An FDA review of sulfamethazine toxicity

Recently, changes have been proposed in the criteria historically used in t he evaluation of the applicability to humans of some of the results obtaine d from the rodent carcinogenicity bioassay data, These questions center on the suitability of the rodent model for agents that exert their toxic effec ts via specific enzyme interactions and endocrine mechanisms which appear t o be inoperative within humans. Within the U.S. Food and Drug Administratio n (FDA), this issue has been brought to the forefront of concern with the r ecent application for a New Animal Drug Application for sulfamethazine (SMZ ). A panel of FDA experts from the National Center for Toxicological Resear ch (NCTR), the Center for Veterinary Medicine (CVM), and the Center for Foo d Safety and Applied Nutrition has reviewed the sum of the scientific evide nce available on the toxicology of SMZ. They noted that, in previous feedin g studies at NCTR, high doses of SMZ were associated with significant incid ences of thyroid tumors in mice and rats. The panel also notes that the tum origenic activity of SMZ in rodents was due to its goitrogenic activity, re sulting in constant stimulation of the thyroid by TSH, Humans, on the other hand, mere found to be insensitive to the SMZ-like inhibition of thyroid f unction. Further, apart from X-irradiation and radioactive iodine, there ar e no other physical or chemical agents known to cause thyroid tumors in hum ans. Thus, the expert panel concludes that the best scientific information available indicates that elevated levels of TSH and the consequent thyroid tumors would not be produced under approved use conditions of SMZ. This con clusion is in agreement with recommendations made by three other panels, vi z. the World Health Organization, the U.S. Environmental Protection Agency, and CVM, which also evaluated the public health risk of SMZ.