The INHAND Project is a joint initiative of the societies of toxicologic pathology from Europe, the United Kingdom, Japan, and North America to standardize diagnostic nomenclature and criteria used in toxicologic studies. The INHAND initiative includes recommended nomenclature for evaluating histologic specimens from nonclinical studies involving laboratory animals including rodents, non-human primates, dogs, minipigs, rabbits, and fish. Specific terminology and criteria are derived from the consensus opinions of senior toxicologic pathologists and subject matter experts who have expertise in the different species of interest. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included government databases, including the Registry of Tumors in Lower Animals (RTLA), academia, and industrial laboratories throughout the world. This introduction provides context for 14 chapters, arranged by organ system, that define the INHAND nomenclature and diagnostic criteria for fish used in nonclinical studies. Additionally, the current introductory chapter describes both general features of INHAND methodology as well as elements characteristic of toxicologic fish studies. The latter includes fish study design and conduct; euthanasia, sampling, the histologic processing of fish tissues, and a general approach to evaluating fish studies.

Bone and cartilage with their ligaments and tendons are the main constituents of the skeleton. Statical support and movement of the organism are the main functions of this organ. In addition, as the main source of mineral storage, bone has homeostatic functions in the uptake and release of ions, in particular calcium. It is also involved in endocrine regulation of energy metabolism and interacts with endocrine pancreas and adipose tissue by the peptide hormone osteocalcin derived from osteoblasts. Although bone contains bone marrow (i.e., hematopoiesis as an additional function), the latter is often considered separately in toxicopathology as part of the lymphohematopoietic system (Chapters 7 and 8), albeit interactions between bone and bone marrow do occur.

Thymic lymphoid hyperplasia is a common age-related finding, which occurs particularly in female CD-1 mice. The main differential diagnoses are malignant lymphoma and thymoma. A systematic investigation of control groups from two carcinogenicity studies was performed including measurements of thymic size, and the immunohistochemistry (IHC) markers pan-Cytokeratin (pan-CK) for thymic epithelial cells; CD3 and CD45R/B220 for T and B lymphocytes, respectively; CD31 for endothelial cells; and F4/80 for macrophages. Thymoma can be differentiated by increased numbers of proliferating epithelial cells demonstrated by pan-CK IHC staining. Differentiation between lymphoid hyperplasia and lymphoma is more challenging as a mixture of B and T lymphocytes can be present in both findings. The present investigation showed that the thymic perivascular space is the compartment where the increased numbers of lymphocytes in hyperplasia are localized and not the medulla, as previously thought. The lymphoepithelial compartment is atrophic to the same extent in thymi diagnosed with age-related involution or lymphoid hyperplasia. Both diagnoses are thus related to variations in lymphoid cellularity of the nonepithelial perivascular space, which is continuous with the perithymic tissue. Likewise, lymphomas have a predilection to colonize the perivascular space and to spare the lymphoepithelial compartment.

Activated protein C (APC) is a plasma serine protease with antithrombotic and cytoprotective functions. Based on the hypothesis that specific inhibition of APC’s anticoagulant but not its cytoprotective activity can be beneficial for hemophilia therapy, 2 types of inhibitory monoclonal antibodies (mAbs) are tested: A type I active-site binding mAb and a type II mAb binding to an exosite on APC (required for anticoagulant activity) as shown by X-ray crystallography. Both mAbs increase thrombin generation and promote plasma clotting. Type I blocks all APC activities, whereas type II preserves APC’s cytoprotective function. In normal monkeys, type I causes many adverse effects including animal death. In contrast, type II is well-tolerated in normal monkeys and shows both acute and prophylactic dose-dependent efficacy in hemophilic monkeys. Our data show that the type II mAb can specifically inhibit APC’s anticoagulant function without compromising its cytoprotective function and offers superior therapeutic opportunities for hemophilia.

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 nonproliferative changes in rats and mice. The purpose of this publication is to provide a standardized nomenclature for classifying changes observed in the hematolymphoid organs, including the bone marrow, thymus, spleen, lymph nodes, mucosa-associated lymphoid tissues, and other lymphoid tissues (serosa-associated lymphoid clusters and tertiary lymphoid structures) with color photomicrographs illustrating examples of the lesions. Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. The nomenclature for these organs is divided into 3 terminologies: descriptive, conventional, and enhanced. Three terms are listed for each diagnosis. The rationale for this approach and guidance for its application to toxicologic pathology are described in detail below.