Dose-dependent toxicity of a commercially available demineralized bone matrix material.
METHODS
A relative risk assessment was performed to determine the safety of three commercially available Grafton demineralized bone matrix quantities used in athymic rats.


OBJECTIVE
To evaluate the possible dose-dependent adverse effects of a commercially available demineralized bone matrix containing glycerol.


BACKGROUND
Commercially available Grafton demineralized bone matrix contains glycerol. The toxic effects of glycerol leading to acute renal failure have been documented. The toxicity of this glycerol-containing substance in higher doses has not been reported.


METHODS
Three doses of Grafton putty were implanted in the upper hind limb muscles of athymic nude rats. The rats were observed for adverse effects and early death. Histologic studies were performed.


RESULTS
All eight of the rats implanted with the highest dose of Grafton putty (0.008 mL/g) died, five of them within 12 hours of implantation and three in 48 to 72 hours. One rat with the intermediate dose (0.004 mL/g) died within 12 hours of implantation. By 72 hours after implantation, three of the six rats (50%) with the intermediate dose had died. All six of the rats receiving the lowest dose (0.002cc/g) survived. The median lethal dose of Grafton putty in athymic rats was estimated to be 0.00469 mL/g body weight. Histologic analysis of the animals that received the high dose showed acute tubular necrosis, probably secondary to rhabdomyolysis.


CONCLUSIONS
In athymic rats, large amounts of Grafton putty lead to death in a dose-dependent manner. Because the median lethal doses of Grafton putty (0.00469 mL/g) and glycerol (0.00442 mL/g) are comparable, a potential source of toxicity is the glycerol contained in the material. The results of this study suggest that high doses have the potential to cause acute renal failure. The authors suggest that clinical usage of Grafton putty in humans should be limited to no more than 2 mL/kg body weight of this material.
Wang
J C
JC
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, School of Medicine 90095-6902, USA. jwang@mednet.ucla.edu
Kanim
L E
LE
Nagakawa
I S
IS
Yamane
B H
BH
Vinters
H V
HV
Dawson
E G
EG
D000818:Animals; D001857:Bone Matrix / Q000637:transplantation*; D018786:Bone Substitutes / Q000009:adverse effects*; D016025:Bone Transplantation / Q000009:adverse effects*; D003451:Cryoprotective Agents / Q000009:adverse effects*; D005990:Glycerol / Q000009:adverse effects*; D007674:Kidney Diseases / Q000139:chemically induced*; D007928:Lethal Dose 50; D008297:Male; D009336:Necrosis; D051381:Rats; D011923:Rats, Nude; D018570:Risk Assessment
D018786:Bone Substitutes; D003451:Cryoprotective Agents; D005990:Glycerol