Non-animal Methods and Strategies for Developmental Toxicity
Request for Data and Information on Technologies Used for Identifying Potential Developmental Toxicants
In May 2018, NICEATM requested available data and information on approaches and/or technologies currently used for identifying potential developmental toxicants. Submitted information will be used to assess the state of the science and determine technical needs for non-animal test methods used to evaluate the potential of chemicals to induce adverse effects in offspring.
Developmental toxicity tests evaluate the extent to which exposure to a chemical can interfere with normal development. Testing for a chemical’s potential to cause developmental toxicity is required by multiple regulatory agencies and uses large numbers of animals. NICEATM supports efforts to develop, validate, and implement alternative approaches for identifying potential developmental toxicants. The goal of these alternative approaches is to replace, reduce, or refine the use of animals in testing.
Respondents to this request should provide information on any activities relevant to the development or validation of alternatives to in vivo developmental toxicity test methods currently used by federal agencies for regulatory and other decision contexts. NICEATM also requests available data from in vivo developmental studies, human or animal studies, or accidental human exposures, using the same chemicals used to evaluate the alternative developmental toxicity test methods.
Respondents to this request for information should include their name, affiliation (if applicable), mailing address, telephone, email, and sponsoring organization (if any) with their communications. The deadline for receipt of the requested information is June 15. Responses to this notice will be posted on this webpage, and persons submitting responses will be identified by name and affiliation or sponsoring organization, if applicable.
Responses Received to the May 2018 Data Request
- Arantza Muriana, Biobide USA: Assays for teratogenicity and other endpoints using zebrafish embryos
- Relevant references:
- Alzualde et al. 2018. Toxicity profiling using a battery of assays in zebrafish embryos including teratogenicity, behavior, cardiotoxicity, ototoxicity, and hepatotoxicity. [Poster]
- Cendoya et al. 2018. Novel computational tools based on bioinformatic and chemoinformatic data to complement zebrafish embryo teratogenicity test. [Poster]
- Quevedo et al. 2018. Special attention to the neurotoxic potential of 91 compounds from NTP, assessment using zebrafish. [Poster]
- Relevant references:
- Jessica Palmer, Stemina, Inc.: devTOX quickPredict assay
- Updated spreadsheet comparing devTOX quickPredict assay with other developmental toxicity test methods
- Relevant references:
- Palmer et al. 2017. A human induced pluripotent stem cell-based in vitro assay predicts developmental toxicity through a retinoic acid receptor-mediated pathway for a series of related retinoid analogues. Reprod Toxicol 73:350-361.
- Palmer et al. 2018. A human pluripotent stem cell-based assay accurately predicts the developmental toxicity potency for a series of valproate analogues. [Poster]
- Cheryl Hobbs, ILS: Toxicogenomics-based assay to measure chemical effects on the stem cell epigenome
- Adrian Fowkes, Lhasa Limited: Identification of potential developmental toxicants using the expert rule-based in silico system Derek Nexus
- Sebastian Hoffmann, SEH Consulting + Services: Performance of the zebrafish embryo test in predicting the presence and absence of malformations in the studies of prenatal development toxicity in rats and rabbits - a systematic review
- Yusuke Marikawa, Burns School of Medicine, University of Hawaii at Manoa: Developmental toxicity assay using cell aggregates derived from mouse pluripotent stem cells
- Li ASW, Marikawa Y. 2015. An in vitro gastrulation model recapitulates the morphogenetic impact of pharmacological inhibitors of developmental signaling pathways. Mol Reprod Dev 82:1015-1036.
- Warkus ELL, Yuen AAYQ, Lau CGY, Marakawa Y. 2016. Use of in vitro morphogenesis of mouse embryoid bodies to assess developmental toxicity of therapeutic drugs contraindicated in pregnancy. Toxicol Sci 149(1):15-30.
- Warkus ELL, Marakawa Y. 2017. Exposure-based validation of an in vitro gastrulation model for developmental toxicity assays. Toxicol Sci 157(1):235-245.
The May 2018 request followed a similar request for available data and information issued in June 2016.
Responses Received to the June 2016 Data Request
- Miguel Sogorb, Miguel Hernandez University: Embryonic stem cell-based method for predicting embryotoxicity
- Estevan C, Fuster E, Del Río E, Pamies D, Vilanova E, Sogorb MA. 2014. Organophosphorus pesticide chlorpyrifos and its metabolites alter the expression of biomarker genes of differentiation in D3 mouse embryonic stem cells in a comparable way to other model neurodevelopmental toxicants. Chem Res Toxicol 27(9):1487-95.
- Estevan C, Vilanova E, Sogorb MA. 2013. Chlorpyrifos and its metabolites alter gene expression at non-cytotoxic concentrations in D3 mouse embryonic stem cells under in vitro differentiation: considerations for embryotoxic risk assessment. Toxicol Lett 217(1):14-22.
- Pamies D, Bal-Price A, Fabbri M, Gribaldo L, Scelfo B, Harris G, Collotta A, Vilanova E, Sogorb MA. 2014. Silencing of PNPLA6, the neuropathy target esterase (NTE) codifying gene, alters neurodifferentiation of human embryonal carcinoma stem cells (NT2). Neuroscience 281:54-67.
- Pamies D, Sogorb MA, Fabbri M, Gribaldo L, Collotta A, Scelfo B, Vilanova E, Harris G, Bal-Price A. 2014.Genomic and phenotypic alterations of the neuronal-like cells derived from human embryonal carcinoma stem cells (NT2) caused by exposure to organophosphorus compounds paraoxon and mipafox. Int J Mol Sci 15(1):905-26.
- Pamies D, Vilanova E, Sogorb MA. 2014. Functional pathways altered after silencing Pnpla6 (the codifying gene of neuropathy target esterase) in mouse embryonic stem cells under differentiation. In Vitro Cell Dev Biol Anim 50(3):261-73.
- Romero AC, Del Río E, Vilanova E, Sogorb MA. 2015. RNA transcripts for the quantification of differentiation allow marked improvements in the performance of embryonic stem cell test (EST). Toxicol Lett 238(3):60-69.
- Romero AC, Vilanova E, Sogorb MA. 2011. Shortening and improving the embryonic stem cell test through the use of gene biomarkers of differentiation. J Toxicol.2011;2011:286034.
- Sogorb MA, Fuster E, Del Río E, Estévez J, Vilanova E. 2016. Effects of mipafox, paraoxon, chlorpyrifos and its metabolite chlorpyrifos-oxon on the expression of biomarker genes of differentiation in D3 mouse embryonic stem cells. Chem Biol Interact doi: 10.1016/j.cbi.2016.04.017.
- Sogorb MA, Pamies D, Estevan C, Estévez J, Vilanova E. 2016. Roles of NTE protein and encoding gene in development and neurodevelopmental toxicity. Chem Biol Interact. doi: 10.1016/j.cbi.2016.07.030.
- Piper Hunt, U.S. Food and Drug Administration: C. elegans models for developmental toxicity
- Boyd WA, Smith MV, Co CA, Pirone JR, Rice JR, Shockley KR, Freedman JH. 2016. Developmental effects of the ToxCast Phase I and Phase II chemicals in Caenorhabditis elegans and corresponding responses in zebrafish, rats, and rabbits. Environ Health Perspect 124(5):586-93.
- Harlow PH, Perry SJ, Widdison S, Daniels S, Bondo E, Lamberth C, Currie RA, Flemming AJ. 2016. The nematode Caenorhabditis elegans as a tool to predict chemical activity on mammalian development and identify mechanisms influencing toxicological outcomes. Sci Rep.
- Hunt P. 2016. The C. elegans model in toxicity testing [published online ahead of print 22 July 2016]. J Appl Toxicol.
- Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Bracken W, Dorato M, Van Deun K, Smith P, Berger B, Heller A. 2000. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 32(1):56-67.
- Sprando RL, Olejnik N, Cinar HN, Ferguson M. 2009. A method to rank order water soluble compounds according to their toxicity using Caenorhabditis elegans, a Complex Object Parameter Analyzer and Sorter, and axenic liquid media. Food Chem Toxicol 47(4):722-8.
- Beth Donley, Stemina, Inc.: devTOX quickPredict assay
- Response to NICEATM Request to Data and Information on Developmental Toxicity Test Methods
- Spreadsheet comparing devTOX quickPredict assay with other developmental toxicity test methods
- Relevant references:
- Egnash et al. 2015. A biomarker-based human stem cell assay applied for ranking a retinoid series based on relative developmental toxicity potential. [Poster]
- Egnash et al. 2014. Toward validation of a human in vitro assay for developmental toxicity assessment. [Poster]
- Egnash et al. 2014. A biomarker-based developmental toxicity screen using human induced pluripotent stem cells for compound prioritization. [Poster]
- Kleinstreuer et al. 2011. Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics. Toxicol Appl Pharmacol 257:111-21.
- Knudsen et al. 2015. Evaluation of 1066 ToxCast chemicals in a human stem cell assay for developmental toxicity. [Poster]
- Palmer et al. 2013. Development of a targeted biomarker assay to predict developmental toxicity using induced pluripotent stem cells. [Poster]
- Sekowski et al. 2012. Key metabolic pathway changes in human embryonic stem cells exposed to methyl parathion and methyl paraoxon . [Poster]
- West et al. 2016. Predicting human developmental toxicity of pharmaceuticals using human embryonic stem cells and metabolomics. Toxicol Appl Pharmacol, in press.
- Additional references
Request for Data and Information on Zebrafish Embryo Screening
In November 2016, NICEATM issued a request for available data and information on zebrafish embryo screening tests and protocol design, including pharmacokinetics measurements. Submitted information will be used to assess the state of the science and determine technical needs for non-animal test methods used to evaluate the potential of chemicals to induce developmental effects in offspring.
While the Federal Register notice asked that data be submitted by December 2016, NICEATM continues to accept submissions of relevant data. Respondents should provide information on any activities relevant to the development or validation of zebrafish embryo screening assays. NICEATM is particularly interested in how study design may influence measures of toxicity/bioactivity and the kinetics associated with chemical uptake. For comparative purposes, NICEATM also requests any available data from in vivo developmental studies using the same chemicals.
NICEATM specifically requests information on efforts to optimize zebrafish embryo screening tests and protocol design including comparisons of (1) zebrafish strains; (2) embryos with and without an intact chorion; and (3) static and static renewal exposures. NICEATM is also interested in developing a better understanding of pharmacokinetics in the zebrafish embryo model and requests available data on chemical uptake.
Respondents to this request for information should include their name, affiliation (if applicable), mailing address, telephone, email, and sponsoring organization (if any) with their communications. Responses to this notice will be posted on this page, therefore no proprietary, classified, confidential, or sensitive information should be included in responses. View NTP guidelines for public comments.
Responses Received to the November 2016 Data Request
- Robert Tanguay, Oregon State University
- Jyotshna Kanungo, U.S. Food and Drug Administration
- Guo X, Dumas M, Robinson BL, Ali SF, Paule MG, Gu Q, Kanungo J. 2016. Acetyl L-carnitine targets adenosine triphosphate synthase in protecting zebrafish embryos from toxicities induced by verapamil and ketamine: an in vivo assessment [published online ahead of print 18 May 2016]. J Appl Toxicol.
- Trickler WJ, Guo X, Cuevas E, Ali SF, Paule MG, Kanungo J. 2014. Ketamine attenuates cytochrome p450 aromatase gene expression and estradiol-17-beta levels in zebrafish early life stages. J Appl Toxicol 35(5):480-8.
- Josh Butler, ExxonMobil Biomedical Sciences
- Butler JD, Parkerton TF, Letinski DJ, Bragin GE, Lampi MA, Cooper KR. 2013. A novel passive dosing system for determining the toxicity of phenanthrene to early life stages of zebrafish. Sci Total Environ 463-464:952-958.
- Butler JD, Parkerton TF, Redman AD, Letinski DJ, Cooper KR. 2016. Assessing aromatic-hydrocarbon toxicity to fish early life stages using passive-dosing methods and target-lipid and chemical-activity models. Env Sci Toxicol 50:8305-8315.