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Office of Research and Development, United States Environmental Protection Agency, Washington DC, USA
Abstract
The Fundamentals chapter covers basic information that every toxicologist needs to know when evaluating animal hematology, clinical pathology, and urinalysis data. It begins with a description of the clinical pathology tests routinely required by animal toxicity test guidelines to assess the health status of animals and discover evidence of toxicity. The value of using clinical pathology panels to further investigate specific diseases and toxicity is explained. This is followed by a description of reference ranges (‘normal’ ranges) and how they can be used to recognize anomalous values that may indicate the presence of disease or toxicity. The importance of identifying ‘outlier’ values is stressed along with the reasons why they should be eliminated from consideration. There is a discussion of the pitfalls of statistical analysis and how to distinguish between statistical and biological significance. Finally, the importance of considering multiple pieces of data is stressed to establish a weight-of-the-evidence diagnosis of animal health and toxicity.
1.1 Introduction
Clinical pathology provides a quantifiable way to assess animal health and to diagnose disease and toxicity. Organic damage can be detected within a few seconds to a few days, and often before clinical signs and microscopic lesions appear. Dozens of tests can be performed using small volumes of blood or urine. These tests are more revealing than merely observing an animal and far less traumatic than biopsy or surgery. Clinical pathology measurements are routinely used to:
screen animals to uncover illness, toxicity, and genetic disease,
diagnose disease,
monitor the progression or reversal of disease and toxicity, and
monitor therapeutic drug regimens.
Clinical pathology encompasses the following:
Hematology—The study of the cellular components of the blood including erythrocytes (red blood cells), leukocytes (white blood cells), thrombocytes (platelets), and the blood forming tissues (e.g. bone marrow).
Clinical Chemistry—The study of the chemical composition of the liquid portion of blood.
Urinalysis—The study of the chemical and cellular composition of urine.
Cytology—The study of cells, including their origin, structure, function, and pathology.
Parasitology—The study of parasites and parasitism (not covered in this guide).
This handbook provides diagnostic hematology, clinical chemistry, and urinalysis information and briefly describes the formation of the various blood cells. Readers seeking information on myeloproliferative disorders and parasitology are advised to search textbooks that specialize in these topics.
1.2 Routine Clinical Pathology Testing
In 1996, the Joint Scientific Committee for International Harmonization of Clinical Pathology Testing (IHCPT), which represents ten scientific organizations, provided minimum clinical pathology test recommendations for use in routine animal toxicity and safety studies (Weingand et al. 1996). These recommendations have been widely accepted and continue to be followed to this day.
The Organisation for Economic Co-operation and Development (OECD) has developed guidelines for an array of toxicity studies by multiple routes of exposure (OECD 2009). Each test guideline lists recommended clinical pathology tests. These guidelines are internationally agreed testing methods used by government, industry and independent laboratories to identify and characterize potential hazards of new and existing chemical substances. Toxicology test guidelines can be found at this OECD website: http://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788.
The U.S. Environmental Protection Agency has also recommended clinical pathology parameters for its various test guidelines (U.S. EPA 2007). Toxicology test guidelines can be found at this EPA website: http://www.gpo.gov/fdsys/granule/CFR-2007-title40-vol31/CFR-2007-title40-vol31-part798/content-detail.html.
Clinical pathology recommendations can vary depending on which test guideline is being used. Table 1.1 summarizes the IHCPT, OECD, and U.S. EPA recommendations for hematology, clinical chemistry, and urinalysis testing for a chronic toxicity study. Additional tests may be performed as needed for diagnostic purposes.
Table 1.1
IHCPT, OECD, and U.S. EPA recommended clinical pathology tests for a chronic toxicology study
Hematology test | IHCPT a | OECD b | U.S. EPA c |
Erythrocyte (RBC) count | √ | √ | √ |
Red blood cell morphology | √ | ||
Reticulocytes | O | ||
Hemoglobin concentration | √ | √ | √ |
Hematocrit (packed cell volume) | √ | √ | √ |
Mean corpuscular volume (MCV) | √ | √ | |
Mean corpuscular hemoglobin (MCH) | √ | √ | |
Mean corpuscular hemoglobin concentration (MCHC) | √ | √ | |
Total leukocyte (WBC) count | √ | √ | √ |
Absolute differential leukocyte count | √ | √ | √ |
Platelet (thrombocyte) count | √ | √ | √ |
Prothrombin time | √ | √ | |
Activated partial thromboplastin time | √ | √ | |
Bone marrow cytology slides | O | ||
Clinical pathology test | IHCPT a | OECD b | U.S. EPA c |
Alanine aminotransferase (ALT) | √ | √ | √ |
Albumin | √ | √ | √ |
Alkaline phosphatase (ALP) | √ | √ | |
Aspartate aminotransferase (AST) | √ | √ | √ |
Bilirubin, total | √ | √ | √ |
Blood urea nitrogen (BUN) | √ | √ | √ |
Calcium | √ | √ | √ |
Cholesterol, total | √ | √ | √ |
Chloride | √ | ||
Creatine phosphokinase | √ | ||
Creatinine | √ | √ | √ |
Gamma glutamyltransferase (GGT) | √ | √ | √ |
Globulin | √ | ||
Glucose | √ | √ | √ |
Glutamate dehydrogenase | √ | √ | |
5′-Nucleotidase (5′-NT) | √ | √ | |
Ornithine decarboxylase | NR | √ | |
Phosphorus | √ | ||
Potassium | √ | √ | √ |
Sodium | √ | √ | √ |
Sorbitol dehydrogenase (SDH) | √ | ||
Total bile acids (TBA) | √ | √ | |
Total protein
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