Tissue distribution and excretion of 14C-labelled cinnamic aldehyde following single and multiple oral administration in male Fischer 344 rats.

14C-labelled cinnamic aldehyde (CNMA) was given as a single oral dose, or 24 hr after multiple oral administration of non-radioactive CNMA for 7 days at 24-hr intervals, to male Fischer 344 rats at dose levels of 5, 50 or 500 mg/kg body weight. Residues of radioactive CNMA were measured. After the single dose radioactivity was distributed primarily in the gastro-intestinal tract, the kidneys and the liver of the rats. The radiolabel was excreted mainly in the urine, and at 24 hr 85.1, 84.2 and 81.2% of the administered radiolabel was recovered in the urine at the 5, 50 and 500 mg/kg dose levels, respectively. Faecal excretion of radiolabel at 24 hr for the 5, 50 and 500 mg/kg doses was 5.1, 4.0 and 3.2% of the administered dose, respectively. At all dose levels, a small amount of the dose was distributed to the fat and was easily measured in animals killed 3 days after dosing at the 50 or 500 mg/kg dose levels. Following multiple oral administration, similar tissue distribution and excretion patterns of radiolabel were found at the three dose levels. After 24 hr the administered radiolabel was distributed mainly to the fat, liver and gastro-intestinal tract. At 24 hr, recoveries of the radiolabel in the urine were 80.4, 80.6 and 81.9% of the dose for the 5, 50 and 500 mg/kg dose levels, respectively. Faecal excretion of radiolabel after multiple dosing at 24 hr accounted for 6.3, 6.9 and 4.5% of the administered radioactivity at the 5, 50 and 500 mg/kg dose levels, respectively. The major metabolic pathway of CNMA for all single and the 5 and 50 mg/kg multiple dose levels in this species of rat was found to be degradation to benzoic acid through beta-oxidation and excretion in the urine mainly as hippuric acid, with much smaller amounts of benzoic and cinnamic acids. At the multiple dose level of 500 mg/kg, benzoic acid was the major urinary metabolite, indicating that in the Fischer 344 male rat at this relatively high oral dose level the detoxification of CNMA proceeds differently and an alternative metabolic pathway is proposed.

Long-term carcinogenicity and toxicity studies of patulin in the rat.

Patulin is a mycotoxin produced by a variety of Penicillium and Aspergillus species which are likely natural contaminants of various foods. The present study was conducted to determine the effects of lifetime administration of patulin in FDRL Wistar rats. Animals received patulin by gastric intubation three times per week at the level of 0.0, 0.1, 0.5 and 1.5 mg per kg body weight. The animals used in this lifetime study were derived from F0 parents exposed to equivalent levels of patulin for 4 weeks before mating, and throughout mating, gestation and lactation. Patulin treatment at 0.5 and 1.5 mg kg-1 to male rats caused a significant decrease in body weight gain in comparison to controls. Body weights of treated female rats were similar to that of control rats. No consistent significant differences among groups were noted in the hematology, clinical chemistry or urine analysis parameters measured during or at the termination of the study. Patulin administered to male and female rats at 1.5 mg kg-1 caused a significantly increased mortality rate as compared to respective control animals. The cause of death appeared to be increased pulmonary and laryngotracheal inflammation. No tumorigenic effect of patulin was observed.

Effect of polychlorinated biphenyl (PCB) on the thyroid gland of rats. Ultrastructural and biochemical investigations.

Polychlorinated biphenyls (PCB) produced ultrastructural lesions in thyroid follicular cells and reductions in serum thyroxine levels in rats that were time- and dose-dependent. The acute effects (4 week) of PCB (50 and 500 ppm) consisted of an accumulation of lysosomal bodies and colloid droplets in follicular cells with abnormalities of microvilli on the luminal surface. The chronic administration (12 week) of PCB (50 and 500/250 ppm) resulted in a striking distention of many follicular cells with large lysosomal bodies with strong acid phosphatase activity and colloid droplets, blunt and abnormally branched microvilli, and mitochondrial vacuolation. These ultrastructural alterations in follicular cells were associated with a highly significant reduction in serum thyroxine with both the low and the high dose of PCB. Follicular cells remained responsive to the lowered thyroxine level after feeding PCB for 4 and 12 weeks and underwent moderate compensatory hypertrophy and hyperplasia. Thyroid follicles were smaller than in controls and were lined by more columnar cells that occasionally formed papillary projections into the colloid. Residual ultrastructural alterations persisted for 12 weeks following cessation of feeding the compound, and serum thyroxine levels were significantly lower than in control rats. However, 35 weeks after discontinuing PCB, thyroid follicular cells were similar to those in controls and serum thyroxine levels had returned to normal. The striking ultrastructural lesions in follicular cells produced by feeding PCB to rats appeared to contribute to the lowering of serum thyroxine levels, in combination with the known stimulation of peripheral thyroxine metabolism by these compounds. Certain metabolic alterations produced by PCB intoxication in experimental animals and human beings may be related to an alteration in thyroid function.

Absorption, distribution, and excretion of [14C]patulin by rats.

Adult rats of both sexes were given a single oral dose of [14C] patulin and were sacrificed at various time intervals from 4 hr to 7 days following administration of the mycotoxin. Two groups of rats were employed; the treated group had been exposed to daily oral doses of unlabeled patulin (dissolved in pH 5.0 citrate buffer) in utero and for 41-66 wk after weaning, while the controls were given the buffer only throughout gestation and for 38-81 wk after weaning. Approximately 49% of the administered 14C radioactivity was recovered from feces and 36% from urine within 7 days after dosing. Most of the excretion of labeled material occurred within the first 24 hr. All of the 14C activity detected in the urine samples was either metabolites and/or conjugates of the original [14C]patulin. About 1-2% of the total radioactivity was recovered as 14CO2 from expired air. Carbon-14 radioactivity in various tissues and organs was determined throughout the 7 day period; the most significant retention site was the red blood cells.

The absorption, distribution, and excretion of 14C-penicillic acid by rats.

Adult male and female rats were given 14C-penicillic acid (labeled in the 1, 3, and 5 positions by fermentation with acetate-1-14C) by oral intubation and were sacrificed at 1, 2, 4, 24, 48, 72, and 168 hours following administration of the labeled compound. Approximately 98 p. 100 of the 14C-radioactivity given was absorbed from the gastrointestinal tract of the rats during the first 48 hours. After 7 days, 82 p. 100 was recovered in the urine and 13 p. 100 in the feces. Less than 1 p. 100 of the total radioactivity was recovered as 14CO2 from the expired air; most of this amount was recovered within the first 72 hours after administration. Various tissues were, analyzed for 14C-radioactivity throughout the 7-day-period; no significant retention of radioactivity was apparent in any of the tissues examined. The level of 14C-penicillic acid reached a maximum in the blood and tissues 2-4 hours after administration. Red blood cells contained the highest concentration of 14C-radioactivity. Liver, bladder, kidneys, heart, and bile also showed a high level of 14C-radioactivity concentration. The estimated biological half-life of penicillic acid was 18.7 and 17.1 hours for the male and female, respectively. The estimated biological half-retention time from the point of administration by the red blood cells, liver, and kidney of the male and female rats was 24.2 and 14.0; 19.8 and 17.8; and 21.3 and 19.0 hours, respectively. Recovery studies indicated no unchanged penicillic acid in the urine.

Intermediate-duration toxicity study of patulin in rats.

The toxicity of patulin was studied in two generations of Sprague-Dawley rats over a period of approximately 10 months. Patulin in 1 mM citrate buffer was administered by gavage to FO generation rats at a dose level of 0, 1.5, 7.5, or 15.0 mg/kg a body weight five times a week for 10-14 wk; females were treated seven times a week during pregnancy. High mortality and insufficient progeny in the groups given 7.5 and 15.0 mg/kg made it impossible to continue those two regimens into the second generation. The study was continued for 20-23 wk with F1A generation animals given 1.5 mg/kg and controls. The only lesion found at necropsy that could be attributed to patulin administration was gaseous distention of the gastrointestinal tract, which was probably the result of the antibiotic effect of this mycotoxin on the normal intestinal flora. A decreased weight gain in male rats of the FO generation was dose-related. An impairment in growth rates of F1A and F2A progeny of both sexes was statistically significant at the 1.5 mg/kg dose level. Fetuses taken from patulin-treated females on day 20 of pregnancy were noticeably smaller than controls fetuses and the difference was significant for F2A males. No other teratological abnormalities related to patulin dosing at the 1.5 mg/kg level were observed consistently in either F1A or F2A fetuses. Patulin did not appear to produce dominant lethal effects at dose levels up to 15.0 mg/kg when given by gavage to the males five times a week for 10 or 11 wk.

Acute, subacute, and residual effects of polychlorinated biphenyl (PCB) in rats. I. Biologic half-life in adipose tissue.

Sprague-Dawley rats were fed diets containing Aroclor 1254 at o, 5, 50, or 500 ppm for 4 wk. The biologic half-life of Aroclor 1254 in adipose tissue of rats fed 500 ppm, as determined by a gas chromatographic method, was 8 wk in males and 12 wk in females. These results are in line with sex-linked differences reported previously for other chlorinated hydrocarbons. It appears that the lower chlorine homologs in the Aroclor mixture are metabolized while those with higher chlorine content are lost more slowly.