Repeat Dermal Models for Systemic Toxicity: A Comparison of the Rabbit, Rat and Guinea Pig
The rabbit repeated dermal toxicity study has been a standard model for skin irritation for years. Reasons for the adoption of this model for systemic toxicity has not been clear. This report presents a complete comparative investigation of three species to determine the utility of each as a model for predicting systemic toxicity by the dermal route. Aqueous mercuric chloride (1% and 7%) was applied, at a dosage of 2 ml/kg body weights to the clipped, unabraded dorsal surface of 10/sex/group/species 5 days per week for 4 weeks. Physical and dermal assessments were performed twice in pretest and weekly thereafter. Hematology, clinical chemistry and urinalysis were performed at termination. Blood, urine and kidney tissue were collected and analyzed for mercury content. Selected tissues were examined microscopically following organ weight analysis. Rats were the most resistant to mortality due to mercuric chloride, whereas mortality in rabbits was demonstrated to be dose related. Dose related incidences in atonia and desquamation were evident in all three species, as was the effect on body weight, protein and occult blood in the urine, BUN elevations, kidney weights, and renal and skin histopathology.
The major observations can be summarised as follows:
Topical application of mercuric chloride at a dose level of 7% (w/v) as conducted in this study causes severe kidney changes, nephritis and mineralization, leading to death in rabbits. The same treatment level in rats cause some kidney tubular damage leading to tubular epithelial regeneration; deaths did not occur. One of ten male and one of ten female guinea pigs receiving the higher dosage level died, but the cause of death was not obvious by microscopic examination of tissue sections. The test compound, mercuric chloride also produced varying degrees of cutaneous lesions when applied topically at the higher level. Changes consisted of ulcerative dermatitis, eschar, acanthosis, and hyperkeratosis. They are most severe in rabbits, somewhat less in rats, and least in guinea pigs. This study verifies the sensitivity of the rabbit model.