The DART committee provides a forum where scientists from industry, government and academia can exchange information and initiate activities to advance science related to DART, and to develop consensus on the appropriate use of experimental data for human health risk assessment.
Announcements
DART Technical Committee 2019 Fall Business Meeting
Save the date! HESI DART Committee and European Teratology Society Workshop on Thyroid Hormone Assessment: Implications for Developmental and Reproductive Toxicology
This satellite workshop to the 45th Annual Meeting of the European Teratology Society is addressed to participants working in industries or regulatory bodies who are involved in testing and assessment of the potential developmental toxicity of chemicals.
This workshop will consider new strategies to identify developmental hazards taking into account the current state of science which may include alternative possibilities or improvements to the current Segment 2 design. These considerations could include the use of new technology to overcome some of the limitations in predicting human response with current animal models or completely new radical approach to developmental toxicity hazard identification. These may range from having a critical paradigm to deciding when non-clinical studies are needed to the use of biotechnology and computational models or hazard characterization. Working groups can consider either strategy, or combinations of the two.
The recently finalized Pregnancy Labeling and Lactation Labeling Rule changes the organization of the current Pregnancy and Nursing Mothers section of the US package insert of prescription drugs. In response to these changes in prescription drug labeling, the HESI Developmental and Reproductive Toxicology (DART) Technical committee sponsored a two-day workshop on this topic.
Recent updates to OECD developmental/reproductive toxicology guidelines and other regulatory guidelines and guidance require the measurement of thyroid hormone levels in the blood of mammalian laboratory species during development. Preliminary analyses indicate that there is a wide variability across laboratories in the methods being used to measure thyroid hormones in young rodents, as well as in the success of obtaining reliable data. Even though publicly available regulatory guidelines and guidance address study design, they allow varied approaches to thyroid hormone measurement in rodents, and an optimal study design or logical approach to thyroid hormone testing in young rodents has not yet been established in a regulatory testing context. Validity, accuracy, sensitivity and reproducibility of the assays are issues of concern. It is not clear to what extent variability in the data can be attributed to methodological issues or to innate biological variability.
WORKSHOP AIMS
Present the state-of-the-science on thyroid hormone assessments, specifically as it relates to preclinical methods and data collection, and identify gaps and knowledge as it relates to regulatory DART testing,
Provide clarification and guidance regarding the collection (timing and methods), assessment (standardization and validation), and interpretation of thyroid hormone data (as it relates to adversity) for regulatory toxicology and risk assessment,
Discuss and come to consensus on recommendations on how to improve data interpretation/understanding of thyroid changes and their relationship to adverse outcomes
The Thyroid Axis - Overview of Anatomy, Physiology, Regulation in Mammalian Systems Mary Gilbert, U.S. EPA (Download presentation)
An AOP Network for Thyroid Hormone Disruption and Adverse Outcomes Kevin Crofton, R3Fellows, LLC (Download presentation)
Mild Thyroid Dysfunction During Pregnancy; Consequences for Pregnancy Outcome and Fetal Development Robin Peeters, Erasmus University (Download presentation)
Session 2: Methodologies & Interpretation
Regulatory Requirements for Evaluation of Thyroid Status Sue Marty, Dow (Download presentation)
Pathology Endpoints: Evaluation of Thyrotoxicants in Animal Studies Brent Walling, Charles River (Download presentation)
Overview of In Vitro Assays to Investigate Chemicals for Thyroid-Axis Disrupting Potential Michael Hornung, U.S. EPA (Download presentation)
Recent updates to OECD developmental/reproductive toxicology guidelines and other regulatory guidelines and guidance require the measurement of thyroid hormone levels in the blood of mammalian laboratory species during development. Preliminary analyses indicate that there is a wide variability across laboratories in the methods being used to measure thyroid hormones in young rodents, as well as in the success of obtaining reliable data. Even though publicly available regulatory guidelines and guidance address study design, they allow varied approaches to thyroid hormone measurement in rodents, and an optimal study design or logical approach to thyroid hormone testing in young rodents has not yet been established in a regulatory testing context. Validity, accuracy, sensitivity and reproducibility of the assays are issues of concern. It is not clear to what extent variability in the data can be attributed to methodological issues or to innate biological variability.
WORKSHOP AIMS
Present the state-of-the-science on thyroid hormone assessments, specifically as it relates to preclinical methods and data collection, and identify gaps and knowledge as it relates to regulatory DART testing,
Provide clarification and guidance regarding the collection (timing and methods), assessment (standardization and validation), and interpretation of thyroid hormone data (as it relates to adversity) for regulatory toxicology and risk assessment,
Discuss and come to consensus on recommendations on how to improve data interpretation/understanding of thyroid changes and their relationship to adverse outcomes
The Thyroid Axis - Overview of Anatomy, Physiology, Regulation in Mammalian Systems Mary Gilbert, U.S. EPA (Download presentation)
An AOP Network for Thyroid Hormone Disruption and Adverse Outcomes Kevin Crofton, R3Fellows, LLC (Download presentation)
Mild Thyroid Dysfunction During Pregnancy; Consequences for Pregnancy Outcome and Fetal Development Robin Peeters, Erasmus University (Download presentation)
Session 2: Methodologies & Interpretation
Regulatory Requirements for Evaluation of Thyroid Status Sue Marty, Dow (Download presentation)
Pathology Endpoints: Evaluation of Thyrotoxicants in Animal Studies Brent Walling, Charles River (Download presentation)
Overview of In Vitro Assays to Investigate Chemicals for Thyroid-Axis Disrupting Potential Michael Hornung, U.S. EPA (Download presentation)
Luc M. De Schaepdrijver, Pieter P. J. Annaert and Connie L. Chen
The HESI Developmental and Reproductive Toxicology (DART) Committee launched a multisector collaborative research effort to increase the knowledge base in the nonclinical neonatal space to better inform decisions made in the clinic.
April Neal-Kluever, Jeffrey Fisher, Lawrence Grylack, Satoko Kakiuchi-Kiyota and Wendy Halpern
This review is part of a multisector collaborative research effort coordinated by the HESI Developmental and Reproductive Toxicology (DART) Committee to increase the knowledge base in the nonclinical neonatal space to better inform clinical treatment decisions made for the newborn patient population (De Schaepdrijver et al., 2018).
Anthony R. Scialli, George Daston, Connie Chen, Prägati S. Coder, Susan Y. Euling, Jennifer Foreman, Alan M. Hoberman, Julia Hui, Thomas Knudsen, Susan L. Makris, LaRonda Morford, Aldert H. Piersma, Dinesh Stanislaus, Kary E. Thompson
Summary from the HESI workshop on embryo‐fetal development testing, considers how we might design developmental toxicity testing if we started over with 21st century knowledge and techniques. The paper considers what might make current protocols more predictive for human risk.
Peter T. Theunissen, Sonia Beken, Bruce Beyer, William J. Breslin, Gregg D. Cappon, Connie L. Chen, Gary Chmielewski, Luc de Schaepdrijver, Brian Enright, Jennifer E. Foreman, Wafa Harrouk, Kok-Wah Hew, Alan M. Hoberman, Julia Y. Hui, Thomas B. Knudsen, Susan B. Laffan, Susan L. Makris, Matthew Martin, Mary Ellen McNerney, Christine L. Siezen, Dinesh J. Stanislaus, Jane Stewart, Kary E. Thompson, Belen Tornesi, Jan Willem Van der Laan, Gerhard F. Weinbauer, Sandra Wood & Aldert H. Piersma
A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmax exposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmax exposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects between rat and rabbit study outcomes for individual compounds, EFDT studies in two species have added value over single studies.
Peter T. Theunissen, Sonja Beken, Bruce K. Beyer, William J. Breslin, Gregg D. Cappon, Connie L. Chen, Gary Chmielewski, Luc De Schaepdrijver, Brian Enright, Jennifer E. Foreman, Wafa Harrouk, Kok-Wah Hew, Alan M. Hoberman, Julia Y. Hui, Thomas B. Knudsen, Susan B. Laffan, Susan L. Makris, Matt Martin, Mary Ellen McNerney, Christine L. Siezen, Dinesh J. Stanislaus, Jane Stewart, Kary E. Thompson, Belen Tornesi, Jan Willem Van der Laan, Gerhard F. Weinbauer, Sandra Wood & Aldert H. Piersma
Regulatory non-clinical safety testing of human pharmaceuticals typically requires embryo–fetal developmental toxicity (EFDT) testing in two species (one rodent and one non-rodent). The question has been raised whether under some conditions EFDT testing could be limited to one species, or whether the testing in a second species could be decided on a case-by-case basis. As part of a consortium initiative, we built and queried a database of 379 compounds with EFDT studies (in both rat and rabbit animal models) conducted for marketed and non-marketed pharmaceuticals for their potential for adverse developmental and maternal outcomes, including EFDT incidence and the nature and severity of adverse findings. Manifestation of EFDT in either one or both species was demonstrated for 282 compounds (74%). EFDT was detected in only one species (rat or rabbit) in almost a third (31%, 118 compounds), with 58% (68 compounds) of rat studies and 42% (50 compounds) of rabbit studies identifying an EFDT signal. For 24 compounds (6%), fetal malformations were observed in one species (rat or rabbit) in the absence of any EFDT in the second species. In general, growth retardation, fetal variations, and malformations were more prominent in the rat, whereas embryo–fetal death was observed more often in the rabbit. Discordance across species may be attributed to factors such as maternal toxicity, study design differences, pharmacokinetic differences, and pharmacologic relevance of species. The current analysis suggests that in general both species are equally sensitive on the basis of an overall EFDT LOAEL comparison, but selective EFDT toxicity in one species is not uncommon. Also, there appear to be species differences in the prevalence of various EFDT manifestations (i.e. embryo–fetal death, growth retardation, and dysmorphogenesis) between rat and rabbit, suggesting that the use of both species has a higher probability of detecting developmental toxicants than either one alone.
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