Toxicological studies of pepleomycin sulfate. V. Short term intermittent toxicity in dogs (author's transl)]

The comparative studies in the short term intermittent toxicity of pepleomycin (NK631) and bleomycin (BLM) were performed on 10 beagle dogs of 13 approximately 15 months old. Two dogs per group were injected intravenously with NK631 and BLM in doses 5.0 and 2.5 mg/kg body weight every fourth day for 11 treatment. Two dogs served as control and were injected with saline solution. In the group of 5.0 mg/kg of NK631, one dog was sacrificed on day 37 of the treatment and another one dog died on day 33 of the treatment. All the dogs of other group survived until the end of the treatment. The toxicity to the hepatic and renal damage caused by NK631 was stronger than the BLM. On the contrary, the toxicity to lung and various mucocutaneous regions was weaker than the BLM. The grade of pulmonary fibrosis of NK631 was about 1/2 and 2/3 of the BLM in dose of 5 mg/kg and 2.5 mg/kg, respectively. Other toxicological changes such as anorexia and weight loss were almost similar to the BLM.     

The effect of L-3, 4-dehydroproline on the antitumor activity and toxicity of bleomycin

Pulmonary fibrosis is a serious side effect that limits the therapeutic utility of bleomycin (BLM). Recently, it has been demonstrated that L-3, 4-dehydroproline (DHP), a proline analog, significantly reduced the extent of pulmonary fibrosis in rats administered BLM intratracheally. The present studies were performed to determine the effect of DHP on the oncolytic and toxicologic effects of BLM. DHP (25 mg/kg/day) administered sc concomitantly with BLM (4 mg/kg/day) for 9 consecutive days following a sc inoculation of B16 melanoma cells in BDF1 had no effect on tumor growth inhibition by BLM when tumor growth rate was assessed by tumor volume and by tumor weight. To determine the effect of DHP on the toxicity of BLM, DHP (25 mg/kg/day) and BLM (10 mg/kg/day) were administered to Sprague-Dawley rats for 5 consecutive days followed by 2 days of rest and 5 additional days of drug administration. BLM administration produced decreased body weight gain, acute leukocytopenia, delayed elevation in blood nitrogen levels, chronic lung and kidney disease, and alopecia. Animals administered BLM plus DHP had a similar toxicologic profile. One striking difference was that no animal administered BLM plus DHP developed alopecia, whereas five of eight rats administered BLM alone displayed this untoward effect. These results suggest that DHP neither diminishes the oncolytic activity nor exacerbates the nonpulmonary toxicity of BLM, DHP would appear, therefore, to be a potential candidate as an antifibrotic adjunct to BLM therapy.     

Effects of an interferon inducer bropirimine on bleomycin-induced lung fibrosis in hamsters.

The antifibrotic effect of an interferon inducer, bropirimine (2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone, ABPP) was evaluated in bleomycin (BLM)-hamster model of lung fibrosis. ABPP is an orally active biological response modifier and has immunomodulatory, antiviral, and antineoplastic activities. The hamsters were randomized in four groups and treated with either bropirimine (100 mg/kg, intraperitoneally) suspended in carboxymethylcellulose (CMC, 10 mg/10 mg/ml) or CMC alone each day for sixteen days. After two days, the hamsters received either single bolus of BLM (7.5 U/5 ml/kg) or an equivalent volume of saline by the transoral endotracheal route. Groupings were assigned as: CMC + saline (CS), ABPP + saline (AS), CMC + BLM (CB) and ABPP + BLM (AB). Animals were sacrificed at fourteen days after intratracheal installation of either BLM or saline. Their lungs were lavaged and processed for morphometric and biochemical studies. ABPP had little effect in preventing BLM-induced weight loss and lung injury. ABPP was found to reduce the BLM-induced accumulation of collagen in the lung as measured by hydroxyproline content. The hamsters in AB group had significantly less collagen than the hamsters in CB group: 995 and 1157 micrograms hydroxyproline/lung, respectively. Administration of ABPP prevented the BLM-induced increase in the lung prolyl hydroxylase activity. The total number of monocytes and eosinophils recovered from the bronchoalveolar lavage fluid (BALF) of the AB group were significantly lower than that of the animals in CB group. However, the BALF supernatant protein content from animals in AB group (7.9 mg/lung) was significantly higher than that of CB group (4.5 mg/lung).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of an Interferon Inducer Bropirimine on Bleomycin-Induced Lung Fibrosis in Hamsters*

Abstract: The antifibrotic effect of an interferon inducer, bropirimine (2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone, ABPP) was evaluated in bleomycin (BLM)-hamster model of lung fibrosis. ABPP is an orally active biological response modifier and has immunomodulatory, antiviral, and antineoplastic activities. The hamsters were randomized in four groups and treated with either bropirimine (100 mg/kg, intraperitoneally) suspended in carboxymethylcellulose (CMC, 10 mg/10 mg/ml) or CMC alone each day for sixteen days. After two days, the hamsters received either single bolus of BLM (7.5 U/5 ml/kg) or an equivalent volume of saline by the transoral endotracheal route. Groupings were assigned as: CMC + saline (CS), ABPP + saline (AS), CMC + BLM (CB) and ABPP + BLM (AB). Animals were sacrificed at fourteen days after intratracheal installation of either BLM or saline. Their lungs were lavaged and processed for morphometric and biochemical studies. ABPP had little effect in preventing BLM-induced weight loss and lung injury. ABPP was found to reduce the BLM-induced accumulation of collagen in the lung as measured by hydroxyproline content. The hamsters in AB group had significantly less collagen than the hamsters in CB group: 995 and 1157 μg hydroxyproline/lung, respectively. Administration of ABPP prevented the BLM-induced increase in the lung prolyl hydroxylase activity. The total number of monocytes and eosinophils recovered from the bronchoalveolar lavage fluid (BALF) of the AB group were significantly lower than that of the animals in CB group. However, the BALF supernatant protein content from animals in AB group (7.9 mg/lung) was significantly higher than that of CB group (4.5 mg/lung). There were no differences in morphometric estimates of the volume of parenchymal lesions and total number of cells recovered in the BALF between CB and AB groups. Results of this study suggest that ABPP has an inhibitory effect on collagen accumulation, and monocyte and eosinophil infiltration, but it potentiates BLM-induced increases in the pulmonary vascular permeability.     

Reproductive and developmental toxicity studies of S-1090, cefmatilen hydrochloride hydrate (1)--A study on oral administration prior to and in the early stages of pregnancy in rats

Cefmatilen hydrochloride hydrate (S-1090) was administered daily by gavage to rats at doses of 100, 300 or 1000 mg potency/kg/day prior to and in the early stage of pregnancy to assess its adverse effects on parental reproductive ability and embryo-fetal development. Loose and/or reddish brown feces were observed in both males and females of all the S-1090 dosing groups, and abdominal distention was also observed in males throughout the dosing period. No drug-related deaths occurred in either males or females. In males, body weight and food consumption were increased at a dose of 1000 mg potency/kg/day throughout the dosing period. In females, body weight gain was restrained during late pregnancy, and food consumption was decreased transiently following the initiation of dosing, and then remained high on the day before parturition in all the S-1090 dosing groups. Necropsy of male and female rats revealed an increase in the cecum weight. The reproductive ability of males and females was normal in all the S-1090 dosing groups. No effects of S-1090 were observed in the implantation ratio, embryo-fetal viability, fetal body weight, and incidence of external, skeletal and visceral anomalies. Based on these results, the no observed adverse effect levels of S-1090 are estimated to be less than 100 mg potency/kg/day for parental general toxicity, 1000 mg potency/kg/day for reproductive toxicity, and 1000 mg potency/kg/day for developmental toxicity in embryo-fetuses under the conditions of the present study.     

Evaluation of the Developmental Toxicity of Methacrylamide and N,N'-Methylenebisacrylamide in Swiss Mice

Timed-pregnant CD-1 outbred albino Swiss mice received eithermethacrylamlde (MAC; 0, 60, 120, or 180 mg/kg/day) or N,N'-methylenebisacrylamide(BAC; 0, 3, 10, or 30 mg/kg/day) po in distilled water on gestationaldays (GD) 6 through 17. Maternal clinical status was monitoreddaily. At termination (GD 17), confirmed-pregnant females (27–30per group, MAC; 24–25 per group, BAC) were evaluated forclinical status and gestational outcome; live fetuses were examinedfor external, visceral, and skeletal malformations. For MAC,no treatment-related maternal mortality was observed. Maternalbody weight on GD 17, maternal weight gain during treatmentand gestation, and corrected maternal weight gain were reducedat the high dose. Relative maternal food and water intake wasnot adversely affected; neurotoxicity was not observed. Relativematernal liver weight was increased at a 120 mg/kg/day; graviduterine weight was decreased at 180 mg/kg/day. The maternalno-observed adverse effect level (NOAEL) was 60 mg/kg/day. TheNOAEL for developmental toxicity was also 60 mg/kg/day. At 120 mg/kg/day, mean fetal body weight was reduced. At 180 mg/kg/day,increased postimplantation death per litter was observed. Morphologicaldevelopment was not affected. The maternal NOAEL for BAC was10 mg/kg/day. At 30 mg/kg/day, decreased maternal body weighton GD 17, maternal body weight change during treatment and gestation,corrected maternal body weight, and gravid uterine weight wereobserved. Relative maternal liver weight increased at 30 mg/kg/day.The developmental NOAEL was 3 mg/kg/day BAC. Mean fetal bodyweight was reduced at 30 mg/kg/day. At 10 mg/kg/day, an increasedincidence of fetal variations (extra rib) was observed, althoughfetal malformation rate was unaffected. MAC and BAC were notteratogenic to Swiss mice at the doses tested. BAC was morepotent than MAC in causing adverse maternal and developmentaleffects.     

Reproductive and developmental toxicity study of S-1090, cefmatilen hydrochloride hydrate (3)--A study on oral administration during the period of organogenesis in rabbits

Cefmatilen hydrochloride hydrate (S-1090) at dosage levels of 6.25, 12.5 and 25 mg potency/kg/day was administered orally by gavage to groups of 13-16 pregnant rabbits daily during the period of organogenesis, and the effects of S-1090 on dams and fetuses were examined. Control animals were treated with a 0.5 w/v% aqueous solution of methylcellulose. Abortion was noted in 1 of the 16 females of the 12.5 mg potency/kg group and in 1 of the 14 females of the 25 mg potency/kg group, and death was noted in 1 of the 14 females of the 25 mg potency/kg group. Regarding the dams, decreased food consumption was noted in the 12.5 mg potency/kg group in the beginning of the dosing period. Suppressed body weight gain and decreased food consumption were noted in the 25 mg potency/kg group during the pregnancy period. At necropsy, thickening of the gastric mucosa, hemorrhage in the cecum, and higher values of cecum weight were also noted in this group. On the other hand, no effects of S-1090 were noted in general signs, body weight changes, food consumption, necropsy findings, or organ weights in the 6.25 mg potency/kg group. No effects of S-1090 were noted in the number of corpora lutea, number of implantations, implantation rate, death or resorption rate, number of live fetuses, sex ratio of live fetuses, fetal body weight of either sex, incidence of external anomalies, incidence of skeletal anomalies or variations, degree of ossification, or incidence of visceral anomalies. On the basis of the above results, the no observed adverse effect levels of S-1090 are estimated at 6.25 mg potency/kg/day for general toxicity and reproductive functions in dams, and at 25 mg potency/kg/day for development in fetuses under the conditions of the present study.     

Absence of embryo-fetal toxicity in rats or rabbits following oral dosing with nelfinavir

The potential for nelfinavir mesylate (VIRACEPT) to induce maternal and embryo-fetal toxicity was evaluated in rats and rabbits following oral administration. The drug was administered by gavage to rats at doses of 200, 500, or 1000mg/kg/day on days 6-17 of gestation and to rabbits at doses of 200, 400, or 1000mg/kg/day on days 7-20 of gestation. Dams and does were euthanized on GD20 and 29, respectively, and the offspring were weighed and examined for external, visceral, and skeletal alterations. Maximum plasma nelfinavir concentrations (C(max)) in rats were comparable to C(max) values in humans and were 3- to 6-fold higher than the reported human trough levels, while plasma nelfinavir levels in rabbits were approximately 0.13-0.17x the human C(max) and 0.25-0.5x the human trough. In rats, no treatment-related maternal or embryo-fetal toxicity was observed at any dose level and the NOAEL for both maternal and fetal toxicity was considered to be 1000mg/kg/day. Two rabbits in the 400mg/kg/day group died prior to scheduled termination. Because no deaths occurred in the high dose group and there were no other treatment-related signs of clinical toxicity in any dose group, these deaths were considered unrelated to nelfinavir. Group mean body weight loss in rabbits was observed at 1000mg/kg/day on gestation days 7-10. Food consumption was also reduced in this treatment group throughout the dosing period. There were no treatment-related findings in other maternal or fetal parameters. Thus, the no-observed-adverse-effect-level (NOAEL) for maternal toxicity in the rabbit was considered to be 400mg/kg/day (based on maternal body weight loss in the high dose group), while the NOAEL for embryo-fetal toxicity in the rabbit was considered to be 1000mg/kg/day. Thus, under the conditions of this study, nelfinavir was not considered to be toxic to the rat or rabbit conceptus.     

Isolation of isoguanosine fromCroton tiglium and its antitumor activity

This paper describes the isolation of isoguanosine from Croton tiglium L. and its cytotoxic effect against several tumor cell lines in culture and newly reports that isoguanosine has an antitumor activity against implanted S-180 ascitic tumor mice. Isoguanosine is effective at the dose of 24 mg/kg/day x 5, with T/C value of 168%. Isoguanosine inhibits the growth of S-180 and Ehrlich solid tumor in mice at the optimal doses of 96 mg/kg/day x 12 and 48 mg/kg/day x 12, with 1-T/C values of 65% and 60%, respectively.     

Chronic toxicity of aclacinomycin A in rats (author's transl)

Male and female Wistar rats were treated with aclacinomycin A, a new anthracycline antitumor antibiotic, at 5 dosage levels (0.08, 0.15, 0.3, 0.6 and 1.2 mg/kg/day) by daily intraperitoneal injections for 180 days for a chronic toxicity study. Recovery was also examined for 30 days after completion of the administration. Mortality was as follows: Male 5/24, female 3/24 in 0.6 mg/kg/day dose group and male 19/24, female 8/24 in 1.2 mg/kg/day dose group. Anorexia, depression of spontaneous activity and unformed feces were observed in rats in 0.6 and 1.2 mg/kg/day dose groups after day 90. Body weight gain decreased during the period. No significant change was found in rats receiving the drug at 0.3 and less mg/kg/day all through the observation period. Remarkable decreases in WBC count were noted in rats in the two highest dose groups on day 90. Autopsy findings included atrophy of the thymus and hyperemia and hemorrhage in the gastrointestinal tract and mesenteric lymph node in the animals treated at 0.6 and 1.2 mg/kg/day in the examination on day 90. Histologically, atrophy of the thymus and hyperplasia of the spleen were observed in the higher dose groups on day 90. But no remarkable abnormalities were found in histological examination on day 180. The changes in general symptom and decrease in body weight gain, which were observed during the dosing period in rats in 0.6 mg/kg/day dose group, recovered within 30 days after the drug administration was discontinued but no complete recovery of the WBC count decrease was observed.     

Evaluation of the teratogenic potential of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame) in the rat and rabbit

To assess its teratogenic potential, advantame (N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate) was administered to mated rats (22/group) in the diet at 0, 5000, 15,000, and 50,000 ppm (providing approximately 465, 1418, and 4828 mg/kg body weight/day), and to mated rabbits (24/group) via oral gavage at 0, 500, 1000, and 2000 mg/kg body weight/day throughout gestation. Shortly before delivery (rats: day 20; rabbits: day 29), animals were killed and subjected to a detailed necropsy. Fetuses were examined for external, visceral, and skeletal alterations. Atypical coloration of the feces and cage liners seen with test diets in both rats and rabbits was attributed to excretion of test material/metabolites in the feces and urine. Advantame had no adverse effect on rat offspring survival or development. The no-observed-adverse-effect level (NOAEL) for both maternal and developmental toxicity in rats was 50,000 ppm, the highest dietary concentration tested. Due to adverse effects associated with reduced food intake and fecal output, approximately 20% of mated rabbits receiving 200 0mg/kg body weight/day and 1 animal at 1000 mg/kg body weight/day had to be terminated before scheduled necropsy. A NOAEL of 500 mg/kg body weight/day was established for maternal toxicity in rabbits. No teratogenic effects were observed in any animals, and based on a slightly increased incidence of fetal deaths at 2000 mg/kg body weight/day, a finding that was considered to be indirectly related to advantame treatment, 1000 mg/kg body weight/day was considered the NOAEL for developmental toxicity.     

Toxicity study of cefmatilen hydrochloride hydrate (S-1090) (7)--Three-month repeated oral dose toxicity study in juvenile dogs

To evaluate the repeated oral dose toxicity of Cefmatilen hydrochloride hydrate (S-1090) in juvenile dogs, S-1090 was administered to juvenile beagle dogs at dose levels of 50, 100, 200 and 400 mg potency/kg/day for 3 months. No deaths occurred. Urinalysis in the 400 mg potency/kg group revealed positive reactions of occult blood and protein, and erythrocytes in sediments. Cystitis was observed in the 200 and 400 mg potency/kg groups. In the thyroids, an increased weight in some animals in the groups dosed at 100 mg potency/kg or more and an increased follicular colloid in the 400 mg potency/kg group were observed. However, no related changes were noted in other examination items. Red to dark-red feces (due to chelated products of S-1090 or its decomposition products with Fe3+ in the diet) were observed in all treated groups. Plasma S-1090 concentrations increased in a manner less than dose-proportional. The lesions of urinary bladder were judged as S-1090-induced toxic changes and the NOAEL of S-1090 in this study was assessed to be 100 mg potency/kg/day.     

Comparative toxicity of ethylene dichloride in F344/N, Sprague-Dawley and Osborne-Mendel rats

Studies were conducted to compare the toxicity of ethylene dichloride (EDC) in F344/N rats, Sprague-Dawley rats, and Osborne-Mendel rats. Ten rats/sex/group were exposed to EDC in drinking-water at 0, 500, 1000, 2000, 4000 and 8000 ppm for 13 wk. The highest concentration was limited by the maximum solubility of EDC in water (about 9000 ppm). In addition, F344/N rats (10/sex/group) were administered EDC in corn oil by gavage to compare toxicity resulting from bolus administration with that of continuous exposure in drinking-water. Gavage doses of EDC were within the range of total daily doses (in mg/kg body weight/day) resulting from exposure in drinking-water. EDC administered by gavage resulted in greater toxicity to F344/N rats than did administration of similar doses in drinking-water. All males receiving 240 and 480 mg/kg body weight and 9/10 females receiving 300 mg/kg body weight by gavage died before the end of the study. Necrosis of the cerebellum was observed in the brains of 3 males receiving 240 mg/kg body weight and 3 females receiving 300 mg/kg body weight. Hyperplasia and inflammation of the forestomach mucosa were observed in 8 male and 3 female rats that died or were killed in moribund condition. EDC caused minimal toxicity to F344/N, Sprague-Dawley and Osborne-Mendel rats at the drinking-water concentrations used in these studies; only female F344/N rats had EDC-related renal lesions. Based on mortality and EDC-related lesions, the no-effect levels for EDC administered by gavage to F344/N rats were 120 mg/kg body weight for males and 150 mg/kg body weight for females.     

Reproductive and developmental toxicity studies of S-1090, cefmatilen hydrochloride hydrate (4)--A study on oral administration during the perinatal and lactation periods in rats

Cefmatilen hydrochloride hydrate (S-1090) was administered daily by gavage to female rats at doses of 100, 300 or 1000 mg potency/kg/day from Day 17 of pregnancy to Day 20 of lactation to assess its effects on pregnant/lactating females and on development of the offspring. In dams, loose feces/reddish brown feces, increased cecum weight, decreased weights of the heart, spleen and submaxillary gland in all the S-1090 dosing groups and a decreased weight of the thymus in the 1000 mg potency/kg dosing group were observed. However, no effects on parturition and lactation were observed in any of the dosing groups. In F1 offspring, although increased cecum weight was found at weaning in all the S-1090 dosing groups, no abnormalities in viability, physical development, sensory functions/reflexes, behavior and reproductive function were observed. No adverse effects were observed in F2 fetuses and offspring. On the basis of these results, the no observed adverse effect levels of S-1090 are estimated to be less than 100 mg potency/kg/day for maternal general toxicity, and 1000 mg potency/kg/day for maternal reproductive toxicity and for developmental and reproductive toxicity in offspring under the conditions of the present study.     

Biological activity of the potent uridine phosphorylase inhibitor 5-ethyl-2,2'-anhydrouridine

5-Ethyl-2,2'-anhydrouridine (ANEUR) proved to be a potent inhibitor of uridine phosphorylase isolated from sarcoma 180 cells with an apparent Ki (Ki(app) value of 99 nM. Coadministration of ANEUR with 5-fluorouridine (FUR) resulted in increased toxicity of FUR. The LD50 value of FUR alone was 9 mg/kg (when administered for 5 consecutive days) while the LD50 was 3 mg/kg when FUR was administered together with ANEUR in vivo. There was no significant difference in mean tumor weight on day 10 between control animals and animals treated with FUR (5 mg/kg/day for 3 days) or ANEUR (280 mg/kg/day for 3 days). When FUR was coadministered with ANEUR, mean tumor weight was 91% less than that of the untreated controls, showing that ANEUR, the potent URPase inhibitor, increases the antitumor effect of FUR.     

Toxicity study of cefmatilen hydrochloride hydrate (S-1090) (5)--Six-month repeated oral dose toxicity study and supplement study in rats

Cefmatilen hydrochloride hydrate (S-1090) was orally administered to rats at dose levels of 100, 300 and 1000 mg potency/kg once daily for 6 months. All the S-1090 treated groups showed soft feces, reddish-brown feces (due to chelated products of S-1090 or its decomposition products with Fe3+ in the diet), abdominal distention, increased food and water consumption, lower urine pH, and a decrease of white blood cells counts (except for males of the 100 mg potency/kg group). One male in the 300 mg potency/kg group showed mucous feces and marked decrease in body weight, and diet in the middle stage of the administration period. In necropsy of the survivors of all treated groups, marked cecal enlargement was noted. No remarkable changes were observed in the other examination items. From the early stage of the withdrawal period, animals in the 1000 mg potency/kg group showed again soft or mucous feces and a marked decrease in body weight. Of these animals, one male died and another male was sacrificed in a moribund state at about 2 weeks of the withdrawal period. Enterocolitis was observed in these cases. Almost all animals recovered within 3 weeks of withdrawal. A supplemental study of the 6-month toxicity study was conducted to examine the mechanisms of enterocolitis and the changes observable in the 100 or 300 mg potency/kg groups after drug withdrawal. As a reference, cefdinir (CFDN), an oral cephem antibiotic the same as S-1090, was added in the 1000 mg potency/kg group. No deaths occurred in any groups. Decreased intestinal flora were noted in all the groups treated with S-1090 or CFDN at the end of the dosing period. At 2 weeks of the withdrawal period, C. difficile and its D-1 toxin in the cecal contents were highly detected in the S-1090 300 and 1000 mg potency/kg groups and CFDN group. Inflammatory changes in the cecum and colon were observed in these groups. At 4 weeks of the withdrawal period, intestinal flora in the S-1090 groups almost returned to the condition before dosing, but those in the CFDN group were retained highly. Cecal D-1 toxin in the CFDN group was positive and higher than in the S-1090 groups. It was thus considered that the critical condition with enterocolitis resulted from C. difficile, which proliferated more rapidly than the other bacteria and D-1 toxin produced by this bacteria in the withdrawal period. Above changes were commonly observed in the CFDN group. The NOAEL of S-1090 was assessed to be 100 mg potency/kg/day which induced no enteritis.     

Toxicity study of cefmatilen hydrochloride hydrate (S-1090) (4)--One- and three-month repeated oral dose toxicity studies in dogs

One- or three-month repeated oral dose toxicity studies of Cefmatilen hydrochloride hydrate (S-1090) were conducted in beagle dogs. Doses were set at 25, 100 and 400 mg potency/kg/day in both studies. In both studies, no deaths occurred, and reddish-brown feces (due to chelated products of S-1090 and its decomposition products with Fe3+ in the diet) were observed in all treated groups. A transient excretion of reddish urine was observed in the 400 mg potency/kg group and a slight increase in plasma irons was also observed in the 100 and 400 mg potency/kg groups of both studies. However, as no changes suggesting anemia or hepatic injury were noted in these groups, the change of plasma irons was considered to have no toxicological significance. Plasma S-1090 concentrations increased in a manner less than dose-proportional in both studies. In the one-month toxicity study, no toxicologically significant changes, including the above findings, were noted, so the NOAEL was assessed to be 400 mg potency/kg/day. In the three-month toxicity study, urinalysis in the 400 mg potency/kg group revealed a positive reaction to occult blood and erythrocytes in sediments. In the pathological examinations, submucosal edema, hemorrhage, inflammatory cell infiltration and occasionally focal mucosal thickening were observed in the urinary bladder of the 400 mg potency/kg group. The cystisis was considered to result from chronic stimulation with the metabolite(s) of S-1090 in urine, and the reversibility was demonstrable upon one-month drug withdrawal. From these results, the NOAEL of S-1090 in the three-month toxicity study was assessed to be 100 mg potency/kg/day.     

Toxicity of melamine and cyanuric acid in broilers and residues in tissues

The purpose of this study was to characterize the toxicity potential of melamine (MEL), cyanuric acid (CYA), and a combination of MEL and CYA in broilers. A total of 720 commercial 1-day-old COBB 500 male broilers were randomly allotted into 6 groups with 6 replicates each and 20 broilers in each replicate. The dietary treatments were as follows: group I was the control group, group II included 10 mg/kg MEL and 3.3 mg/kg CYA, group III included 30 mg/kg MEL and 10 mg/kg CYA, group IV included 100 mg/kg MEL and 33.3 mg/kg CYA, group V included 100 mg/kg MEL, and group VI included 33.3 mg/kg CYA. The trial lasted for 42 days. CYA alone and the combination of MEL and CYA had adverse effects on the performance, but MEL alone had no effects on the performance. On day 21, the uric acid (UA) content of group IV was increased in serum (p < 0.05); on day 42, the serum aspartate aminotransferase (AST) activity and the level of tumor necrosis factor (TNF)-α and interleukin (IL)-8 increased in group IV (p < 0.05); 100 mg/kg MEL alone increased the level of TNF-α and the rate of renal apoptosis (p < 0.05); and 33.3 mg/kg CYA alone increased the level of IL-8 and the rate of renal apoptosis (p < 0.05). The livers contained MEL concentrations of 17-125 μg/kg wet weight and CYA concentrations of 28-73 μg/kg, and the muscle contained MEL concentrations of 14-105 μg/kg wet weight. It was indicated that MEL alone, CYA alone, and a combination of MEL and CYA inhibit the growth and damage the kidney and liver.