Threshold of Toxicological Concern - an update for non-genotoxic carcinogens

The Threshold of Toxicological Concern (TTC) concept can be applied to organic compounds with known chemical structure to derive a threshold for exposure below which a toxic effect on human health by the compound is not expected. The TTC concept distinguishes between carcinogens that may act as genotoxic and non-genotoxic compounds. A positive prediction of a genotoxic mode of action, either by structural alerts or experimental data, leads to the application of the threshold value for genotoxic compounds. Non-genotoxic substances are assigned to the TTC value of their respective Cramer class even though it is recognized that they could test positive in a rodent cancer bioassay. This study investigated the applicability of the Cramer classes specifically to provide adequate protection for non-genotoxic carcinogens. For this purpose, benchmark dose levels based on tumour incidence were compared with no observed effect levels (NOEL) derived from non-, pre- or neoplastic lesions. One key aspect was the categorization of compounds as non-genotoxic carcinogens. The recently finished CEFIC LRI project B18 classified the carcinogens of the CPDB as either non- or genotoxic compounds based on experimental or in silico data. A detailed consistency check resulted in a data set of 137 non-genotoxic organic compounds. For these 137 compounds, NOEL values were derived from high quality animal studies with oral exposure and chronic duration using well known repositories including RepDose, ToxRef and COSMOS DB. Further, an effective tumour dose (ETD10) was calculated and compared to the lower confidence limit on benchmark dose levels (BMDL10) derived by model averaging. Comparative analysis of NOEL/EDT10/BMDL10 values showed that potentially bioaccumulative compounds in humans, as well as steroids, which both belong to the exclusion categories, occur predominantly in region of the 5th percentiles of the distributions. Excluding these 25 compounds resulted in significantly higher, but comparable 5th percentile chronic NOEL and BMDL10 values, while the 5th percentile EDT10 value was slightly higher, but not statistically significant. The comparison of the obtained distributions of NOELs with the existing Cramer classes and their derived TTC values supports the application of Cramer class thresholds to all non genotoxic compounds, including non_genotoxic carcinogens

Pharmacokinetics and metabolism of dietary kaempferol and its metabolite 4-hydroxy-phenylacetic acid in rats

Scope Kaempferol is a major flavonoid in the human diet and in medicinal plants. The compound exerts anxiolytic activity when administered orally in mice, while no behavioural changes were observed upon intraperitoneal administration, or upon oral administration in gut sterilized animals. 4-Hydroxyphenylacetic acid (4-HPAA), which possesses anxiolytic effects when administered intraperitoneally, is a major intestinal metabolite of kaempferol. Pharmacokinetic properties of the compounds are currently not clear. Methods and results UHPLC-MS/MS methods were validated to support pharmacokinetic studies of kaempferol and 4-HPAA in rats. Non-compartmental and compartmental analyses were performed. After intravenous administration, kaempferol followed a one-compartment model, with a rapid clearance (4.40–6.44 l/h/kg) and an extremely short half-life of 2.93–3.79 min. After oral gavage it was not possible to obtain full plasma concentration–time profiles of kaempferol. Pharmacokinetics of 4-HPAA was characterized by a two-compartment model, consisting of a quick distribution phase (half-life 3.04–6.20 min) followed by a fast elimination phase (half-life 19.3–21.1 min). Conclusion Plasma exposure of kaempferol is limited by poor oral bioavailability and extensive metabolism. Both compounds are rapidly eliminated, so that effective concentrations at the site of action do not appear to be reached. At present, it is not clear how the anxiolytic-like effects reported for the compounds can be explained

GC/Mass analysis of the volatile compounds of P. hyrcanicum diethyl ether extract and GC profiling of some Iranian Polygonum species

In this study, the relationship among four species of Polygonum (including P. hyrcanicum (three samples), P. persicaria, P. avicular, and P. hydropiper) was investigated by GC profiling. Furthermore, the major compounds of the ethylic ether extract of P. hyrcanicum were identified by GC/MS as: α-bisabolol (17.5%), cedrol (15.9%), sesquisabinene hydrate (13.0%), α-elemol (10.5%) and trans-longipinocarveol (10.1%). All the identified compounds were sesquiterpenes and no monoterpene, fatty acid and/or hydrocarbone were detected in the extract. Chemical distances among the mentioned species were calculated in order to construct the dendrogram of closely related samples. Results indicated that the distance between two samples of P. hyrcanicum was considered to be short and their GC profiles were quite similar to each other and also there was a close relationship between the two samples of Polygonum with P. avicular. P. hydropiper was observed far from the two samples of P. hyrcanicum in comparison to other samples. Interestingly, P. hyrcanicum, gathered from Veresk, had no close relationship with other pairs of P. hyrcanicum.The results of this study support the phylogenetic relationships among these Polygonum species which was previously reported

Caco-2 permeability studies and hERG liability assessment of tryptanthrin and indolinone

Tryptanthrin and (E,Z)-3-(4-hydroxy-3,5-dimethoxybenzylidene)indolinone (indolinone) were recently isolated from Isatis tinctoria as potent anti-inflammatory and antiallergic alkaloids, and shown to inhibit COX-2, 5-LOX catalyzed leukotriene synthesis, and mast cell degranulation at low µM to nM concentrations. To assess their suitability for oral administration, we screened the compounds in an in vitro intestinal permeability assay using human colonic adenocarcinoma cells. For exact quantification of the compounds, validated UPLC-MS/MS methods were used. Tryptanthrin displayed high permeability (apparent permeability coefficient > 32.0 × 10(-6) cm/s) across the cell monolayer. The efflux ratio below 2 ( 10 µM) and indolinone (IC50 of 24.96 µM). The analysis of compounds using various in silico methods confirmed favorable pharmacokinetic properties, as well as a slight inhibition of the human ether-a-go-go-related gene potassium channel at micromolar concentrations