immature DCs but not on CD14+ DC precursors or mature DCs. HBECs were stimulated with pro-inflammatory cytokines tumor necrosis factor-alpha and interleukin (IL)-1beta or, because of their critical role in allergic diseases, IL-4 and IL-13. Cells were also exposed to small size-fractions of ambient particulate matter. Each of these stimuli induced MIP-3alpha/CCL20 gene and protein expression. Moreover, these agents upregulated mitogen-activated protein kinase pathways in HBECs. Inhibition of the ERK1/2 pathway or p38 reduced cytokine-induced MIP-3alpha/CCL20 expression. These data suggest a mechanism by which AEC may facilitate recruitment of DC subsets to the airway
— id: 39223, year: 2003, vol: 28, page: 648, stat: Journal Article,

Effects of inhaled ambient particulate matter on pulmonary antimicrobial immune defense
Zelikoff, Judith T; Chen, Lung Chi; Cohen, Mitchell D; Fang, Kaijie; Gordon, Terry; Li, Yun; Nadziejko, Christine; Schlesinger, Richard B
2003 Feb;15(2):131-150, Inhalation toxicology
Respiratory-tract infection, specifically pneumonia, contributes substantially to the increased morbidity and mortality among elderly individuals exposed to airborne particulate matter of <10 micro m diameter (PM(10)). These epidemiological findings suggest that PM(10) may act as an immunosuppressive factor that can undermine normal pulmonary antimicrobial defense mechanisms. To investigate whether, and how, compromised pulmonary immunocompetence might contribute to increased mortality, two sets of laboratory studies were performed. The first examined the effects of a single inhalation exposure to concentrated ambient PM(2.5) (CAPS) from New York City air on pulmonary/systemic immunity and on the susceptibility of exposed aged rats to subsequent infection with Streptococcus pneumoniae. The second set of studies determined whether CAPS exposure, at a concentration approximating or somewhat greater than the promulgated 24-h NAAQS of 65 micro g/m(3), could exacerbate an ongoing infection. Taken together, results demonstrated that a single exposure of healthy animals to CAPS had little effect on pulmonary immune function or bacterial clearance during subsequent challenge with S. pneumoniae. Alterna-tively, CAPS exposure of previously infected rats significantly increased bacterial burdens and decreased percentages of lavageable neutrophils and proinflammatory cytokine levels compared to those in infected filtered-air-exposed controls. These studies demonstrate that a single exposure to ambient PM(2.5) compromises a host's ability to handle ongoing pneumococcal infections and support the epidemiological findings of increased pneumonia-related deaths in ambient PM-exposed elderly individuals
— id: 34379, year: 2003, vol: 15, page: 131, stat: Journal Article,

Second inter-laboratory study comparing endotoxin assay results from cotton dust
Chun, David T W; Chew, Victor; Bartlett, Karen; Gordon, Terry; Jacobs, Robert; Larsson, Britt-Marie; Lewis, Daniel M; Liesivuori, Jyrki; Michel, Olivier; Rylander, Ragnar; Thorne, Peter S; White, Eugene M; Gunn, Varina C; Wurtz, Helle
2002 ;9(1):49-53, Annals of agricultural & environmental medicine
Previously, a large two-part inter-laboratory round robin endotoxin assay study was completed. This first study showed that when cotton dust samples, which are practically identical, are assayed for endotoxin that the intra- laboratory results had a very small variation while intra-laboratory results of the sample had a very high variation. In the first part of the study, each laboratory followed its own in-house assay protocol; but in the second part of the study, when the extraction protocol was standardized, the inter-laboratory results showed a lower variation, which suggested that with further standardization, further reduction of differences between laboratories might be achieved in order that results between laboratories would become more comparable. The results stimulated interest in extending the study to include cotton dust with two levels of endotoxin, standardization of the extraction protocol, and using the same assay kit from the same production lot. The results of this second round robin endotoxin assay study indicate that differences between laboratories are still high, but most of the laboratories could discern the cotton dusts with the different levels of endotoxin
— id: 93832, year: 2002, vol: 9, page: 49, stat: Journal Article,

In vitro bioavailability of heavy metals in pressure-treated wood dust
Gordon, Terry; Spanier, Jonathan; Butala, John H; Li, Ping; Rossman, Toby G
2002 May;67(1):32-37, Toxicological sciences
Pressure treatment with chromium, copper, and arsenic (CCA) is the most prevalent method for protecting wood used in outdoor construction projects. Although these metals are tightly bound to the wood fibers and are not released under most conditions of use, we examined the bioavailability of metals in CCA pressure-treated wood dust in vitro. Cytotoxicity and metallothionein (MT) mRNA expression were examined in V79 Chinese hamster lung fibroblast cells incubated with respirable-size wood dust generated by sanding CCA-treated and untreated (control) Southern yellow pine. In colony survival studies, increased cytotoxicity (p < 0.05) occurred in V79 cells treated with CCA wood dust (351 +/- 77 microg/ml, mean +/- SE) compared with control wood dust (883 +/- 91 microg/ml). Increased cytotoxicity with CCA wood dust also occurred in an arsenic resistant subline of V79 cells, thus suggesting that arsenic was not responsible for the increased cytotoxicity. Metallothionein mRNA was significantly increased after 48 h of treatment with CCA wood dust compared with control wood dust. Incubation of CCA wood dust in cell culture media resulted in the transfer of copper, but not chromium or arsenic, into the media. Moreover, the treatment of cells with this filtered extract resulted in significantly increased metallothionein mRNA, suggesting that bioavailable copper is responsible for inducing metallothionein mRNA in V79 cells. Thus, these bioassays suggest that metals become bioavailable during in vitro culture of phagocytic V79 cells with CCA wood dust
— id: 39673, year: 2002, vol: 67, page: 32, stat: Journal Article,

Quantitative analysis of cardiac data from rats monitored by telemetry: reducing within- and between-animal variability
Nadziejko, Christine; Fang, Kaijie; Chen, Lung Chi; Gordon, Terry; Nadas, Arthur
2002 ;2(4):237-244, Cardiovascular toxicology
Few studies have examined the sources of variability in cardiac function measurements in unrestrained animals and the impact of this variability on detection of treatment effects. The heart rate was monitored with implanted ECG transmitters in two groups of male rats, age 7 and 23 mo. Animals were monitored in their cages to determine optimal heart rate sampling frequency and sources of variability in heart rate, including whether there were persistent animal-to-animal differences. Ambient temperature was transiently increased to test whether correction for animal-to-animal differences improved sensitivity for detection of treatment effects. Animal-to-animal differences were statistically significant and accounted for about 18.3% and 11.5% of the total variance for old and young rats, respectively. In both the old and young rats, the heart rate decreased during the heat challenges relative to the control group, but the noncorrected differences were not statistically significant. When pre-exposure baseline values for each rat (average of 72 h prior to the first temperature challenge) were subtracted, the decrease in heart rate was statistically significant during all three challenges for both old and young rats. Subtraction of preexposure heart rate data to correct for baseline differences between animals is important for measuring treatment effects
— id: 43215, year: 2002, vol: 2, page: 237, stat: Journal Article,

Mouse models of diisocyanate asthma
Redlich, Carrie A; Wisnewski, Adam V; Gordon, Terry
2002 Oct;27(4):385-390, American journal of respiratory cell & molecular biology
— id: 138502, year: 2002, vol: 27, page: 385, stat: Journal Article,

Size fractions of ambient particulate matter induce granulocyte macrophage colony-stimulating factor in human bronchial epithelial cells by mitogen-activated protein kinase pathways
Reibman, Joan; Hsu, Yanshen; Chen, Lung Chi; Kumar, Asok; Su, Wei Cheng; Choy, Wanda; Talbot, Anita; Gordon, Terry
2002 Oct;27(4):455-462, American journal of respiratory cell & molecular biology
Environmental pollutants, including ambient particulate matter (PM), increase respiratory morbidity. Studies of model PM particles, including residual oil fly ash and freshly generated diesel exhaust particles, have demonstrated that PM affects inflammatory airway responses. Neither of these particles completely represents ambient PM, and therefore questions remain about ambient particulates. We hypothesized that ambient PM of different size fractions collected from an urban environment (New York City air), would activate primary culture human bronchial epithelial cells (HBECs). Because of the importance of granulocyte-macrophage colony-stimulating factor (GM-CSF) on inflammatory and immunomodulatory processes, we focused our studies on this cytokine. We demonstrated that the smallest size fraction (ultrafine/fine; < 0.18 micro m) of ambient PM (11 micro g/cm(2)), upregulated GM-CSF production (2-fold increase). The absence of effect of carbon particles of similar size, and the day-to-day variation in response, suggested that the chemical composition, but not the particle itself, was necessary for GM-CSF induction. Activation of the extracellular signal-regulated kinase and the p38 mitogen-activated protein kinase was associated with, and necessary for, GM-CSF release. These studies serve to corroborate and extend those on model particles. Moreover, they emphasize the role of the smallest size ambient particles in airway epithelial cell responses
— id: 34380, year: 2002, vol: 27, page: 455, stat: Journal Article,

Ozone differentially modulates airway responsiveness in atopic versus nonatopic guinea pigs
Schlesinger, Richard B; Cohen, Mitchell D; Gordon, Terry; Nadziejko, Christine; Zelikoff, Judith T; Sisco, Maureen; Regal, Jean F; Menache, Margaret G
2002 May;14(5):431-457, Inhalation toxicology
While acute exposures to ozone (O(3)) can alter airway responsiveness, effects from long-term exposures at low concentrations are less clear. This study assessed whether such exposures could induce nonspecific hyperresponsiveness in nonatopic (nonsensitized) guinea pigs and/or could exacerbate the pre-existing hyperresponsive state in atopic (sensitized) animals, and whether gender was a factor modulating any effect of O(3). Responsiveness was measured during and following exposures to 0.1 and 0.3 ppm O(3) for 4 h/day, 4 days/wk for 24 wk in male and female nonsensitized animals, those sensitized to allergen (ovalbumin) prior to initiation of O(3) exposures, and those sensitized concurrently with exposures. Ozone did not produce hyperresponsiveness in nonsensitized animals, but did exacerbate hyperresponsiveness to both specific and nonspecific bronchoprovocation challenges in sensitized animals, an effect that persisted through at least 4 wk after exposures ended. Gender was not a factor modulating response to O(3). Induced effects on responsiveness were not associated with numbers of eosinophils in the lungs nor with any chronic pulmonary inflammatory response, but were correlated with antigen-specific antibodies in blood. This study supports a role for chronic O(3) exposure in the exacerbation of airways dysfunction in a certain segment of the general population, namely, those demonstrating atopy
— id: 34505, year: 2002, vol: 14, page: 431, stat: Journal Article,

Ozone-induced modulation of airway hyperresponsiveness in guinea pigs
Schlesinger, Richard B; Cohen, Mitchell; Gordon, Terry; Nadziejko, Christine; Zelikoff, Judith T; Sisco, Maureen; Regal, Jean F; Menache, Margaret G
2002 Jun;49(109):1-40, Research report (Health Effects Institute)
Although acute exposure to ozone (03*) has been shown to influence the severity and prevalence of airway hyperresponsiveness, information has been lacking on effects due to long-term exposure at relatively low exposure concentrations. The goals of this study were to determine whether long-term repeated ozone exposures could induce nonspecific hyperresponsiveness in normal, nonatopic (nonsensitized) animals, whether such exposure could exacerbate the preexisting hyperresponsive state in atopic (sensitized) animals, or both. The study was also designed to determine whether gender modulated airway responsiveness related to ozone exposure. Airway responsiveness was measured during and after exposure to 0.1 and 0.3 ppm ozone for 4 hours/day, 4 days/week for 24 weeks in normal, nonsensitized guinea pigs, in guinea pigs sensitized to an allergen (ovalbumin) prior to initiation of ozone exposures, and in animals sensitized concurrently with ozone exposures. Both male and female animals were studied. Ozone exposure did not produce airway hyperresponsiveness in nonsensitized animals. Ozone exposure did exacerbate airway hyperresponsiveness to specific and nonspecific bronchoprovocation in both groups of sensitized animals, and this effect persisted at least 4 weeks after the end of the exposures. Although the overall degree of airway responsiveness did differ between genders (males had more responsive airways than did females), the airway response to ozone exposure did not differ between the two groups. Ozone-induced effects upon airway responsiveness were not associated with the number of pulmonary eosinophils or with any chronic pulmonary inflammatory response. Levels of antigen-specific antibodies increased in sensitized animals, and a significant correlation was observed between airway responsiveness and antibody levels. The results of this study provide support for a role of ambient ozone exposure in exacerbation of airway dysfunction in persons with atopy
— id: 34490, year: 2002, vol: 49, page: 1, stat: Journal Article,

Crucial role of interleukin-1beta and nitric oxide synthase in silica-induced inflammation and apoptosis in mice
Srivastava, Kamal D; Rom, William N; Jagirdar, Jaishree; Yie, Ting-An; Gordon, Terry; Tchou-Wong, Kam-Meng
2002 Feb 15;165(4):527-533, American journal of respiratory & critical care medicine
Crystalline silica stimulates macrophages in vitro to release interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO) and induces apoptosis of macrophages. Because the fibrogenic potential of a particulate paralleled its ability to induce apoptosis in macrophages, we investigated the underlying mechanisms by which IL-1beta and NO mediate apoptosis and inflammation in murine silicosis. First, we demonstrated that silica induced NO production and apoptosis in vitro using the IC-21 macrophage cell line. Both NO release and apoptosis could be inhibited by neutralizing anti-IL-1beta antibody or the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine-methyl ester (L-NAME), demonstrating the requirement for IL-1beta-mediated NO release in silica-induced apoptosis. We exposed IL-1beta knockout (IL-1beta(-/-)) mice, inducible NOS knockout (iNOS(-/-)) mice, and wild-type mice to 250 mg/m(3) silica for 5 h/d for 10 d using an inhalation chamber. Exposure of wild-type mice to silica resulted in lung inflammation, apoptosis, and significantly larger and more numerous silicotic lesions than in IL-1beta(-/-) mice over a 12-wk course. We also exposed iNOS(-/-) mice via inhalation in the same protocol and compared with wild-type mice and demonstrated that iNOS(-/-) mice had significantly reduced apoptosis and inflammation. These results demonstrated an association between apoptosis and inflammation in murine silicosis and support a potential role for IL-1beta-dependent NO-mediated apoptosis in the evolution of silicosis
— id: 39712, year: 2002, vol: 165, page: 527, stat: Journal Article,

Lung-specific expression of dominant-negative mutant p53 in transgenic mice increases spontaneous and benzo(a)pyrene-induced lung cancer
Tchou-Wong, Kam-Meng; Jiang, Yixing; Yee, Herman; LaRosa, Jennifer; Lee, Theodore C; Pellicer, Angel; Jagirdar, Jaishree; Gordon, Terry; Goldberg, Judith D; Rom, William N
2002 Aug;27(2):186-193, American journal of respiratory cell & molecular biology
Mutations in the p53 gene have been implicated to play an important role in the development of various human cancers. To evaluate the importance of p53 in lung cancer, a transgenic mouse model was established by utilizing the Clara cell secretory protein (CCSP) promoter to target the expression of a dominant-negative mutant form of p53 (dnp53) in the lung. In two transgenic CCSP-dnp53 founder lines, the dnp53 protein was expressed exclusively in the lungs. The incidence of spontaneous lung cancer in 18-month-old transgenic mice was 45%, whereas that in age-matched control mice was 20%. The relative risk of lung tumors in CCSP-dnp53 mice was 2.3 times that of wild-type mice (exact confidence limits of 0.69, 17.5). In addition to the increased incidence of spontaneous lung tumor, these mice were more susceptible to the development of lung adenocarcinoma after exposure to benzo(a)pyrene (BaP). Six months after intratracheal instillation of benzo(a)pyrene, the tumor incidence in wild-type and CCSP-dnp53 mice was 39% and 73%, respectively. The risk of lung tumors was 25.3 times greater in BaP-treated mice adjusted for transgene expression (95% confidence limits of 3.29, 678, mid-p corrected). These results suggest that p53 function is important for protecting mice from both spontaneous and BaP-induced lung cancers
— id: 32452, year: 2002, vol: 27, page: 186, stat: Journal Article,

Action of deferoxamine against Pneumocystis carinii
Clarkson AB Jr; Turkel-Parrella D; Williams JH; Chen LC; Gordon T; Merali S
2001 Dec;45(12):3560-3565, Antimicrobial agents & chemotherapy
We found earlier that deferoxamine (DFO), a drug used for treatment of iron overload, is active against a rat model of Pneumocystis carinii pneumonia (PCP). We had assumed a mode of action by deprivation of nutritional iron; however, data here show that DFO penetrates P. carinii, causing irreversible damage, thus indicating a different mode of action. Penetration was demonstrated by showing DFO uptake by high-pressure liquid chromatography analysis. By using calcein-AM as an indicator, exposure to DFO was shown to cause a reduction in P. carinii cytoplasmic free iron. Exposure to >or=100 microM DFO for >or=8 h in vitro caused growth to cease and cell numbers to decline over several days. This direct and irreversible damage to P. carinii led to the prediction that infrequent delivery of DFO to the lungs via an aerosol would be an effective treatment in the animal model of PCP. This prediction was confirmed by demonstrating that a once-a-week aerosol treatment of rats was 100% effective both as a prophylactic and as a curative treatment in a rat model of PCP
— id: 34381, year: 2001, vol: 45, page: 3560, stat: Journal Article,

Dr. Mary Amdur Memorial Lecture
Costa, DL; Gordon, T
2001 JUN ;13(6):557-558, Inhalation toxicology
— id: 55073, year: 2001, vol: 13, page: 557, stat: Journal Article,

Development of pulmonary tolerance in mice exposed to zinc oxide fumes
Wesselkamper SC; Chen LC; Gordon T
2001 Mar;60(1):144-151, Toxicological sciences
As a result of repeated exposures to inhaled toxicants such as zinc oxide (ZnO), numerous individuals acquire tolerance to the exposures and display reduced symptoms. To ascertain whether tolerance is developed in an animal model, NIH-Swiss mice were exposed to 1.0 mg/m(3) ZnO for 1, 3, or 5 days (1X, 3X, or 5X), and polymorphonuclear leukocyte (PMN) and protein levels in bronchoalveolar lavage (BAL) were measured. Mice acquired tolerance to neutrophil infiltration into the lungs, as total PMNs returned near baseline in 5X-exposed animals as compared to that of the 1X exposure group (1X = 2.7 +/- 0.4 x 10(4), 5X = 0.2 +/- 0.1 x 10(4), mean +/- SE, p < 0.05). Development of tolerance to changes in lavageable protein, however, was not observed (1X = 313 +/- 29 microg/ml, 5X = 684 +/- 71 microg/ml, p < 0.05). Tolerance to PMN influx did not persist following re-exposure to ZnO after 5 days of rest. In contrast to ZnO exposure, following single and repeated exposure to aerosolized endotoxin there was development of tolerance to protein in BAL (1X = 174 +/- 71 microg/ml, 5X = 166 +/- 14 microg/ml, p > 0.05), but not to PMN influx (1X = 5.5 +/- 1.7 x 10(4), 13.9 +/- 1.7 x 10(4), p < 0.05). Induction of lung metallothionein (MT) was also observed in mice exposed once or repeatedly exposed to ZnO, suggesting that MT may play a role in its molecular mechanism
— id: 21244, year: 2001, vol: 60, page: 144, stat: Journal Article,

Genetic variability in the development of pulmonary tolerance to inhaled pollutants in inbred mice
Wesselkamper SC; Chen LC; Kleeberger SR; Gordon T
2001 Nov;281(5):L1200-L1209, American journal of physiology. Lung cellular & molecular physiology
After repeated exposures, many individuals develop tolerance to the adverse health effects of inhaled pollutants. Pulmonary tolerance can be characterized as the ability of the lung to withstand the adverse actions of a toxic compound after repeated exposures. To determine whether genetic background is important to the development of pulmonary tolerance to inhaled pollutants, 11 inbred strains of mice were exposed once (1x) or for 5 consecutive days (5x) to 1.0 mg/m(3) of zinc oxide (ZnO). Development of pulmonary tolerance was assessed by measuring polymorphonuclear leukocyte and protein levels in bronchoalveolar lavage fluid and comparing the responses of the 1x and 5x groups. Significant interstrain variation in polymorphonuclear leukocyte and protein responses was observed between the groups with 1x and 5x exposures, which indicates that genetic background has an important role in the development of pulmonary tolerance. The BALB/cByJ strain and the DBA/2J strain were the most tolerant and nontolerant, respectively. The CByD2F1/J offspring were uniformly nontolerant. The development of tolerance was also investigated in BALB/cByJ and DBA/2J mice after 1x and 5x exposure to ozone and aerosolized endotoxin. Discordance in the phenotypic pattern of pulmonary tolerance among strains after exposure to ZnO, ozone, and endotoxin suggested that different mechanisms may be responsible for the development of pulmonary tolerance to these agents
— id: 26600, year: 2001, vol: 281, page: L1200, stat: Journal Article,

Mary O. Amdur
Costa D; Gordon T
2000 Jul;56(1):5-7, Toxicological sciences
— id: 39558, year: 2000, vol: 56, page: 5, stat: Journal Article,

Characterization of clinical tolerance to inhaled zinc oxide in naive subjects and sheet metal workers
Fine JM; Gordon T; Chen LC; Kinney P; Falcone G; Sparer J; Beckett WS
2000 Nov;42(11):1085-1091, Journal of occupational & environmental medicine
Clinical tolerance to the acute effects of zinc oxide inhalation develops in workers during periods of repeated exposure. The aims of this study were to determine whether clinical tolerance is accompanied by a reduction in the acute pulmonary inflammatory and cytokine responses to zinc oxide exposure and whether tolerance can be demonstrated in sheet metal workers who chronically inhale low levels of zinc oxide. Naive (never-exposed) subjects inhaled 5 mg/m3 zinc oxide on 1 or 3 days and underwent bronchoalveolar lavage 20 hours after the final exposure. Sheet metal workers inhaled zinc oxide on 1 day and control furnace gas on another day. Among naive subjects in whom tolerance was induced, bronchoalveolar lavage fluid percent neutrophils and interleukin-6 (IL-6) levels were significantly decreased compared with subjects who underwent only a single exposure. Sheet metal workers were much less symptomatic, but they still experienced a significant increase in plasma IL-6. The results indicate that clinical tolerance to zinc oxide is accompanied by reduced pulmonary inflammation and that chronically exposed sheet metal workers are not clinically affected by exposure to zinc oxide fume at the Occupational Safety and Health Administration Permissible Exposure Limit. The increase in IL-6 levels observed in the clinically responsive, and to a lesser extent, tolerant, states following zinc oxide inhalation is consistent with the dual role of IL-6 as a pyrogen and anti-inflammatory agent
— id: 34382, year: 2000, vol: 42, page: 1085, stat: Journal Article,

Effects of concentrated ambient particles in rats and hamsters: an exploratory study [In Process Citation]
Gordon T; Nadziejko C; Chen LC; Schlesinger R
2000 Apr;(93):1-34, Research report (Health Effects Institute)
— id: 10112, year: 2000, vol: , page: 1, stat: Journal Article,

Cardiovascular toxicity of inhaled ambient particulate matter
Gordon T; Reibman J
2000 Jul;56(1):2-4, Toxicological sciences
— id: 11633, year: 2000, vol: 56, page: 2, stat: Journal Article,

Effects of concentrated ambient particles in rats and hamsters : an exploratory study
Gordon, Terry
Cambridge MA : Health Effects Institute, 2000,
— id: 1270, year: 2000, vol: , page: , stat: ,

Inhaled particulate matter causes expression of nuclear factor (NF)-kappa B-related genes and oxidant-dependent NF-kappa B activation in vitro
Shukla, A; Timblin, C; BeruBe, K; Gordon, T; McKinney, W; Driscoll, K; Vacek, P; Mossman, BT
2000 AUG ;23(2):182-187, American journal of respiratory cell & molecular biology
High levels of ambient air pollution are associated with exacerbation of asthma and respiratory morbidity, yet little is known concerning the mechanisms of inflammation and toxicity by components of inhaled particulate matter (PM), Brief inhalation of PM2.5 (particles of an aerodynamic diameter of <2.5 microns) (300 mu g/m(3) air for 6 h followed by a period of 24 h in clean air) by either C3H/HeJ or C57/BL6 mice caused significant (P less than or equal to 0.05) increases in steady-state messenger RNA (mRNA) levels of a number of nuclear factor (NF)-kappa B-associated and/or -regulated genes, including tumor necrosis factor-alpha and -beta, interleukin-6, interferon-gamma, and transforming growth factor-beta. Lung mRNA levels of lymphotoxin-beta and macrophage migration inhibitory factor were unchanged. In murine C10 alveolar cells and an NF-kappa B-luciferase reporter cell line, exposure to PM2.5 at noncytotoxic concentrations resulted in increases in transcriptional activation of NF-kappa B-dependent gene expression which were inhibited in the presence of catalase. Early and persistent increases in intracellular oxidants, as measured by flow cytometry and cell imaging using the oxidant probe 2'-7'-dichlorofluoroscin diacetate, were observed in epithelial cells exposed to PM2.5, and ultrafine carbon black particles. Studies here are the first to show NF-kappa B-related inflammatory and cytokine gene expression after inhalation of PM2.5 and oxidant-dependent induction of NF-kappa B activity by PM2.5 in pulmonary epithelial cells
— id: 54550, year: 2000, vol: 23, page: 182, stat: Journal Article,

Factors contributing to the acute and subchronic adverse respiratory effects of machining fluid aerosols in guinea pigs
Gordon T; Galdanes K
1999 May;49(1):86-92, Toxicological sciences
Several physical, chemical, and microbial factors are potential contributors to the adverse pulmonary effects associated with occupational exposure to machining fluid aerosols. The present study examined the relative toxicity of 3 major classes of machining fluids (soluble, semi-synthetic, and synthetic) as well as that of unused (fresh) versus used (grab samples taken from manufacturing sites) machining fluids. Pulmonary function and changes in cellular and biochemical indices in bronchoalveolar lavage fluid were examined during and 24 h after exposure, respectively. Statistically significant differences in toxicity were observed in guinea pigs exposed for 3 h to respirable aerosols of unused machining fluids (semi-synthetic > soluble >> synthetic). In addition, greater toxicity was observed in animals exposed to used, machining fluid aerosols compared to unused fluids. Moreover, within the used machining fluid types, significantly greater adverse effects were observed in animals exposed to poorly maintained fluids (i.e., heavy microbial contamination) versus well-maintained fluids. Changes in biochemical and cellular parameters in bronchoalveolar lavage fluid occurred after a single exposure to 5 mg/m3 of the poorly maintained used machining fluid aerosols. Changes in inflammation but not LDH and protein were observed in animals repeatedly exposed to semi-synthetic machining fluid aerosols. A statistically significant increase in lavage fluid neutrophils was observed in guinea pigs exposed to 5 mg/m3 used, semi-synthetic machining fluid aerosols for 4 weeks. In separate experiments, physicochemical properties of unused machining fluids were found to contribute to the production of adverse effects. Adjustment of the alkaline and hypotonic nature of the unused semi-synthetic machining fluid to isotonicity and pH 7 significantly reduced adverse effects. Together, these findings strongly suggest that multiple factors contribute to the adverse respiratory effects associated with occupational exposure to machining fluid aerosols
— id: 12003, year: 1999, vol: 49, page: 86, stat: Journal Article,

A Centrifugal Particle Concentrator for Use in Inhalation Toxicology
Gordon T; Gerber H; Fang CP; Chen LC
1999 Jan;11(1):71-87, Inhalation toxicology
Epidemiologic studies have provided strong evidence that episodic exposure to ambient particulate matter is associated with increases in morbidity and mortality. These adverse effects have been demonstrated at concentrations far below the National Ambient Air Quality Standard (NAAQS), and thus, the biological plausibility of these effects has been questioned. For the purpose of exposing test animals to relevant and reproducible exposure concentrations of ambient particulate matter (PM), we have developed a simple and inexpensive concentrator system that can concentrate ambient particles 10-fold. A high-volume blower is used to deliver ambient air to the inlet manifold of a centrifugal concentrator and the entrained particles travel along a concentric annulus formed by a stationary solid outer cylinder and a porous inner cylinder rotating at high speed (up to 12,500 rpm). Suction applied at one end of the porous shaft causes the dispersion medium (air) to pass through the porous cylinder and into the shaft. Since the rotational velocity of airborne particles is comparable to that of the rotating cylinder near its surface, the particles move radially outward due to the centrifugal force, in addition to their motion laterally along the cylinder and inward due to the suction of air into the rotating porous cylinder. The particles reach their highest concentration near the outlet manifold, where they enter the exposure chamber under positive pressure (~0.4 cm H2O). Except for coarse particle loss due to impaction and diffusional loss of ultrafine particles in the concentrator, the increase in particle concentration is the ratio of the flow rates for the inlet air and the air delivered to the exposure chamber. We have used the centrifugal concentrator to deliver concentrated ambient urban PM to a nose-only exposure chamber and examined the concentrating effect across ambient particle sizes
— id: 12000, year: 1999, vol: 11, page: 71, stat: Journal Article,

Induction of metallothionein and heme oxygenase in rats after inhalation of endotoxin
Hur T; Squibb K; Cosma G; Horowitz S; Piedboeuf B; Bowser D; Gordon T
1999 Feb 12;56(3):183-203, Journal of toxicology & environmental health
Various stress proteins appear to play a role in injury and repair produced by inhaled pollutants. The present study examined the effect of inhaled endotoxin on the expression of the metallothionein and heme oxygenase genes. Rats were exposed to saline or endotoxin aerosols for 3 h and sacrificed up to 3 d following exposure. The significant induction of metallothionein mRNA in both the lung (fourfold increase) and liver (one-fold) were greatest at 3 h and returned to basal levels by 24 h after endotoxin exposure. Similarly, the increase in tissue metallothionein was greater in the lung. In situ hybridization in mice showed large increases in the relative abundance of metallothionein transcripts in epithelial cells of the conducting airways, in surrounding airway tissue, and in the nearby gas exchange region. While an endotoxin-induced significant increase in heme oxygenase mRNA followed a time course similar to that observed for metallo thionein, the relative magnitude was reversed for the lung and liver. Heme oxygenase mRNA was induced greater in the liver (twofold) than in the lung (60% above control). Our findings demonstrate that metallothionein and heme oxygenase are early response genes that are rapidly activated after inhalation of occupationally relevant concentrations of endotoxin
— id: 7352, year: 1999, vol: 56, page: 183, stat: Journal Article,

Pulmonary and cardiovascular effects of acute exposure to concentrated ambient particulate matter in rats
Gordon T; Nadziejko C; Schlesinger R; Chen LC
1998 Aug;96-97:285-288, Toxicology letters
To examine the biological plausibility of the adverse health effects of ambient particulate matter (PM), we have studied the cardio-pulmonary effects of PM in an animal model of pulmonary hypertension. Normal and monocrotaline-treated rats were exposed, nose-only, for 3 h to filtered air or concentrated ambient PM. At 3 h--but not 24 h--post-exposure, the percentage of neutrophils in peripheral blood was significantly elevated in PM-exposed animals while the percentage of lymphocytes was decreased with no change in white blood cell counts. These changes in white blood cell differential occurred in both normal and monocrotaline-treated animals. Small, but consistent changes in heart rate, but not core temperature, were observed after exposure to concentrated ambient PM. Pulmonary injury, as evidenced by increased protein levels in lavage fluid, occurred only in monocrotaline-treated animals exposed to > 360 microg/m3 PM. The observed pattern of hematological and cardiac changes suggests an activation of the sympathetic stress response
— id: 7580, year: 1998, vol: 96-97, page: 285, stat: Journal Article,

Expression of metallothionein protein in the lungs of Wistar rats and C57 and DBA mice exposed to cadmium oxide fumes
McKenna IM; Gordon T; Chen LC; Anver MR; Waalkes MP
1998 Dec;153(2):169-178, Toxicology & applied pharmacology
Chronic exposure to inhaled cadmium (Cd) has been shown to induce lung tumors in rats (Wistar strain) but not in mice (NMRI strain). The protein metallothionein (MT) plays an important role in Cd detoxification, and it has been suggested that differential inducibility of pulmonary MT may lead to interspecies susceptibility differences to inhaled Cd. Interstrain differences in the pulmonary response of the MT gene to Cd stimuli have not been examined in rats or mice. We compared pulmonary MT expression in Wistar Furth (WF) rats with that in DBA and C57 mice, following a single 3-h exposure to CdO fumes containing 1 mg Cd/m3. Induction of the MT gene was assessed by the levels of MT-I and MT-II transcripts, MT-protein content, and number of MT-labeled alveolar and bronchiolar epithelial cells immediately after Cd exposure and 1, 3, and 5 days later. Control animals were exposed to air/argon furnace gases. We observed differential intra- and interspecies inducibility of the MT gene in the lung following Cd inhalation. DBA mice exhibited greater levels of MT-mRNA, mainly for the MT-I isoform, MT-protein content, and number of MT positive cells relative to C57 mice. WF rats showed lower transcription and translation responses of the MT gene upon Cd stimuli than C57 mice. The present results, in concert with our previous findings of higher lung cell proliferation in Cd-exposed C57 relative to DBA mice, predict greater susceptibility of C57 to the carcinogenic effects of inhaled Cd. Furthermore, the low transcriptional and translation responses of the MT gene to Cd stimuli in WF rats might explain the higher susceptibility of this rat strain to develop malignant lung tumors after chronic exposure to Cd via inhalation. Parallel to our findings in mice, differences in the responsiveness of lung MT gene may exist across rat strains. Thus intraspecies genetic variability in pulmonary MT may influence the susceptibility of rats or mice to lung carcinogenesis induced by inhalation of Cd compounds.
— id: 7404, year: 1998, vol: 153, page: 169, stat: Journal Article,

Ambient particulate matter causes activation of the c-jun kinase/stress-activated protein kinase cascade and DNA synthesis in lung epithelial cells
Timblin C; BeruBe K; Churg A; Driscoll K; Gordon T; Hemenway D; Walsh E; Cummins AB; Vacek P; Mossman B
1998 Oct 15;58(20):4543-4547, Cancer research
Numerous epidemiological studies have demonstrated a positive association between ambient air pollution and adverse health effects including respiratory morbidity, asthma, and lung cancer. It has been suggested in some experimental studies that airborne particulate matter (PM) can produce inflammatory effects, but nothing is known about the possible proliferative and carcinogenic effects of these particles on cells of the lung. We show here that exposure of pulmonary epithelial cells, a cell type affected in acute lung injury, asthma, and lung carcinomas, to nontoxic concentrations of PM in vitro results in increases in c-jun kinase activity, levels of phosphorylated cJun immunoreactive protein, and transcriptional activation of activator protein-1-dependent gene expression. These changes are accompanied by elevations in numbers of cells incorporating 5'-bromodeoxyuridine, a marker of unscheduled DNA synthesis and/or cell proliferation. Data here are the first to demonstrate that interaction of ambient PM with target cells of the lung initiates a cell signaling cascade related causally to aberrant cell proliferation and carcinogenesis
— id: 7824, year: 1998, vol: 58, page: 4543, stat: Journal Article,

Metal fume fever: characterization of clinical and plasma IL-6 responses in controlled human exposures to zinc oxide fume at and below the threshold limit value
Fine JM; Gordon T; Chen LC; Kinney P; Falcone G; Beckett WS
1997 Aug;39(8):722-726, Journal of occupational & environmental medicine
Results from animal and preliminary human exposure studies have called into question whether the 5 mg/m3 8-hour time-weighted average threshold limit value (TLV) for zinc oxide fume is sufficient to protect workers against metal fume fever. The objectives of this study were to determine the clinical effects of exposures to low concentrations of zinc oxide and to ascertain whether these exposures elevated circulating levels of specific cytokines, which could account for the symptoms of the metal fume fever syndrome. Thirteen resting naive subjects inhaled, on separate days, air and 2.5 and 5 mg/m3 of furnace-generated zinc oxide fume for 2 hours. Subjects recorded symptoms and temperature and had blood drawn before and after each exposure. The mean (+/- SE) maximum rise in oral temperature at 6 to 12 hours after exposure was 1.4 +/- 0.3 degrees F after 5 mg/m3, compared with 0.6 +/- 0.5 degrees F after air exposure (P < 0.05). Mean temperature was also elevated after exposure to 2.5 mg/m3 zinc oxide (1.2 +/- 0.3 degrees F). In a parallel fashion, plasma levels of interleukin 6 (IL-6), a pyrogen, were significantly elevated after exposure to 5 mg/m3 zinc oxide. Mean IL-6 values (pg/mL) at pre-exposure and at 3 and 6 hours post-exposure were 1.9 (+/- 0.6), 2.8 (+/- 0.7), and 2.9 (+/- 0.6), respectively, on the air day and 1.6 (+/- 0.6), 4.4 (+/- 1.2), and 6.4 (+/- 1.1) on the 5 mg/m3 zinc oxide day. Zinc oxide exposure did not significantly affect plasma levels of tumor necrosis factor. Total symptom scores peaked 9 hours after the 5 mg/m3 zinc oxide exposure. Myalgias, cough, and fatigue were the predominant symptoms reported. Inhalation of zinc oxide for 2 hours at the current TLV of 5 mg/m3 produces fever and symptoms along with elevation in plasma IL-6 levels
— id: 30815, year: 1997, vol: 39, page: 722, stat: Journal Article,

Comparison of inflammatory lung responses in Wistar rats and C57 and DBA mice following acute exposure to cadmium oxide fumes
McKenna IM; Waalkes MP; Chen LC; Gordon T
1997 Oct;146(2):196-206, Toxicology & applied pharmacology
Inhalation of cadmium oxide (CdO) is a significant form of human exposure to cadmium (Cd). Furthermore, there is epidemiological and experimental data relating Cd inhalation with lung cancer. Animal studies indicate that rats are more susceptible to Cd-induced lung cancer than mice, but interstrain sensitivity differences to Cd-induced pulmonary inflammation or carcinogenesis have not been addressed in either species. We compared pulmonary inflammatory processes in Wistar Furth (WF) rats with those in C57 and DBA mice exposed to freshly generated CdO fumes in nose-only inhalation chambers. Animals were exposed to 1 mg Cd/m3 for 3 hr and terminated immediately or 1, 3, and 5 days after exposure. Control animals were exposed to air/argon furnace gases. Cd-induced lung injury was assessed by bronchoalveolar lavage fluid (BALF) analyses, histopathology, and immunohistochemical detection of cell proliferation. Inhalation of CdO resulted in pulmonary inflammatory processes that varied widely across species and strains. C57 mice responded with faster and greater influx of neutrophils and proliferation of alveolar macrophages, type II epithelial cells, and bronchiolar epithelial cells compared to DBA mice or WF rats. DBA mice retained a greater percentage of inhaled Cd in the lungs and presented higher levels of BALF protein than C57 mice or rats. In comparison to mice, WF rats responded with a more transient inflammatory response in BALF parameters and higher degree of acute inflammation in lung tissue. The more pronounced proliferation of alveolar and bronchiolar epithelial cells observed in C57 mice might indicate higher susceptibility of this mice strain to Cd-induced lung carcinogenesis compared to DBA mice or WF rats. Furthermore, the present results of fewer inflammatory cells and lower proliferation of epithelial cells in DBA mice in association with our previous observation of higher Cd-induced metallothionein protein in this strain suggest that DBA might be less susceptible to the pulmonary carcinogenic effects of inhaled Cd than C57 mice or WF rats. We conclude that mice might not necessarily be more resistant than rats to the carcinogenic effects of inhaled Cd, since intraspecies susceptibility differences are strongly suggested by the present data. An extrapolation of this conclusion is that genetic variations in the human population may determine individual sensitivity differences to inhaled Cd
— id: 34383, year: 1997, vol: 146, page: 196, stat: Journal Article,

In vivo exposure to ozone produces an increase in a 72-kDa heat shock protein in guinea pigs
Su WY; Gordon T
1997 Sep;83(3):707-711, Journal of applied physiology (Bethesda)
Although several lines of evidence have suggested that oxidizing agents can induce heat shock proteins (HSPs) in vitro, little is known about the induction of HSPs during in vivo exposure to oxidants. Guinea pigs were exposed to ozone for 6 h and euthanized up to 72 h later. Proteins from lavage cells and lung tissue were characterized by immunoblotting with 72- and 73/72-kDa HSP monoclonal antibodies. Although 73-kDa HSP was expressed constituitively in lung tissue, it was not affected by ozone. In contrast, 72-kDa HSP was significantly increased in lavage cells and lung tissue of animals exposed to 0.4 and 0.66 parts/million of ozone. Both heat treatment and arsenite induced 72-kDa HSP in cultured alveolar macrophages. The increase in 72-kDa HSP in the lavage cell pellet peaked at 24 h after ozone, whereas the influx of polymorphonuclear leukocytes peaked at 4 h. Examination of the induction of HSPs by ozone may provide clues to the development of ozone tolerance in humans and animals
— id: 7264, year: 1997, vol: 83, page: 707, stat: Journal Article,

One-month exposure to inhaled endotoxin produces a dose-dependent increase in stored mucosubstances in rat intrapulmonary airways
Gordon T; Nadziejko C; Plant M; Rodger IW; Pon DJ
1996 Sep-Oct;22(5):509-523, Experimental lung research
This study examined the production of stored mucosubtances in rats after repeated exposure to aerosolized endotoxin, a common contaminant of bioaerosols. Male Fischer 344 rats were exposed to aerosolized saline (sham control) or endotoxin (target concentrations of 0.05, 0.5, and 5.0 micrograms/m3) for 3 h/day, 5 days/week for 4 weeks. Following the final exposure, the left lung of each animal was lavaged and the right lung and nasal cavity were fixed with buffered formalin. Morphometric examination of Alcian blue/Periodic acid Schiffs-stained (AB/PAS) lung sections demonstrated dose-dependent increases in stored intraepithelial mucosubstances in the intrapulmonary airways of endotoxin-exposed rats. Threefold and eightfold increases in stored mucosubstances were observed in generation 5 airways of animals exposed to 0.5 or 5.0 microgram/m3 endotoxin, respectively (p < .05). This mucous cell metaplasia in the intrapulmonary airways was not accompanied by evidence of lung inflammation or increased AB/PAS-staining high molecular weight material in lavage fluid. Furthermore, despite significant deposition of endotoxin aerosols (mass median aerodynamic diameter of 1.9 microns) in the nasal cavity, no significant changes in stored mucosubstances were observed in the nasal septum. In animals repeatedly exposed to 5.0 micrograms/m3 endotoxin and allowed to recover for 1 month, stored mucosubstances in the intrapulmonary airway were still more than fivefold greater than control values. Thus, in rats, repeated exposure to inhaled endotoxin produced a persistent mucous cell metaplasia only in the intrapulmonary airways
— id: 6999, year: 1996, vol: 22, page: 509, stat: Journal Article,

Biomarkers of lung inflammation in recreational joggers exposed to ozone
Kinney PL; Nilsen DM; Lippmann M; Brescia M; Gordon T; McGovern T; El-Fawal H; Devlin RB; Rom WN
1996 Nov;154(5):1430-1435, American journal of respiratory & critical care medicine
Humans exhibit an acute inflammatory response in the lungs after controlled laboratory exposure to ozone. The present study was designed to test whether biomarkers of inflammation are detectable in humans exposed to ozone and associated copollutants under natural conditions outdoors. Bronchoscopy with bronchoalveolar lavage (BAL) was carried out on 19 normal volunteer joggers from Governors Island, NY, who exercised in the afternoon during the 1992 summer (S1) season. Fifteen subjects were retested during the following, low ozone, winter season (W). The BAL protocol involved an initial instillation of 20 ml saline followed by four sequential 50-ml saline washes carried out in both the right middle lobe and the lingula. The eight 50-ml samples were pooled as the 'alveolar' sample. Analyses performed on the alveolar lavage samples included cell differentials, release of IL-8, TNF-alpha, and reactive oxygen species (ROS) by pooled cells, and levels of IL-8, protein, LDH, fibronectin, alpha1-antitrypsin (alpha1-AT), complement fragment 3a (C3a), and prostaglandin E2 (PGE2) in lavage fluids. Release of ROS by stimulated BAL cells was lower in S1 than in W (p = 0.03). In contrast, LDH levels in BAL fluids were 2-fold higher in S1 than in W (p = 0.02), as were IL-8 (p = 0.12) and PGE2 (p = 0.06). These results suggest a possible ongoing inflammatory response in the lungs of recreational joggers exposed to ozone and associated copollutants during the summer months
— id: 12497, year: 1996, vol: 154, page: 1430, stat: Journal Article,

Alterations in surfactant protein A after acute exposure to ozone
Su WY; Gordon T
1996 May;80(5):1560-1567, Journal of applied physiology (Bethesda)
The surfactant layer covering the gas-exchange region of the lung serves as the initial site of interaction with inhaled oxidant gases. Among the endogenous compounds potentially vulnerable to oxidative injury are surfactant proteins. This study focused on the effect of ozone on surfactant protein A (SP-A) function, content, and gene expression. To determine the time course of response to ozone, guinea pigs were exposed to 0.2-0.8 parts/million (ppm) ozone for 6 h and were killed up to 120 h postexposure. To determine the effect of repeated exposure, animals were exposed to 0.8 ppm ozone for 6 h/day and were killed on days 3 and 5. A significant increase in surfactant's ability to modulate the respiratory burst induced by phorbol 12-myristate 13-acetate in naive macrophages was observed at 24 h after a single 0.8 ppm ozone exposure. Because neutralizing antibodies to SP-A blunted this stimulatory effect, we hypothesized that ozone enhanced the modulatory role of SP-A in macrophage function. This alteration in function was accompanied by an influx of inflammatory cells and only marginal changes in SP-A levels as determined by an enzyme-linked immunosorbent assay. No significant changes in steady-state levels of SP-A mRNA were observed after single or repeated exposure to ozone. Thus the inflammation that accompanies in vivo ozone exposure may result in a change in the structure and thus functional role of SP-A in modulating macrophage activity
— id: 12612, year: 1996, vol: 80, page: 1560, stat: Journal Article,

Cotton dust produces an increase in intraepithelial mucosubstances in rat airways
Gordon T; Harkema JR
1995 Jun;151(6):1981-1988, American journal of respiratory & critical care medicine
Occupational exposure to endotoxin-contaminated organic dusts is associated with a variety of adverse pulmonary effects, including chronic bronchitis and sputum production. We have previously demonstrated in F344 rats that inhaled endotoxin rapidly induces an increase in the volume of stored intraepithelial mucosubstances (Vs) in the respiratory tract. The present study examined whether endotoxin-contaminated cotton dust can produce a similar increase in Vs in this animal model. Rats were exposed to air or 1.5 to 15.0 mg/m3 cotton dust for 2 h/d for 3 d. Twenty-four hours after the final exposure, the nasal cavity and lungs were fixed in formalin and the presence of Alcian blue/periodic acid-Schiff-staining mucosubstances determined by morphometry. Exposure to cotton dust produced concentration-dependent changes in Vs in the nasal septum and intrapulmonary airways. Statistically significant increases in Vs were observed in the epithelial lining of the nasal septum of animals exposed to 5.3 and 14.5 mg/m3 cotton dust (equivalent to 2.8 and 8.9 micrograms/m3 endotoxin). Vs in the intrapulmonary airways was also significantly increased at these concentrations. No significant changes were observed in the nasal septum or intrapulmonary airways after exposure to 1.8 mg/m3 cotton dust. These results are consistent with the hypothesis that endotoxin may contribute to the increase in human cases of chronic bronchitis reported in occupational settings in which endotoxin-contaminated dusts are encountered
— id: 6635, year: 1995, vol: 151, page: 1981, stat: Journal Article,

Mucous cell metaplasia in the airways of rats exposed to machining fluids
Gordon T; Harkema JR
1995 Dec;28(2):274-282, Fundamental & applied toxicology
Occupational exposure to microbial-contaminated machining fluids is associated with a variety of adverse pulmonary effects including chronic bronchitis and increased sputum production. We have previously demonstrated in F344 rats that inhaled endotoxin can increase the amount of stored intraepithelial mucosubstances (Vs) in the respiratory tract. The purpose of the present study was to examine the effect of endotoxin-contaminated machining fluid aerosols on mucous production. Rats were exposed to aerosols of pyrogen-free water, 1 or 10 mg/m3 used machining fluid, or 10 mg/m3 unused machining fluid for 3 hr/day for 3 days. Twenty-four hours after the final exposure, right lung lobes were lavaged and the nasal cavity and left lung were fixed in formalin. The amount of Alcian blue/periodic acid-Schiff-stained mucosubstances was determined by morphometry. Exposure to 10 mg/m3 used machining fluid (equivalent to 0.8 micrograms/m3 endotoxin) produced a significant increase in Vs in the epithelial lining of both the nasal septum and intrapulmonary airways. These changes in Vs were accompanied by a significant increase in total cells and neutrophils in the lavage fluid. No changes in stored mucosubstances or lavage parameters were found in animals exposed to 1 mg/m3 used machining fluid aerosols. A significant increase in Vs was observed in the nasal septum but not in the intrapulmonary airways of animals exposed to 10 mg/m3 unused machining fluids (no measurable endotoxin). These results suggest that in addition to endotoxin, nonendotoxin components of machining fluids may contribute to the increase in sputum and chronic bronchitis reported for workers exposed to machining fluid aerosols
— id: 7936, year: 1995, vol: 28, page: 274, stat: Journal Article,

Effect of inhaled endotoxin on intraepithelial mucosubstances in F344 rat nasal and tracheobronchial airways
Gordon T; Harkema JR
1994 Feb;10(2):177-183, American journal of respiratory cell & molecular biology
Increased sputum production and chronic bronchitis are associated with occupational exposure to endotoxin-contaminated organic ducts. The present study examined whether repeated exposure to occupationally relevant concentrations of airborne endotoxin in the F344 rat can alter the volume density of stored intraepithelial mucosubstances (Vs) in the respiratory tract. Rats were exposed to saline or endotoxin aerosols for 3 h/day for 3 days and were killed 24 h after the last exposure. Quantitative histochemistry of Vs in airway epithelium was examined at three distinct levels of the respiratory tract (nose, trachea, and lung). Exposure to endotoxin produced a dose-dependent increase in Vs in the intrapulmonary airways. The quantity of Vs in the intrapulmonary airways was significantly increased in animals exposed to as little as 0.3 micrograms/m3 endotoxin. Significant increases in Vs were observed in the trachea only after exposure to > or = 3.1 micrograms/m3 endotoxin, whereas no significant changes were observed in the nasal airways even at concentrations as high as 52.4 micrograms/m3. These results are consistent with earlier findings in which repeated instillation of endotoxin produced significant increases in Vs in the epithelial lining of the pulmonary airways and demonstrate that inhaled endotoxin may play a role in the increase in sputum and chronic bronchitis reported for workers exposed to organic dusts
— id: 6393, year: 1994, vol: 10, page: 177, stat: Journal Article,

ROLE OF THE COMPLEMENT-SYSTEM IN THE ACUTE RESPIRATORY EFFECTS OF INHALED ENDOTOXIN AND COTTON DUST
GORDON, T
1994 MAY-JUN ;6(3):253-266, Inhalation toxicology
Components of the complement system are thought to play a role in the respiratory effects of inhaled organic dusts encountered in occupational settings such as grain storage sites and cotton mills. This hypothesis is based upon observations that grain dusts and endotoxin can activate complement in vitro and in vivo and that the complement system appears to contribute to the endotoxin-induced lung injury of septic shock. The present study examined whether the inflammatory effects of inhaled endotoxin and cotton dust were (1) blocked by decomplementing animals with cobra venom factor (CVF) or (2) present in animals genetically deficient in specific components of the complement system. In untreated and sham-treated guinea pigs, inhaled endotoxin produced significant increases in biochemical and cellular indices of pulmonary injury in bronchoalveolar lavage fluid. Treatment of guinea pigs with 200 units CVF/kg at 24 h prior to exposure did not block the biochemical and cellular changes produced by inhaled endotoxin or cotton dust. Guinea pigs deficient in the fourth component of complement (C4) also demonstrated evidence of pulmonary injury roughly equivalent to that of normal guinea pigs exposed to inhaled endotoxin or cotton dust. Finally, mice genetically deficient in the fifth component of complement (C5) did not exhibit a decreased pulmonary response to inhaled endotoxin compared to C5-sufficient mice. These studies suggest that despite in vitro and in vivo evidence of complement activation by endotoxin and extracts of organic dusts, the complement system may not play a major role in the acute respiratory effects of inhaled endotoxin and cotton dust
— id: 52423, year: 1994, vol: 6, page: 253, stat: Journal Article,

Metal fume fever
Gordon T; Fine JM
1993 Jul-Sep;8(3):504-517, Occupational medicine
Metal fume fever is an acute self-limited illness induced most commonly by inhalation of zinc oxide fumes. The affected individual characteristically experiences the rapid onset of intense shaking chills, fever, and body aches a few hours after exposure, and symptoms dissipate spontaneously. While the occurrence of metal fume fever appears to be widespread and the current TLV/PEL of 5 mg/m3 and STEL of 10 mg/m3 may not be fully protective, no chronic health sequelae have been documented to date. Nonetheless, as any worker who has experienced a full-blown case will likely testify, metal fume fever remains one of the more noxious short-term illnesses contracted in the workplace, and its prevention deserves serious attention
— id: 13124, year: 1993, vol: 8, page: 504, stat: Journal Article,

Increased pulmonary response to inhaled endotoxin in lactating rats
Gordon T; Weideman PA; Gunnison AF
1993 May;147(5):1100-1104, American review of respiratory disease
An important aspect of risk assessment is identification of subpopulations particularly susceptible to the effects of inhaled pollutants. The present study examined whether female rats were more sensitive during lactation to the acute pulmonary injury produced by inhaled endotoxin. Lactating and age-matched virgin female rats were exposed to aerosols of saline or endotoxin for 3 h and lavaged at 24 h after exposure. No significant differences in lactate dehydrogenase, beta-glucuronidase, total protein, and total cell and PMN counts were observed between virgin and lactating rats after exposure to saline. Each marker of pulmonary injury except beta-glucuronidase was 1.5- to 3-fold greater in lactating than in virgin female rats exposed to 29.6 micrograms/m3 endotoxin. PMNs (6-fold), total cell counts, and protein were also significantly increased (p < 0.05) in lactating rats exposed to 1.3 micrograms/m3 endotoxin, a concentration reported to occur in a number of agricultural settings. These results demonstrate that the physiologic state of lactation is associated with an increased sensitivity to the acute pulmonary injury produced by inhaled endotoxin and are consistent with previous work demonstrating a similar increased sensitivity to ozone exposure. The possibility of a similar pattern of enhanced response in analogous groups of humans merits examination
— id: 6392, year: 1993, vol: 147, page: 1100, stat: Journal Article,

Alteration of pulmonary macrophage intracellular pH regulation by sulfuric acid aerosol exposures
Qu QS; Chen LC; Gordon T; Amdur M; Fine JM
1993 Jul;121(1):138-143, Toxicology & applied pharmacology
In vivo exposure to sulfuric acid aerosols produces profound effects on pulmonary macrophage (PM phi) phagocytic function and cytokine release and perturbs intracellular pH (pHi) homeostasis. Because pHi influences a multitude of cellular processes, we sought to investigate the mechanism by which acid aerosol exposure affects its regulation. Guinea pigs underwent a single or 5 repeated 3-hr exposures to sulfuric acid aerosol (969 and 974 micrograms/m3 for single and repeated exposures, respectively). PM phi harvested immediately after exposure were incubated in HCO3-free media and their pHi recovery from an intracellular acid load was examined. The overall pHi recovery was depressed after single and multiple exposures to sulfuric acid aerosol. delta pHi (the difference between initial pHi and the one measured at 150 sec) decreased by 15.6 and 23.3% (p < 0.05) for single and repeated exposures, respectively. Initial dpHi/dt (maximum pHi recovery rate) after cytoplasmic acidification diminished by 20.3 and 32.2%, which were not statistically significant (p = 0.08 for repeated exposure). To determine whether the activity of the H(+)-ATPase pump the Na(+)-H+ exchanger was specifically altered by the acid exposures, PM phi were first incubated in Na+ and HCO3-free media with NBD-Cl (7-chloro-4-nitrobenz-2-oxa-1,3-diazol, blocking H(+)-ATPase and leaving only the Na(+)-H+ exchanger in effect) and then challenged with 30 mM NaCl. The pHi recovery of PM phi after Na challenge was significantly reduced in acid aerosol exposed guinea pigs (p < 0.05) compared to controls (for delta pHi, 18.2% lower in single exposure and 22.7% in multiple exposure groups; for initial dpHi/dt, 26.9% lower in single exposure and 22.4% in multiple exposure groups). In contrast, the H(+)-ATPase pump was inconsistently affected as indicated by delta pHi and initial dpHi/dt measured in the presence of MIA (amiloride-5-N-methylisobutyl, inhibiting the Na(+)-H+ exchanger and leaving only the H(+)-ATPase pump in effect). These results suggest that in vivo exposure to sulfuric acid aerosols induces alterations in pHi regulation in guinea pig PM phi attributable to changes in Na(+)-H+ exchanger activity
— id: 13111, year: 1993, vol: 121, page: 138, stat: Journal Article,

Effects of fine and ultrafine sulfuric acid aerosols in guinea pigs: alterations in alveolar macrophage function and intracellular pH
Chen LC; Fine JM; Qu QS; Amdur MO; Gordon T
1992 Mar;113(1):109-117, Toxicology & applied pharmacology
Acidic sulfate is the most toxicologically important sulfur oxide which exists in the ambient air. To determine if particle size influences toxic effects of sulfuric acid, we investigated the effects of sulfuric acid aerosols of two different sizes on biochemical and cellular parameters of bronchoalveolar lavage fluid from exposed guinea pigs. Guinea pigs were exposed to fine (mass median diameter, 0.3 micron), and ultrafine (mass median diameter, 0.04 micron) sulfuric acid aerosols at 300 micrograms/m3 for 3 hr/day. The animals were euthanized immediately and 24 hr after 1 and 4 days of exposure and lungs were lavaged. Elevated beta-glucuronidase, lactate dehydrogenase activities, and total protein concentration as well as decreased cell viability were observed in the lavage after a single exposure to sulfuric acid aerosols of both sizes. These alterations were small, though statistically significant, and transient. No alteration in these parameters was observed after 4 days of exposure to acid aerosols. In contrast, sulfuric acid-induced alterations in alveolar macrophage function were more pronounced and longer lasting. Immediately after a single exposure to fine acid, there was a 2.7-fold increase in the spontaneous tumor necrosis factor (TNF) release over that in the control group while endotoxin-stimulated TNF release was increased by 2.2-fold. In addition, acid aerosols of both sizes increased the TNF release from macrophages after 4 days of exposure, although there was no clear temporal pattern of induction or recovery. Furthermore, immediately after 4 days of exposure to either fine or ultrafine acid, the amount of H2O2 that could be induced from baseline production by alveolar macrophages was 2.2-fold higher than that of the controls. The phagocytic function of macrophages was also altered by exposure to sulfuric acid aerosols. Twenty-four hours after single or multiple exposure, fine acid enhanced (as high as 78% above control) the in vitro phagocytic activity of alveolar macrophages while ultrafine acid depressed the phagocytic capacity (as much as 50% below that in the control). In addition to these biochemical parameters and cellular functions, we also measured the intracellular pH (pHi) of macrophages harvested after exposures to these acid aerosols using a pH-sensitive fluorescent dye. The resting pHi was depressed after a single exposure to both acid aerosols. The depression in pHi persisted 24 hr after ultrafine acid exposure.(ABSTRACT TRUNCATED AT 400 WORDS)
— id: 13672, year: 1992, vol: 113, page: 109, stat: Journal Article,

Airway hyperresponsiveness in guinea pigs exposed to acid-coated ultrafine particles
Chen LC; Miller PD; Amdur MO; Gordon T
1992 Mar;35(3):165-174, Journal of toxicology & environmental health
Although several epidemiological studies have provided evidence that airborne sulfate particles can produce adverse health effects in susceptible individuals, there is only limited data demonstrating respiratory effects in human volunteers and experimental animals at near ambient concentrations. We have demonstrated previously that the mixing of metal oxide particles with SO2 under humid conditions produces acid-coated particles that are significantly more potent in causing pulmonary function changes than pure acid droplets. The present study examined the nonspecific airway responsiveness to acetylcholine in guinea pigs exposed to acid-coated zinc oxide particles. One and a half hours after a 1-h exposure to the aerosols or a control atmosphere, pulmonary resistance (RL) was measured in awake, spontaneously breathing animals before and during a challenge with increasing doses of iv acetylcholine (Ach). The provocative infusion rate of Ach that resulted in a 100% increase in RL (PR100) was significantly decreased (p less than .05) in animals exposed to sulfuric acid-coated metal oxide particles (approximately 30 micrograms/m3 sulfate) compared to control animals exposed to furnace gases (79.6 +/- 19.4 vs. 179.6 +/- 16.2 micrograms/kg/min, mean +/- SE, respectively). The PR100 of animals exposed to SO2 (109.1 +/- 45.4) or metal oxide particles (106.7 +/- 38.1) alone was not significantly different from that of furnace gas control animals, indicating that the acid coating on the metal oxide particles and not the particles themselves or the SO2 was responsible for the decrease in the PR100. Moreover, a 10-fold greater amount of total sulfate as a pure aqueous sulfuric acid aerosol was necessary to produce a decrease in PR100 (88.6 +/- 11.0 micrograms/kg/min) equivalent to that produced by coated particles. These results suggest that acute exposure to near-ambient concentrations of sulfuric acid under conditions that promote the formation of acid as a surface coating in respirable particles can induce a nonspecific airway hyperresponsiveness. In a similar manner, a dose-dependent significant decrease in PR100 was also produced in animals exposed to sodium sulfite droplets. Thus a single exposure to different forms of sulfur oxide aerosols can induce an alteration in the responsiveness of airway smooth muscle in the guinea pig
— id: 13662, year: 1992, vol: 35, page: 165, stat: Journal Article,

Rat lung metallothionein and heme oxygenase gene expression following ozone and zinc oxide exposure
Cosma G; Fulton H; DeFeo T; Gordon T
1992 Nov;117(1):75-80, Toxicology & applied pharmacology
We have conducted exposures in rats to determine pulmonary responses following inhalation of two common components of welding fumes, zinc oxide and ozone. To examine their effects on target-inducible gene expression, we measured mRNA levels of two metal-responsive genes, metallothionein (MT) and heme oxygenase (HO), in lung tissue by RNA slot-blot analysis. A 3-hr exposure to ZnO fume via a combustion furnace caused a substantial elevation in lung MT mRNA at all concentrations tested. Exposures to 5 and 2.5 mg/m3 ZnO resulted in peak 8-fold increases in MT mRNA levels (compared to air-exposed control animal values) immediately after exposure, while 1 mg/m3 ZnO exposure caused a 3.5-fold elevation in MT mRNA. These levels returned to approximate control gene expression values 24 hr after exposure. In addition, ZnO exposure caused an immediate elevation in lung HO gene expression levels, with 8-, 11-, and 5-fold increases observed after the same ZnO exposure levels (p < 0.05). Like MT gene induction, HO mRNA values returned to approximate control levels 24 hr after exposure. In striking contrast to the induction of MT and HO gene expression after ZnO exposures, there was no elevation in gene expression following a 6-hr exposure to 0.5 and 1 ppm ozone, even when lungs were examined as late as 72 hr after exposure. Our results demonstrate the induction of target gene expression following the inhalation of ZnO at concentrations equal to, and below, the current recommended threshold limit value of 5 mg/m3 ZnO. Furthermore, the lack of effect of ozone exposure on MT and HO gene expression suggests no involvement of these genes in the acute respiratory response to this oxidant compound
— id: 8365, year: 1992, vol: 117, page: 75, stat: Journal Article,

Acute respiratory effects of endotoxin-contaminated machining fluid aerosols in guinea pigs
Gordon T
1992 Jul;19(1):117-123, Fundamental & applied toxicology
Exposure to machining fluid aerosols in the automotive industry is associated with a variety of respiratory symptoms including cross-shift changes in pulmonary function, cough, asthma, and phlegm. Lubricating and cooling fluids used in machining operations are predominantly water and thus are susceptible to microbial growth. In the present study, the role of endotoxin in the acute pulmonary injury produced by machining fluid aerosols was examined in guinea pigs. Animals were exposed to nebulized water, unused machining fluid, or used machining fluid. At the end of a 3-hr exposure, specific airway conductance (SGaw) was not affected by exposure to the vehicle water, but was decreased in a dose-dependent manner by exposure to aerosols of the used machining fluid. SGaw decreased from preexposure baseline values by 0, 7, and 40% in animals exposed to 1, 10, and 100 mg/m3 used machining fluid, respectively. These exposure levels also produced acute lung injury as evidenced by changes in cellular and biochemical indices in lavage fluid. These adverse respiratory effects may have been due to microbial contamination of the used machining fluid as the aerosol exposures were associated with airborne endotoxin concentrations of 0.3, 1.9, and 5.3 micrograms/m3, respectively. Animals exposed to aerosols of the endotoxin-free unused machining fluid had no statistically significant adverse functional, cellular, or biochemical effects except for a fourfold increase in neutrophils at 100 mg/m3. These results suggest that contamination of machining fluid during use or storage may lead to the adverse respiratory effects of aerosolized machining fluids.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 13547, year: 1992, vol: 19, page: 117, stat: Journal Article,

Dose-dependent pulmonary effects of inhaled endotoxin in guinea pigs
Gordon T
1992 Dec;59(2):416-426, Environmental research
As a cell wall component of gram-negative bacteria, endotoxin is thought to play a significant role in the respiratory effects of inhaled organic dusts which are microbially contaminated. Assessment of occupational survey data and clinical studies suggests that few measureable, acute functional changes occur below 30-50 ng/m3 endotoxin (as sampled in airborne dust with a vertical elutriator). Little information is available on the inflammatory effects of inhaled endotoxin at these low concentrations. The present study examined the dose-response relationship between inhaled endotoxin and functional, biochemical, and histological endpoints in the lungs of guinea pigs. Animals were exposed to 0.03 to 50.5 micrograms/m3 aerosolized endotoxin or the vehicle water for 4 hr. At 2 hr into exposure, significant decreases in specific airway conductance were observed only in animals exposed to 9.6 and 50.5 micrograms/m3 endotoxin (17.3 +/- 1.2 and 35.5 +/- 0.5% decreases from baseline values, respectively (mean +/- SE)). Total cell count and lactate dehydrogenase levels in bronchoalveolar lavage fluid were significantly elevated at 24 hr after exposure in all endotoxin-exposed groups except the lowest dose, 0.03 micrograms/m3 (P < 0.05). Polymorphonuclear leukocyte influx into the alveolar region was also dependent on the concentration of inhaled endotoxin. Thus, LDH activity, a biochemical marker of cell injury, and total cell counts and polymorphonuclear leukocytes, markers of inflammation, were more sensitive indices of adverse pulmonary effects from inhaled endotoxin than a functional measurement. These results suggest that subtle inflammatory changes may occur at airborne endotoxin concentrations which may produce no acute respiratory symptoms
— id: 13350, year: 1992, vol: 59, page: 416, stat: Journal Article,

Pulmonary effects of inhaled zinc oxide in human subjects, guinea pigs, rats, and rabbits
Gordon T; Chen LC; Fine JM; Schlesinger RB; Su WY; Kimmel TA; Amdur MO
1992 Aug;53(8):503-509, American Industrial Hygiene Association journal
Occupational exposure to freshly formed zinc oxide (ZnO) particles (less than 1.0 micron aerodynamic diameter) produces a well-characterized response known as metal fume fever. An 8-hr threshold limit value (TLV) of 5 mg/m3 has been established to prevent adverse health effects because of exposure to ZnO fumes. Because animal toxicity studies have demonstrated pulmonary effects near the current TLV, the present study examined the time course and dose-response of the pulmonary injury produced by inhaled ZnO in guinea pigs, rats, rabbits, and human volunteers. The test animals were exposed to 0, 2.5, or 5.0 mg/m3 ZnO for up to 3 hr and their lungs lavaged. Both the lavage fluid and recovered cells were examined for evidence of inflammation or altered cell function. The lavage fluid from guinea pigs and rats exposed to 5 mg/m3 had significant increases in total cells, lactate dehydrogenase, beta-glucuronidase, and protein content. These changes were greatest 24 hr after exposure. Guinea pig alveolar macrophage function was depressed as evidenced by in vitro phagocytosis of opsonized latex beads. Significant changes in lavage fluid parameters were also observed in guinea pigs and rats exposed to 2.5 mg/m3 ZnO. In contrast, rabbits showed no increase in biochemical or cellular parameters following a 2-hr exposure to 5 mg/m3 ZnO. Differences in total lung burden of ZnO, as determined in additional animals by atomic absorption spectroscopy, appeared to account for the observed differences in species responses. Although the lungs of guinea pigs and rats retained approximately 20% and 12% of the inhaled dose, respectively, rabbits retained only 5%.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 8450, year: 1992, vol: 53, page: 503, stat: Journal Article,

Airway oedema and obstruction in guinea pigs exposed to inhaled endotoxin
Gordon T; Balmes J; Fine J; Sheppard D
1991 Sep;48(9):629-635, British journal of industrial medicine
Protein extravasation and airway conductance (SGaw) were examined in awake guinea pigs exposed to inhaled endotoxin or saline for three hours. A significant increase in protein extravasation (as estimated by the leakage of protein bound Evans blue dye) was seen in the conducting airways of endotoxin exposed animals compared with saline exposed animals. Mean dye extravasation was significantly increased by one to threefold in the mainstem and hilar bronchi of endotoxin exposed animals. These changes in extravasation were accompanied by decrements in pulmonary function and by an influx of polymorphonuclear leucocytes into the airway wall. The SGaw decreased significantly by 60-90 minutes into exposure to endotoxin and had decreased by 22% and 34% at the end of exposure in the low and high dose endotoxin groups, respectively. Similar findings were obtained in animals exposed to cotton dust. Contrary to studies suggesting that platelet activating factor (PAF) is involved in the systemic and peripheral lung effects of endotoxin, pretreatment with the PAF antagonist WEB2086 did not prevent the conducting airway injury produced by inhaled endotoxin
— id: 13912, year: 1991, vol: 48, page: 629, stat: Journal Article,

THE ROLE OF INFLAMMATORY MEDIATORS IN AIRWAY EDEMA AND OBSTRUCTION PRODUCED IN GUINEA-PIGS EXPOSED TO INHALED ENDOTOXIN OR COTTON DUSTS
GORDON, T
1990 JAN ;17(1):107-108, American journal of industrial medicine
— id: 98513, year: 1990, vol: 17, page: 107, stat: Journal Article,

The role of titratable acidity in acid aerosol-induced bronchoconstriction
Fine JM; Gordon T; Thompson JE; Sheppard D
1987 Apr;135(4):826-830, American review of respiratory disease
We evaluated the importance of pH, titratable acidity, and specific chemical composition in acid aerosol-induced bronchoconstriction in 8 asthmatic subjects. We administered aerosols of HCl and H2SO4 at pH 2.0 in an unbuffered state and buffered with glycine. The buffered acids were given in order of increasing titratable acidity (defined as the number of ml of 1 N NaOH required to neutralize 100 ml of acid solution to pH 7.0). Each set of buffered or unbuffered acid aerosols was given on a separate day and each aerosol was inhaled through a mouthpiece during 3 min of tidal breathing. Bronchoconstriction was assessed by measurement of specific airway resistance (SRaw) before and after inhalation of each aerosol. SRaw increased by more than 50% above baseline in 1 of 8 subjects after inhalation of unbuffered HCl and in no subjects after inhalation of unbuffered H2SO4, even at pH 2.0. In contrast, SRaw increased by greater than 50% in all 8 subjects after inhalation of HCl and glycine at pH 2.0 and 7 of 8 subjects after inhalation of H2SO4 and glycine at pH 2.0. The mean titratable acidity required to increase SRaw by 50% above baseline was calculated for each challenge by linear interpolation; these values for H2SO4 and glycine (5.1 ml of 1 N NaOH) and HCl and glycine (2.2 ml of 1 N NaOH) were slightly, but significantly, different (p = 0.01) and were considerably higher than the titratable acidity of the unbuffered acids at pH 2 (1.0 ml of 1 N NaOH).(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 34492, year: 1987, vol: 135, page: 826, stat: Journal Article,

Apparent effect of catalase on airway edema in guinea pigs. Role of endotoxin contamination
Gordon T; Milligan SA; Levin J; Thompson JE; Fine JM; Sheppard D
1987 Apr;135(4):854-859, American review of respiratory disease
The airway edema that develops in guinea pigs after exposure to toluene diisocyanate (TDI) requires the presence of polymorphonuclear leukocytes (PMN). To determine whether this airway edema is mediated by the release of hydrogen peroxide from PMN, we treated animals intravenously with catalase bound to polyethylene glycol and examined the extravasation of Evans blue dye into the tracheal wall after exposure to air or 3 ppm TDI for 1 h. Catalase (25,000, 100,000, and 300,000 IU/kg) caused a dose-dependent inhibition of the TDI-induced increase in dye extravasation. However, treatment with catalase, inactivated at the peroxide binding site with 3-aminotriazole, inhibited dye extravasation after exposure to TDI as effectively as the equimolar 100,000 IU/kg dose of active catalase. Injection of polyethylene glycol alone was without effect. Dose-dependent decreases in extravascular migration of PMN and in circulating PMN also were noted after catalase treatment. These results suggest that the catalase preparations used in these studies inhibited the PMN-dependent airway edema by an effect other than hydrogen peroxide scavenging. Examination of this and other commercially available catalase preparations revealed trace concentrations of endotoxin at levels that could be responsible for the observed effects on PMN function. Treatment of animals with doses of Escherichia coli endotoxin similar to those inadvertantly administered to the catalase-treated groups (0.1 ng/kg to 100 ng/kg, intravenously) inhibited TDI-induced extravasation of Evans blue dye in a dose-dependent manner. These results suggest that contaminating endotoxin may contribute to some of the protective effects of preparations of catalase observed in previous studies of vascular permeability
— id: 34493, year: 1987, vol: 135, page: 854, stat: Journal Article,

A 90-day inhalation toxicity study of raw shale oil in Fischer 344 rats
Gordon T; Strother DE; Cramer DV; Goode JW
1987 Aug;9(2):287-296, Fundamental & applied toxicology
The potential health effects of a raw shale oil were evaluated in a 90-day inhalation study in Fischer 344 rats. Groups of 15 male and 15 female rats were exposed 6 hr/day, 5 days/week for 13 weeks to aerosol concentrations of 0, 56, 120, or 492 mg/m3. In the high-dose group, 10 males and 7 females died prior to the termination of the study, most within the first 5 weeks of the experiment. A dose-dependent suppression in weight gain was seen in all of the shale oil-exposed groups. The failure to gain weight was associated with a variety of clinicopathologic abnormalities, including a dose-related decrease in red and white blood cells, with lowered plasma protein levels and increased serum alkaline phosphatase, and with total bilirubin levels in males. The exposure of the test animals to aerosolized raw shale oil was also associated with inflammatory and hyperplastic lesions in the lungs and upper respiratory tract, atrophy of the thymus and thymic-dependent portions of the peripheral lymphoid system, and bone marrow. These changes demonstrate that inhalation of raw shale oil aerosol can produce major organ toxicity similar to that found after exposure to other unrefined oil products
— id: 34491, year: 1987, vol: 9, page: 287, stat: Journal Article,

The roles of pH, titratable acid and specific chemical composition in mediating effects of acid aerosols in the airways : research contract final report to State of California Air Resources Board
Sheppard, Dean; Gordon, Terry; Fine, Jonathan M
[Sacramento CA : California Air Resources Board], 1987,
— id: 1271, year: 1987, vol: , page: , stat: ,

Purity of catalase preparations: contamination by endotoxin and its role in the inhibition of airway inflammation
Gordon T
1986 ;2(5-6):373-375, Journal of free radicals in biology & medicine
— id: 34494, year: 1986, vol: 2, page: 373, stat: Journal Article,

Airway hyperresponsiveness and inflammation induced by toluene diisocyanate in guinea pigs
Gordon T; Sheppard D; McDonald DM; Distefano S; Scypinski L
1985 Nov;132(5):1106-1112, American review of respiratory disease
We examined the changes in airway responsiveness to increasing doses of an acetylcholine aerosol in anesthetized and ventilated guinea pigs 2, 6, or 24 h after exposure to 2 ppm toluene diisocyanate (TDI) or 2 h after exposure to air or 1 ppm TDI. Pulmonary resistance (RL) after the animals inhaled a buffered saline aerosol was used as baseline and was similar for air and TDI groups. The concentration of acetylcholine calculated to cause a 200% increase in RL was significantly lower for animals studied at 2 h (0.68%) or at 6 h (0.77%), but not at 24 h (2.39%), after TDI than for air animals (3.07%). The increase in airway responsiveness in the TDI-exposed animals was associated with histologic changes in the trachea and intrapulmonary airways. Exposure to 2 ppm TDI caused a patchy loss of cilia, shedding of epithelial cells into the airway lumen, and an influx of inflammatory cells into the trachea and other airways. In the lamina propria of the trachea, the concentration of extravascular polymorphonuclear leukocytes (PMN) was 13- to 26-fold greater in animals studied 2 or 6 h after exposure to 2 ppm TDI or at 2 h after 1 ppm TDI than in animals exposed to air. The concentration of PMN in the epithelium was significantly increased only in animals examined 2 h after 2 ppm TDI. Exposure to TDI also caused an influx of eosinophils into the tracheal mucosa. This influx occurred later and was more persistent than the influx of PMN. These results indicate that a single exposure to TDI can cause an increase in airway responsiveness that is associated with epithelial injury and acute airway inflammation
— id: 34495, year: 1985, vol: 132, page: 1106, stat: Journal Article,

Ozone induced airway hyperactivity in guinea pigs
Gordon, Terry
[S.l. : s.n.], 1981,
Thesis (Ph.D.) -- Massachusetts Institute of Technology, 1982
— id: 1272, year: 1981, vol: , page: , stat: ,