Use of Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to Predict<i>In Vivo</i>Acute Toxicity of Tetrodotoxin in Rodents

Noorlander, Annelies; Zhang, Mengying; Ravenzwaay, Bennard van; Rietjens, Ivonne M.C.M.

doi:10.1093/toxsci/kfac022

Cited by 11 publications

(11 citation statements)

References 51 publications

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“…PBK models describing the toxicokinetics of STX for rodents and humans were developed based on a model for tetrodotoxin (TTX) with some modifications. 20 As shown in the conceptual model presented in Figure 2 , the PBK model contained liver, blood, kidney, fat, slowly perfused tissue, and rapidly perfused tissue compartments. Species-specific physiological parameters are summarized in Table S1 .…”

Section: Methodsmentioning

confidence: 99%

Integrating In Vitro Data and Physiologically Based Kinetic Modeling to Predict and Compare Acute Neurotoxic Doses of Saxitoxin in Rats, Mice, and Humans

Chen

Noorlander

Wesseling

et al. 2023

Environ. Sci. Technol.

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Current climate trends are likely to expand the geographic distribution of the toxigenic microalgae and concomitant phycotoxins, making intoxications by such toxins a global phenomenon. Among various phycotoxins, saxitoxin (STX) acts as a neurotoxin that might cause severe neurological symptoms in mammals following consumptions of contaminated seafood. To derive a point of departure (POD) for human health risk assessment upon acute neurotoxicity induced by oral STX exposure, a physiologically based kinetic (PBK) modeling-facilitated quantitative in vitro to in vivo extrapolation (QIVIVE) approach was employed. The PBK models for rats, mice, and humans were built using parameters from the literature, in vitro experiments, and in silico predictions. Available in vitro toxicity data for STX were converted to in vivo dose–response curves via the PBK models established for these three species, and POD values were derived from the predicted curves and compared to reported in vivo toxicity data. Interspecies differences in acute STX toxicity between rodents and humans were found, and they appeared to be mainly due to differences in toxicokinetics. The described approach resulted in adequate predictions for acute oral STX exposure, indicating that new approach methodologies, when appropriately integrated, can be used in a 3R-based chemical risk assessment paradigm.

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Section: Methodsmentioning

confidence: 99%

Integrating In Vitro Data and Physiologically Based Kinetic Modeling to Predict and Compare Acute Neurotoxic Doses of Saxitoxin in Rats, Mice, and Humans

Chen

Noorlander

Wesseling

et al. 2023

Environ. Sci. Technol.

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“…Bonferroni-corrected p values of p< 0.05 were considered significant for all tests. In addition, half-maximal effective concentrations (EC 50 ) were calculated for PZQ racemate, (R)-(-)-PZQ, (S)-(-)-PZQ, NTZ, and MMV-X as described in [ 66 ]. The EC 50 values for NIC were calculated as described in [ 67 ], because the lowest concentration tested (0.4 ppm or 1.3 μM) still had an impact on the motility of protoscoleces.…”

Section: Methodsmentioning

confidence: 99%

Establishment and application of unbiased in vitro drug screening assays for the identification of compounds against Echinococcus granulosus sensu stricto

et al. 2023

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Echinococcus multilocularis and E. granulosus s.l. are the causative agents of alveolar and cystic echinococcosis, respectively. Drug treatment options for these severe and neglected diseases are limited to benzimidazoles, which are not always efficacious, and adverse side effects are reported. Thus, novel and improved treatments are needed. In this study, the previously established platform for E. multilocularis in vitro drug assessment was adapted to E. granulosus s.s. In a first step, in vitro culture protocols for E. granulosus s.s. were established. This resulted in the generation of large amounts of E. granulosus s.s. metacestode vesicles as well as germinal layer (GL) cells. In vitro culture of these cells formed metacestode vesicles displaying structural characteristics of metacestode cysts generated in vivo. Next, drug susceptibilities of E. multilocularis and E. granulosus s.s. protoscoleces, metacestode vesicles and GL cells were comparatively assessed employing established assays including (i) metacestode vesicle damage marker release assay, (ii) metacestode vesicle viability assay, (iii) GL cell viability assay, and (iv) protoscolex motility assay. The standard drugs albendazole, buparvaquone, mefloquine, MMV665807, monepantel, niclosamide and nitazoxanide were included. MMV665807, niclosamide and nitazoxanide were active against the parasite in all four assays against both species. MMV665807 and monepantel were significantly more active against E. multilocularis metacestode vesicles, while albendazole and nitazoxanide were significantly more active against E. multilocularis GL cells. Albendazole displayed activity against E. multilocularis GL cells, but no effects were seen in albendazole-treated E. granulosus s.s. GL cells within five days. Treatment of protoscoleces with albendazole and monepantel had no impact on motility. Similar results were observed for both species with praziquantel and its enantiomers against protoscoleces. In conclusion, in vitro culture techniques and drug screening methods previously established for E. multilocularis were successfully implemented for E. granulosus s.s., allowing comparisons of drug efficacy between the two species. This study provides in vitro culture techniques for the reliable generation of E. granulosus s.s. metacestode vesicles and GL cell cultures and describes the validation of standardized in vitro drug screening methods for E. granulosus s.s.

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“…TTX is at increased risk of accidental ingestion, but studies on the effects of sustained ingestion of a low dose of TTX in humans are still scarce. Given the high number of acute toxicity studies on TTX [ 18 , 19 , 20 ], people are better prepared for acute toxicity of TTX, so the European Food Safety Authority (EFSA) has emphasized the need for chronic toxicity studies on TTX. The short-term accumulation distribution and metabolism of TTX in mammals and the extent of damage to body tissues are not known.…”

Section: Introductionmentioning

confidence: 99%

Hepatorenal Toxicity after 7-Day Oral Administration of Low-Dose Tetrodotoxin and Its Distribution in the Main Tissues in Mice

Zhong,

Zhang,

Yang

et al. 2023

Toxins

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Tetrodotoxin (TTX) is a highly toxic compound detected in various edible marine animals even in European waters. To characterize the hazard by oral exposure to TTX, its tissue distribution was evaluated after single (75 μg/kg) or 7-day (25–125 μg/kg) oral administration in mice. Moreover, TTX liver and renal toxicity was evaluated after 7-day oral administration. The elimination cycle of a single oral dose of TTX (75 µg/kg) was found to be approximately 168 h (7 days). Daily oral administration of TTX at doses of 25, 75, and 125 µg/kg for 7 consecutive days revealed dose-dependent toxic effects on the liver and kidney. Histopathological examination showed increased inflammatory cell infiltration in the liver and kidney with higher TTX doses, along with disorganization of the hepatic cord and renal tubular cell arrangement. The study results indicated that TTX had more hepatotoxicity than nephrotoxicity in mice. These findings provide insights into the unintentional ingestion of a low dose of TTX in mammals, including humans, and emphasize the importance of food safety.

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Use of Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to PredictIn VivoAcute Toxicity of Tetrodotoxin in Rodents

Cited by 11 publications

References 51 publications

Integrating In Vitro Data and Physiologically Based Kinetic Modeling to Predict and Compare Acute Neurotoxic Doses of Saxitoxin in Rats, Mice, and Humans

Integrating In Vitro Data and Physiologically Based Kinetic Modeling to Predict and Compare Acute Neurotoxic Doses of Saxitoxin in Rats, Mice, and Humans

Establishment and application of unbiased in vitro drug screening assays for the identification of compounds against Echinococcus granulosus sensu stricto

Hepatorenal Toxicity after 7-Day Oral Administration of Low-Dose Tetrodotoxin and Its Distribution in the Main Tissues in Mice

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