The practice of toxicology is changing rapidly, as demonstrated by the response to the 2007 NRC report on "Toxicity Testing in the 21(st) Century." New assays are being developed to replace animal testing; yet the use of data from these assays in decision making is not clear. A Health and Environmental Sciences Institute committee held a May 2011 workshop to discuss approaches to identifying adverse effects in the context of the NRC report. Scientists from industry, government, academia, and NGOs discussed two case studies and explored how information from new, high data content assays developed for screening can be used to differentiate adverse effects from adaptive responses. The terms "adverse effect" and "adaptive response" were defined, as well as two new terms, the relevant pathways of toxicological concern (RPTCs) and relevant responses for regulation (RRRs). RPTCs are biochemical pathways associated with adverse events and need to be elucidated before they are used in regulatory decision making. RRRs are endpoints that are the basis for risk assessment and may or may not be at the level of pathways. Workshop participants discussed the criteria for determining whether, at the RPTC level, an effect is potentially adverse or potentially indicative of adaptability, and how the use of prototypical, data-rich compounds could lead to a greater understanding of RPTCs and their use as RRRs. Also discussed was the use of RPTCs in a weight-of-evidence approach to risk assessment. Inclusion of data at this level could decrease uncertainty in risk assessments but will require the use of detailed dosimetry and consideration of exposure context and the time and dose continuum to yield scientifically based decisions. The results of this project point to the need for an extensive effort to characterize RPTCs and their use in risk assessment to make the vision of the 2007 NRC report a reality.
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.
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.
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.
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