title: Absence of developmental toxicity in a canine model after infusion of a hemoglobin-based oxygen carrier: Implications for risk assessment.
abstract: Bovine-derived hemoglobin-based oxygen carriers (HBOCs) have been investigated for use in humans (HBOC-201) and approved for veterinary medicine (HBOC-301). We infused pregnant beagles with HBOC-201 to test whether HBOC-induced developmental toxicity previously observed in rats would occur in a species devoid of an inverted visceral yolk sac (invVYS). Phase 1 assessed developmental toxicity of 6g/kg HBOC-201 on gestational day (GD) 21. Phase 2 investigated single infusions of 6g/kg HBOC-201 on one of GDs 21, 25, 29 or 33. Phase 3 studied multiple sequential infusions on GDs 21, 23,25,27,29, 31, and 33 at 0.52g/kg/day (3.6g/kg total dose). Mild to moderate maternal toxicity occurred in all phases. There was an unequivocal absence of developmental toxicity in all phases. Overall, our hypothesis that HBOC, which interferes with the function of the invVYS, would not affect the offspring in dogs was supported. The implications relative to human risk are discussed.
authors.affiliation: Ashland, OH, United States.
authors.forename: J F
authors.initials: JF
authors.lastname: Holson
authors.affiliation: WIL Research Laboratories, Ashland, OH, United States.
authors.forename: D G
authors.initials: DG
authors.lastname: Stump
authors.affiliation: Biologics Consulting Group, Alexandria, VA, United States.
authors.forename: L B
authors.initials: LB
authors.lastname: Pearce
authors.affiliation: SNBL USA, Everett, WA, United States.
authors.forename: R E
authors.initials: RE
authors.lastname: Watson
authors.affiliation: Exponent, Inc., Alexandria, VA, United States; Georgetown University School of Medicine, Washington, DC, United States. Electronic address: jdesesso@exponent.com.
authors.forename: J M
authors.initials: JM
authors.lastname: DeSesso
mesh_terms: D000818:Animals; D001802:Blood Substitutes; D004285:Dogs; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D005865:Gestational Age; D006454:Hemoglobins / Q000633:toxicity*; D023421:Models, Animal; D038081:Organogenesis / Q000187:drug effects; D010108:Oxyhemoglobins / Q000633:toxicity*; D011247:Pregnancy
chemical_list: D001802:Blood Substitutes; D006454:Hemoglobins; D010108:Oxyhemoglobins; C096798:HBOC 201; C415598:HBOC 301
keywords: Dog; Hemoglobin-based oxygen carriers; Inverted yolk sac