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Preclinical toxicity studies in animals with species-specific recombinant DNA products have now been performed for several years. An interim statement on the significance of these animal tests and their ability to predict adverse effects in humans therefore appears indicated, with the aim of deducing future testing strategies. The experience accumulated so far shows that the animal models have failed to predict adverse effects subsequently observed in man. Immunogenicity of these proteins further restricted the usefulness of standard toxicity tests. There is also increasing evidence that animal tests on the toxic potential of impurities contained in the products are markedly inferior in sensitivity to analytical and quality control methods. Thus, modified testing programs are proposed to demonstrate safety rather than target organ toxicity using rodents and small non-rodent species and restricted dosing; furthermore the study duration should be limited by the detection of immunogenic responses.

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The combination of the results of mouse antipapilloma tests with those from hypervitaminosis A tests in mice as the basis for calculating a therapeutic index has been used for more than 20 years in the search for retinoids as useful drugs in human dermatology. A number of retinoids identified as active or inactive when administered systemically in these mouse systems have gone into clinical trials; clinical results on 11 retinoids were available for a retrospective analysis on the predictive relevance of the mouse models for retinoid activity in human psoriasis. This analysis revealed that the therapeutic index in mice correctly identified eleven compounds and differentiated them into markedly active moderately active or inactive retinoids when subsequently used clinically in the treatment of various forms of psoriasis. Acidic retinoids were more difficult to assess than nonacidic ones and the therapeutic index appeared to underestimate their potency in humans. One retinoid, motretinide, showed a favorable therapeutic index but failed to demonstrate antipsoriatic activity in the clinic. The reason for this discrepancy is that humans and mice metabolize this compound differently. Thus, although chemically induced skin papillomas in mice reflect only certain analogies to human psoriasis and other keratinizing dermatoses, they may be considered a useful tool in the search for retinoids for the treatment of keratinization disorders.

Repeated ingestion of high doses of retinoids cause the so-called hypervitaminosis A syndrome. In rats the main symptoms are weight loss, alopecia, erythema, desquamation of the skin, and alterations of the skeletal system, including bone fractures. In the present study, three retinoids (Ro 15-1570, arotinoid ethylsulfone, 6 mg/kg; retinoic acid, 100 mg/kg and etretinate, 50 mg/kg) were administered orally to rats for 1 and 2 weeks, respectively, to six male and six female rats/group. All the above changes were induced by all three retinoids, with the exception that the arotinoid ethylsulfone Ro 15-1570 did not cause bone alterations. The absence of toxic effects on the bones by Ro 15-1570 was confirmed by X-ray-film examinations, densitometry of the X-rayed femora and tibiae, examination of the thickness of the femoral and tibial compacta in histological slides plus the determination of the femoral ash weight and its main inorganic constituents (calcium, magnesium, sodium, and potassium). The present demonstration that the arotinoid ethylsulfone Ro 15-1570 was devoid of bone toxicity constitutes major progress in the pharmacologic development of retinoids with a better balance between therapeutic and adverse effects.