Assessment Of Long-term Toxicity Research Articles

Preclinical safety evaluation of Macleaya Cordata extract: A re-assessment of general toxicity and genotoxicity properties in rodents.

Macleaya cordata extract (MCE) is widely used for its diverse pharmacological actions and beneficial effects on farm animals. Modern pharmacological studies have shown that it has anti-inflammatory, anti-cancer, and anti-bacterial activities, and is gradually becoming a long-term additive veterinary drug used to improve animal intestinal health and growth performance. Although some evidence points to the DNA mutagenic potential of sanguinarine (SAN), a major component of MCE, there is a lack of sufficient basic toxicological information on the oral route, posing a potential safety risk for human consumption of food of animal origin. In this study, we assessed the acute oral toxicity, repeated 90-day oral toxicity and 180-day chronic toxicity of MCE in rats and mice and re-evaluated the genotoxicity of MCE using a standard combined in vivo and ex vivo assay. In the oral acute toxicity test, the LD50 for MCE in rats and mice was 1,564.55 mg/kg (95% confidence interval 1,386.97–1,764.95 mg/kg) and 1,024.33 mg/kg (95% confidence interval 964.27–1,087.30 mg/kg), respectively. The dose range tested had no significant effect on hematology, clinical chemistry, and histopathological findings in rodents in the long-term toxicity assessment. The results of the bacterial reverse mutation, sperm abnormality and micronucleus test showed negative results and lack of mutagenicity and teratogenicity; the results of the rat teratogenicity test showed no significant reproductive or embryotoxicity. The results indicate that MCE was safe in the dose range tested in this preclinical safety assessment. This study provides data to support the further development of maximum residue limits (MRLs) for MCE.

Irinotecan (CPT-11) Treatment Induces Mild Gonadotoxicity.

Background:Gonadal toxicity following chemotherapy is an important issue among the population of young cancer survivors. The inhibitor of DNA topoisomerase I, irinotecan (CPT-11), is widely used for several cancer types. However, little is known about the effect of irinotecan on the fertility of both genders. Thus, the aim of the present study was to evaluate irinotecan gonadotoxicity, using a mouse model.MethodsMature male and female mice were injected intraperitoneally with either saline (), irinotecan (100 mg/kg) or cyclophosphamide (100 mg/kg); and sacrificed one week or three months later for an acute or long-term toxicity assessment, respectively. We used thorough and advanced fertility assessment by already established methods: Gonadal and epididymal weights, as well as sperm count and sperm motility were determined; serum anti-Müllerian hormone (AMH) was measured by ELISA. Immunohistochemistry (Ki-67), immunofluorescence (PCNA, CD34), terminal transferase-mediated deoxyuridine 5-triphosphate nick-end labeling (TUNEL) and computerized analysis were performed to examine gonadal proliferation, apoptosis and vascularization. qPCR was used to assess the amount of testicular spermatogonia (Id4 and Gafra1 mRNA) and ovarian primordial oocytes reserves (Sohlh2, Nobox and Figla mRNA).ResultsFemales: Irinotecan administration induced acute ovarian apoptosis and decreased vascularity, as well as a mild, statistically significant, long-term decrease in the number of growing follicles, ovarian weight, and ovarian reserve. Males: Irinotecan administration caused an acute testicular apoptosis and reduced testicular spermatogenesis, but had no effect on vascularity. Irinotecan induced long-term decrease of testicular weight, sperm count and testicular spermatogonia and caused elevated serum AMH.ConclusionOur findings imply a mild, though irreversible effect of irinotecan on mice gonads.

Treatment-related Cardiovascular Toxicity in Long-term Survivors of Testicular Cancer.

BackgroundsTesticular cancer is the most common malignancy in young men. Considering increasing incidence, exceptionally high cure rate, as well as long life expectancy, assessment of long term toxicity in testicular cancer survivors is of great importance. In the last decades a major effort has been made in order to reduce toxicity of treatment, while maintaining its high effectiveness.ConclusionsActual knowledge on treatment toxicity is based on outdated treatment modalities. Hopefully, modern treatment modalities could reduce toxicity, but, there is no firm confirmation for that at the moment, as data dealing with late sequelae of modern treatment of testicular cancer are not available yet due to the short period of observation. The life-threatening cardiovascular toxicity in testicular cancer survivors is major complication of platinum-based chemotherapy, mediastinal radiotherapy and even subdiaphragmatic radiotherapy.

Role of a Comprehensive Toxicity Assessment and Monitoring Program in the Management and Ecological Recovery of a Wastewater Receiving Stream

National Pollution Discharge Elimination Permit (NPDES)-driven effluent toxicity tests using Ceriodaphnia dubia and fathead minnows were conducted for more than 20 years to assess and monitor the effects of wastewaters at the United States (U.S.) Department of Energy Y-12 National Security Complex (Y-12 Complex) in Oak Ridge, Tennessee. Toxicity testing was also conducted on water samples from East Fork Poplar Creek (EFPC), the wastewater receiving stream, as part of a comprehensive biological monitoring and assessment program. In this paper, we evaluate the roles of this long-term toxicity assessment and monitoring program in the management and ecological recovery of EFPC. Effluent toxicity testing, associated toxicant evaluation studies, and ambient toxicity monitoring were instrumental in identifying toxicant sources at the Y-12 Complex, guiding modifications to wastewater treatment procedures, and assessing the success of various pollution-abatement actions. The elimination of untreated wastewater discharges, the dechlorination of remaining wastewater streams, and the implementation of flow management at the stream headwaters were the primary actions associated with significant reductions in the toxicity of stream water in the upper reaches of EFPC from the late 1980s through mid 1990s. Through time, as regulatory requirements changed and water quality improved, emphasis shifted from comprehensive toxicity assessments to more focused toxicity monitoring efforts. Ambient toxicity testing with C. dubia and fathead minnows was supplemented with less-standardized but more sensitive alternative laboratory toxicity tests and in situ bioassays. The Y-12 Complex biological monitoring experience demonstrates the value of toxicity studies to the management of a wastewater receiving stream.

Multigeneration effects of insect growth regulators on the springtail Folsomia candida

Multigeneration tests are very useful for the assessment of long term toxicity of pollutants such as endocrine disruptor compounds. In this study, multigeneration reproduction tests adapted from the ISO standard 11267 were conducted with the Collembola Folsomia candida. Springtails were exposed to artificial soil contaminated with four insect growth regulators (methoprene, fenoxycarb, teflubenzuron, and precocene II) according to two different experimental set-ups. In the first set-up, the parental generation (F 0) of Collembola was exposed to a pollutant for 28 days. Juveniles from the F 1 generation were transferred to uncontaminated soil for another 28-day period to generate the F 2 generation. In the second set-up, the F 0 generation was exposed to a pollutant for 10 days before being transferred to uncontaminated soil to reproduce. After 18–28 days, juveniles from the F 1 were transferred to clean soil to generate the F 2 generation. An effect on the number of hatched juveniles of the F 2 generation was observed for methoprene after exposure of the F 0 for 28 days and hatching of F 1 in contaminated soil. For methoprene and teflubenzuron, significant effects were even observed on the F 2 generation with the second experimental set-up, when only the F 0 generation was exposed for 10 days. This shows that the impact of these substances is transgenerational, which can have important consequences for the population of these or other organisms. No effect on the F 2 generation was observed with fenoxycarb and precocene II with the 10-day exposure experiment. Our results show that the developed experimental procedures are appropriate to assess the long term effects of endocrine disrupting compounds on the reproduction of the non-target species F. candida. Another important finding is that two substances with the same predicted mode of action (i.e., the two juvenile hormone analogues fenoxycarb and methoprene) do not necessarily affect the same endpoints in F. candida.