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Harmonization of Animal Clinical Pathology Testing in Toxicity and Safety Studies*
1The Joint Scientific Committee for International Harmonization of Clinical Pathology Testing consisting of delegate from American Association for Clinical Chemistry's Division of Animal Clinical Chemistry United States 2The Joint Scientific Committee for International Harmonization of Clinical Pathology Testing consisting of delegate from Association for Comparative Haematology United Kingdom 3The Joint Scientific Committee for International Harmonization of Clinical Pathology Testing consisting of delegate from American Society for Veterinary Clinical Pathology United States 4The Joint Scientific Committee for International Harmonization of Clinical Pathology Testing consisting of delegate from Animal Clinical Chemistry Association United Kingdom 5The Joint Scientific Committee for International Harmonization of Clinical Pathology Testing consisting of delegate from International Society for Animal Clinical Biochemistry (multinational) 6The Joint Scientific Committee for International Harmonization of Clinical Pathology Testing consisting of delegate from Japanese Pharmaceutical Manufacturer's Association Japan 7The Joint Scientific Committee for International Harmonization of Clinical Pathology Testing consisting of delegate from Dutch Association for Comparative Haematology Netherlands 8The Joint Scientific Committee for International Harmonization of Clinical Pathology Testing consisting of delegate from Arbeitsgruppe Klinische Chemie bei Laboratoriumstieren der Deutschen Gesellschaft fur Klinische Chemie E.V. Germany 9The Joint Scientific Committee for International Harmonization of Clinical Pathology Testing consisting of delegate from Association des Biologistes Cliniciens pour Ammaux de Laboratoire France 10The Joint Scientific Committee for International Harmonization of Clinical Pathology Testing consisting of delegate from Gruppo di Ematologia ed Ematochimica Applicate alla Tossicologia Italy
Received December 19, 1994; accepted August 29, 1995
Ten scientific organizations formed a joint international committee to provide expert recommendations for clinical pathology testing of laboratory animal species used in regulated toxicity and safety studies. For repeated-dose studies in rodent species, clinical pathology testing is necessary at study termination. Interim study testing may not be necessary in long-duration studies provided that it has been done in short-duration studies using dose levels not substantially lower than those used in the long-duration studies. For repeated-dose studies in nonrodent species, clinical pathology testing is recommended at study termination and at least once at an earlier interval. For studies of 2 to 6 weeks in duration in nonrodent species, testing is also recommended within 7 days of initiation of dosing, unless it compromises the health of the animals. If a study contains recovery groups, clinical pathology testing at study termination is recommended. The core hematology tests recommended are total leukocyte (white blood cell) count, absolute differential leukocyte count, erythrocyte (red blood cell) count, evaluation of red blood cell morphology, platelet (thrombocyte) count, hemoglobin concentration, hematocrit (or packed cell volume), mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration. In the absence of automated reticulocyte counting capabilities, blood smears from each animal should be prepared for reticulocyte counts. Bone marrow cytology slides should be prepared from each animal at termination. Prothrombin time and activated partial thromboplastin time (or appropriate alternatives) and platelet count are the minimum recommended laboratory tests of hemostasis. The core clinical chemistry tests recommended are glucose, urea nitrogen, creatinine, total protein, albumin, calculated globulin, calcium, sodium, potassium, total cholesterol, and appropriate hepatocellular and hepatobiliary tests. For hepatocellular evaluation, measurement of a minimum of two scientifically appropriate blood tests is recommended, e.g., alanine aminotransferase, aspartate aminotransferase, sorbitol dehydrogenase, glutamate dehydrogenase, or total bile acids. For hepatobiliary evaluation, measurement of a minimum of two scientifically appropriate blood tests is recommended, e.g., alkaline phosphatase, gamma glutamyltransferase, 5'-nucleotidase, total bilirubin, or total bile acids. Urinalysis should be conducted at least once during a study. For routine urinalysis, an overnight collection (approximately 16 hr) is recommended. It is recommended that the core tests should include an assessment of urine appearance (color and turbidity), volume, specific gravity or osmolality, pH, and either the quantitative or semiquantitative determination of total protein and glucose. For carcinogenicity studies, only blood smears should be made from unscheduled sacrifices (decedents) and at study termination to aid in the identification and differentiation of hematopoietic neoplasia.