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In the constantly evolving field of toxicologic pathology, a pathologist’s career is often characterized by multiple career transitions. However, these transitions can be challenging and/or overwhelming and may require a shift in focus, strategic approach, and acquisition of new skills and expertise. In order to provide a forum to discuss challenges associated with career transitions and skill set/competencies required to navigate career changes effectively and successfully, the Career Development and Outreach Committee of the Society of Toxicologic Pathology (STP) sponsored a career development workshop entitled “Transitions in a Pathologist’s Career” in conjunction with the STP 36th annual symposium. The presentations at this workshop provided perspectives of managers from pharmaceutical companies and Contract Research Organizations as well as consultants. This article is designed to provide brief summaries of their talks in this well-received career development workshop. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study is to compare the life cycle energy and costs derived from the production and occupation of social interest housing models located in two different types of neighborhoods: compact and sprawling. Two neighborhood development alternatives in Mexico City were established and evaluated including the potential impacts analysis of the built environment/infrastructure and the commuting of the occupants. Methods: The study includes the conventional phases of a building life cycle (LC)-preoccupation, occupation, and post-occupation-but it was expanded to include a fourth phase, 'occupant transportation,' to cover the commuting potential impacts. The methodology consists of four main stages: (1) definition of function, functional unit, and scope; (2) data collection-divided in three main steps: architectural, land costs and transformations, and commuting data; (3) impact assessment-we used software SimaPro v8.0.1 to manage the LC inventory data; and (4) interpretation of results and sensitivity analysis. Results and discussion: In the preoccupation phase, the sprawling neighborhood cell (NC) cumulative energy demand (CED) is 30 % larger than the compact NC ones. Regarding the LC costs, land costs strongly impact the compact NC, but when aggregated in the preoccupation phase, the LC costs for the sprawling NC are only 14 % above those of the compact NC. For the occupation phase, results show that the compact NC has lower CED (by 10 %) and LC costs (16 %) than the sprawling NC. The occupant transportation phase plays a highly important role, since it represents up to 28 % of total LC CED and up to 54 % of total LC costs. This phase affects significantly the sprawling NC, which has a 25 % higher CED and doubles LC costs, when compared with the compact NC. Post-occupation phase contributes just in a small proportion of the total CED and LC costs for both NC, since it accounts for 3 % or less of the total energy and LC costs. Overall results show that the compact NC has lower CED and LC costs than the sprawling NC. Conclusions: The results show that occupant transportation phase plays a highly important role in the neighborhood performance. Neighborhood development assessment should consider a number of variables beyond CED and costs. However, in order to improve the sector's energy efficiency and household's economy, we recommend to consider house location as it can be as important as other energy or cost-reduction actions in neighborhood development. [ABSTRACT FROM AUTHOR]

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Examination of H&E-stained tongue samples from a 26-week intravenous infusion study of Beagle dogs, utilizing a compound with no recognized effect on mineral metabolism, exhibited superficial stratum corneum calcification in both treated and control animals. This resulted in the search for possible causes of the finding to help clarify confounding issues. Retrospective examination of 11 studies performed before the signal case indicated that the problem existed in the testing facility but was not recognized. Prior to 2008, this finding was not observed, perhaps indicating the requirement for a change in procedures or suppliers. Based on the hypothesis that the calcium salts were deposited from bone during processing, a series of tests was performed by fixing tongue and femur along with different tissues, processed routinely to slide, and stained with H&E and von Kossa stains. We conclude that the presence of superficial stratum corneum calcification of the tongue in dogs demonstrated in toxicology studies is an artifactual change related to the processing of tissues, specifically the fixation of tongue in the same container as bone and stomach. This change should not be confused with compound-related effects, even when the incidence varies between controls and treated animals. [ABSTRACT FROM AUTHOR]

Historically, nitrogen oxides (NOx) in food, drinking water, as well as in the atmosphere have been believed to be associated with adverse health consequences. More recently, NOx have been implicated in normal homeostatic regulation, and exogenous administration has been associated with health benefits. One such potential health benefit is the prospect that inhaled nitrite will lower pulmonary blood pressure (BP) in patients with pulmonary arterial hypertension (PAH), a disease with poor prognosis due to the lack of effective treatment. To characterize potential chronic toxicity associated with inhaled AIR001 (sodium nitrite) for use in the treatment of PAH, 26-week exposures to AIR001 were carried out by inhalation administration in rats and by intravenous infusion in dogs. The studies revealed that methemoglobinemia was the primary adverse effect in both species. Methemoglobin levels less than 40% were well tolerated in both species, while levels greater than 50% methemoglobin caused death in some rats. Additionally, a decrease in systemic BP was also observed with inhaled AIR001 exposure in dogs. These acute secondary and exaggerated pharmacological effects occurred daily throughout the 26-week treatment period. Chronic exposure did not alter the magnitude of either methemoglobinemia or hypotension or result in additional toxicity or compensatory responses. Based on the exposure levels that produced these pharmacodynamic responses in animals, relative to those measured in early clinical studies, it appears that an adequate margin of safety exists to support the continued clinical development of inhaled AIR001. [ABSTRACT FROM AUTHOR]

The 2011 annual National Toxicology Program (NTP) Satellite Symposium, entitled “Pathology Potpourri,” was held in Denver, Colorado in advance of the Society of Toxicologic Pathology’s 30th Annual Meeting. The goal of the NTP Symposium is to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers’ presentations, including diagnostic or nomenclature issues that were presented, along with select images that were used for audience voting or discussion. Some lesions and topics covered during the symposium include: proliferative lesions from various fish species including ameloblastoma, gas gland hyperplasia, nodular regenerative hepatocellular hyperplasia, and malignant granulosa cell tumor; spontaneous cystic hyperplasia in the stomach of CD1 mice and histiocytic aggregates in the duodenal villous tips of treated mice; an olfactory neuroblastoma in a cynomolgus monkey; various rodent skin lesions, including follicular parakeratotic hyperkeratosis, adnexal degeneration, and epithelial intracytoplasmic accumulations; oligodendroglioma and microgliomas in rats; a diagnostically challenging microcytic, hypochromic, responsive anemia in rats; a review of microcytes and microcytosis; nasal lesions associated with green tea extract and Ginkgo biloba in rats; corneal dystrophy in Dutch belted rabbits; valvulopathy in rats; and lymphoproliferative disease in a cynomolgus monkey. [ABSTRACT FROM PUBLISHER]

The June 2009 Town Hall meeting of the Society of Toxicologic Pathology (STP) and a subsequent survey considered whether or not STP should endorse a published proposal (Toxicol Pathol 37: 553-561, 2009) by the International Federation of Societies of Toxicologic Pathologists (IFSTP) to provide global recognition by credential review for toxicologic pathologists engaged in regulatory-type, nonclinical toxicology studies. One-third (374 of 1082) of STP members answered the survey. The majority of respondents rejected the IFSTP proposal (55% against) but favored the concept of global recognition (57% for), if available to both anatomic pathologists and clinical pathologists (67% for). Members preferred recognition by credential review (49% for) or via an internationally authored ‘‘best practices’’ document detailing the ideal educational and work experiences required for entry-level proficiency in toxicologic pathology (43% for). Therefore, the STP Executive Committee does not endorse the current IFSTP proposal but will continue discussions on global recognition of qualified toxicologic pathologists with other societies of toxicologic pathology. [ABSTRACT FROM PUBLISHER]

The article discusses the impact of the World Bank's global political economy proposition that was raised during the 2004 Annual Meetings of the World Bank and the International Monetary Fund by Bank president James D. Wolfensohn and senior vice president and chief economist François Bourguignon. The proposition includes the construction of the project promoting the global architecture of governance.

Accurate interpretation of microscopic changes in tissues is critical in hazard identification and risk assessment. To address a possible confounder, the effects of postmortem interval on hepatocyte vacuolation and liver weight were studied in fasted and nonfasted Sprague-Dawley rats. Male and female rats (5/sex/interval) were euthanized with CO 2 , weighed, and necropsied either immediately or after remaining in the closed CO 2 chamber for 5, 10, or 25 minutes after respirations ceased. The liver was removed, weighed, and fixed for light microscopy, immunohistochemistry, and electron microscopy. The liver weight and liver to body weight ratio increased significantly in both male and female rats. Postmortem hepatocellular vacuolation was more prominent in males than in females. Both fasted and nonfasted males were similarly affected, however, fasted females were affected more than nonfasted females at the 25-minute interval. Ultrastructurally, intracytoplasmic vacuoles in hepatocytes and/or endothelial cells contained electron-lucent material that was morphologically similar to plasma in sinusoidal spaces. Results of our study suggest that hepatocyte vacuoles were formed in a postmortem time-dependent manner as a result of plasma influx into the cytoplasm. This change was associated with hepatic sinusoidal congestion and increases in liver weight. Males were more sensitive than females to postmortem hepatocyte vacuolation. [ABSTRACT FROM AUTHOR]

Cystic degeneration/spongiosis hepatis in rats has been proposed to be a preneoplastic and/or neoplastic lesion by some authors, because of its proliferative properties and persistent increased cell turnover rate in stop experiments using hepatocarcinogens, and the assumption that it can develop into a sarcoma. The neoplastic potential of cystic degeneration is questioned in this review article. Cystic degeneration, which appears to derive from altered Ito cells, does nothave neoplastic histomorphologic characteristics, although it may be composed of cells with an increased mitotic index. In this regard, persistent proliferation is also seen with other nonneoplastic lesions. Arguments are presented to show that the induced, probably extremely rare sarcoma that was associated with cystic degeneration most likely derives from the very rare induced spherical Ito-cell aggregate with an unusually high cellular turnover rate in rats treated with hepatocarcinogens, and not from cystic degeneration. Also, in none of 12 referenced standard oncogenicity studies with chemically induced cystic degeneration was the lesion associated with mesenchymal (Ito-cell) tumors. Consequently, evidence is lacking that cystic degeneration in rats should be classified as a preneoplastic or neoplastic lesion. The 12 oncogenicity studies in rats with induced cystic degeneration showed a marked sex predilection, with males more likely to develop either spontaneous or chemically induced lesions. In these 12 studies, cystic degeneration was more often associated with hepatocellular hypertrophy or hepatotoxicity, rather than hepatocarcinogenicity. Thus, it is concluded that hepatocarcinogens induce cystic degeneration, not because they are carcinogenic, but because they have other effects on the liver, and that cystic degeneration may be a secondary/reparative change. Cystic degeneration in fish parallels the situation in rats in many respects, yet the existence of the lesion in other species, including man, is not as well supported. Based on the data presented in this review, spontaneous and induced cystic degeneration in rats and fish is not a preneoplastic or neoplastic lesion and risk assessment for man can be based on no-effect levels and safety margins, as for other nonneoplastic adverse effects that have no counterpart in man. [ABSTRACT FROM AUTHOR]

Presents information on a collaborative research program organized under the auspices of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute's Alternatives to Carcinogenicity Testing (ACT) Committee. Acknowledgment of individuals who participated in the research initiative; Laboratories participating in the ILSI ACT Collaborative Research Program; Background on the ILSI Health and Environmental Sciences Institute.

Presents poster abstracts from the International Life Sciences Institute Alternative Methods for Carcinogenicity Testing Workshop held from November 1-3, 2000 in Leesburg, Virginia. Description of the neonatal mouse model for short-term carcinogenicity testing; Cyclophosphamide results in the neonatal mouse model.

The generation, evaluation, and presentation of data from the ILSI Alternatives to Carcinogenicity Testing (ACT) program was standardized to ensure that the results of studies performed in multiple laboratories could be reliably compared. To this end, standardized experimental protocols, tissue collection procedures, histopathology nomenclature, diagnoses, and terminology were employed by study participants. In the experimental phase, this approach provided important cross-model consistency. To ensure comparability in the data evaluation phase of the project, interpretive criteria were defined to allow the characterization of study outcome as positive, negative, or equivocal in regards to carcinogenic response. These criteria helped to provide consistency across models because separate Assay Working Groups were established to evaluate the results of each model. To organize and compile the data from the ILSI ACT program, a database has been developed and data entered in standardized format to facilitate cross- and intramodel comparisons. In summary, the early development of standardized test protocols, evaluation procedures, and interpretive criteria has resulted in a data set in which users can have a high level of assurance that results in the database reflect consistently applied experimental and interpretive guidelines. [ABSTRACT FROM AUTHOR]

The performance of the p53 +/- transgenic (knockout) mouse model was evaluated through review of the data from 31 short-term carcinogenicity studies with 21 compounds tested as part of the International Life Sciences Institute's (ILSI) Alternatives to Carcinogenicity Testing (ACT) project, together with data from other studies which used comparable protocols. As expected based on the hypothesis for the model, a significant number (12/16 or 75%) of the genotoxic human and/or rodent carcinogens tested were positive and the positive control, p-cresidine, gave reproducible responses across laboratories (18/19 studies positive in bladder). An immunosuppressive human carcinogen, cyclosporin A, was positive for lymphomas but produced a similar response in wild type mice. Two hormones that are human tumorigens, diethylstilbestrol and 17β-estradiol, gave positive and equivocal results, respectively, in the pituitary with p53-defi cient mice showing a greater incidence of proliferative lesions than wild type. None of the 22 nongenotoxic rodent carcinogens that have been tested produced a positive response but 2 compounds in this category, chloroform and diethylhexylphthalate, were judged equivocal based on effects in liver and kidney respectively. Four genotoxic noncarcinogens and 6 nongenotoxic, noncarcinogens were also negative. In total (excluding compounds with equivocal results), 42 of 48 compounds or 88% gave results that were concordant with expectations. The technical lessons learned from the ILSI ACT-sponsored testing in the p53+/- model are discussed. [ABSTRACT FROM PUBLISHER]

Four-week toxicity studies with the 21-aminosteroid tirilazad mesylate were conducted in Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys to support development of the drug for use in various clinical syndromes of injury to the central nervous system of humans. As the immune system is Involved in many of the obvious side effects of glucocorticoids used currently for this indication, particular attention was directed to the lymphoid system; results were contrasted with similar data from studies with methylprednisolone, a classical glucocorticoid. Administration of tirilazad mesylate to rats, dogs and monkeys for 4 weeks had no effects at the highest doses tested on parameters assessed, including absolute peripheral blood lymphocyte counts, thymus or adrenal weights, circulating levels of cortisol, or lymphocyte proliferation response to phytohemagglutinin-P. Germinal centers in lymphoid tissues from dogs given high doses of tirilazad contained small numbers of macrophages with vacuolated cytoplasm but no other changes; lymphoid tissues in rats and monkeys given tirilazad were morphologically normal. Administration of methylprednisolone for a similar duration in rats and dogs at high dose levels was associated with increased death rates due to bacterial infections, markedly decreased peripheral blood lymphocyte counts and weights of thymus and adrenal glands, and prominent lymphoid atrophy as well as decreased circulating levels of cortisol. Female dogs infused for 10 days with a high dose of methylprednisolone had depression of the proliferation response of peripheral blood lymphocytes to phytohemagglutinin-P. [ABSTRACT FROM PUBLISHER]