TOXICOLOGICAL EVALUATION OF U-HEGF

The toxicological evaluation of urinary human epidermal growth factor (u-hEGF) included mutagenicity, single and repeated dose general toxic ity, and teratogenicity studies in various animal species. The mutagen ic potential of u-hEGF was tested in vitro (Ames test, chromosome aber ration in human lymphocytes, unscheduled DNA synthesis in HeLa cells) and in vivo (chromosome aberration in Chinese hamster bone marrow and micronucleus test in rat bone marrow). No mutagenic or clastogenic eff ects were found. The acute toxicity of u-hEGF was evaluated in mice an d rats, using single subcutaneous (sc) or intravenous (iv) injection o f 15 mg/kg. No toxic effects were observed. Four-week iv daily adminis tration of u-hEGF at the doses of 0.3, 0.9, and 3 mg/kg in the SD rat followed by 2 wk of compound withdrawal induced pronounced and general ly dose-related effects (i.e., epithelial hyperplasia) in a wide range of tissues and organs, at all doses. However, these effects were not apparently detrimental to the general health of the rats. The repeated sc administration of u-hEGF to cynomolgus monkeys for 4 wk at the sam e doses as used in the rat study resulted in lethality after about 7 d ays of treatment in the 2 higher dose groups or after 14 days at the l owest dose. The main clinical signs observed were gastrointestinal eff ects, respiratory distress, sedation, marked loss of body weight, and cutaneous desquamation. At histology, hyperplasia of most epithelia wa s seen in all groups. In addition, atrophy of the ovarian follicles an d necrosis of the uterine endometrium were noted. Changes considered s econdary to physical distress were atrophy of the hemopoietic and lymp hatic system and hepatic steatosis. The embryofetal toxicity and terat ogenicity of u-hEGF was tested, using the iv route in the SD rat and t he iv and sc routes in the New Zealand White rabbit. In both species, the compound was administered at the doses of 0, 0.3, 0.9, and 3 mg/kg /day, from day 6 to 15 of pregnancy in rats and 6-18 in rabbits. In th e rat, an increase in body weight was noted in the dams and fetuses at the 2 high doses. No embryotoxic or teratogenic effects were observed . In the rabbit studies, mortality and severe clinical signs involving various systems, with marked effects on the eyes, were observed at al l doses tested during the first days of treatment by both routes. From the reproductive point of view, most of the surviving treated gravid females showed only resorptions.