Interpretation of Hematologic Data in Nonclinical Studies
Jeffrey McCartney
Search for more papers by this authorJeffrey McCartney
Search for more papers by this authorMarjory B. Brooks DVM, DACVIM
Director, Comparative Coagulation Section
Animal Health Diagnostic Center, Cornell University, Ithaca, New York, USA
Search for more papers by this authorKendal E. Harr DVM, MS, DACVP
URIKA, LLC, Mukilteo, Washington, USA
Search for more papers by this authorDavis M. Seelig DVM, PhD, DACVP
Associate Professor, Clinical Pathology
Department of Veterinary Clinical Sciences, University of Minnesota, College of Veterinary Medicine, St. Paul, Minnesota, USA
Search for more papers by this authorK. Jane Wardrop DVM, MS, DACVP
Professor and Director, Clinical Pathology Laboratory
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA
Search for more papers by this authorDouglas J. Weiss DVM, PhD, DACVP
Emeritus Professor
College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, USA
Search for more papers by this authorSummary
Interpretation of hematological data is important at all stages of drug discovery and development. Recommendations for the core clinical pathology parameters in nonclinical toxicity studies have been published. The standard panel for hematology includes white and red blood cell parameters with differential counts and blood and bone marrow smears prepared for each animal. Reference ranges are also referred to as historical control data and are generally available from the laboratory generating the hematology data from the nonclinical study. Test-item-related differences in hematology parameters in nonclinical studies are typically described using the following qualitative terms: increased, higher, decreased, lower. Evaluations are determined directly from animals involved in nonclinical safety studies or from a designated toxicokinetic group of animals and determine systemic exposure, any dose–response relationship, and degree of interanimal variability. An interpretative report is typically produced to capture all test-item-related findings in all clinical pathology data in the nonclinical study.
REFERENCES
- Bloom JC . Principles of hematotoxicology: laboratory assessment and interpretation of data . Toxicol Pathol 1993 ; 21 : 130 – 134 .
- Brecher RW . Risk assessment . Toxicol Pathol 1997 ; 25 : 23 – 26 .
- Burkhard MJ , Brown DE , McGrath JP , et al. Evaluation of the erythroid regenerative response in two different models of experimentally induced iron deficiency anemia . Vet Clin Pathol 2001 ; 30 : 76 – 85 .
- Carakostas MC . Interpreting clinical laboratory data in safety assessment studies . Toxicol Pathol 1992 ; 20 ( 3–2 ): 480 – 483 .
- Carakostas MC , Banerjee AK . Interpreting rodent clinical laboratory data in safety assessment studies: biological and analytical components of variation . Fund Appl Toxicol 1990 ; 15 : 744 – 753 .
- Cwiertniewicz J . Introduction to the Good Laboratory Practice Regulations . Lab Anim (NY) 2005 ; 34 : 29 – 32 .
- Dahlem AM , Allerheiligen SR , Vodicnik MJ . Concomitant toxicokinetics: techniques for and interpretation of exposure data obtained during the conduct of toxicology studies . Toxicol Pathol 1995 ; 23 : 170 – 178 .
- Doeing DC , Borowicz JL , Crockett ET . Gen der dimorphism in differential peripheral blood leukocyte counts in mice using cardiac, tail, foot, and saphenous vein puncture methods . BMC Clin Pathol 2003 ; 3 : 3 .
- Dorato MA , Engelhardt JA . The no-observed-adverse-effect level in drug safety evaluations: use, issues, and definition(s) . Regul Toxicol Pharmacol 2005 ; 42 : 265 – 274 .
- Everds N . Evaluation of Clinical Pathology Data: Correlating Changes with Other Study Data . Tox Pathol 2015 ; 43 : 90 – 97 .
- Friedrichs K , Harr K , Freeman K , et al. ASVCP reference interval guidelines: determination of de novo reference intervals in veterinary species and other related topics . Vet Clin Pathol 2012 ; 41 : 441 – 453 .
- Hall RL . Clinical pathology for preclinical safety assessment: current global guidelines . Toxicol Pathol 1992 ; 20 : 472 – 476 .
- Hall RL . Lies, damn lies, and reference intervals (or hysterical control values for clinical pathology data) . Toxicol Pathol 1997 ; 25 : 647 – 649 .
- Hall RL . Principles of clinical pathology for toxicology studies . In: WA Hayes , ed. Principles and Methods of Toxicology . Philadelphia : Taylor and Francis , 2001 ; 1001 – 1038 .
- Haschec WM , Rousseaux CG . Blood and bone marrow . In: WM Haschec , ed. Fundamentals of Toxicologic Pathology . San Diego : Academic Press , 1998 ; 215 – 232 .
- Jain NC. The neutrophils. In: Essentials of Veterinary Hematogy . Malvern, PA : Lea & Feabiger , 1993 ; 229 .
- Jeffer EH . Biochemical basis of toxicity . In: WM Haschec , ed. Handbook of Toxicology and Pathology. San Diego : Academic Press , 1998 ; 49 – 70 .
- Karbe E , Williams GM , Lewis RW , et al. Distinguishing between adverse and non-adverse effects. Session summary . Exp Toxicol Pathol 2002 ; 54 : 51 – 55 .
- Levin S , Semler D , Ruben Z . Effects of two weeks of feed restriction on some common toxicologic parameters in Sprague–Dawley rats . Toxicol Pathol 1993 ; 21 : 1 – 14 .
- Lewis RW , Billington R , Debryune E , et al. Recognition of adverse and nonadverse effects in toxicity studies . Toxicol Pathol 2002 ; 30 : 66 – 74 .
- Lumsden JH . Normal or reference values: questions and comments . Vet Clin Pathol 1998 ; 27 : 102 – 106 .
- Moch RW , Dua PN , Hines FA . Food and Drug Administration risk assessment-process and toxicologic pathology . Toxicol Pathol 1997 ; 25 : 61 – 67 .
- Morton D , Kemp RK , Francke-Carroll S , et al. Best practices for reporting pathology interpretations within GLP toxicology studies . Toxicol Pathol 2006 ; 34 : 806 – 809 .
- Nemzek JA , Bolgos GL , Williams BA , et al. Differences in normal values for murine white blood cell counts and other hematological parameters based on sampling site . Inflam Res 2001 ; 50 : 523 – 527 .
- Ogawa Y , Matsumoto K , Kamata E , et al. Effect of feed restriction on the peripheral blood and bone marrow cell counts of Wistar rats . Jikken Dobutsu 1985 ; 34 : 407 – 416 .
- Okasaki K . Twenty-six-week repeat-dose toxicity study of a recombinant human granulocyte colony-stimulating factor derivative (Nartogastrim) in cynomolgus monkeys . Toxicol Sci 2001 ; 65 : 246 – 255 .
- Olin MR , Diters RW , Freden GO . The effect of collection site on the cytogram of the BASO/lobularity channel of a hematology system in the mouse . Vet Clin Pathol 1997 ; 26 : 63 – 65 .
- Petterino C , Argentino-Storino A . Clinical chemistry and haematology historical data in control Sprague–Dawley rats from pre-clinical toxicity studies . Exp Toxicol Pathol 2006 ; 57 : 213 – 219 .
- Reagan WJ , Irizarry-Rovira A , Poitout-Belissent F , et al. Best Practices for Evaluation of Bone Marrow in Nonclinical Toxicity Studies . Tox Pathol 2011 ; 39 : 435 – 448 .
- Schultze AE , Bounous DI , Bolliger AP . Veterinary clinical pathologists in the biopharmaceutical industry . Vet Clin Pathol 2008 ; 37 : 146 – 158 .
-
Smith GS
.
Applied clinical pathology in preclinical toxicology testing
. In:
WM Hascheck
, ed.
Handbook of Toxicologic Pathology
.
New York
:
Academic Press
,
2002
:
123
–
156
.
10.1016/B978-012330215-1/50007-7 Google Scholar
- Thompson MB . Clinical pathology in the National Toxicology Program . Toxicol Pathol 1992 ; 20 : 484 – 488 .
- Tomlinson L , Boone L , Ramaiah , et al. Best Practices for Veterinary Toxicologic Clinical Pathology, with Emphasis on the Pharmaceutical and Biotechnology Industries . Vet Clin Pathol 2013 ; 42 : 252 – 269 .
- Tomlinson L , Ramaiah L , Tripathi N , et al. STP Best Practices for Evaluating Clinical Pathology in Pharmaceutical Recovery Studies . Toxicol Pathol 2016 ; 44 : 163 – 172 .
- Walter GL . Effects of carbon dioxide inhalation on hematology, coagulation, and serum clinical chemistry values in rats . Toxicol Pathol 1999 ; 27 : 217 – 225 .
- Weingand K , Hall R , Davies D , et al. Harmonization of animal clinical pathology testing in toxicity and safety studies . The Joint Scientific Committee for International Harmonization of Clinical Pathology Testing. Fund Appl Toxicol 1996 ; 29 : 198 – 201 .
