Search

Harmonization of diagnostic terminology used during the histopathologic analysis of rodent tissue sections from nonclinical toxicity studies will improve the consistency of data sets produced by laboratories located around the world. The INHAND Project ( International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a cooperative enterprise of 4 major societies of toxicologic pathology to develop a globally accepted standard vocabulary for proliferative and nonproliferative lesions in rodents. A prior manuscript ( Toxicol Pathol 2012;40[4 Suppl]:87S-157S) defined multiple diagnostic terms for toxicant-induced lesions, common spontaneous and age-related changes, and principal confounding artifacts in the rat and mouse central nervous system (CNS) and peripheral nervous system (PNS). The current article defines 9 new diagnostic terms and updates 2 previous terms for findings in the rodent CNS and PNS, the need for which has become evident in the years since the publication of the initial INHAND nomenclature for findings in rodent neural tissues. The nomenclature presented in this document is also available electronically on the Internet at the goRENI website ( http://www.goreni.org/ ).

The European Society of Toxicologic Pathology organized an expert workshop in May 2018 to address adversity considerations related to thyroid follicular cell hypertrophy and/or hyperplasia (FCHH), which is a common finding in nonclinical toxicity studies that can have important implications for risk assessment of pharmaceuticals, food additives, and environmental chemicals. The broad goal of the workshop was to facilitate better alignment in toxicologic pathology and regulatory sciences on how to determine adversity of FCHH. Key objectives were to describe common mechanisms leading to thyroid FCHH and potential functional consequences; provide working criteria to assess adversity of FCHH in context of associated findings; and describe additional methods and experimental data that may influence adversity determinations. The workshop panel was comprised of representatives from the European Union, Japan, and the United States. Participants shared case examples illustrating issues related to adversity assessments of thyroid changes. Provided here are summary discussions, key case presentations, and panel recommendations. This information should increase consistency in the interpretation of adverse changes in the thyroid based on pathology findings in nonclinical toxicity studies, help integrate new types of biomarker data into the review process, and facilitate a more systematic approach to communicating adversity determinations in toxicology reports.

Henriette Schuppener: „Ihr trugt die Schande nicht Ihr wehrtet Euch.“ Das Gedenken an den 20. Juli 1944 im Wandel der Zeit (Martin Moll) Gerhard Sälter, Johanna Dietrich, Fabian Kuhn: Die vergessenen Toten. Todesopfer des DDR-Grenzregimes in Berlin von der Teilung bis zum Mauerbau (1948-1961) (Jens Schöne) Eckard Michels: Schahbesuch 1967. Fanal für die Studentenbewegung (Harald Möller) Heinrich August Winkler: Geschichte des Westens. Band 3: Vom Kalten Krieg zum Mauerfall (Andreas Lutsch) Friedemann Weckbach-Mara: Deutschland – deine Politiker. Machtkämpfe, Staatsgeheimnisse, Amtsmissbrauch und Privates von Helmut Schmidt bis Angela Merkel (Wolfgang Kaufmann) Claudia Kemper (Hg.): Gespannte Verhältnisse. Frieden und Protest in Europa während der 1970er und 1980er Jahre (Benjamin Ziemann) Jan Ole Wiechmann: Sicherheit neu denken. Die christliche Friedensbewegung in der Nachrüstungsdebatte (1977-1984) (Markus Henkel) Jan Mohnhaupt: Der Zoo der Andern. Als die Stasi ihr Herz für Brillenbären entdeckte und Helmut Schmidt mit Pandas aufrüstete (Laura Metz) Andreas Apelt, Robert Grünbaum (Hg.): Das letzte Jahr der DDR. Von der Volkskammerwahl zur Wiedervereinigung (Sebastian Prinz)

Peter Böhm: For Eyes Only. Die wahre Geschichte des Agenten Horst Hesse Horst Kopp: Der Desinformant. Erinnerungen eines DDR-Geheimdienstlers Klaus Eichner, Gotthold Schramm (Hg.): Top-Spione im Westen. Spitzenquellen der DDR-Aufklärung erinnern sich Gabriele Gast: Kundschafterin des Friedens. 17 Jahre Top-Spionin der DDR beim BND Werner Großmann, Peter Böhm: Der Überzeugungstäter Uwe Krähnke, Matthias Finster, Philipp Reimann, Anja Tschirpe: Im Dienste der Staatssicherheit. Eine soziologische Studie über die hauptamtlichen Mitarbeiter des DDR-Geheimdienstes Jens Gieseke, Andrea Bahr: Die Staatssicherheit und die Grünen. Zwischen SED-Westpolitik und Ost-West-Kontakten

The potential for developmental neurotoxicity (DNT) of environmental chemicals may be evaluated using specific test guidelines from the US Environmental Protection Agency or the Organisation for Economic Cooperation and Development (OECD). These guidelines generate neurobehavioral, neuropathological, and morphometric data that are evaluated by regulatory agencies globally. Data from these DNT guideline studies, or the more recent OECD extended one-generation reproductive toxicity guideline, play a pivotal role in children's health risk assessment in different world areas. Data from the same study may be interpreted differently by regulatory authorities in different countries resulting in inconsistent evaluations that may lead to inconsistencies in risk assessment decisions internationally, resulting in regional differences in public health protection or in commercial trade barriers. These issues of data interpretation and reporting are also relevant to juvenile and pre-postnatal studies conducted more routinely for pharmaceuticals and veterinary medicines. There is a need for development of recommendations geared toward the operational needs of the regulatory scientific reviewers who apply these studies in risk assessments, as well as the scientists who generate DNT data sets. The workshops summarized here draw upon the experience of the authors representing government, industry, contract research organizations, and academia to discuss the scientific issues that have emerged from diverse regulatory evaluations. Although various regulatory bodies have different risk management decisions and labeling requirements that are difficult to harmonize, the workshops provided an opportunity to work toward more harmonized scientific approaches for evaluating DNT data within the context of different regulatory frameworks. Five speakers and their coauthors with neurotoxicology, neuropathology, and regulatory toxicology expertise discussed issues of variability, data reporting and analysis, and expectations in DNT data that are encountered by regulatory authorities. In addition, principles for harmonized evaluation of data were suggested using guideline DNT data as case studies.

Florian Huber: Tauchgang ins Totenreich. Archäologie unter dem Meeresspiegel (Wolfgang Kaufmann) Günther Hirschfelder, Manuel Trummer: Bier. Eine Geschichte von der Steinzeit bis heute (Wolfgang Kaufmann) Thomas Franke: Russian Angst. Einblicke in die postsowjetische Seele (Jürgen W. Schmidt)

Peter Böhm: For Eyes Only. Die wahre Geschichte des Agenten Horst Hesse Horst Kopp: Der Desinformant. Erinnerungen eines DDR-Geheimdienstlers Klaus Eichner, Gotthold Schramm (Hg.): Top-Spione im Westen. Spitzenquellen der DDR-Aufklärung erinnern sich

International and U.S. guidance for developmental neurotoxicity (DNT) testing of chemicals are provided by OECD DNT test guideline 426, OECD extended one-generation reproductive toxicity study (EOGRTS) test guideline 443, and U.S. EPA DNT test guideline 870.6300. These guidelines with their multiple behavioral and neuropathology endpoints are among the most logistically complex, labor-intensive bioassays conducted for regulatory purposes. This article identifies key issues in the practical implementation and analysis of neurobehavioral and neuropathology endpoints, with emphasis on quantitative brain morphometry testing requirements. This article also reviews the development of DNT guidelines, strengths and limitations of validation efforts, regulatory triggers for DNT testing, and recent guidance from government and workgroup efforts to enhance conduct and interpretation of studies for regulatory risk assessment purposes.

Paul-Moritz Rabe: Die Stadt und das Geld. Haushalt und Herrschaft im nationalsozialistischen MünchenMargit Szöllösi-Janze (Hg.): München im Nationalsozialismus

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) project is a joint initiative of the societies of toxicological pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP). Its aim is to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory rodents. A widely accepted international harmonization of nomenclature in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and will provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists. The purpose of this publication is to provide a standardized nomenclature for classifying microscopical lesions observed in the integument of laboratory rats and mice. Example colour images are provided for most lesions. The standardized nomenclature presented in this document and additional colour images are also available electronically at http://www.goreni.org. The nomenclature presented herein is based on histopathology databases from government, academia, and industrial laboratories throughout the world, and covers lesions that develop spontaneously as well as those induced by exposure to various test materials. (DOI: 10.1293/tox.26.27S; J Toxicol Pathol 2013; 26: 27S-57S).

Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors. DOI: http://dx.doi.org/10.7554/eLife.20722.001, eLife digest Healthy cells in the human body can become cancerous if they gain genetic mutations that allow them to rapidly grow and divide. Some types of cancer respond better to drug treatments than others and tumors often develop resistance to a particular drug treatment after a while. Because of this, researchers are always searching for new molecules to develop into anticancer drugs. Recently, a team of researchers identified some small molecules that could inactivate two closely related proteins called CDK8 and CDK19. CDK8 is essential for the WNT signaling pathway – which enables cells to communicate with one another – and has been extensively studied in various cancers. Previous studies indicate that this protein can either promote or inhibit the growth of tumors, depending on the type and stage of the cancer. Furthermore, CDK8 regulates a type of molecular switch called a “super-enhancer”, which controls the activity of many genes. In contrast, the role of CDK19 in cells was not as well understood. Here Clarke, Ortiz-Ruiz et al. investigated whether two different classes of small molecules that target CDK8 and CDK19 (referred to as “prototype CDK8/19 drugs”) could inhibit the growth of cancers, and whether they have any harmful side effects on healthy cells. For the experiments, human cancer cells were implanted into mice. Treating these mice with prototype CDK8/19 drugs inhibited the activity of CDK8 and CDK19 in the cancer cells and slowed the growth of colorectal tumors. A type of blood cancer called acute myeloid leukaemia was particularly sensitive to the drugs. However, Clarke, Ortiz-Ruiz et al. also observed that the prototype drugs altered the activity of many genes with roles in healthy tissues such as immune, bone and stem cells. Further experiments in mice and cells grown in the laboratory confirmed that these prototype drugs have adverse effects on healthy intestinal and bone marrow stem cells and trigger changes to immune cells. These concerning side effects were also evident when the prototype drugs were tested in rats and dogs. Furthermore, the experiments indicate that there is not a suitable range of doses of these drugs in which the therapeutic benefits outweigh the toxic side effects. Clarke, Ortiz-Ruiz et al. conclude that the clinical development of CDK8/19 drugs will be extremely challenging and that their prototype drugs would not currently be suitable for use as cancer treatments. However, the small molecules they describe will be important probes in research to study exactly how CDK8/19 regulate gene activity in both healthy cells and cancers. DOI: http://dx.doi.org/10.7554/eLife.20722.002

The identification of adverse health effects has a central role in the development and risk/safety assessment of chemical entities and pharmaceuticals. There is currently a need for better alignment regarding how nonclinical adversity is determined and characterized. The European Society of Toxicologic Pathology (ESTP) therefore coordinated a workshop to review available definitions of adversity, weigh determining and qualifying factors of adversity based on case examples, and recommend a practical approach to define and characterize adversity in toxicology reports, to serve as a valuable prerequisite for future organ- or lesion-specific workshops planned by the ESTP.

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 PPARα. 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.

Karina Urbach: Hitlers heimliche Helfer. Der Adel im Dienst der Macht Hubertus Büschel: Hitlers adliger Diplomat. Der Herzog von Coburg und das Dritte Reich

Feasibility of the ILSI-HESI (ACSA) extended one-generation protocol was tested with vinclozolin (dietary 0, 4, 20, 100 mg/kg/day). Parental Wistar rats (n = 25/sex/dose) were dosed pre-mating (males 4, females 2 weeks) through F1 offspring weaning (postnatal day PND21); F1 dosing continued through PND70. At PND21, 3 subsets (each 1 pup/sex/litter) were selected for neurotoxicology (functional observational battery, motor activity, neuropathology), clinical pathology (hematology, clinical chemistry, urinalysis, thyroid hormone assay) (subsets 1a, 1b; each n = 10/sex/dose), immunotoxicology (IgM) SRBC antibody response and natural killer cell assays (subset 2; n = 25/sex/dose), and estrus cycle (subset 3; n = 25/dose). Vinclozolin reduced parental and offspring bodyweight and prostate, seminal vesicles and epididymides weight, and increased adrenal weight/induced adrenal cortical hypertrophy at 100 mg/kg. Mating, fertility, gestation and lactation were unaffected. At 20 and 100 mg/kg, F1 males had reduced anogenital distance and retained areolae; at 100 mg/kg only, there was hypospadias, purulent prostatitis and seminal vesicle inflammation with atrophy, and Leydig cell hyperplasia, and in F1 females accelerated vaginal opening. These effects are consistent with vinclozolin’s known anti-androgenic developmental effects. Neuro- and immunotoxicology tests were unaffected. F1 Only T4 was reduced at 20 and 100 mg/kg. The overall sensitivity of the extended one-generation protocol is comparable to or even greater than the current two-generation study. Thus it reduces animal use while maintaining or enhancing information for risk assessment.

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.

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.

One of the challenges for toxicologic pathologists is to translate the diverse range of morphologic changes that are observed in toxicity studies into a consistent and readily understood set of diagnostic terms to be tabulated and summarized in regulatory reports or peer-reviewed publications. Historically, there have been multiple efforts to provide uniform nomenclature for lesions observed in laboratory animals. These efforts began as early as 1973 and have culminated in various textbooks, workshop reports, and monographs. The efforts have typically focused on the rat and mouse and, in many cases, were limited to proliferative lesions. Many of the texts or documents that describe suggested nomenclature are either not widely available or are out of print. To address this issue, members of the major societies of toxicologic pathology (JSTP, BSTP, ESTP, and STP) have been engaged in an international collaborative effort to codify and publish uniform nomenclature for both proliferative and nonproliferative lesions in laboratory rodents. Several features unique to this effort include (1) a truly international scope, (2) implementation of an open comment period allowing a wide group of toxicologic pathologists the opportunity to provide input, and (3) availability in a Web-based format. The project goes under the acronym INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice). Project oversight is provided by the Global Editorial and Steering Committee (GESC), which consists of members from each of the major societies of toxicologic pathology. The most important components of the INHAND project are the Organ System Working Groups. Formation of these groups is coordinated by the GESC, and they consist of a global chairperson and members from each of the major societies of toxicologic pathology. The GESC actively seeks out organ system experts to serve on these groups. In addition, the GESC often accommodates requests from pathologists who volunteer for a specific organ working group. The Organ System Working Groups have the responsibility to prepare the nomenclature guidelines for both proliferative and nonproliferative lesions of rats and mice for their assigned organ system. In addition to lesions that occur spontaneously, the groups are asked to determine if there are common, xenobiotic-induced lesions for which standardized nomenclature might be needed. The working groups draw heavily from existing nomenclature documents, Web sites, and publications including prior work of the Registry of Industrial Toxicology Animal-Data (RITA) and the Standardized System of Nomenclature and Diagnostic Criteria (SSNDC). For each diagnostic entity, the working group selects a preferred diagnosis and acceptable alternative diagnoses, provides diagnostic criteria and differential diagnosis, and prepares representative photomicrographs. An important feature of the INHAND project is the access provided to the global open Registry Nomenclature Information System (goRENI; www.goreni.org) (Figure 1). Access is provided to all members of toxicologic pathology societies worldwide. Access is free but must be requested through the goRENI Web site (Figure 2). Once access is granted, pathologists can navigate by organ systems (Figure 3) and ultimately select a diagnosis they would like to view. Within the goRENI system, each diagnostic entity is referred to as a ‘‘manuscript.’’ An example is the written information, and photographic illustrations, provided for a bronchiolo-alveolar carcinoma as shown in Figure 4. Once an organ working group has prepared a draft document, the nomenclature is placed on the goRENI Web site for review and discussion. Members of the contributing STPs are notified of the dates of the review period through their respective societies. Following the designated comment period, the working group revises the nomenclature documents and, in consultation with the GESC, finalizes the nomenclature for that organ system. Finalized nomenclature will be available to toxicologic pathologists in two forms: (1) electronic access via the goRENI Web site and (2) print-based publication in the toxicologic pathology journals. Due to the substantial costs associated with print-based This is an opinion article submitted to the Regulatory Forum and does not constitute an official position of the Society of Toxicologic Pathology or the journal Toxicologic Pathology. The views expressed in this article are those of the authors and do not necessarily represent the policies, positions, or opinions of their respective agencies and organizations. Conflict of interest: The authors have not declared any conflict of interest.

The revision of the OECD TG 407 test guideline (repeated dose 28-day oral toxicity study in rodents) focuses on endpoints to detect endocrine activities of chemicals. The new endpoints are likely to influence other previously established core endpoints of this study type. An expert group of pathologists and toxicologists within the European Society of Toxicologic Pathologists (ESTP) has contributed to the scientific discussion of the draft guideline. The advantages and disadvantages of methodical changes as necropsy of all females in dioestrus, blood collection for clinical chemistry and haematology at the same cycle stage, weighing of the thyroid gland and separate weighing of ventral and dorsolateral lobes of the prostate are considered. Possible alternatives are pointed out covering scientific as well as practical aspects.

Neuropathology methods in rodent developmental neurotoxicity (DNT) studies have evolved with experience and changing regulatory guidance. This article emphasizes principles and methods to promote more standardized DNT neuropathology evaluation, particularly procurement of highly homologous brain sections and collection of the most reproducible morphometric measurements. To minimize bias, brains from all animals at all dose levels should be processed from brain weighing through paraffin embedding at one time using a counterbalanced design. Morphometric measurements should be anchored by distinct neuroanatomic landmarks that can be identified reliably on the faced block or in unstained sections and which address the region-specific circuitry of the measured area. Common test article–related qualitative changes in the developing brain include abnormal cell numbers (yielding altered regional size), displaced cells (ectopia and heterotopia), and/or aberrant differentiation (indicated by defective myelination or synaptogenesis), but rarely glial or inflammatory reactions. Inclusion of digital images in the DNT pathology raw data provides confidence that the quantitative analysis was done on anatomically matched (i.e., highly homologous) sections. Interpreting DNT neuropathology data and their presumptive correlation with neurobehavioral data requires an integrative weight-of-evidence approach including consideration of maternal toxicity, body weight, brain weight, and the pattern of findings across brain regions, doses, sexes, and ages.

Tocotrienols exert hypocholesterolaemic and antioxidant effects, and may hence have anti-atherogenic properties. Therefore, the aim of this study was to investigate the cholesterol-lowering and anti-atherogenic effects of tocotrienols in cholesterol-fed rabbits. Rabbits were fed a basal diet (control) supplemented with γ-tocotrienol, γ-tocotrienyl acetate, mixed tocotrienols or α-tocotrienol for 12 weeks. All treatments resulted in significant increases in plasma tocotrienols. None of the treatments, however, had significant effects on serum lipids or size of atherosclerotic lesions. A trend towards a decrease in plasma cholesterol was observed following γ-tocotrienol treatment (−22%) after 6 weeks. The decrease was mainly attributable to a reduction in LDL cholesterol (23%), whereas HDL cholesterol increased (14%). This trend was mirrored in a non-significant reduction in lesion area (20%). Our results demonstrate that tocotrienols are absorbed, but have little effect on plasma lipids and atherosclerosis in cholesterol-fed rabbits.