International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Nonproliferative and Proliferative Lesions of the Dog.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions) Project (www.toxpath.org/inhand.asp) 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 lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in most tissues and organs from the dog used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions, lesions induced by exposure to test materials, and relevant infectious and parasitic lesions. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.

Spontaneous and Drug-induced Arteritis/Polyarteritis in the Göttingen Minipig-Review.

Arteritis/polyarteritis occurs spontaneously in many species used in preclinical toxicology studies. In Göttingen minipigs, arteritis/polyarteritis is an occasionally observed background change. In the minipig, this finding differs in frequency and nature from age-related polyarteritis nodosa in rats or monkeys, and Beagle pain syndrome in dogs. In minipigs, it can be present in a single small- or medium-sized artery of an organ or a few organs and is most commonly recorded in the cardiac and extracardiac blood vessels, vagina, oviduct, rectum, epididymis, spinal cord, pancreas, urinary bladder, kidneys, and stomach. The etiology is unknown although it has been considered in minipigs as well as in rats, dogs, and monkeys to be possibly immune mediated. This background change is important with respect to its nature and distribution in the minipig in order to distinguish it from drug-induced vascular changes, which might occur in similar locations and have similar morphologic features. This review summarizes the morphology, incidence, and predilection sites of arteritis as a spontaneously occurring background change and as a drug-induced vasculopathy in the minipig, and also describes the main aspects to consider when evaluating vascular changes in Göttingen minipig toxicity studies and their human relevance.

Ocular toxicity of AUY922 in pigmented and albino rats.

AUY922, a heat shock protein 90 inhibitor is associated with ocular adverse events (AEs). To provide a better understanding of ocular AEs in patients, 4 investigative studies were performed in a step-wise approach to assess retinal structure and function in pigmented (Brown Norway) and albino (Wistar) rats. In rats administered 30mg/kg of AUY922, the AUC0-24h and Cmax are comparable to that in patients at 70mg/m(2). AUY922 at ≥30mg/kg was poorly tolerated by rats with morbidity or mortality generally after the third weekly treatment. Electroretinography (ERG) changes were observed at doses ≥30mg/kg. The ERG changes were dose dependent, consistent with an effect on the photoreceptors, and fully reversible. The ERG effects could not be minimized by decreasing the Cmax while maintaining AUC. Histopathological changes were seen mainly when rats were administered AUY922 at 100mg/kg. The 2-hour infusion of AUY922 at 100mg/kg caused disorganization of the outer segment photoreceptor morphology in male Brown Norway rats; the severity of the disorganization increased with the number of administrations, but was reversible during a 4-week posttreatment period. There was no major difference in ocular response between Brown Norway and Wistar rats. No changes in serum iron levels, and no changes in rhodopsin, PDE6α, ß-transducin concentrations, or retinal pigment epithelium-specific protein RPE65 expression were observed after single and multiple infusions of AUY922 at 100mg/kg compared to vehicle-treated controls. AUY922 retinal toxicity in rats recapitulates and further characterizes that reported in patients and is shown to be reversible, while a precise molecular mechanism for the effect was not determined.

Reduced Activity of Sphingosine-1-Phosphate Lyase Induces Podocyte-related Glomerular Proteinuria, Skin Irritation, and Platelet Activation.

Sphingosine-1-phosphate (S1P) lyase is considered as a drug target in autoimmune diseases based on the protective effect of reducing activity of the enzyme in animal models of inflammation. Since S1P lyase deficiency in mice causes a severe, lethal phenotype, it was of interest to investigate any pathological alterations associated with only partially reduced activity of S1P lyase as may be encountered upon pharmacological inhibition. Both genetic reduction of S1P lyase activity in mice and inhibition of S1P lyase with a low-molecular-weight compound in rats consistently resulted in podocyte-based kidney toxicity, which is the most severe finding. In addition, skin irritation and platelet activation were observed in both instances. The similarity of the findings in both the genetic model and the pharmacological study supports the value of analyzing inducible partially target-deficient mice for safety assessment. If the findings described in rodents translate to humans, target-related toxicity, particularly podocyte dysfunction, may limit chronic systemic treatment of autoimmune diseases with S1P lyase inhibitors. Furthermore, partial deficiency or inhibition of S1P lyase appears to provide an in vivo rodent model to enable studies on the mechanism of podocyte dysfunction.