Strategies to Replace in Vivo Acute Systemic Toxicity Testing: The Report and Recommendations of ECVAM Workshop 50<sup>,</sup>

Gennari, Alessandra; Berghe, C. Van den; Casati, Silvana; Castell, José V.; Clemedson, Cecilia; Coecke, Sandra; Colombo, Alessandra; Curren, Rodger; Negro, Gianni Dal; Goldberg, Alan M.; Gosmore, Catherine; Hartung, Thomas; Langezaal, Ingrid; Lessigiarska, Iglika; Maas, Wilfred; Mangelsdorf, Inge; Parchment, Ralph E.; Prieto, Pilar; Sintes, Juan Riego; Ryan, Michael P.; Schmuck, Gabriele; Stitzel, Katherine; Stokes, William S.; Vericat, Joan Albert; Gribaldo, Laura

doi:10.1177/026119290403200417

Cited by 26 publications

(19 citation statements)

References 33 publications

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“…The present study employed an in vitro system to expose mammalian cells to BHA. Cell cultures have been described as useful tools in toxicology, since it has been found that in vitro cytotoxicity EC 50 data correlates quite well with the correspondent rodent and human acute toxicity LD 50 data (Clemedson et al, 2000;Gennari et al, 2004).…”

Section: Discussionmentioning

confidence: 89%

“…Although a wide spectrum of experimental systems could be used to investigate the consequences deriving from exposure to chemicals, human and other mammalian cell lines very likely represent the best compromise between the reductionist approach and the prediction of human toxicity (Clemedson et al, 2000;Eisenbrand et al, 2002;Gennari et al, 2004;Zucco et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Cytotoxicity of butylated hydroxyanisole in Vero cells

et al. 2006

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Butylated hydroxyanisole (BHA) is perhaps the most extensively used synthetic antioxidant in the food and cosmetic industry, although considerable controversy exists in the literature regarding the safety of this compound. Most in vitro studies describing the effects of BHA have been performed in cancer cells, but it is unclear whether normal cells are equally susceptible to BHA exposure. The present study investigate the toxic potential of BHA in mammalian cells, using biochemical and morphological parameters, which reveal interference with structures essential for cell survival, proliferation and/or function. Cell growth inhibition was assessed by using colorimetric assays, whereas cellular alterations after BHA exposure, were evaluated using conventional light and fluorescence microscopy. Low doses of BHA exerted a significant cytotoxic effect, associated with loss of mitochondrial function. As the concentration of BHA was increased, morphological alterations in critical subcellular targets such as lysosomes, mitochondria and actin cytoskeleton, were observed. In parallel, BHA induced an irreversible loss of cell proliferative capacity, preceding apoptosis induction. Thus, the dose-dependent activity of BHA on Vero cells appears to be cytotoxic as well as cytostatic. Our observations, although simplified with respect to the in vivo situations, allowed the assessment of the specific damage at the cellular level, and provide some clue about the effects of BHA in non-tumoral mammalian cells.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Cytotoxicity of butylated hydroxyanisole in Vero cells

et al. 2006

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“…Towards this goal, an integrated publicly funded research program supplementary to REACH is required. Many techniques have been recommended (Hartung et al, 2003;Gennari et al, 2004;Zuang and Hartung, 2005) that could be included into such a scientific research program. Here we summarize some methods we consider to be among the most promising:…”

Section: A Unique Chance To Establish New Methods For Prediction Of Tmentioning

confidence: 99%

The REACH concept and its impact on toxicological sciences

Hengstler¹,

Foth²,

Kahl³

et al. 2006

Toxicology

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“…The committee notes that European approaches to improve toxicity testing emphasize the replacement of animal tests with in vitro methods (Gennari et al, 2004). However, a major goal of the European approaches is to develop in vitro batteries that can predict the outcome of high-dose testing in animals.…”

Section: Visionmentioning

confidence: 99%

Toxicity Testing in the 21st Century: A Vision and a Strategy

Krewski

Acosta

Andersen

et al. 2010

Journal of Toxicology and Environmental Health, Part B

787

475

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With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.

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Strategies to Replace in Vivo Acute Systemic Toxicity Testing: The Report and Recommendations of ECVAM Workshop 50^,

Cited by 26 publications

References 33 publications

Cytotoxicity of butylated hydroxyanisole in Vero cells

Cytotoxicity of butylated hydroxyanisole in Vero cells

The REACH concept and its impact on toxicological sciences

Toxicity Testing in the 21st Century: A Vision and a Strategy

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Strategies to Replace in Vivo Acute Systemic Toxicity Testing: The Report and Recommendations of ECVAM Workshop 50,

Cited by 26 publications

References 33 publications

Cytotoxicity of butylated hydroxyanisole in Vero cells

Cytotoxicity of butylated hydroxyanisole in Vero cells

The REACH concept and its impact on toxicological sciences

Toxicity Testing in the 21st Century: A Vision and a Strategy

Contact Info

Product

Resources

About

Strategies to Replace in Vivo Acute Systemic Toxicity Testing: The Report and Recommendations of ECVAM Workshop 50^,