Archives: 2015 – 2010 I 2009 – 2005 I 2004 – 2000 I 1999 – 1995 I Earlier
Gum ghatti, a polysaccharide of natural origin, is used in foods as a thickening, gelling, emulsifying and stabilizing agent. In a 90-day toxicity study following Organization for Economic Co-operation and Development (OECD) Guideline #408, male and female Sprague–Dawley rats were exposed to 0 (control), 0.5, 1.5 and 5% gum ghatti in AIN-93M basal diet. Expected changes included increased full and empty cecal weights in 5% groups. Incidentally 2/10 females from the 5% gum ghatti group had a single colon ulcer with associated acute inflammation. In a second 90-day study increased cecal weights were present in Sprague–Dawley females exposed to 5% gum ghatti in AIN-93M and NIH-07 basal diets. A single colon ulcer with associated acute inflammation occurred in 1/20 control females given AIN-93M basal diet. The colon ulcers were considered a sporadic change possibly attributable to AIN-93M basal diet. In the second study a few statistically significant alterations in clinical chemistry were considered sporadic and unrelated to treatment. Feed consumption among treated and control groups was similar for each sex. Gum ghatti intake at the 5% dietary level ranged from 3044 to 3825 mg/kg body weight/day. The 5% dietary administration was a NOAEL in both studies. NOAELs for males and females in the first study were 3044 and 3309 mg/kg/day, respectively. NOAELs for females in the second study were 3670 and 3825 mg/kg/day for AIN-93M and NIH-07 diets, respectively.
**********secured...******Need to get text...*******.Mei quot doctus omittantur an, agam nonumes constituto mel in. Utamur invidunt rationibus cum ei, primis equidem qualisque eam an, at eruditi propriae vis. Modo dissentias reprehendunt ut vim, est mundi adipisci ut. In suas erat vis, quo enim tantas inciderint id. In vis gubergren intellegebat, id sed sint putent nominavi.Mei quot doctus omittantur an, agam nonumes constituto mel in. Utamur invidunt rationibus cum ei, primis equidem qualisque eam an, at eruditi propriae vis. Modo dissentias reprehendunt ut vim, est mundi adipisci ut. In suas erat vis, quo enim tantas inciderint id. In vis gubergren intellegebat, id sed sint putent nominavi.Mei quot doctus omittantur an, agam nonumes constituto mel in. Utamur invidunt rationibus cum ei, primis equidem qualisque eam an, at eruditi propriae vis. Modo dissentias reprehendunt ut vim, est mundi adipisci ut. In suas erat vis, quo enim tantas inciderint id. In vis gubergren intellegebat, id sed sint putent nominavi.Mei quot doctus omittantur an, agam nonumes constituto mel in. Utamur invidunt rationibus cum ei, primis equidem qualisque eam an, at eruditi propriae vis. Modo dissentias reprehendunt ut vim, est mundi adipisci ut. In suas erat vis, quo enim tantas inciderint id. In vis gubergren intellegebat, id sed sint putent nominavi....
**********secured...******Need to get text...*******.Mei quot doctus omittantur an, agam nonumes constituto mel in. Utamur invidunt rationibus cum ei, primis equidem qualisque eam an, at eruditi propriae vis. Modo dissentias reprehendunt ut vim, est mundi adipisci ut. In suas erat vis, quo enim tantas inciderint id. In vis gubergren intellegebat, id sed sint putent nominavi.Mei quot doctus omittantur an, agam nonumes constituto mel in. Utamur invidunt rationibus cum ei, primis equidem qualisque eam an, at eruditi propriae vis. Modo dissentias reprehendunt ut vim, est mundi adipisci ut. In suas erat vis, quo enim tantas inciderint id. In vis gubergren intellegebat, id sed sint putent nominavi.Mei quot doctus omittantur an, agam nonumes constituto mel in. Utamur invidunt rationibus cum ei, primis equidem qualisque eam an, at eruditi propriae vis. Modo dissentias reprehendunt ut vim, est mundi adipisci ut. In suas erat vis, quo enim tantas inciderint id. In vis gubergren intellegebat, id sed sint putent nominavi.Mei quot doctus omittantur an, agam nonumes constituto mel in. Utamur invidunt rationibus cum ei, primis equidem qualisque eam an, at eruditi propriae vis. Modo dissentias reprehendunt ut vim, est mundi adipisci ut. In suas erat vis, quo enim tantas inciderint id. In vis gubergren intellegebat, id sed sint putent nominavi.
Inflammation may play a role in the etiology of both degenerative and rheumatic cardiac valve diseases. We report here that mice deficient in tristetraprolin (TTP), a protein with known anti-inflammatory functions, develop severe left-sided cardiac valvulitis. TTP is an mRNA binding protein that inhibits inflammation by destabilizing the mRNA encoding tumor necrosis factor (TNF). This leads in turn to a TNF-excess syndrome characterized by systemic inflammation. Evaluation of hearts from TTP/ mice demonstrated gross thickening of the mitral and aortic but not the tricuspid or pulmonary valves, accompanied by inflammatory cell infiltrates. To determine whether TNF played a role in the development of this valvulitis, we examined mice deficient in both TNF receptors and in TTP; four of five of these mice exhibited no histological evidence of valvulitis, but one mouse had aortic valve leaflet thickening with a cellular infiltrate. Four additional mice had no external evidence of valvular thickening. Cardiac valves of transgenic mice expressing human TNF developed mild aortic valve leaflet edema without evidence of hypercellularity. Thus, TTP deficiency in mice leads to left-sided cardiac valvulitis with prominent inflammatory cell involvement, due, at least in part, to excess TNF. These findings support the potential involvement of TNF and inflammation in the development of cardiac valve disease in man.
The National Toxicology Program (NTP) Satellite Symposium is a one-day meeting that is held in conjunction with the annual Society of Toxicologic Pathology (STP) meeting. The topic of the 2009 Symposium was “Tumor Pathology and INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Nomenclature.” The goal of this article is to provide summaries of each speaker’s presentation, including the diagnostic or nomenclature issues that were presented, along with a few select images that were used for voting. The results of the voting process and interesting points of discussion that were raised during the presentation are also provided. A supplemental file with voting choices and voting results for each case presented at the symposium is available at http://tpx.sagepub.com/supplemental.
The plant Angelica keiskei contains two main physiologically active flavonoid chalcones, 4-hydroxyderricin and xanthoangelol. Known as ashitaba in Japan, powder from the sap is widely consumed for its medicinal properties in Asia as a dietary supplement. Limited previously reported mammalian studies were without evidence of toxicity. GLP studies reported here, including a bacterial reverse mutation assay, a chromosome aberration assay, and an in vivo micronucleus assay are negative for genotoxicity. A GLP compliant 90-day repeated oral gavage study of ashitaba yellow sap powder containing 8.45% chalcones in Sprague Dawley rats resulted in expected known physiological effects on coagulation parameters and plasma lipids at 300 and 1000 mg/kg/day. Ashitaba-related pathology included a dose-related male rat specific alpha 2-urinary globulin nephropathy at 100, 300, and 1000 mg/kg/day and jejunal lymphangiectasia in both sexes at 1000 mg/kg/day. All other study parameters and histopathological changes were incidental or not of toxicological concern. Based on these studies ashitaba chalcone powder is not genotoxic with a NOAEL of 300 mg/kg in male and female rats.
The recent discovery of active Brown Adipose Tissue (BAT) in adult humans has opened new avenues for obesity research and treatment, as reduced BAT activity seem to be implicated in human energy imbalance, diabetes, and hypertension. However, clinical applications are currently limited by the lack of non-invasive tools for measuring mass and function of this tissue in humans. Here we present a new magnetic resonance imaging method based on the normally invisible intermolecular multiple-quantum coherence 1H MR signal. This method, which doesn’t require special hardware modifications, can be used to overcome partial volume effect, the major limitation of MR-based approaches that are currently being investigated for the detection of BAT in humans. With this method we can exploit the characteristic cellular structure of BAT to selectively image it, even when (as in humans) it is intimately mixed with other tissues. We demonstrate and validate this method in mice using PET scans and histology. We compare this methodology with conventional 1H MR fat fraction methods. Finally, we investigate its feasibility for the detection of BAT in humans.
Gum ghatti is a food additive in some parts of the world, serving as an emulsifier, a stabilizer, and a thickening agent. To evaluate its genotoxic potential, we conducted Good Laboratory Practice compliant in vitro and in vivo studies in accordance with the Organisation for Economic Co-operation and Development (OECD) guidelines. No evidence of toxicity or mutagenicity was detected in a bacterial reverse mutation assay using five tester strains evaluating gum ghatti at up to 6 mg/plate, with or without metabolic activation. Gum ghatti also did not induce chromosome structural damage in a chromosome aberration assay using Chinese hamster ovary cells. To assess the ability to induce DNA damage in rodents, a combined micronucleus/Comet assay was conducted in male B6C3F1 mice. Gum ghatti was administered at 1000, 1500, and 2000 mg/kg/day by gavage once daily for 4 days and samples were collected 4 h after the final dosing. No effect of gum ghatti was measured on micronucleated reticulocyte (MN-RET) frequency in peripheral blood, or DNA damage in blood leukocytes or liver as assessed by the Comet assay. Our results show no evidence of genotoxic potential of gum ghatti administered up to the maximum concentrations recommended by OECD guidelines.
The National Toxicology Program (NTP) Satellite Symposium is a one-day meeting that is traditionally held in conjunction with the annual scientific symposium of the Society of Toxicologic Pathology (STP) (Bach et al. 2010). Continuing education on the interpretation of pathology slides has been the primary goal of the NTP Symposium. To achieve this goal, multiple presentations show and discuss lesions that are rare and interesting, present a diagnostic challenge, are controversial, and/or have nomenclature dilemmas. Audience participation is encouraged through anonymous voting with wireless keypads and real-time tabulation software. The voting results are immediately displayed on the screen as bar graphs with voting percentages, which allows for lively and productive discussion with audience members immediately after the voting. The theme of the NTP Symposium in previous years, spanning 2000 to 2009, has been kept flexible to allow for current issues to be presented. In some years the entire session focuses on a single theme; past topics included tumor pathology, pathology of the urinary system, pathology of the immune system, hepatic pathology, an exercise in peer review: the pathology working group, techniques in toxicologic pathology, and establishing an NTP database for non-neoplastic lesions of kidney and urinary bladder. For two of these years, the theme has been “pathology potpourri,” in which a number of lesions and issues are dealt with briefly. For 2010, the “pathology potpourri” theme was used again, allowing the presentation of unusual lesions in the liver, pancreas, preputial gland, kidney, nasal septum, retina, skin, lung, ovary, and vascular system. Also included were example definitions and discussion of proposed INHAND(International Harmonization ofNomenclature and Diagnostic Criteria for Lesions in Rats and Mice) nomenclature for proliferative and nonproliferative entities of the central (CNS) and peripheral (PNS) nervous system and cardiovascular system. This input from the toxicologic pathology community is of value as the Organ Working Groups are preparing their draft nomenclature documents. This article provides synopses of all presentations including the diagnostic or nomenclature issues, a selection of images presented for voting and discussion, voting choices, voting results, and major discussion points.
Hepatic enzyme induction is generally an adaptive response associated with increases in liver weight, induction of gene expression, and morphological changes in hepatocytes. The additive growth and functional demands that initiated the response to hepatic enzyme induction cover a wide range of stimuli including pregnancy and lactation, hormonal fluctuations, dietary constituents, infections associated with acute-phase proteins, as well as responses to exposure to xenobiotics. Common xenobiotic enzyme inducers trigger pathways involving the constitutive androstane receptor (CAR), the peroxisome proliferator-activated receptor (PPAR), the aryl hydrocarbon receptor (AhR), and the pregnane-X-receptor (PXR). Liver enlargement in response to hepatic enzyme induction is typically associated with hepatocellular hypertrophy and often, transient hepatocyte hyperplasia. The hypertrophy may show a lobular distribution, with the pattern of lobular zonation and severity reflecting species, strain, and sex differences in addition to effects from specific xenobiotics. Toxicity and hepatocarcinogenicity may occur when liver responses exceed adaptive changes or induced enzymes generate toxic metabolites. These undesirable consequences are influenced by the type and dose of xenobiotic and show considerable species differences in susceptibility and severity that need to be understood for assessing the potential effects on human health from similar exposures to specific xenobiotics.
The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and differential diagnosis for classifying microscopic lesions observed in the hepatobiliary system of laboratory rats and mice, with color microphotographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available for society members electronically on the internet (http://goreni.org). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for lesions of the hepatobiliary system in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.
Magnetic resonance imaging (MRI) is widely used in preclinical research and drug development and is a powerful noninvasive method for assessment of phenotypes and therapeutic efficacy in murine models of disease. In vivo MRI provides an opportunity for longitudinal evaluation of tissue changes and phenotypic expression in experimental animal models. Ex vivo MRI of fixed samples permits a thorough examination of multiple digital slices while leaving the specimen intact for subsequent conventional hematoxylin and eosin (H&E) histology. With the advent of new compact MRI systems that are designed to operate in most conventional labs without the cost, complexity, and infrastructure needs of conventional MRI systems, the possibility of MRI becoming a practical modality is now viable. The purpose of this study was to investigate the capabilities of a new compact, high-performance MRI platform (M22; Aspect Imaging, Israel) as it relates to preclinical toxicology studies. This overview will provide examples of major organ system pathologies with an emphasis on how compact MRI can serve as an important adjunct to conventional pathology by nondestructively providing 3-dimensional (3-D) digital data sets, detailed morphological insights, and quantitative information. Comparative data using compact MRI for both in vivo and ex vivo are provided as well as validation using conventional H&E.
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Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long-term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPARa. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach.
A panel and audience discussion co-sponsored by the International Academy of Toxicologic Pathology (IATP) and the Society of Toxicologic Pathology (STP) at the STP Annual Meeting in Denver in June 2011 generated some lively dialogue. The theme of the ninety-minute session was “Responsible Authorship and Publication Practices.” Following some general introductory comments related to the ethics of publication, audience and panel discussion was prompted by presentation of case scenarios related to authorship and publication practices. This review summarizes some of the discussion points and includes additional information and practical guidelines for publication ethics. According to the Uniform Requirement for Manuscripts and guidelines promulgated by the International Committee of Medical Journal Editors (http://www.icmje.org/), accepted criteria for authorship include substantial intellectual contributions to all three of the following study aspects: (1) study conception and design, acquisition of data, or analysis and interpretation of data; (2) participation in substantively drafting and/or revising the manuscript; and (3) giving final approval of the version submitted for publication. To confirm the legitimacy of authorship, some journals have a policy of requesting a statement from the corresponding author regarding the exact contribution of each co-author on the submitted manuscript. In some situations, such as providing pathology diagnostic support for a research project, a substantial contribution from a specialist may represent just one component of the work to be published. For that contributor to be listed as an author, he or she must be confident of the contributions of the other authors and be thoroughly familiar with the individual with responsibility for the submitted work as a whole.
Early and specific detection of metastatic cancer cells in the lung (the most common organ targeted by metastases) could significantly improve cancer treatment outcomes. However, the most widespread lung imaging methods use ionizing radiation and have low sensitivity and/or low specificity for cancer cells. Here we address this problem with an imaging method to detect submillimeter-sized metastases with molecular specificity. Cancer cells are targeted by iron oxide nano-particles functionalized with cancer-binding ligands, then imaged by high-resolution hyperpolarized 3He MRI. We demonstrate in vivo detection of pulmonary micrometastates in mice injected with breast adenocarcinoma cells. The method not only holds promise for cancer imaging but more generally suggests a fundamentally unique approach to molecular imaging in the lungs.
Triclosan (2,4,4′-trichloro-2′-hydroxy-diphenyl ether) is an antibacterial compound that has been used in consumer products for about 40 years. The tolerability and safety of triclosan has been evaluated in human volunteers with little indication of toxicity or sensitization. Although information in humans from chronic usage of personal care products is not available, triclosan has been extensively studied in laboratory animals. When evaluated in chronic oncogenicity studies in mice, rats, and hamsters, treatment-related tumors were found only in the liver of male and female mice. Application of the Human Relevance Framework suggested that these tumors arose by way of peroxisome proliferator-activated receptor α (PPARα) activation, a mode of action not considered to be relevant to humans. Consequently, a Benchmark Dose (BMDL10) of 47 mg/kg/day was developed based on kidney toxicity in the hamster. Estimates of the amount of intake from in the use of representative personal care products for men, women, and children were derived in two ways: (1) using known or assumed triclosan levels in various consumer products and assumed usage patterns (product-based estimates); and (2) using upper bound measured urinary triclosan levels from human volunteers (biomonitoring-based estimates) using data from the Centers for Disease Control and Prevention. For the product-based estimates, the margin of safety (MOS) for the combined exposure estimates of intake from the use of all triclosan-containing products considered were approximately 1000, 730, and 630 for men, women, and children, respectively. The MOS calculated from the biomonitoring-based estimated intakes were 5200, 6700, and 11,750 for men, women, and children, respectively. Based on these results, exposure to triclosan in consumer products is not expected to cause adverse health effects in children or adults who use these products as intended
Rodents have been used extensively in virtually all fields of biomedical research and have been the primary species used in toxicologic and carcinogenic research. Over many years it has become obvious that some conditions and in particular some tumors in rodents have questionable relevance in humans. Some of these include peroxisome proliferatoractivator receptor-α (PPAR-α) agonist-induced liver tumors, alpha2μ-globulin-induced renal tumors in male rats, and bladder tumors induced in rats by urinary calculi. In this chapter we review the human relevance of Leydig cell tumors (LCTs), which have been induced in rodents by a number of compounds. We will consider the similarities and differences between humans and rats in the physiology of the Leydig cell (LC) and the pathology of LCTs. Most importantly, we will examine the mechanisms of action that induce LCTs in rats and humans and present data on incidence, physiology, human endocrine disease, and comparative epidemiological studies that strongly indicate LCTs in rodents, in particular the rat, are of little relevance to human health.
**********secured...******Need to get text...*******.Mei quot doctus omittantur an, agam nonumes constituto mel in. Utamur invidunt rationibus cum ei, primis equidem qualisque eam an, at eruditi propriae vis. Modo dissentias reprehendunt ut vim, est mundi adipisci ut. In suas erat vis, quo enim tantas inciderint id. In vis gubergren intellegebat, id sed sint putent nominavi.Mei quot doctus omittantur an, agam nonumes constituto mel in. Utamur invidunt rationibus cum ei, primis equidem qualisque eam an, at eruditi propriae vis. Modo dissentias reprehendunt ut vim, est mundi adipisci ut. In suas erat vis, quo enim tantas inciderint id. In vis gubergren intellegebat, id sed sint putent nominavi.Mei quot doctus omittantur an, agam nonumes constituto mel in. Utamur invidunt rationibus cum ei, primis equidem qualisque eam an, at eruditi propriae vis. Modo dissentias reprehendunt ut vim, est mundi adipisci ut. In suas erat vis, quo enim tantas inciderint id. In vis gubergren intellegebat, id sed sint putent nominavi.Mei quot doctus omittantur an, agam nonumes constituto mel in. Utamur invidunt rationibus cum ei, primis equidem qualisque eam an, at eruditi propriae vis. Modo dissentias reprehendunt ut vim, est mundi adipisci ut. In suas erat vis, quo enim tantas inciderint id. In vis gubergren intellegebat, id sed sint putent nominavi.
The “omics,” high-throughput screening, computational modeling, and database mining revolutions have each arrived with euphoric expectations, considerable hand waving, and promises to set toxicity testing priorities and reduce reliance on conventional animal toxicity and carcinogenicity testing. Reflecting back on prior experience with other predictive approaches and alternatives, what follows the rush to endorse a promising new technology or different approach to toxicity/carcinogenicity testing is years of grinding out data for validation and optimization. Much of what has driven the enthusiasm for each new emerging technology and approach is the costly, labor-intensive, and sometimes irrelevant and inefficient rodent bioassay-testing paradigm. However, no one should expect abandonment of all animal testing for the foreseeable future, especially for agrochemicals and environmental xenobiotic exposures. It is reasonable to anticipate the future will bring still new approaches to safety testing and human risk assessment. In the past, each new approach has not achieved the inflated expectations for safety testing and human risk assessment but often has become a useful research tool with tangible contributions to basic biology and clinical medicine. The toxicologic pathologist is embedded in the matrix of a mixed disciplinary milieu and is faced with some critical challenges and important opportunities in the postgenomic decades ahead. So what advice do we give to the journeyman toxicologic pathologist who will hopefully function effectively in the postgenomic decades ahead? And what advice do we also give to the experienced bench pathologist confronted with emerging technologies each accompanied by a bewildering array of techno-jargon so that he or she can remain effective as a toxicologic pathology practitioner?
The following three articles represent the output of a combined effort initiated by the Scientific Regulatory Policy Committee of the Society of Toxicologic Pathology to provide a unified review of current scientific practices and relevant literature and provide suggestions regarding the recognition, interpretation, and risk assessment of hepatic drug metabolizing enzyme (DME) induction studies. The core objective was to provide a review that the scientific community including pathologists, regulatory scientists, toxicologists, investigative scientists, and others would find valuable for managing, designing, and interpreting toxicity studies supporting regulatory filings. Three working groups composed of scientists from industry, academia, and regulatory agencies were convened to review the available literature on important aspects of the interpretation and risk assessment of hepatic microsomal DME enzyme induction in three publications. The three reviews are as follows:
“Effects of Hepatic Drug Metabolizing Enzyme Induction on Clinical Pathology Parameters in Animals and Man,” Toxicol Pathol
“Hepatic Drug Metabolizing Enzyme Induction: Microscopic and Ultrastructural Appearance,” Toxicol Pathol
“Hepatic Drug Metabolizing Enzyme Induction and Implications for Preclinical and Clinical Risk Assessment,” Toxicol Pathol
The purpose of this introduction is not to summarize the articles but rather to frame the series and to provide a common mechanistic introduction.
This issue of Toxicologic Pathology contains an article by Morton et al. that provides recommendations for pathology peer review of nonclinical studies. This is overall a clear, very detailed, and very well-organized manuscript summarizing current recommended practices by experts in the profession and clearly defines the value that peer review lends to the final diagnostic process in toxicological pathology. Although many articles have provided commentary and recommendation on the evolving role of the peer review in creating quality, creditable pathology data, the present article consolidates and expands the preferred pathology peer review practices. It is anticipated that pathology peer review will continue to evolve, and this article documents the state of the art at the present time.
Mexico City (MC) residents are exposed to severe air pollution and exhibit olfactory bulb inflammation. We compared the olfactory function of individuals living under conditions of extreme air pollution to that of controls from a relatively clean environment and explore associations between olfaction scores, apolipoprotein E (APOE) status, and pollution exposure. The olfactory bulbs (OBs) of 35 MC and 9 controls 20.878.5 years were assessed by light and electron microscopy. The University of Pennsylvania Smell Identification Test (UPSIT) was administered to 62 MC/25 controls 21.272.7 years. MC subjects had significantly lower UPSIT scores: 34.2470.42 versus controls 35.7670.40, p ¼ 0.03. Olfaction deficits were present in 35.5% MC and 12% of controls. MC APOE e 4 carriers failed 2.470.54 items in the 10-item smell identification scale from the UPSIT related to Alzheimer’s disease, while APOE 2/3 and 3/3 subjects failed 1.3670.16 items, p ¼ 0.01. MC residents exhibited OB endothelial hyperplasia, neuronal accumulation of particles (2/35), and immunoreactivity to beta amyloid bA42 (29/35) and/or a-synuclein (4/35) in neurons, glial cells and/or blood vessels. Ultrafine particles were present in OBs endothelial cytoplasm and basement membranes. Control OBs were unremarkable. Air pollution exposure is associated with olfactory dysfunction and OB pathology, APOE 4 may confer greater susceptibility to such abnormalities, and ultrafine particles could play a key role in the OB pathology. This study contributes to our understanding of the influences of air pollution on olfaction and its potential contribution to neurodegeneration.
