Effects of organic solvent vehicles on the viability and morphology of isolated perfused porcine skin.
Although many organic solvents are known to be cutaneous irritants, they are commonly utilized as vehicles in percutaneous absorption and toxicity studies. The isolated perfused porcine skin flap (IPPSF) is an alternative animal model that has been used to study percutaneous absorption and cutaneous toxicity. The purpose of this study was to evaluate the effect of five organic solvents (ethanol, acetone, dimethyl sulfoxide (DMSO), toluene, and cyclohexane) on biochemical viability parameters, vascular response, and epidermal morphology of the IPPSF. Cumulative glucose utilization (CGU), the ratio of lactate production/glucose utilization (L/CGU ratio), and the leakage of lactate dehydrogenase (LDH) were used as biochemical indicators of alterations in glucose metabolism and flap viability. Only ethanol resulted in a statistically significant decrease in the average rate of CGU over the perfusion period. All of the solvent treatments resulted in slight increases in LDH release versus the controls. Vascular resistance (VR) was measured to examine the response of the cutaneous vasculature to these solvents, and most treatments resulted in a decreased VR in the terminal phases of perfusion. Ethanol was the only solvent to cause an apparent increase in terminal VR. Light microscopy demonstrated a moderate increase in intracellular edema in the DMSO, toluene, and acetone flaps. Ultrastructural evaluation showed focal blebbing of the nuclear envelope and vesiculation of the rough endoplasmic reticulum in cells of the stratum basale and stratum spinosum layers with DMSO treatment. The IPPSF allowed the evaluation of subtle biochemical, vascular, and morphological changes associated with non-occlusive topical exposure to these organic solvents. These findings support the necessity of documenting vehicle effects which might mask or otherwise alter subtle, but potentially important, compound-specific responses.
Cutaneous Pharmacology and Toxicology Center, North Carolina State University, College of Veterinary Medicine, Raleigh 27606.
J R
JR
King
N A
NA
Monteiro-Riviere
D000096:Acetone / Q000633:toxicity; D000818:Animals; D003510:Cyclohexanes / Q000633:toxicity; D004121:Dimethyl Sulfoxide / Q000633:toxicity; D000431:Ethanol / Q000633:toxicity; D005260:Female; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008854:Microscopy, Electron; D014677:Pharmaceutical Vehicles / Q000633:toxicity; D012867:Skin / Q000187:drug effects* / Q000648:ultrastructure; D012997:Solvents / Q000633:toxicity*; D013552:Swine; D014050:Toluene / Q000633:toxicity; D014655:Vascular Resistance / Q000187:drug effects
D003510:Cyclohexanes; D014677:Pharmaceutical Vehicles; D012997:Solvents; D000096:Acetone; D014050:Toluene; D000431:Ethanol; D007770:L-Lactate Dehydrogenase; D005947:Glucose; D004121:Dimethyl Sulfoxide