Absence of developmental toxicity in a canine model after infusion of a hemoglobin-based oxygen carrier: Implications for risk assessment

- HBOC infused into pregnant rats interferes with invYSP function.
- HBOC interference with invYSP function causes developmental toxicity in rats.
- Infusion of HBOC into pregnant dogs, which lack invYSP, led to no embryotoxicity.
- Like dogs, humans lack invYSP, and are likely to be unaffected by HBOC.
- Suggests that poisoning of invYSP is a mode of action that does not occur in humans.

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 6 g/kg HBOC-201 on gestational day (GD) 21. Phase 2 investigated single infusions of 6 g/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 0.52 g/kg/day (3.6 g/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.