title: Clinical and anatomic pathology effects of serial blood sampling in rat toxicology studies, using conventional or microsampling methods.
abstract: As a general practice in rodent toxicology studies, satellite animals are used for toxicokinetic determinations, because of the potential impact of serial blood sampling on toxicological endpoints. Besides toxicological and toxicokinetic determinations, blood samples obtained longitudinally from a same animal may be used for the assessment of additional parameters (e.g., metabolism, pharmacodynamics, safety biomarkers) to maximize information that can be deduced from rodents. We investigated whether removal of up to 6 × 200 μL of blood over 24h can be applied in GLP rat toxicology studies without affecting the scientific outcome.
  
  
  METHODS
  8 week-old female rats (200-300 g) were dosed for up to 1 month with a standard vehicle and subjected or not (controls) to serial blood sampling for sham toxicokinetic/ancillary determinations, using miniaturized methods allowing collection of 6 × 50, 100 or 200 μL over 24h. In-life endpoints, clinical pathology parameters and histopathology of organs sensitive to blood volume reduction were evaluated at several time points after completion of sampling.
  
  
  RESULTS
  In sampled rats, minimal and reversible changes in red blood cell mass (maximally 15%) and subtle variations in liver enzymes, fibrinogen and neutrophils were not associated with any organ/tissue macroscopic or microscopic correlate.
  
  
  CONCLUSIONS
  Serial blood sampling (up to 6 × 200 μL over 24h) is compatible with the assessment of standard toxicity endpoints in adult rats.
authors.affiliation: Sanofi-Aventis Recherche & Développement, Disposition, Safety & Animal Research, Paris, France. Electronic address: alexis.caron@sanofi.com.
authors.forename: Alexis
authors.initials: A
authors.lastname: Caron
authors.affiliation: Sanofi-Aventis Recherche & Développement, Disposition, Safety & Animal Research, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lelong
authors.affiliation: Sanofi-Aventis Recherche & Développement, Disposition, Safety & Animal Research, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Bartels
authors.affiliation: Sanofi-Aventis Recherche & Développement, Disposition, Safety & Animal Research, Paris, France.
authors.forename: O
authors.initials: O
authors.lastname: Dorchies
authors.affiliation: Sanofi-Aventis Recherche & Développement, Disposition, Safety & Animal Research, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Gury
authors.affiliation: Sanofi-Aventis Recherche & Développement, Disposition, Safety & Animal Research, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chalier
authors.affiliation: Sanofi-Aventis Recherche & Développement, Disposition, Safety & Animal Research, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Benning
mesh_terms: D000818:Animals; D001800:Blood Specimen Collection / Q000379:methods*; D005260:Female; D006403:Hematologic Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D018675:Toxicity Tests / Q000379:methods*
keywords: Anatomic pathology; Clinical pathology; Rodent; Serial blood sampling; Toxicokinetic