The value of information generated by long-term toxicity studies in the dog for the nonclinical safety assessment of pharmaceutical compounds.
Data on 117 pharmaceutical compounds in the CMR toxicology database have been analyzed to determine what new toxicological information was provided by the dog in chronic (6 months or longer) toxicity testing. For more than half of the 117 compounds, all salient effects in the dog were seen for the first time within 3 months. For just under one-third of the compounds, any effects that occurred for the first time beyond 3 months in the dog were also seen in studies in the rat. Only 13 of the 117 compounds showed new and possibly important effects in the chronic study. No particular therapeutic class nor any other single circumstance was implicated in these 13 cases. Types of late-onset findings in the dog occurring with more than 1 compound included nonspecific effects or hypertrophic/hyperplastic changes. There may be several reasons, pragmatic as well as scientific, why it can sometimes be desirable to carry out chronic repeat-dose studies of 6 months or longer in the dog. However, the results of this retrospective evaluation have demonstrated that in the large majority of cases analyzed, long-term toxicity studies in the dog provide relatively little qualitatively new toxicological information not already gained from a short-term (3 month) study in the dog in conjunction with short- and long-term studies in the rat.
Parkinson
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Centre for Medicines Research, Carshalton, Surrey, United Kingdom.
Lumley
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Walker
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D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000191:economics; D007390:International Agencies; D051381:Rats; D012189:Retrospective Studies; D013997:Time Factors; D018675:Toxicity Tests / Q000191:economics; D014481:United States; D014486:United States Food and Drug Administration