Mitchell D Cohen, Ph.D.

How environment affects drug activity: Localization, compartmentalization and reactions of a vanadium insulin-enhancing compound, dipicolinatooxovanadium(V)
Crans, Debbie C.; Trujillo, Alejandro M.; Pharazyn, Philip S.; Cohen, Mitchell D.
2011 OCT ;255(19-20):2178-2192, Coordination chemistry reviews
The chemical and biological properties of a simple and traditional V(5+) coordination complex, dipicolinatooxovanadium(V) (abbreviated [VO(2)dipic](-)), are described in order to present a hypothesis for a novel mode of action wherein a hydrophobic membrane environment plays a key role. Specifically, we propose that the compartmentalization and both chemical and biological transformations of vanadium-complexes direct whether beneficial or toxic effects will be observed with this class of compounds. This concept is based on the formation of high levels of uncontrollable reactive oxygen species (ROS) from one-electron reactions or alternative events possibly initiated by a two-electron reaction which may be directly or indirectly beneficial by reducing the high levels of ROS. The properties of dipicolinatooxovanadium(V) compounds in aqueous solution (D.C. Crans, et al., Inorg. Chem. 39 (2000) 4409-4416) are very different from those in organic solvents (S.K. Hanson, et al., J. Am. Chem. Soc. 131 (2009) 428-429) and these differences may be key for their mode of action. Since other vanadium complexes are known to hydrolyze upon administration, the low stability of the aqueous complex requires entrapment in hydrophobic environments for such a complex to exist sufficiently long to have an effect. The suggestion that the environment changes the reactivity of the compounds is consistent with the very different modes of action by which one complex act. In short, a novel hypothesis is presented for a mode of action of vanadium compounds based on differences in properties resulting from environmental conditions. These considerations are supported by recent evidence supporting a role for membranes and signal transduction events (D.A. Roess, et al. Chem. Biodivers. 5 (2008) 1558-1570) of the insulin-enhancing properties of these compounds. (C) 2011 Elsevier B.V. All rights reserved
— id: 139065, year: 2011, vol: 255, page: 2178, stat: Journal Article,

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,

ED to catheterization laboratory: A roundtable integrating trials with practice
Pollack Jr. C.V.; Brogan Jr. G.X.; Cohen M.; Diercks D.; Grines C.; Henry T.D.; Kleiman N.S.; Giugliano R.P.
2011 ;29(9):1203-1216, American journal of emergency medicine
Background: Clinical trials are the foundation underlying clinical decision-making. However, stringent inclusion and exclusion criteria may reduce the generalizability of their results, especially for patients seen in the emergency department (ED). Guideline recommendations, based on clinical trials and pertinent registries, apply to broad populations, but not all patients cared for at the bedside fit the predefined categories that make guidelines practical. Furthermore, these documents may not incorporate the latest evidence. As a result, other factors (eg, individual patient characteristics, clinician experience, cost, regulatory labels, expert opinions) often result in clinical decision-making that varies from strict adherence to guideline recommendations. Objectives: These challenges demonstrate a need to integrate clinical data and guidelines advice with actual ED practice in a manner that will be consistent with decisions made later in the continuum of care. Discussion: In recognition of these issues, a roundtable was convened in New York City on June 5, 2009, to discuss the implications of recent trials involving patients with non-ST-segment elevation acute coronary syndromes. Eight physicians, representing both emergency medicine and cardiology, shared information on advances and clinical trial results in antiplatelet treatment, guidelines, and other developments in patient care. This article is based on transcripts of their presentations and the ensuing discussions that were of particular importance for emergency physicians. Conclusions: Although guidelines and clinical registries can provide broad direction for practice, there is no substitute for a prospective, multidisciplinary, institution-specific, consistent, evidence-based approach to patient management. 2011 Elsevier Inc. All rights reserved
— id: 141789, year: 2011, vol: 29, page: 1203, stat: Journal Article,

Interactive effect of cigarette smoke extract and world trade center dust particles on airway cell cytotoxicity
Xu, Alice; Prophete, Colette; Chen, Lung-Chi; Emala, Charles W; Cohen, Mitchell D
2011 Jan;74(14):887-902, Journal of toxicology & environmental health. Pt. A
Rescue workers and residents exposed to the environment surrounding the collapse of the World Trade Center (WTC) on September 11, 2001, have suffered a disproportionate incidence of chronic lung disease attributed to the inhalation of airborne dust. To date, the pathophysiology of this lung disease is poorly understood. The aim of this study was to examine whether airborne dust contaminants recovered from the surrounding area 24-48 h after the collapse of the WTC demonstrate direct cytotoxicity to two airway cell types that were most directly exposed to inhaled dust, airway epithelial and smooth muscle cells. It was also of interest to determine whether the presence of these dusts could modulate the effects of cigarette smoke on these cell types in that some of the individuals who responded to the collapse site were also smokers. Human cultured airway epithelial (BEAS-2B) cells were exposed to 10% cigarette smoke extract (CSE), WTC dust particles (10-53 mum; 0.01-0.5 mug/mul), or a combination of the two for 2-24 h. Cell viability was measured by determining mitochondrial integrity (MTT assays) and apoptosis (poly-ADP-ribose polymerase [PARP] immunoblotting). Conditioned cell culture media recovered from the CSE- and/or WTC dust-exposed BEAS-2B cells were then applied to cultured human airway smooth muscle cells that were subsequently assayed for mitochondrial integrity and their ability to synthesize cyclic AMP (a regulator of airway smooth muscle constriction). BEAS-2B cells underwent necrotic cell death following exposure to WTC dust or CSE for 2-24 h without evidence of apoptosis. Smooth muscle cells demonstrated cellular toxicity and enhanced cyclic AMP synthesis following exposure to conditioned media from WTC- or CSE-exposed epithelial cells. These acute toxicity assays of WTC dust and CSE offer insights into lung cell toxicity that may contribute to the pathophysiology of chronic lung disease in workers and residents exposed to WTC dust. These studies clearly showed that WTC dust (at least the supercoarse particle fraction) or CSE alone exerted direct adverse effects on airway epithelial and smooth muscle cells, and altered the signaling properties of airway smooth muscle cells. In addition the combination of CSE and WTC exerted an interactive effect on cell toxicity. It remains to be determined whether these initial cell death events might account, in part, for the chronic lung effects associated with WTC dust exposure among First Responders and others
— id: 135195, year: 2011, vol: 74, page: 887, stat: Journal Article,

Effects of metal compounds with distinct physicochemical properties on iron homeostasis and antibacterial activity in the lungs: chromium and vanadium
Cohen, Mitchell D; Sisco, Maureen; Prophete, Colette; Yoshida, Kotaro; Chen, Lung-chi; Zelikoff, Judith T; Smee, Jason; Holder, Alvin A; Stonehuerner, Jacqueline; Crans, Debbie C; Ghio, Andrew J
2010 Feb;22(2):169-178, Inhalation toxicology
In situ reactions of metal ions or their compounds are important mechanisms by which particles alter lung immune responses. The authors hypothesized that major determinants of the immunomodulatory effect of any metal include its redox behavior/properties, oxidation state, and/or solubility, and that the toxicities arising from differences in physicochemical parameters are manifest, in part, via differential shifts in lung iron (Fe) homeostasis. To test the hypotheses, immunomodulatory potentials for both pentavalent vanadium (V(V); as soluble metavanadate or insoluble vanadium pentoxide) and hexavalent chromium (Cr(VI); as soluble sodium chromate or insoluble calcium chromate) were quantified in rats after inhalation (5 h/day for 5 days) of each at 100 mug metal/m(3). Differences in effects on local bacterial resistance between the two V(V), and between each Cr(VI), agents suggested that solubility might be a determinant of in situ immunotoxicity. For the soluble forms, V(V) had a greater impact on resistance than Cr(VI), indicating that redox behavior/properties was likely also a determinant. The soluble V(V) agent was the strongest immunomodulant. Regarding Fe homeostasis, both V(V) agents had dramatic effects on airway Fe levels. Both also impacted local immune/airway epithelial cell Fe levels in that there were significant increases in production of select cytokines/chemokines whose genes are subject to regulation by HIF-1 (whose intracellular longevity is related to cell Fe status). Our findings contribute to a better understanding of the role that metal compound properties play in respiratory disease pathogenesis and provide a rationale for differing pulmonary immunotoxicities of commonly encountered ambient metal pollutants
— id: 105696, year: 2010, vol: 22, page: 169, stat: Journal Article,

Changes in biologic and/or immunologic parameters induced by intratracheal instillation of pregnant mice with benzo(a)pyrene are potentially confounded by anesthesia
Urso, Paul; Wirsiy, Yungri G; Cohen, Mitchell D; Adkins, Bernard Jr
2010 Jun;22(7):571-579, Inhalation toxicology
Benzo(alpha)pyrene (B(alpha)P) is a potent multiorgan carcinogen released into the atmosphere from commercial, domestic, and industrial sources. Studies using animal models have shown that giving B(alpha)P parenterally to pregnant animals (i.e., dams) led to increased tumor frequency and sensitivity to tumorigenesis in their progeny. The authors' studies also showed that the progeny of the B(alpha)P-exposed dams displayed increased deficiencies in cell-mediated and humoral immune functions, changes among T-cell subsets in developing lymphoid tissues, and significant expression of B(alpha)P-7,8-dihydrodiol-9,10-epoxide (BPDE)-DNA adducts in thymic, splenic, and (fetal) liver tissues. The authors evaluated whether similar biologic/immunologic effects of B(alpha)P seen earlier in parenterally exposed mouse dams (and offspring) occurred if dams were exposed to B(alpha)P via the lungs. Pregnant dams were subjected to intratracheal instillation of B(alpha)P (at 1 mg/ml corn oil, 0.1 ml/instillate) beginning on day 11 of pregnancy (GD 11) and again on GDs 12 and 14. In each case, the dams were anesthetized with metofane. Other dams were left untreated (controls), anesthetized only, or anesthetized and then instilled with vehicle. Effects of the B(alpha)P exposures included lower dam body weights during gestation, decreased postbirth pup survival, increased pup tumor frequency, and decreased mixed-lymphocyte responses by pup lymphocytes. These studies also revealed that metofane imparted effects on the dams and progeny. These effects equaled the B(alpha)P treatments alone; in other instances, the metofane had no impact, and thus questions the observed biologic/immunologic effects of B(alpha)P induced in pregnant mice (and their progeny), which might have been confounded by use of this (or potentially other) anesthesia
— id: 133508, year: 2010, vol: 22, page: 571, stat: Journal Article,

Roles of MAPK pathway activation during cytokine induction in BEAS-2B cells exposed to fine World Trade Center (WTC) dust
Wang, Shang; Prophete, Colette; Soukup, Joleen M; Chen, Lung-Chi; Costa, Max; Ghio, Andrew; Qu, Qingshan; Cohen, Mitchell D; Chen, Haobin
2010 Oct-Dec;7(4):298-307, Journal of immunotoxicology
The World Trade Center (WTC) collapse on September 11, 2001 released copious amounts of particulate matter (PM) into the atmosphere of New York City. Follow-up studies on persons exposed to the dusts have revealed a severely increased rate for asthma and other respiratory illnesses. There have only been a few studies that have sought to discern the possible mechanisms underlying these untoward pathologies. In one study, an increased cytokine release was detected in cells exposed to WTC fine dusts (PM. fraction or WTC.). However, the mechanism(s) for these increases has yet to be fully defined. Because activation of the mitogen-activated protein kinase (MAPK) signaling pathways is known to cause cytokine induction, the current study was undertaken to analyze the possible involvement of these pathways in any increased cytokine formation by lung epithelial cells (as BEAS-2B cells) exposed to WTC.. Our results showed that exposure to WTC. for 5 hr increased interleukin-6 (IL-6) mRNA expression in BEAS-2B cells, as well as its protein levels in the culture media, in a dose-dependent manner. Besides IL-6, cytokine multiplex analyses revealed that formation of IL-8 and -10 was also elevated by the exposure. Both extracellular signal-regulated kinase (ERK) and p38, but not c-Jun N-terminal protein kinase, signaling pathways were found to be activated in cells exposed to WTC.. Inactivation of ERK signaling pathways by PD98059 effectively blocked IL-6, -8, and -10 induction by WTC.; the p38 kinase inhibitor SB203580 significantly decreased induction of IL-8 and -10. Together, our data demonstrated activation of MAPK signaling pathway(s) likely played an important role in the WTC.-induced formation of several inflammatory (and, subsequently, anti-inflammatory) cytokines. The results are important in that they help to define one mechanism via which the WTC dusts may have acted to cause the documented increases in asthma and other inflammation-associated respiratory dysfunctions in the individuals exposed to the dusts released from the WTC collapse
— id: 138258, year: 2010, vol: 7, page: 298, stat: Journal Article,

Nickel compounds
Cohen M; Klein C; Costa M
Environmental and occupational medicine Philadelphia : Wolters Kluwer/Lippincott Williams & Wilkins, 2007,
— id: 4440, year: 2007, vol: , page: ?, stat: Chapter,

Chromium compounds
Cohen MD; Costa M
Environmental and occupational medicine Philadelphia : Wolters Kluwer/Lippincott Williams & Wilkins, 2007,
— id: 4439, year: 2007, vol: , page: ?, stat: Chapter,

Toxicity of Vanadium Compounds: Pulmonary and Immune System Targets
Cohen, MD
2007 AUG 26 ;974(8):217-239, ACS symposium series
Inhalation is the most prevalent route of human exposure to insoluble pentavalent vanadium(V) oxides and soluble salts in urban/occupational settings. While initial pulmonary clearance of both soluble and insoluble forms of V is fairly rapid, complete clearance/degree of absorption of any V agent is ultimately a function of its solubility. Nevertheless, there are still several general toxicologic outcomes that arise from lung deposition of various V agents (as pure compounds or V-contaminated dusts). Workers exposed to V-bearing dusts or fumes display an. increased incidence of several lung diseases (e.g., asthma, bronchitis, pneumonia). Similarly, after deposition of urban particulate matter (PM) or residual oil fly ash (ROFA), animals develop states of immunomodulation (inflammation, neutrophilic alveolitis, modified resistance to infection) that correlate with the levels of V in the particles. This presentation focused on how general (and in some cases agent-specific) mechanisms have been formulated to explain how entrained V agents induce toxicity and immunomodulation in the lungs
— id: 101938, year: 2007, vol: 974, page: 217, stat: Journal Article,

Bacterial host resistance models in the evaluation of immunotoxicity
Cohen, Mitchell D
2007 Jan;41(1):20-30, Methods
To assess potential immunomodulatory effects of a drug, pollutant, or natural product, an analysis of an exposed host's ability to resist challenge with a viable bacteria is one of the best gauges. Many factors govern whether a host exposed to a test agent and then infected becomes ill or dies at rates greater than infected control counterparts. Beyond the status of the host's immunocompetence, a bacterium's route of entry into the host and its inherent virulence are important variables determining how (and rate at which) an infection resolves. A pre-determination of endpoint(s) to be defined is critical during planning of resistance assays. If a study is to determine overall changes in immunocompetence due to exposure (regardless of regimen or dosage of test agent), then assessing shifts in morbidity/mortality at a defined lethal dose [LD(x)] value for the chosen route of infection would suffice. However, if a study is to define extent of immunomodulation in a particular body organ/cavity--or specific alterations in particular aspects of the humoral or cell-mediated immune responses--then careful selection of the pathogen, dose of the inoculum, means of infection of target site, and extent of the post-infection period to be examined, need to be made prior to host exposure to the test toxicant. This review will provide the Reader with background information about bacterial infections and how endpoint selection could be approached when designing resistance assays. An overview of protocols involved in the assays (e.g., bacterial preparation, host infection, post-infection endpoint analyses) and information about three bacteria that are among the most commonly employed in resistance assays is provided as well
— id: 70876, year: 2007, vol: 41, page: 20, stat: Journal Article,

Pulmonary immunotoxic potentials of metals are governed by select physicochemical properties: vanadium agents
Cohen, Mitchell D; Sisco, Maureen; Prophete, Colette; Chen, Lung-Chi; Zelikoff, Judith T; Ghio, Andrew J; Stonehuerner, Jacqueline D; Smee, Jason J; Holder, Alvin A; Crans, Debbie C
2007 Jan;4(1):49-60, Journal of immunotoxicology
The in situ reactions of metal ions/complexes are important in understanding the mechanisms by which environmental and occupational metal particles alter lung immune responses. A better understanding of these reactions in situ will also allow for the improved specificity and controlled toxicity of novel metallocompounds to be used as inhaled diagnostics or therapeutics. Our previous work showed that inhalation of metals (e.g., chromium, vanadium, nickel) caused altered lung immune cell function and host resistance. The data also suggested that the degree of immunomodulation induced depended not only on the amount of metal deposited, but also the compound used. If specificity governs pulmonary immunomodulatory potential, it follows that physicochemical properties inherent to the metal have a role in the elicited effects. We hypothe-size that major determinants of any metal compound's potential are its redox behavior, valency (generally referred to as oxidation state and considered speciation in chemical literature), and/or solubility. In accord with the extensive work carried out with vanadium (chemical symbol V) compounds showing the importance of form used, differences in potential for a range of V agents (pentavalent [V(V)] insoluble vanadium pentoxide and soluble sodium metavanadate, tetravalent [V(IV)] vanadyl dipicolinate, and trivalent [V(III)] bis(dipicolinato)vanadium) were quantified based on induced changes in local bacterial resistance after host inhalation of each agent at 100 mu g V/m(3) (5 hr/d for 5 d). Differences in effect between V(V) forms indicated that solubility was a critical property in in situ pulmonary immunotoxicity. Among the soluble forms, oxidizing vanadate had the greatest impact on resistance; reducing V(III) altered resistance to a lesser extent. Both the V(IV) and insoluble V(V) had no effect. When data was analyzed in the context of pre-infection lung V burdens, soluble V agents with different oxidation states induced varying responses, supporting the hypothesis that differences in immunomodulatory potential might be attributed to redox behavior or valency. Our findings both provide a basis for understanding why some metals could be a greater health risk than others (when encountered in equal amounts) and will assist in the design of inhalable metallopharmaceuticals by allowing researchers to preempt selection of certain metal ions or complexes for use in such products
— id: 94113, year: 2007, vol: 4, page: 49, stat: Journal Article,

Detection of Changes in Alveolar Macrophage Iron Status Induced by Select PM(2.5)-Associated Components Using Iron-Response Protein Binding Activity
Doherty, S P; Prophete, C; Maciejczyk, P; Salnikow, K; Gould, T; Larson, T; Koenig, J; Jaques, P; Sioutas, C; Zelikoff, J T; Lippmann, M; Cohen, M D
2007 May;19(6):553-562, Inhalation toxicology
The extent of adverse health effects, including induction/exacerbation of infectious lung disease, arising from entrainment of equivalent amounts (or exposure to a fixed increment) of fine particulate matter (PM(2.5)) can vary from region to region or city to city in a region. To begin to explain how differing effects on host resistance might arise after exposure to PM(2.5) from various sites, we hypothesized that select metals (e.g., V, Al, and Mn) in each PM(2.5) caused changes in alveolar macrophage (AM) Fe status that, ultimately, would lead to altered antibacterial function. To test this, iron-response protein (IRP) binding activity in a rat AM cell line was assessed after exposure to Fe alone and in conjunction with V, Mn, and/or Al at ratios of V:Fe, Al:Fe, or Mn:Fe encountered in PM(2.5) samples from New York City, Los Angeles, and Seattle. Results indicated that V and Al each significantly altered IRP activity, though effects were not consistently ratio-(i.e., dose-) dependent; Mn had little impact on activity. We conclude that the reductions in Fe status detected here via the IRP assay arose, in part, from effects on transferrin-mediated Fe(3 +) delivery to the AM. Ongoing studies using this assay are allowing us to better determine: (1) whether mass (and/or molar) relationships between Fe and V, Al, and/or Mn in any PM(2.5) sample consistently govern the extent of change in AM Fe status; (2) how much any specified PM(2.5) constituent (metal or nonmetal) contributes to the overall disruption of Fe status found induced by an intact parent sample; and (3) whether induced changes in binding activity are relatable to other changes expected to occur in the AM, that is, in IRP-dependent mRNA/levels of ferritin/transferrin receptor and Fe-dependent functions. These studies demonstrate that pollutant-induced effects on lung cell Fe status can be assessed in a reproducible manner using an assay that can be readily performed by investigators who might otherwise have no access to other very costly analytical equipment, such as graphite atomic absorption or x-ray fluorescence spectro(photo)meters
— id: 72616, year: 2007, vol: 19, page: 553, stat: Journal Article,

Pulmonary immunotoxic potentials of metals are governed by select physicochemical properties: chromium agents
Cohen, Mitchell D; Prophete, Colette; Sisco, Maureen; Chen, Lung-Chi; Zelikoff, Judith T; Smee, Jason J; Holder, Alvin A; Crans, Debbie C
2006 Jul 1;3(2):69-81, Journal of immunotoxicology
Increasing the understanding of how metal ions/complexes react in situ will allow for the improved specificity and controlled toxicity of novel synthetic metallocompounds that will be used as inhaled diagnostics or therapeutics. Our previous work showed that inhalation of select metals (e.g., chromium, vanadium, nickel, iron) caused alterations in lung immune cell function and in local bacterial resistance. The data also suggested that variations in the degree of immuno-modulation induced were not solely dependent on the amount of metal deposited in the lung, but also on the specific compound. If specificity governs immunomodulatory potential, it follows that physicochemical properties inherent to the metal may have a role in the elicited effects. We hypothesize that major determinants of any metal compound's immunomodulatory potential in situ are its redox behavior, valency, and/or solubility. Using changes in local bacterial resistance as an endpoint, differences in immunotoxic potential in the lungs were quantified for a range of chromium agents (insoluble calcium chromate(VI), and soluble sodium chromate(VI), potassium bis(dipicolinato)chromate(III) and sodium bis(dipicolinato)chromate(II)). Results indicated that among the latter three forms of Cr, strongly oxidizing hexavalent Cr (Cr[VI]) had the greatest impact on resistance, while reducing divalent and fairly unreactive trivalent forms of Cr had no effect at an equal exposure level (i.e., 100 mug Cr/m(3), 5 hr/d, for 5 d). Insoluble Cr(VI) had a greater effect than its soluble form. When data was analyzed in the context of pre-infection lung Cr burdens, it was seen that immunomodulatory potentials for both Cr(VI) agents did not differ significantly; however, complexes with different oxidation states did induce varying responses, suggesting that differences in potential might be attributed to redox behavior. From this it was concluded that for Cr, certain physicochemical properties are likely more important to any in situ pulmonary immunotoxicity than others (i.e., redox behavior is more critical than solubility). Our findings, in part, will help provide a basis for understanding why certain metals could be a greater health risk than others, even when encountered in equal amounts. This, in turn, will help researchers in the design of inhalable diagnostic/therapeutic metallopharmaceuticals by pre-empting the selection of certain metal ions/complexes for potential use in these products
— id: 94114, year: 2006, vol: 3, page: 69, stat: Journal Article,

Persistent organic pollutants in dusts that settled at indoor and outdoor locations in lower Manhattan after September 11, 2001
Offenberg JH; Eusebreucg JJ; Gigliotti CL; Chen LC; Cohen MD; et al
2006 ;919:103-113, ACS symposium series
— id: 72669, year: 2006, vol: 919, page: 103, stat: Journal Article,

Effects of select PM-associated metals on alveolar macrophage phosphorylated ERK1 and -2 and iNOS expression during ongoing alteration in iron homeostasis
Prophete, Colette; Maciejczyk, Polina; Salnikow, Konstantin; Gould, Timothy; Larson, Timothy; Koenig, Jane; Jaques, Peter; Sioutas, Constantinos; Lippmann, Morton; Cohen, Mitchell
2006 May;69(10):935-951, Journal of toxicology & environmental health. Pt. A
It was hypothesized that relative mass relationships among select constituent metals and iron (Fe3+) govern the pulmonary immunotoxic potential of any PM(2.5) sample, as these determine the extent to which Fe3+ binding by transferrin is affected (resulting in altered alveolar macrophage [AM] Fe status and subsequent antibacterial function). Iron response protein (IRP) binding activity is a useful indirect measurement of changes in Fe status, as reductions in cell Fe levels lead to increases in IRP binding. However, AM IRP activity can be affected by an increased presence of nitric oxide generated by inducible nitric oxide synthase (iNOS). This study sought to determine if any changes in AM IRP activity induced by PM(2.5) constituents V, Mn, or Al were independent from effects of the metals on cell NO formation. NR8383 rat AM were exposed to Fe3+ alone or combined with V, Mn, or Al at metal:Fe ratios representative of those in PM(2.5) collected in New York City, Los Angeles, and Seattle during fall 2001. Cells were then assessed for changes in IRP activity and iNOS expression. Phosphorylated extracellular signal-regulated kinase (ERK) 1 and 2 levels were also measured since activated ERKs are involved in signaling pathways that lead to increased iNOS expression. The results indicate that V and Al, and to a lesser extent Mn, altered IRP activity, though the effects were not consistently concentration dependent. Furthermore, while V and Mn treatments did not induce iNOS expression, Al did. These results confirmed our hypothesis that certain metals associated with PM(2.5) might alter the pulmonary immunocompetence of exposed hosts by affecting the Fe status of AM, a major class of deep lung defense cells
— id: 64659, year: 2006, vol: 69, page: 935, stat: Journal Article,

Disruption of iron homeostasis as a mechanism of biologic effect by ambient air pollution particles
Ghio, Andrew J; Cohen, Mitchell D
2005 Dec 1;17(13):709-716, Inhalation toxicology
Several features of the clinical presentation and changes in physiology and pathology following exposure to many diverse ambient air pollution particles are comparable, suggesting a common mechanism for their biological effect. We propose that a mechanism of biological effect common to many ambient air pollution particles is a disruption of iron homeostasis in cells and tissues. Among traits shared by every particle-related lung injury is the introduction of a solid-liquid interface into the respiratory tract. All surfaces of particulate matter have some concentration of oxygen-containing functional groups. As a result of its electropositivity, Fe(3+) has a high affinity for oxygen-donor ligands and will react with these groups at the particle surface. Retained particles accumulate metal from available sources in a cell and tissue, and this complexed iron mediates oxidant generation. In addition to complexation onto the solid-liquid interface provided by the surface of particulate matter (PM), there are several alternative pathways by which metal homeostasis in the lower respiratory tract can be disrupted following exposure to ambient air pollution particles to affect an oxidative stress. Evidence suggests that disruption in iron homeostasis following exposures to ambient air pollution particles is an initial event in their biological effect. An association between metal equilibrium in the lower respiratory tract and biological effect in the lung could explain the observed differential toxicity of ultrafine, fine, and coarse particles and disparities in host susceptibility
— id: 96224, year: 2005, vol: 17, page: 709, stat: Journal Article,

Preface
Cohen, Mitchell D
2004 Jan;1(1):1-1, Journal of immunotoxicology
— id: 96223, year: 2004, vol: 1, page: 1, stat: Journal Article,

Pulmonary immunotoxicology of select metals: aluminum, arsenic, cadmium, chromium, copper, manganese, nickel, vanadium, and zinc
Cohen, Mitchell D
2004 Jan;1(1):39-69, Journal of immunotoxicology
— id: 96222, year: 2004, vol: 1, page: 39, stat: Journal Article,

Impact of coexposure to ozone on the carcinogenic potential of inhaled chromium. 1. effects on retention and on extra- and intracellular distribution
Cohen, Mitchell D; Sisco, Maureen; Baker, Kathy; Bowser, Darlene; Chen, Lung-Chi; Schlesinger, Richard B
2003 Jan 10;66(1):39-55, Journal of toxicology & environmental health. Pt. A
A health hazard to welders is development of lung cancer. It is believed that this is likely due, in part, to the presence in welding fumes of several hexavalent chromium (Cr[VI]) species, whose solubility depends primarily on which process (i.e., manual metal arc verus metal-inert gas) is used. However, inhalation of Cr alone is uncommon in this setting. Thus, an examination of potential contributions from other coinhalants in creating or enhancing conditions whereby inhaled fume-associated Cr (primarily the insoluble forms) may initiate cancer is critical to increasing our understanding and preventing this particular occupational disease. One major chemical species formed and released during welding is ozone (O3). Though implications of adverse pulmonary effects from individual exposure to Cr or O3 have been investigated, those from simultaneous exposure are unclear. To begin to address whether the carcinogenic potential of insoluble Cr[VI] agents might be enhanced in hosts inhaling mixtures of Cr and O3 versus Cr alone, analyses of total lung Cr burden, Cr retention in lung epithelium and interstitium, and potential shifts in lung cell distribution of Cr from the cytoplasm to nuclei were undertaken in F-344 rats exposed nose-only (5 h/d, 5 d/wk for up to 48 wk) to an extrapolated occupationally relevant level of Cr (360 micrograms Cr/m3 as calcium chromate) alone and in combination with 0.3 ppm O3. Overall, there was only a nominal effect from O3 on Cr retention or on distribution of Cr particles among extracellular sites and within lung cells. However, there were O3-related effects upon mechanisms for clearing the Cr from the deep lung, specifically at the levels of particle uptake and postphagocytic/endocytic processing by macrophages. This O3 exposure-related shift in normal pulmonary clearance might potentially increase the health risk in workers exposed to other insoluble or poorly soluble carcinogenic Cr compounds
— id: 34500, year: 2003, vol: 66, page: 39, stat: Journal Article,

Respiratory toxicological effects of world trade center fine particulate matter in mice
Gavett, SH; Haykal-Coates, N; Chen, L; Cohen, MD; Costa, DL
2003 MAR ;72(1):59-60, Toxicological sciences
— id: 38493, year: 2003, vol: 72, page: 59, stat: Journal Article,

World Trade Center fine particulate matter causes respiratory tract hyperresponsiveness in mice
Gavett, Stephen H; Haykal-Coates, Najwa; Highfill, Jerry W; Ledbetter, Allen D; Chen, Lung Chi; Cohen, Mitchell D; Harkema, Jack R; Wagner, James G; Costa, Daniel L
2003 Jun;111(7):981-991, Environmental health perspectives
Pollutants originating from the destruction of the World Trade Center (WTC) in New York City on 11 September 2001 have been reported to cause adverse respiratory responses in rescue workers and nearby residents. We examined whether WTC-derived fine particulate matter [particulate matter with a mass median aerodynamic diameter < 2.5 microm (PM2.5)] has detrimental respiratory effects in mice to contribute to the risk assessment of WTC-derived pollutants. Samples of WTC PM2.5 were derived from settled dust collected at several locations around Ground Zero on 12 and 13 September 2001. Aspirated samples of WTC PM2.5 induced mild to moderate degrees of pulmonary inflammation 1 day after exposure but only at a relatively high dose (100 microg). This response was not as great as that caused by 100 microg PM2.5 derived from residual oil fly ash (ROFA) or Washington, DC, ambient air PM [National Institute of Standards and Technology, Standard Reference Material (SRM) 1649a]. However, this same dose of WTC PM2.5 caused airway hyperresponsiveness to methacholine aerosol comparable to that from SRM 1649a and to a greater degree than that from ROFA. Mice exposed to lower doses by aspiration or inhalation exposure did not develop significant inflammation or hyperresponsiveness. These results show that exposure to high levels of WTC PM2.5 can promote mechanisms of airflow obstruction in mice. Airborne concentrations of WTC PM2.5 that would cause comparable doses in people are high (approximately 425 microg/m3 for 8 hr) but conceivable in the aftermath of the collapse of the towers when rescue and salvage efforts were in effect. We conclude that a high-level exposure to WTC PM2.5 could cause pulmonary inflammation and airway hyperresponsiveness in people. The effects of chronic exposures to lower levels of WTC PM2.5, the persistence of any respiratory effects, and the effects of coarser WTC PM are unknown and were not examined in these studies. Degree of exposure and respiratory protection, individual differences in sensitivity to WTC PM2.5, and species differences in responses must be considered in assessing the risks of exposure to WTC PM2.5
— id: 66669, year: 2003, vol: 111, page: 981, stat: Journal Article,

Chemical analysis of World Trade Center fine particulate matter for use in toxicologic assessment
McGee, John K; Chen, Lung Chi; Cohen, Mitchell D; Chee, Glen R; Prophete, Colette M; Haykal-Coates, Najwa; Wasson, Shirley J; Conner, Teri L; Costa, Daniel L; Gavett, Stephen H
2003 Jun;111(7):972-980, Environmental health perspectives
The catastrophic destruction of the World Trade Center (WTC) on 11 September 2001 caused the release of high levels of airborne pollutants into the local environment. To assess the toxicity of fine particulate matter [particulate matter with a mass median aerodynamic diameter < 2.5 microm (PM2.5)], which may adversely affect the health of workers and residents in the area, we collected fallen dust samples on 12 and 13 September 2001 from sites within a half-mile of Ground Zero. Samples of WTC dust were sieved, aerosolized, and size-separated, and the PM2.5 fraction was isolated on filters. Here we report the chemical and physical properties of PM2.5 derived from these samples and compare them with PM2.5 fractions of three reference materials that range in toxicity from relatively inert to acutely toxic (Mt. St. Helens PM; Washington, DC, ambient air PM; and residual oil fly ash). X-ray diffraction of very coarse sieved WTC PM (< 53 microm) identified calcium sulfate (gypsum) and calcium carbonate (calcite) as major components. Scanning electron microscopy confirmed that calcium-sulfur and calcium-carbon particles were also present in the WTC PM2.5 fraction. Analysis of WTC PM2.5 using X-ray fluorescence, neutron activation analysis, and inductively coupled plasma spectrometry showed high levels of calcium (range, 22-33%) and sulfur (37-43% as sulfate) and much lower levels of transition metals and other elements. Aqueous extracts of WTC PM2.5 were basic (pH range, 8.9-10.0) and had no evidence of significant bacterial contamination. Levels of carbon were relatively low, suggesting that combustion-derived particles did not form a significant fraction of these samples recovered in the immediate aftermath of the destruction of the towers. Because gypsum and calcite are known to cause irritation of the mucus membranes of the eyes and respiratory tract, inhalation of high doses of WTC PM2.5 could potentially cause toxic respiratory effects
— id: 66670, year: 2003, vol: 111, page: 972, stat: Journal Article,

Persistent organic pollutants in the dusts that settled across lower Manhattan after September 11, 2001
Offenberg, J H; Eisenreich, S J; Chen, L C; Cohen, M D; Chee, G; Prophete, C; Weisel, C; Lioy, P J
2003 Feb 1;37(3):502-508, Environmental science & technology
The explosion and collapse of the World Trade Center (WTC) was a catastrophic event that produced an aerosol impacting many workers, residents, and commuters during the first few days after September 11, 2001. During the initial days that followed, 14 bulk samples of the settled dust were collected at locations surrounding the epicenter of the disaster, including one indoor location. Some samples were analyzed for many potential hazards, including inorganic and organic constituents as well as morphology. The results of the analyses for persistent organic pollutants are described herein, including polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and select organochlorine pesticides on settled dust samples. The sigma86-PCBs comprising less than 0.001% by mass of the bulk in the three bulk samples analyzed indicated that PCBs were of limited significance in the total settled dust across lower Manhattan. Likewise, organochlorine pesticides, including chlordanes, hexachlorobenzene, heptachlor, 4,4'-DDE, 2,4'-DDT, 4,4'-DDT, and Mirex, were found at low concentrations in the bulk samples. Conversely, the sigma37-PAHs comprised up to nearly 0.04% (<0.005-0.039%) by mass of the bulk settled dust in the six bulk samples. Further size segregation of these three initial bulk samples and seven additional samples indicates that sigma37-PAHs were found in higher concentrations on relatively large particles (10-53 microm), representing up to 0.04% of the total dust mass. Significant concentrations were also found on fine particles (<2.5 microm), often accounting for approximately 0.005% by mass. We estimate that approximately 100-1000 tons of sigma37-PAHs were spread over a localized area immediately after the WTC disaster on September 11
— id: 42718, year: 2003, vol: 37, page: 502, stat: Journal Article,

Inhalation of cadmium at a concentration associated with sidestream cigarette smoke alters antimicrobial host defense
Zelikoff, JT; Chee, G; Schermerhorn, K; Prophete, C; Cohen, MD
2003 MAR ;72(1):293-293, Toxicological sciences
— id: 38506, year: 2003, vol: 72, page: 293, 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,

Rapid communication: effect of inhaled chromium on pulmonary A1AT
Cohen, Mitchell D; Sisco, Maureen; Baker, Kathy; Chen, Lung-Chi; Schlesinger, Richard B
2002 Jul;14(7):765-771, Inhalation toxicology
A major health hazard to coal miners is development of emphysema following long-term exposure to coal dust. One mechanism underlying development of emphysema is the oxidation of critical methionine (Met) residues in antiproteolytic factor, alpha1-antitrypsin (A1AT) resulting in a protease-antiprotease imbalance in the lung. Several studies have documented an association between the incidence and severity of emphysema among miners and their exposure to crystalline silica (i.e., SiO(2)). However, what remains unclear is the role of other co-inhaled nonemphysematogenic nonoxidant inorganic constituent in disease pathogenesis. We hypothesize that in miners, inhaled trivalent chromium (Cr(3+), the only form of Cr in coal) may potentially affect lung A1AT activity in situ via Cr complexing with Met residues, and thereby exacerbate any SiO(2)-induced imbalance. To ascertain if Cr(3+) could, in fact, affect A1AT activity, in vitro studies were done to assess elastase inhibitory activity following A1AT incubation with soluble Cr(3+). In addition, to determine if Cr(3+) found in the lungs as detoxification products of inhaled hexavalent Cr (Cr(6+)) could affect A1AT in situ, lavages from the lungs of chromate-exposed rats were also analyzed for elastase inhibitory activity The in vitro results indicate that Cr(3+) ions clearly inhibited A1AT function, with an IC50 of 1.1 mM being estimated under the experimental conditions used. The in vivo results indicate that long-term inhalation (12 wk or longer) of chromate-bearing atmospheres also gave rise to significant (i.e., 50-70%) inhibition of the antielastase activity of A1AT. Together, these results clearly suggest that the Cr(3+) present in coal dusts could potentially act to inhibit A1AT activity in the lungs of miners and thereby promote the emphysematogenicity of SiO(2) or of other emphysematogens present as coconstituents in these dusts
— id: 34504, year: 2002, vol: 14, page: 765, stat: Journal Article,

Effects of inhaled ozone on pulmonary immune cells critical to antibacterial responses in situ
Cohen, Mitchell D; Sisco, Maureen; Baker, Kathy; Li, Yun; Lawrence, David; van Loveren, Henk; Zelikoff, Judith T; Schlesinger, Richard B
2002 Jun;14(6):599-619, Inhalation toxicology
The goal of this study was to examine effects from repeated exposure to ozone (O3) on immune cells involved in cell-mediated antibacterial responses in the lungs. Rats exposed to 0.1 or 0.3 ppm O3 for 4 h/day, 5 days/wk, for 1 or 3 wk were analyzed for the ability to clear an intrapulmonary challenge with Listeria monocytogenes or had their lungs processed to obtain pulmonary alveolar macrophages (PAM) and lung-associated lymphocytes for analyses of select cell functions and surface marker expression. The results indicate that repeated inhalation exposure to O3 affected local cell-mediated immunity (CMI) responses as evidenced by effects on clearance of Listeria. However, this modulation was not consistently dependent on exposure concentration or duration. Short-term repeat exposures had more effect on host resistance than did the more prolonged regimen, with rats exposed to 0.1 ppm O3 most adversely impacted. Clearance patterns suggest modifications in innate resistance following 1 wk of exposure to 0.1 ppm O3, but no similar effect following a 3-wk regimen. Exposure to 0.3 ppm O3 appeared to affect both innate and acquired resistance after a 1-wk regimen, but mainly the former after an additional 2 wk of exposure. We conclude that these two mechanisms of resistance are differentially affected by O3 and that distinct time- and O3 concentration-dependent adaptation phenomena evolve for each; that is, in situ adaptation to higher levels of O3 may occur more readily with acquired than with innate/PAM-dependent resistance. A similar pattern of inconsistent effect on PAM and lung-associated lymphocytes was also evident. For example, while 3-wk exposures had a greater effect on PAM reactive oxygen intermediate ROI production, evidence for a significant effect on antibacterial activity was only notable among PAM from rats exposed for 1 wk. Among lung lymphocytes, while 3-wk exposure to 0.1 ppm O3 led to a significant increase in CD25 expression, there was no corresponding increase in responsivity to concanavalin A (ConA); only among cells from 1-wk-exposed rats did lymphoproliferative responses increase. Though investigations of altered immune cell cytokine receptor expression/binding activity are ongoing, results herein provide further evidence to support our longstanding hypothesis that some well-documented effects of O3 exposure on human health are quite likely linked to changes in local immune cell (i.e., PAM and lung-associated lymphocytes) functions, with the latter being related to changes in the capacities of these cells to interact with immunoregulatory cytokines
— id: 32458, year: 2002, vol: 14, page: 599, stat: Journal Article,

Characterization of the dust/smoke aerosol that settled east of the World Trade Center (WTC) in lower Manhattan after the collapse of the WTC 11 September 2001
Lioy, Paul J; Weisel, Clifford P; Millette, James R; Eisenreich, Steven; Vallero, Daniel; Offenberg, John; Buckley, Brian; Turpin, Barbara; Zhong, Mianhua; Cohen, Mitchell D; Prophete, Colette; Yang, Ill; Stiles, Robert; Chee, Glen; Johnson, Willie; Porcja, Robert; Alimokhtari, Shahnaz; Hale, Robert C; Weschler, Charles; Chen, Lung Chi
2002 Jul;110(7):703-714, Environmental health perspectives
The explosion and collapse of the World Trade Center (WTC) was a catastrophic event that produced an aerosol plume impacting many workers, residents, and commuters during the first few days after 11 September 2001. Three bulk samples of the total settled dust and smoke were collected at weather-protected locations east of the WTC on 16 and 17 September 2001; these samples are representative of the generated material that settled immediately after the explosion and fire and the concurrent collapse of the two structures. We analyzed each sample, not differentiated by particle size, for inorganic and organic composition. In the inorganic analyses, we identified metals, radionuclides, ionic species, asbestos, and inorganic species. In the organic analyses, we identified polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls, polychlorinated dibenzodioxins, polychlorinated dibenzofurans, pesticides, phthalate esters, brominated diphenyl ethers, and other hydrocarbons. Each sample had a basic pH. Asbestos levels ranged from 0.8% to 3.0% of the mass, the PAHs were > 0.1% of the mass, and lead ranged from 101 to 625 microg/g. The content and distribution of material was indicative of a complex mixture of building debris and combustion products in the resulting plume. These three samples were composed primarily of construction materials, soot, paint (leaded and unleaded), and glass fibers (mineral wool and fiberglass). Levels of hydrocarbons indicated unburned or partially burned jet fuel, plastic, cellulose, and other materials that were ignited by the fire. In morphologic analyses we found that a majority of the mass was fibrous and composed of many types of fibers (e.g., mineral wool, fiberglass, asbestos, wood, paper, and cotton). The particles were separated into size classifications by gravimetric and aerodynamic methods. Material < 2.5 microm in aerodynamic diameter was 0.88-1.98% of the total mass. The largest mass concentrations were > 53 microm in diameter. The results obtained from these samples can be used to understand the contact and types of exposures to this unprecedented complex mixture experienced by the surviving residents, commuters, and rescue workers directly affected by the plume from 11 to 12 September and the evaluations of any acute or long-term health effects from resuspendable dust and smoke to the residents, commuters, and local workers, as well as from the materials released after 11 September until the fires were extinguished. Further, these results support the need to have the interior of residences, buildings, and their respective HVAC systems professionally cleaned to reduce long-term residential risks before rehabitation
— id: 42719, year: 2002, vol: 110, page: 703, stat: Journal Article,

Backing into cancer: effects of arsenic on cell differentiation
Salnikow, Konstantin; Cohen, Mitchell D
2002 Feb;65(2):161-163, Toxicological sciences
— id: 34651, year: 2002, vol: 65, page: 161, 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,

The toxicology of inhaled woodsmoke
Zelikoff, Judith T; Chen, Lung Chi; Cohen, Mitchell D; Schlesinger, Richard B
2002 Jul-Sep;5(3):269-282, Journal of toxicology & environmental health. Pt. B. Critical reviews
In addition to developing nations relying almost exclusively upon biomass fuels, such as wood for cooking and home heating, North Americans, particularly in Canada and the northwestern and northeastern sections of the United States, have increasingly turned to woodburning as an alternate method for domestic heating because of increasing energy costs. As a result, the number of households using woodburning devices has increased dramatically. This has resulted in an increase in public exposure to indoor and outdoor woodsmoke-associated pollutants, which has prompted widespread concern about the adverse human health consequences that may be associated with prolonged woodsmoke exposure. This mini-review article brings together many of the human and animal studies performed over the last three decades in an attempt to better define the toxicological impact of inhaled woodsmoke on exposed children and adults; particular attention is given to effects upon the immune system. General information regarding occurrence and woodsmoke chemistry is provided so as to set the stage for a better understanding of the toxicological impact. It can be concluded from this review that exposure to woodsmoke, particularly for children, represents a potential health hazard. However, despite its widespread occurrence and apparent human health risks, relatively few studies have focused upon this particular area of research. More laboratory studies aimed at understanding the effects and underlying mechanisms of woodsmoke exposure, particularly on those individuals deemed to be at greatest risk, are badly needed, so that precise human health risks can be defined, appropriate regulatory standards can be set, and accurate decisions can be made concerning the use of current and new woodburning devices
— id: 34503, year: 2002, vol: 5, page: 269, stat: Journal Article,

A role for associated transition metals in the immunotoxicity of inhaled ambient particulate matter
Zelikoff, Judith T; Schermerhorn, Kimberly R; Fang, Kaijie; Cohen, Mitchell D; Schlesinger, Richard B
2002 Oct;110 Suppl 5(2):871-875, Environmental health perspectives
Epidemiologic studies demonstrate that infection, specifically pneumonia, contributes substantially to the increased morbidity and mortality among elderly individuals following exposure to ambient particulate matter (PM). This laboratory has previously demonstrated that a single inhalation exposure of Streptococcus pneumoniae-infected rats to concentrated ambient PM(2.5) (particulate matter with aerodynamic diameter < or =2.5 microm) from New York City (NYC) air exacerbates the infection process and alters pulmonary and systemic immunity. Although these results provide some basis for explaining the epidemiologic findings, the identity of specific PM constituents that might have been responsible for the worsening pneumonia in exposed hosts remains unclear. Thus, studies were performed to correlate the physicochemical attributes of ambient PM(2.5) with its in vivo immunotoxicity to identify and characterize the role of constitutive transition metals in exacerbating an ongoing streptococcal infection. Uninfected or previously infected rats were exposed in the laboratory to soluble divalent Fe, Mn, or Ni chloride salts. After exposure, uninfected rats were sacrificed and their lungs were lavaged. Lungs from infected hosts were used to evaluate changes in bacterial clearance and effects of exposure on the extent/severity of infection. Results demonstrated that inhalation of Fe altered innate and adaptive immunity in uninfected hosts, and both Fe and Ni reduced pulmonary bacterial clearance in previously infected rats. The effects on clearance produced in infected Fe-exposed rats were similar to those seen in infected rats exposed to ambient NYC PM. Taken together, these studies demonstrate that inhaled ambient PM can worsen the outcome of an ongoing pulmonary infection and that associated Fe may play some role in the immunotoxicity
— id: 34502, year: 2002, vol: 110 Suppl 5, page: 871, stat: Journal Article,

Ozone-induced modulation of cell-mediated immune responses in the lungs
Cohen MD; Sisco M; Li Y; Zelikoff JT; Schlesinger RB
2001 Mar 1;171(2):71-84, Toxicology & applied pharmacology
Most pulmonary immunotoxicology studies of ambient pollutants have been broadly designed to discern if overall humoral or cell-mediated immunity (CMI) was altered; few have assessed effects on particular aspects of immune function. We hypothesized that effects from ozone (O3) exposure on pulmonary CMI are linked in part to changes in local immune cell capacities to form and/or to interact with immunoregulatory cytokines. Rats exposed to 0.1 or 0.3 ppm O3 4 h/day 5 days/week, for 1 or 3 weeks were assessed for resistance to, and pulmonary clearance of, a subsequent Listeria monocytogenes challenge. In situ cytokine release and immune cell profiles were also analyzed at different stages of the antilisterial response. Although O3 exposure modulated CMI, effects were not consistently concentration- or duration-dependent. Exposure did not effect cumulative mortality from infection, but induced concentration-related effects upon morbidity onset and persistence. All 1-week exposed rats had listeric burdens trending higher than controls; 0.3 ppm rats displayed continual burden increases rather than any onset of resolution. Rats exposed for 3 weeks had no O3-related changes in clearance. No exposure-related effect on neutrophil or pulmonary macrophage (PAM) numbers or percentages was noted. Bacterial burden analyses with respect to cell type showed that Listeria:PAM ratios in 0.3 ppm rats ultimately became greatest compared to all other rats. In situ IL-1alpha and TNFalpha levels were consistently higher in O3-exposed rats. All rats displayed increasing in situ IFNgamma levels as infection progressed, but no constant relationship was evident between IFNgamma and initial IL-1alpha/TNFalpha levels in O3-exposed hosts. It seems that short-term (i.e., 1 week) repeated O3 exposures imparted more effects upon CMI than a more prolonged (i.e., 3 week) regimen, with effects manifesting at the level of the PAM and in the cytokine network responsible for immunoactivation
— id: 26782, year: 2001, vol: 171, page: 71, stat: Journal Article,

Chromium
Cohen M; Costa M
Environmental toxicants : human exposures and their health effects New York : Wiley, 2000,
— id: 4430, year: 2000, vol: , page: 173, stat: Chapter,

Pulmonary immunotoxicology
Cohen, Mitchell D.; Schlesinger, Richard B.; Zelikoff, Judith T.
Boston, Mass. ; London : Kluwer, c2000,
— id: 710, year: 2000, vol: , page: , stat: ,

Composition of particulate matter as the determinant of cellular response
Chen, LC; Su, WC; Jin, X; Cohen, MD; Schlesinger, RB; Jaspers, I; Cheng, TJ; Hwang, JS; Chan, CC
1999 MAR ;159(3):A26-A26, American journal of respiratory & critical care medicine
— id: 53869, year: 1999, vol: 159, page: A26, stat: Journal Article,

Symposium overview: alterations in cytokine receptors by xenobiotics
Cohen MD; Schook LB; Oppenheim JJ; Freed BM; Rodgers KE
1999 Apr;48(2):163-169, Toxicological sciences
A symposium entitled Alterations in Cytokine Receptors by Xenobiotics was held at the 37th Annual Meeting of the Society of Toxicology (SOT) in Seattle, Washington. The symposium was sponsored by the Immunotoxicology Specialty Section of SOT and was designed to present information on the effect of several different classes of xenobiotics on various aspects of receptor function (i.e., post-receptor signal transduction of receptor expression), or the involvement of cytokine receptors in the action of the toxicant under consideration. This symposium brought together scientists in the area of receptor immunobiology whose expertise in receptor modulation encompassed those major signaling agents involved in the normal immune response, i.e., proinflammatory cytokines, chemokines, interleukins, and interferons. The following is a summary of each of the individual presentations
— id: 6124, year: 1999, vol: 48, page: 163, stat: Journal Article,

Chromium compounds
Cohen MD; Costa M
Environmental and occupational medicine Philadelphia : Lippincott-Raven, 1998,
— id: 4427, year: 1998, vol: , page: 1045, stat: Chapter,

Immunotoxicologic effects of inhaled chromium: role of particle solubility and co-exposure to ozone
Cohen MD; Zelikoff JT; Chen LC; Schlesinger RB
1998 Sep;152(1):30-40, Toxicology & applied pharmacology
Soluble and insoluble hexavalent chromium (Cr6+) agents are concomitantly released with ozone (O3) during welding. Although pulmonary/immunologic implications from exposure to each agent individually have been investigated, the effects from simultaneous exposure, as occurs under actual working conditions, are unclear. To investigate immunomodulatory effects of inhaled Cr6+, F-344 rats were exposed for 5 h/day, 5 days/week for 2 or 4 weeks to atmospheres containing soluble potassium chromate (K2CrO4) or insoluble barium chromate (BaCrO4), each alone at 360 micrograms Cr/m3 or in combination with 0.3 ppm O3. One day after the final exposure, rats were euthanized, their lungs were lavaged, and pulmonary macrophages (PAM) were recovered for assessment of basal and inducible functions. Rats inhaling K2CrO4-containing atmospheres had greater levels of total recoverable cells, neutrophils, and monocytes in bronchopulmonary lavage compared to rats exposed to insoluble Cr6+ atmospheres, O3 alone, or air; these rats also had a reduced percentage of PAM, although total PAM levels remained unaffected. Although Cr exposure-related changes in PAM functionality were evident, any dependence upon Cr solubility was variable. K2CrO4-containing atmospheres modulated PAM-inducible interleukins-1 and -6, and tumor necrosis factor-alpha production to a greater degree than those containing BaCrO4. Conversely, BaCrO4-containing atmospheres affected PAM basal nitric oxide production and interferon-gamma-primed/zymosan-stimulated reactive oxygen intermediate production to a greater extent than did those containing K2CrO4. In none of the PAM assays did co-inhalation of O3 result in a modulation of the effects obtained with either Cr6+ compound itself. The results indicate that, while immunomodulatory effects of inhaled Cr6+ upon PAM are related to particle solubility, the co-inhalation of O3 apparently does not cause further modifications of the metal-induced effects.
— id: 7314, year: 1998, vol: 152, page: 30, stat: Journal Article,

Effects of vanadium upon polyl:C-induced responses in rat lung and alveolar macrophages
Cohen MD; Becker S; Devlin R; Schlesinger RB; Zelikoff JT
1997 Aug 29;51(6):591-608, Journal of toxicology & environmental health
Hosts exposed to vanadium (V) display a subsequent decrease in their resistance to infectious microorganisms. Our earlier studies with rats inhaling occupationally relevant levels of V (as, ammonium metavanadate, NH4VO3) indicated that several nascent/inducible functions of pulmonary macrophages (PAM) were reduced. In the present study, V-exposed rats were examined to determine whether some of the same effects might also occur in situ. Rats were exposed nose-only to air or 2 mg V/m3 (as NH4VO3) for 8 h/d for 4 d, followed, 24 h later, by intratracheal (it) instillation of polyinosinic:polycytidilic acid (polyl:C) or saline. Analysis of lavaged lung cells/fluids after polyl:C instillation indicated that total lavageable cell/neutrophil numbers and protein levels, while significantly elevated in both exposure groups (as well as in saline-treated V-exposed rats), were always greater in V-exposed hosts. Exposure to V also affected the inducible production of interleukin 6 (IL-6) and interferon gamma (IFN gamma), but apparently not that of tumor necrosis factor-alpha (TNF alpha) or IL-1. Although polyl:C induced significant increases in lavage fluid IL-6 and IFN gamma levels in both exposure groups, levels were greater in V-exposed rats. If calculated with respect to total lavaged protein, however, V-exposed rats produced significantly less cytokine. Following polyl:C instillation, there were no marked exposure-related differences in basal or stimulated superoxide anion production by pooled lavaged cells or PAM specifically. With V-exposed rats, pooled cells recovered 24 h after saline instillation displayed reduced production (in both cases) compared to the air control cells; PAM-specific production was affected only after stimulation. In both exposure groups, polyl:C caused decreased superoxide production in recovered cells. Though less apparent with pooled cells, there was a time post polyl:C instillation-dependent decrease in stimulated PAM-specific superoxide production; this effect was greater in PAM from V-exposed rats than in PAM from air controls. Phagocytic activity of PAM from rats in both exposure groups was significantly increased by polyl:C instillation, although total activity in cells obtained from V-exposed rats was always significantly lower compared to air control cells. Our results indicate that short-term, repeated inhalation of occupationally relevant levels of V by rats modulates pulmonary immunocompetence. Modified cytokine production and PAM functionality in response to biological response modifiers (such as lipopolysaccharide, IFN gamma, or polyl:C) may be, at least in part, responsible for the increases in bronchopulmonary disease in humans occupationally exposed to V
— id: 7133, year: 1997, vol: 51, page: 591, stat: Journal Article,

Pulmonary retention and distribution of inhaled chromium: Effects of particle solubility and coexposure to ozone
Cohen, MD; Zelikoff, JT; Chen, LC; Schlesinger, RB
1997 DEC ;9(9):843-865, Inhalation toxicology
Soluble and insoluble chromium (Cr) agents are concomitantly released with ozone (O-3) during welding. Although pulmonary implications from exposure to each agent individually have been investigated, the effects from simultaneous exposure, as occurs under actual working conditions, are unclear. To investigate the retention/distribution of inhaled Cr, male F-344 rats were exposed nose-only to atmospheres containing soluble potassium chromate (K2CrO4) or O-3, either alone or in combination, at 360 mu g Cr/m(3) and 0.3 ppm O-3. In a second phase of the study, insoluble barium chromate (BaCrO4) was used in place of K2CrO4. Rats were exposed for 5 h/day, 5 days/wk for 2 or 4 wk. One day after the final exposure, rats were euthanized and their lungs either removed intact or lavaged for quantitation of tissue-, lavaged cell-, and acellular lavage fluid-associated Cr. In general, rats inhaling insoluble Cr had greater total lung Cr burdens than did rats exposed to soluble Cr. Simultaneous inhalation of O-3 and K2CrO4 led to reduced lung Cr levels compared to those in rats receiving K2CrO4 only; with BaCrO4 coexposure to O-3 resulted in increased lung BaCrO, levels compared to BaCrO3 alone. Particle solubility also affected Cr levels in lavageable cells, with those from rats inhaling BaCrO, alone or BaCrO4 + O-3 consistently having greater burdens than their K2CrO4 counterparts; the presence of O-3 itself had no effect upon cell Cr levels when either compound was used. Solubility-dependent differences were also apparent in acellular lavage fluid, with Cr levels initially being greater in fluids from rats inhaling K2CrO4 alone; as exposures continued, these burdens became greater in the rats inhaling BaCrO4 alone. Although inhalation of either Cr/O-3 mixture yielded significant differences in fluid Cr levels, the presence of 4 did lead to reductions in levels compared to those in rats inhaling either Cr agent alone. In postlavage lung tissue, there were time-dependent increases in Cr levels in rats from all exposure groups; however, the most dramatic increase occurred with rats exposed to BaCrO4 + O-3. Lastly, while significant solubility-dependent differences in the relative distribution of Cr among the three pulmonary compartments were discerned, a specific effect attributable to O-3 itself was not evident. The results of this study indicate that Cr retention and distribution within the lungs, as well as any effect from coexposure to O-3, are modulated by the solubility of the inhaled Cr particles
— id: 53149, year: 1997, vol: 9, page: 843, stat: Journal Article,

Carcinogenicity and genotoxicity of lead, beryllium, and other metals
Cohen MD; Bowser DH; Costa M
Toxicology of metals Boca Raton FL : Lewis Publishers, 1996,
— id: 4422, year: 1996, vol: , page: 253, stat: Chapter,

Vanadium affects macrophage interferon-gamma-binding and -inducible responses
Cohen MD; McManus TP; Yang Z; Qu Q; Schlesinger RB; Zelikoff JT
1996 May;138(1):110-120, Toxicology & applied pharmacology
Mouse WEHI-3 cells were exposed overnight to vanadium [V; ammonium metavanadate (NH4VO3) or vanadium pentoxide (V2O5)] to determine whether documented V-induced immunomodulation might arise from altered macrophage (M phi) interactions with interferon-gamma (IFN gamma) or altered IFN gamma-inducible responses. Binding studies performed at 22 degrees C indicated that although NH4VO3-pretreated cells had approximately 48% fewer actively-binding Class I IFN gamma receptors, binding affinities were 1.5-fold greater than that of control cell receptors; Class II expression was unaffected but affinities were reduced 2-fold. Postbinding IFN gamma-receptor complex internalization was unaffected by V pretreatment. Spontaneous production of both hydrogen peroxide and superoxide anion was significantly increased by treatment with both V compounds. Total hydrogen peroxide and superoxide production was increased by stimulation of IFN gamma-primed cells with zymosan, but relative increases in primed V-treated cells were lower than that in controls. Vanadium-treated cells also displayed decreased rates of IFN gamma-induced changes in [Ca2+]i levels secondary to increased resting [Ca2+]i levels. Although V-treated cells did not display significant increases in I-A expression after IFN gamma treatment, increased numbers of I-A+ cells (irrespective of priming) and lower maximal antigen densities than observed on I-A+ control cells were evident. Results from this study show that V exposure may produce alterations in M phi-mediated functions, in part, by modifying cell interactions with IFN gamma and subsequent IFN gamma-dependent functional parameters
— id: 6988, year: 1996, vol: 138, page: 110, stat: Journal Article,

Pulmonary immunotoxicity of inhaled ammonium metavanadate in Fisher 344 rats
Cohen MD; Yang Z; Zelikoff JT; Schlesinger RB
1996 Oct;33(2):254-263, Fundamental & applied toxicology
Male Fisher 344 rats were exposed to 2 mg vanadium(V)/m3 (as ammonium metavanadate NH4VO3, 0.32 micron MMD) atmospheres for 8 hr/day for 4 days in a nose-only exposure system. In exposed rats, lung V burdens increased in a time-dependent fashion. Analysis of lung cells and lavage fluid 24 hr after the final exposure suggested that tissue damage and a strong inflammatory response was elicited; numbers of neutrophil and small macrophages (Mo), as well as levels of lavageable protein and lactate dehydrogenase, were significantly elevated as compared with levels observed with air-exposed rats. Vanadium also affected pulmonary alveolar Mo (PAM) capacities to produce and respond to immunoregulating cytokines. Inducible PAM production of tumor necrosis factor-alpha was significantly inhibited, as was the ability to increase cell surface Class II/I-A molecule expression in response to interferon-gamma (IFN gamma). PAM from V-exposed hosts were also inhibited in their ability to be primed by IFN gamma to produce superoxide anion and hydrogen peroxide in response to stimulation with opsonized zymosan. These studies indicate that short-term repeated exposure of rats to atmospheric V, at levels encountered in an occupational setting, can alter host pulmonary immunomocompetence, with one major effect occurring at the level of cytokine-related functions. These alterations may be underlying mechanisms for the well-documented increases in bronchopulmonary infections and cancers in workers chronically exposed to V-containing atmospheres
— id: 12523, year: 1996, vol: 33, page: 254, stat: Journal Article,

Effects of ozone upon macrophage-interferon interactions
Cohen MD; Zelikoff JT; Qu Q; Schlesinger RB
1996 Dec 18;114(3):243-252, Toxicology
Lung cell populations may be directly exposed to environmental airbone toxicants such as ozone (O3). Since pulmonary macrophages (M phi) play a pivotal role in host pulmonary immunocompetence, their function in this regard may be compromised by pollutant exposure thereby giving rise to an increased incidence of pulmonary disease. The current in vitro study was designed to provide some insight into possible mechanisms by which O3 induces decreased host pulmonary resistance against microbial pathogens. Specifically, this study investigated the impact of an acute O3 exposure upon the ability of a cultured mouse M phi cell line (WEHI-3) to interact with, and respond to, the major M phi-activating cytokine, interferon-gamma (IFN gamma). The results of this study indicate that WEHI-3 exposure to 1 ppm O3 for 4 h reduced both the binding of, and responsivity to, IFN gamma. Among the functional parameters affected by this inability to properly bind/respond to IFN gamma were: reactive oxygen intermediate production, phagocytic activity, and cellular calcium ion elevation; IFN gamma-enhanced expression of surface histocompatibility antigens was unaffected by O3 exposure. The reduced activity of any one of these critical M phi functions could provide a basis for previously-documented increases in microbial pathogen survival in the lungs, and overall compromise of host health following O3 exposure
— id: 10366, year: 1996, vol: 114, page: 243, stat: Journal Article,

The effect of divalent nickel (Ni2+) on in vitro DNA replication by DNA polymerase alpha
Chin YE; Snow ET; Cohen MD; Christie NT
1994 May 1;54(9):2337-2341, Cancer research
The effects of the carcinogenic metal nickel on DNA polymerase alpha (pol alpha) activity and fidelity have been analyzed. In the absence of Mg2+, the presence of Ni2+ ions at concentrations below 0.25 mM gave rise to a dose-dependent activation of pol alpha as monitored by [3H]dTMP incorporation into an activated DNA template. The apparent Km for Ni(2+)-dependent pol alpha incorporation of dTTP was estimated to be 25 microM, which was about 10 times higher than the Km for Mg2+ (2.3 microM). Above 0.25 mM, Ni2+ caused a dose-dependent inhibition of pol alpha activity and the Ki was calculated to be 1.5 mM. Scatchard analyses showed that Ni2+ binds to affinity-purified pol alpha and associated proteins at two tight binding sites with a Kd of approximately 50 microM and at eight weak binding sites with a Kd of approximately 4 mM. In the presence of 2 mM Mg2+, the addition of Ni2+ to the reactions caused an inhibition of polymerase activity. The inhibition patterns tended to switch from competitive to mixed-type to noncompetitive as a function of Ni2+ concentration. Lastly, Ni2+ increased the incorporation of the modified nucleotide dideoxy-CMP in reactions using varying ratios of dideoxy-CTP/dCTP
— id: 6334, year: 1994, vol: 54, page: 2337, stat: Journal Article,

Immunotoxicity of particulate lead: in vitro exposure alters pulmonary macrophage tumor necrosis factor production and activity
Cohen MD; Yang Z; Zelikoff JT
1994 Aug;42(4):377-392, Journal of toxicology & environmental health
Rabbit pulmonary macrophages were exposed in vitro to particulate lead oxide (PbO) for periods of up to 72 h and then assayed for the activity of tumor necrosis factor-alpha (TNF alpha) released after stimulation with lipopolysaccharide (LPS). The levels of TNF alpha obtained from PbO-treated cells were decreased in a dose-dependent manner as compared with metal-free control cells for each time point examined. Cells treated simultaneously with both LPS and PbO yielded less monokine than did cells receiving LPS alone. In addition, incubation of cell-free TNF alpha with PbO resulted in a diminution of cytotoxicity directed against TNF alpha-sensitive tumor target cells. Macrophage burdens of PbO particles increased with both the length of incubation and concentration of PbO used; increases in cellular lead burdens were paralleled by reductions in cell viability. Thus, under in vitro conditions, PbO affects the levels of the immunoregulatory monokine TNF alpha and also disrupts its cytotoxic properties after release from activated macrophages
— id: 8386, year: 1994, vol: 42, page: 377, stat: Journal Article,

Immunotoxicity of sulfuric acid aerosol: effects on pulmonary macrophage effector and functional activities critical for maintaining host resistance against infectious diseases
Zelikoff JT; Sisco MP; Yang Z; Cohen MD; Schlesinger RB
1994 Sep 6;92(1-3):269-286, Toxicology
Despite the widespread occurrence of acidic sulfur oxides in the ambient environment and their potential risks to human health, effects associated with pulmonary immune defenses have been poorly studied. The current in vivo study was designed to provide some insight into this relatively unexplored area by investigating the impact of inhaled sulfuric acid on immune defense mechanisms critical for maintaining pulmonary resistance against infectious diseases. Results of this study demonstrate that repeated inhalation of sulfuric acid reduces the uptake and intracellular killing of pathogenic bacteria by exposed pulmonary macrophages, and depresses the activity/production of important biological modifiers critical for maintaining pulmonary immunocompetence. These findings have important implications for human health, and may contribute to a better understanding of the possible mechanism(s) underlying the epidemiological evidence which suggests an association between total sulfates in the ambient air and increased incidence of acute bronchitis and lower respiratory illness in school-age children
— id: 6788, year: 1994, vol: 92, page: 269, stat: Journal Article,

Mechanisms of chromium carcinogenicity and toxicity
Cohen MD; Kargacin B; Klein CB; Costa M
1993 ;23(3):255-281, Critical reviews in toxicology
Chromium, like many transition metal elements, is essential to life at low concentrations yet toxic to many systems at higher concentrations. In addition to the overt symptoms of acute chromium toxicity, delayed manifestations of chromium exposure become apparent by subsequent increases in the incidence of various human cancers. Chromium is widely used in numerous industrial processes, and as a result is a contaminant of many environmental systems. Chromium, in its myriad chemical forms and oxidation states, has been well studied in terms of its general chemistry and its interactions with biological molecules. However, the precise mechanisms by which chromium is both an essential metal and a carcinogen are not yet fully clear. The following review does not seek to embellish upon the proposed mechanisms of the toxic and carcinogenic actions of chromium, but rather provides a comprehensive review of these theories. The chemical nature of chromium compounds and how these properties impact upon the interactions of chromium with cellular and genetic targets, including animal and human hosts, are discussed
— id: 6337, year: 1993, vol: 23, page: 255, stat: Journal Article,

Immunotoxicity of in vitro vanadium exposures: effects on interleukin-1, tumor necrosis factor-alpha, and prostaglandin E2 production by WEHI-3 macrophages
Cohen MD; Parsons E; Schlesinger RB; Zelikoff JT
1993 Apr;15(3):437-446, International journal of immunopharmacology
Treatment of cultured mouse macrophages with either of two different vanadium compounds was shown to affect the production/release of two major immunoregulatory cytokines. The pentavalent vanadium compound ammonium metavanadate was shown previously to disrupt cell-mediated immunity at the earliest stages of an in vivo anti-Listerial response, in that mice treated with vanadium displayed decreased accessory cell recruitment and numbers of activated macrophages at infection sites. To determine whether these effects were due to vanadium-induced alterations in the production of biologically-active mediators, mouse macrophage-like WEHI-3 cells were treated in vitro with ammonium metavanadate or vanadium pentoxide prior to stimulation with lipopolysaccharide endotoxin (LPS). After stimulation, monokine (tumor necrosis factor-alpha and interleukin-1) and prostaglandin E2 (PGE2) activities were assessed. Both vanadium compounds decreased recovered monokine activities; measured TNF alpha concentrations were also reduced. Spontaneous release of the IL-1/TNF-regulating prostanoid PGE2 was significantly increased by the highest concentration of vanadate tested, although LPS-stimulated PGE2 production was unaffected by either compound. These results indicate that, in vitro, pentavalent vanadium can interfere with immunoregulatory mediators critical for maintaining host immunocompetence
— id: 8422, year: 1993, vol: 15, page: 437, stat: Journal Article,

CONTRIBUTION OF SULFURIC-ACID TO RESPIRATORY-INFECTIONS
ZELIKOFF, JT; COHEN, MD; SISCO, MP; SCHLESINGER, RB
1993 APR ;147(4):A384-A384, American review of respiratory disease
— id: 54156, year: 1993, vol: 147, page: A384, stat: Journal Article,

Chromium compounds
Cohen MD; Costa M
Environmental and occupational medicine Boston : Little Brown, 1992,
— id: 4413, year: 1992, vol: , page: 799, stat: Chapter,

Forward mutations and DNA-protein crosslinks induced by ammonium metavanadate in cultured mammalian cells
Cohen MD; Klein CB; Costa M
1992 Sep;269(1):141-148, Mutation research
Ammonium metavanadate yielded a dose-dependent increase in mutation frequency at the V79 hprt locus following a 24-h exposure period in serum-free F12 medium. Vanadate also increased the mutation frequency of V79 cells by exposure of cells in salts-glucose medium, but these effects were not as striking, or as dose-dependent as they were in serum-free F12 medium. Ammonium metavanadate enhanced the mutation frequency in a V79 variant containing a transfected bacterial gpt gene. These cells are known to be more responsive to oxidative type mutations, and to mutations involving deletions. Although the absolute level of mutations was greater in these cells with ammonium metavanadate, so was the background, and these cells did not exhibit an enhanced mutagenic response to vanadate when compared to the wild-type V79 cells. The vanadate results were compared to a positive control potassium chromate, which exhibited a dose-dependent increase in mutation frequency. Ammonium metavanadate induced DNA-protein crosslinks formation in both Chinese hamster ovary and human MOLT4 cells, and the role of these relatively unrepaired genetic lesions in the mutations produced by vanadate and chromate are discussed
— id: 13468, year: 1992, vol: 269, page: 141, stat: Journal Article,

Alteration in restriction enzyme digestion patterns detects DNA--protein complexes induced by chromate
Chen Y; Cohen MD; Snow ET; Costa M
1991 Sep;12(9):1575-1580, Carcinogenesis
DNA--protein complexes isolated from CHO cells treated with at least 10-30 microM potassium chromate exhibited an alteration in the degradation of the DNA by restriction enzymes compared to DNA--protein complexes isolated from untreated cells. This alteration in restriction enzyme digestion of DNA--protein complexes induced by chromate was shown to depend upon the binding of trivalent chromium to the DNA and upon the protein associated with the DNA, since both EDTA pretreatment and protease K reversed the inhibition of restriction enzyme degradation of the DNA. The inhibition of restriction enzyme degradation of DNA--protein complexes may be utilized as an indirect way to detect DNA--protein complexing induced by chromate and perhaps other agents
— id: 13934, year: 1991, vol: 12, page: 1575, stat: Journal Article,

Senescence of nickel-transformed cells by an X chromosome: possible epigenetic control
Klein CB; Conway K; Wang XW; Bhamra RK; Lin XH; Cohen MD; Annab L; Barrett JC; Costa M
1991 Feb 15;251(4995):796-799, Science
Transfer of a normal Chinese hamster X chromosome (carried in a mouse A9 donor cell line) to a nickel-transformed Chinese hamster cell line with an Xq chromosome deletion resulted in senescense of these previously immortal cells. At early passages of the A9/CX donor cells, the hamster X chromosome was highly active, inducing senescence in 100% of the colonies obtained after its transfer into the nickel-transformed cells. However, senescence was reduced to 50% when Chinese hamster X chromosomes were transferred from later passage A9 cells. Full senescing activity of the intact hamster X chromosome was restored by treatment of the donor mouse cells with 5-azacytidine, which induced demethylation of DNA. These results suggest that a senescence gene or genes, which may be located on the Chinese hamster X chromosome, can be regulated by DNA methylation, and that escape from senescence and possibly loss of tumor suppressor gene activity can occur by epigenetic mechanisms
— id: 8211, year: 1991, vol: 251, page: 796, stat: Journal Article,

Complexing of actin and other nuclear proteins to DNA by cis-diamminedichloroplatinum(II) and chromium compounds
Miller CA 3d; Cohen MD; Costa M
1991 Feb;12(2):269-276, Carcinogenesis
Actin was found to be the major protein crosslinked to the DNA of intact Chinese hamster ovary cells that were treated with either potassium chromate (hexavalent) or cis-diamminedichloroplatinum(II) (cis-platinum). This protein was identified as actin by its mol. wt (45 kd), its isoelectric point (pI = 5.4), positive reactivity with an actin antibody, and by protease mapping. Additionally, a purified actin standard migrated to the same location in a two-dimensional gel system as p45. Actin comprised approximately 20% of the protein component in chromate-induced DNA-protein crosslinks. In addition, to actin, several other major proteins (e.g. 53 kd, pI = 5.2, 50 kd, pI = 9) were crosslinked to DNA following exposure to cis-platinum or chromate. These proteins were abundant in the nuclear matrix fraction. Hexavalent chromate is the toxicologically active form because it is readily taken up into cells by an anion transport system. In contrast, trivalent chromium is considerably less toxic because it cannot enter the cell; however, most of the hexavalent form is eventually reduced to the trivalent form inside the cell. Previous studies have suggested that the trivalent form of chromium participates in complexing DNA with proteins. DNA-protein crosslinks were formed in isolated nuclei or in mixtures of purified DNA and protein incubated with trivalent chromium. However, the formation of these complexes required at least 16 h of incubation to exchange the parent compound ligands. Hexavalent chromate did not form these complexes in vitro under similar conditions. Incubation of trivalent chromium with purified actin and DNA resulted in DNA-actin crosslinks as detected by an electrophoretic mobility different from that of either free actin or DNA when the complex was transferred from a gel to nitrocellulose and stained for protein. These studies describe a new technique for detecting DNA-protein complexes and demonstrate that actin-DNA structures in intact cells create sites that selectively react with metal DNA-protein crosslinking agents
— id: 14136, year: 1991, vol: 12, page: 269, stat: Journal Article,

A blotting method for monitoring the formation of chemically induced DNA-protein complexes
Cohen MD; Miller CA; Xu LS; Snow ET; Costa M
1990 Apr;186(1):1-7, Analytical biochemistry
The formation and identification of DNA-protein crosslinks are usually detected by filter binding assays such as alkaline elution. We describe a modified blotting method to selectively identify DNA-protein complexes (DPCs) formed in vitro by either Cr3+ ion or formaldehyde. This protocol allows DPC formation in vitro to be assayed with various chemical agents, requires minimal usage of radioactivity, and is performed in a shorter time frame than that commonly used to resolve DPCs from free proteins and unbound DNA
— id: 36437, year: 1990, vol: 186, page: 1, stat: Journal Article,