The Assessment of Repeated Dose Toxicity <i>In Vitro</i>: A Proposed Approach

Prieto, Pilar; Baird, Alan W.; Blaauboer, Bas J.; Ripoll, Jose Vicente Castell; Corvi, Raffaella; Dekant, W.; Dietl, Paul; Gennari, Alessandra; Gribaldo, Laura; Griffin, Julian L.; Hartung, Thomas; Heindel, Jerry; Hoet, Peter; Jennings, Paul; Marocchio, Luciana; Noraberg, Jens; Pazos, Patricia; Westmoreland, Carl; Wolf, Armin; Wright, Jayne; Pfaller, Walter

doi:10.1177/026119290603400307

Cited by 42 publications

(23 citation statements)

References 119 publications

(99 reference statements)

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“…Cell lines have often lost the specific functional properties of their in vivo equivalents and do not always provide full and stable phenotypes (Prieto et al 2006). There are a number of differences between in vitro and in vivo studies (e.g., different species, exposure doses and times).…”

Section: Discussionmentioning

confidence: 99%

Toxicity assessment of air-delivered particle-bound polybrominated diphenyl ethers

et al. 2014

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Human exposure to polybrominated diphenyl ether (PBDE) can occur via ingestion of indoor dust, inhalation of PBDE-contaminated air and dust-bound PBDEs. However, few studies have examined the pulmonary toxicity of particle-bound PBDEs, mainly due to the lack of an appropriate particle-cell exposure system. In this study we developed an in vitro exposure system capable of generating particle-bound PBDEs mimicking dusts containing PBDE congeners (BDEs 35, 47, 99) and delivering them directly onto lung cells grown at an air-liquid interface (ALI). The silica particles and particle-coated with PBDEs ranged in diameter from 4.3 to 4.5 μm and were delivered to cells with no apparent aggregation. This experimental set up demonstrated high reproducibility and sensitivity for dosing control and distribution of particles. ALI exposure of cells to PBDE-bound particles significantly decreased cell viability and induced reactive oxygen species generation in A549 and NCI-H358 cells. In male Sprague-Dawley rats exposed via intratracheal insufflation (0.6 mg/rat), particle-bound PBDE exposures induced inflammatory responses with increased recruitment of neutrophils to the lungs compared to sham-exposed rats. The present study clearly indicates the potential of our exposure system for studying the toxicity of particle-bound compounds.

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Section: Discussionmentioning

confidence: 99%

Toxicity assessment of air-delivered particle-bound polybrominated diphenyl ethers

et al. 2014

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“…Usually risk assessment in humans is based on data extrapolated from animals. As Prieto et al (2006) pointed out, this approach is not based on scientific evidence, and additional data on the mechanism of animal and human toxic effects are needed. With the ban of animal testing in cosmetic ingredients, in vitro techniques and IVIVE methods are required.…”

Section: Discussionmentioning

confidence: 99%

“…However, as Adler et al (2011) reported, repeated dose toxicity is difficult to predict, especially based on in vitro data alone, since it results from longterm repeated exposure to a chemical leading to the deterioration of cells or organs as a result of their interplay. As discussed in Prieto et al (2006), the toxicity of the most affected isolated organ after repeated exposure can be assessed based on in vitro data provided relevant in vitro approaches are developed and kinetics is accounted for through modelling. Since the liver is the organ most frequently affected by chronic toxicity following repeated oral exposure to xenobiotics (Bitsch et al, 2006), the priority in the development of alternatives to repeated dose toxicity testing have focused on hepatotoxicity.…”

Section: Introductionmentioning

confidence: 99%

BK/TD models for analyzing in vitro impedance data on cytotoxicity

et al. 2015

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The ban of animal testing has enhanced the development of new in vitro technologies for cosmetics safety assessment. Impedance metrics is one such technology which enables monitoring of cell viability in real time. However, analyzing real time data requires moving from static to dynamic toxicity assessment. In the present study, we built mechanistic biokinetic/toxicodynamic (BK/TD) models to analyze the time course of cell viability in cytotoxicity assay using impedance. These models account for the fate of the tested compounds during the assay. BK/TD models were applied to analyze HepaRG cell viability, after single (48 h) and repeated (4 weeks) exposures to three hepatotoxic compounds (coumarin, isoeugenol and benzophenone-2). The BK/TD models properly fit the data used for their calibration that was obtained for single or repeated exposure. Only for one out of the three compounds, the models calibrated with a single exposure were able to predict repeated exposure data. We therefore recommend the use of long-term exposure in vitro data in order to adequately account for chronic hepatotoxic effects. The models we propose here are capable of being coupled with human biokinetic models in order to relate dose exposure and human hepatotoxicity.

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“…Therefore, current efforts are geared toward replacing animal chronic toxicity models with technologically driven human cell-based models. These nonanimal alternative models for chronic toxicity testing include human and animal perfused organs; organ tissue slices; isolated, suspended cells; primary cultured cells; cultured cell lines; genetically engineered cell lines; reaggregating cell cultures; three-dimensional cell cultures and co-cultures; and (quantitative) structure activity relationship [(Q)SAR] computational systems [84,85].…”

Section: Nonanimal Alternative Methodsmentioning

confidence: 99%

“…Like the liver, perfused whole kidney and kidney slices have been used to test drugs and chemicals for short periods of time [83]. Kidney tubule cell cultures and cell lines have been developed, and some can be maintained for extended periods [85]. Likewise, cells from other human organs such as lung and brain, as well as blood and immune cells have been cultured for toxicity testing.…”

Section: Nonanimal Alternative Methodsmentioning

confidence: 99%

Subchronic and Chronic Toxicities of African Medicinal Plants

Adeneye

2014

Toxicological Survey of African Medicinal Plants

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The Assessment of Repeated Dose Toxicity In Vitro: A Proposed Approach

Cited by 42 publications

References 119 publications

Toxicity assessment of air-delivered particle-bound polybrominated diphenyl ethers

Toxicity assessment of air-delivered particle-bound polybrominated diphenyl ethers

BK/TD models for analyzing in vitro impedance data on cytotoxicity

Subchronic and Chronic Toxicities of African Medicinal Plants

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