The short-term toxicity of sanguinarine, a benzophenanthridine alkaloid, and of two alkaloid extracts of Sanguinaria canadensis L. are presented. The acute oral LD50 in rats of sanguinarine was calculated to be 1658 mg/kg, and of the two alkaloid extracts, 1440 and 1250 mg/kg. The acute iv LD50 in rats of sanguinarine was found to be 29 mg/kg. No toxic effects were observed in rats fed up to 150 ppm sanguinarine in the diet for 14 d and in rats treated by gavage with up to 0.6 mg/kg body weight for 30 d. The acute dermal LD50 in rabbits was found to be greater than 200 mg/kg.

A series of experiments was conducted to determine the efficacy of 15 synthetic retinoic acid amides (retinamides) as inhibitors of chemical carcinogenesis of the urinary bladder in C57BL/6 x DBA/2F1 mice. Eight of the retinamides tested had significant protective activity when administered at nontoxic levels in the diet. Minor structural alterations, such as the addition of a methyl or hydroxyl group to the terminal amide moiety had a major influence on the anticarcinogenic activity of the retinamides. Although 13-cis retinamides generally were less toxic on a molar basis than were their all-trans isomers, no consistent pattern of differential anticarcinogenic activity was noted among the six pairs of all-trans and 13-cis isomers tested. All-trans-4-hydroxyphenyl retinamide was among the most active and least toxic of the retinoids tested, and appears to be the compound of choice for further study.

The effects of lifetime dietary administration of zearalenone, a fungal estrogen produced by Fusarium spp., were studied in FDRL Wistar rats. Animals were fed a control diet or a diet supplemented with zearalenone at levels of 0.1, 1.0 or 3.0 mg per kg body weight per day. The afiimals used were derived from Fo parents fed equivalent levels of zearalenone for 5 weeks before mating, and throughout mating and gestation, but not during lactation. Feeding of zearalenone at 1.0 and 3.0 mg kg-' to male rats caused a significant decrease in body weight gain compared with controls. During the study, sporadic depressions in body weights occurred in females fed 1 .O and 3.0 mg per kg. However, no differences were noted at the end of the study. No significant differences among groups were found in the hematology, clinical chemistry or urine analysis data measured during or at the termination of the study. At the end of the study, significantly increased liver weights at the 3.0 mg kg-' dose level and uterine weights at 1.0 and 3.0 mg kg-' were noted in female rats. These weight differences did not correlate with any clinical or morphological finding. In rats receiving the high dose level of zearalenone, a greater incidence of increased medullary trabeculation of the femur was noted. The degree of medullary trabeculation was scored on a scale from 0 to 4; statistically significant increased scores were found in male and female rats at the high dose level compared to control rats. Other microscopic findings were unremarkable; no tumorigenic effect of zearalenone was noted.

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The toxicity of zearalenone was studied in two generations of Wistar rats over approximately 10 months. Zearalenone was administered in the diet; the dose levels used were 0, 0.1, 1.0 and 10.0 mg per kg body weight per day in all generations. Animals in the F0 generation were bred twice to produce F1A and F1B generations. The F1A generation was bred to produce the F2A generation. The only lesion found at necropsy that could be attributed to zearalenone administration was increased medullary trabeculation of the femur in animals given the high dose. A dose-related increase in absolute and relative thyroid, pituitary and adrenal gland weights occurred in male and female rats of both the F1 and F1A generation. The alteration in the weights of these endocrine organs is probably a result of the estrogenic activity of zearalenone. Feeding of zearalenone caused decreases in fertility, number of viable offspring per litter and numbers of corpora lutea, implantations and resorptions per dam. Statistically significant differences were noted in the incidences of a number of skeletal and soft tissue abnormalities in both the F1B and F2A1 fetuses, especially at doses of 1.0 and 10.0 mg kg-1. These lesions most likely indicate a delay in fetal development. Unequivocal teratogenic effects could not be defined.