Practical Aspects of the Validation of Toxicity Test Procedures

Balls, Michael; Blaauboer, Bas J.; Fentem, Julia H.; Bruner, Leon H.; Combes, Robert; Ekwall, Björn; Fielder, R.J.; Guillouzo, André; Lewis, Richard; Lovell, David P.; Reinhardt, Christoph A.; Repetto, Guillermo; Śladowski, Dariusz; Spielmann, Horst; Zucco, Flavia

doi:10.1177/026119299502300116

Cited by 146 publications

(110 citation statements)

References 8 publications

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“…Additional design elements were considered for inclusion in the study to address concerns over reported disruption of sexual differentiation of the brain and sexually dimorphic mating behaviors (e.g., lordosis). However, these end points were not selected for inclusion in the study because none has undergone the elaborate and extensive process involving multiple laboratories and reference chemicals, with ultimate consideration for relevance to human health required for validation ( Balls et al , 1994 ; Makris et al , 2009 ; Moser, 1997 ). In addition, the multigeneration reproduction studies of BPA would have identified any substantive effect on mating behaviors through the alteration of some reproductive end points (e.g., time to mating, mating index, fertility index); these end points were clearly unaffected by BPA at any dose ( Ema et al , 2001 ; Tyl et al , 2002 , 2008d ).…”

Section: Discussionmentioning

confidence: 99%

Developmental Neurotoxicity Study of Dietary Bisphenol A in Sprague-Dawley Rats

Stump

Beck

Radovsky

et al. 2010

Toxicological Sciences

102

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This study was conducted to determine the potential of bisphenol A (BPA) to induce functional and/or morphological effects to the nervous system of F1 offspring from dietary exposure during gestation and lactation according to the Organization for Economic Cooperation and Development and U.S. Environmental Protection Agency guidelines for the study of developmental neurotoxicity. BPA was offered to female Sprague-Dawley Crl:CD (SD) rats (24 per dose group) and their litters at dietary concentrations of 0 (control), 0.15, 1.5, 75, 750, and 2250 ppm daily from gestation day 0 through lactation day 21. F1 offspring were evaluated using the following tests: detailed clinical observations (postnatal days [PNDs] 4, 11, 21, 35, 45, and 60), auditory startle (PNDs 20 and 60), motor activity (PNDs 13, 17, 21, and 61), learning and memory using the Biel water maze (PNDs 22 and 62), and brain and nervous system neuropathology and brain morphometry (PNDs 21 and 72). For F1 offspring, there were no treatment-related neurobehavioral effects, nor was there evidence of neuropathology or effects on brain morphometry. Based on maternal and offspring body weight reductions, the no-observed-adverse-effect level (NOAEL) for systemic toxicity was 75 ppm (5.85 and 13.1 mg/kg/day during gestation and lactation, respectively), with no treatment-related effects at lower doses or nonmonotonic dose responses observed for any parameter. There was no evidence that BPA is a developmental neurotoxicant in rats, and the NOAEL for developmental neurotoxicity was 2250 ppm, the highest dose tested (164 and 410 mg/kg/day during gestation and lactation, respectively).

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Section: Discussionmentioning

confidence: 99%

Developmental Neurotoxicity Study of Dietary Bisphenol A in Sprague-Dawley Rats

Stump

Beck

Radovsky

et al. 2010

Toxicological Sciences

102

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“…These stages reflect the sequence of steps to be performed for a prospective validation exercise. They are well documented in a number of publications (Balls and Karcher, ; Balls et al, ; Curren et al, ; Worth and Balls, ; Balls et al, ). The process proved to be successful and led to the regulatory acceptance of several alternative tests (Hartung et al, ).…”

Section: The Concept Of Validationmentioning

confidence: 84%

Overview of Alternative Methodologies in Toxicology

Gribaldo

2007

CP Toxicology

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In vitro toxicology generally refers to the study of toxicological phenomena in non-whole-animal models. This broader connotation includes studies utilizing isolated organs, tissue slices, explants cultures, and isolated primary cells, as well as cell lines and subcellular fractions (e.g., microsomes). These model systems have made major contributions to toxicological sciences, particularly in our understanding of the mechanisms of toxicity, xenobiotic metabolism, and species differences in expressions of toxicity. This unit reviews the use of in vitro models and their value in toxicology testing.

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“…Moreover, more compounds will render proper sensitivity and specificity values to compare our test with current alternatives such as the SHE assay, among others. Compound selection will be based on previous and current overviews 30 55 , and future strategies will be based on OECD test guidelines, among others 56 57 58 .…”

Section: Discussionmentioning

confidence: 99%

Stem cell proliferation patterns as an alternative for in vivo prediction and discrimination of carcinogenic compounds

Stevens

Willems

Plusquin

et al. 2017

Sci Rep

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One of the major challenges in the development of alternative carcinogenicity assays is the prediction of non-genotoxic carcinogens. The variety of non-genotoxic cancer pathways complicates the search for reliable parameters expressing their carcinogenicity. As non-genotoxic and genotoxic carcinogens have different cancer risks, the objective of this study was to develop a concept for an in vivo test, based on flatworm stem cell dynamics, to detect and classify carcinogenic compounds. Our methodology entails an exposure to carcinogenic compounds during the animal’s regeneration process, which revealed differences in proliferative responses between non-genotoxic and genotoxic carcinogens during the initial stages of the regeneration process. A proof of concept was obtained after an extensive study of proliferation dynamics of a genotoxic and a non-genotoxic compound. A pilot validation with a limited set of compounds showed that the proposed concept not only enabled a simple prediction of genotoxic and non-genotoxic carcinogens, but also had the power to discriminate between both. We further optimized this discrimination by combining stem cell proliferation responses with a phenotypic screening and by using specific knockdowns. In the future, more compounds will be tested to further validate and prove this concept.

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Practical Aspects of the Validation of Toxicity Test Procedures

Cited by 146 publications

References 8 publications

Developmental Neurotoxicity Study of Dietary Bisphenol A in Sprague-Dawley Rats

Developmental Neurotoxicity Study of Dietary Bisphenol A in Sprague-Dawley Rats

Overview of Alternative Methodologies in Toxicology

Stem cell proliferation patterns as an alternative for in vivo prediction and discrimination of carcinogenic compounds

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