- Email: [email protected]
Integrated approaches to testing and assessment (IATA) in developmental toxicology
20
Abstracts / Reproductive Toxicology 72 (2017) 15–21
the toxicity pathways within the physiology, and of the critical key events therein that need monitoring, and of the availability of sufficient alternative assays to cover those critical key events in a quantitative fashion. An essential part of the interpretation in the IATA in terms of risk assessment is the quantitative extrapolation from in vitro to in vivo exposure levels (qivive). It follows that it is clearly an immense challenge to make this approach work. However, components of each of these aspects have already been worked out as proof of principle. Further expansion and integration is needed for a full coverage of toxicity pathways in the innovative approach. Fine-tuning the model to the human situation will generate a mechanistically based integral model for toxicity prediction for man, which has the advantage of avoiding the animal model and the classical black box approach of considering adverse effects at the level of the organism only. This will enhance the relevance of testing for human risk assessment and enable a much more informative and reliable mechanism-based risk assessment for man. Developmental toxicity, with its moving target of the embryo-fetus, provides specific challenges for such an approach, and requires serious investments. In addition to the necessary transition to mode of action based toxicological risk assessment, the high pressure on animal use in developmental toxicology warrants specific attention in this field.
high-throughput screening and high-content screening (HTS/HCS) data, and web-based chemistry dashboards. For example, the ToxCast/Tox21 program has provided HTS/HCS data on thousands of chemicals and hundreds of in vitro assays that include biochemical assays, reporter cell lines, and zebrafish developmental toxicity. Newer assays derive from pluripotent stem cell platforms (mouse, human) in the near-term with microscale organotypic culture models and engineered microphysiological systems on the horizon. Vast collections of HTS/HCS data and chemistry information, in combination with AOPs, can flip the emphasis from descriptive end-points to mechanistic chemical-biological interactions. Translating local interactions into quantitative predictions of developmental toxicity is challenged by the complex cellular dynamics in an embryo (cell signaling, migration, proliferation, apoptosis, differential adhesion, matrix remodeling, etc.). Mechanistic modeling through computational embryology can help navigate this complexity. Steady progress has been made with multicellular agent-based models (ABMs) that recapitulate morphogenetic drivers for somitogenesis, urethrogenesis, palatogenesis, and other events. Computational systems models such as these offer a novel heuristic approach to reconstruct tissue dynamics from the bottom-up, cell-by-cell and interaction-by-interaction. Individually, they simulate emergent phenotypes and can be used to predict adverse outcomes or cybermorphs that bring an AOP to life. Collectively, they form an integrative platform or ‘virtual embryo’ that represents the spatial and temporal diversity of morphological development for predictive DART. This abstract does not reflect US EPA policy.
Preterm birth – Epidemiology, consequences and possible interventions
http://dx.doi.org/10.1016/j.reprotox.2017.06.079
Gil Klinger 1,2,3
http://dx.doi.org/10.1016/j.reprotox.2017.06.080
1
Center for Health Protection, National Institute for Public Health and the Environment RIVM, Bilthoven, The Netherlands
Neonatal Intensive Care Unit, Tel Aviv University, Tel Aviv, Israel 2 Schneider Children’s Medical Center of Israel and Beilinson Teratology Information Service, Tel Aviv University, Tel Aviv, Israel 3 Rabin Medical Center, Petah Tikva, Israel and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Developmental toxicology is an area of particular challenges when it comes to innovative animal-free approaches. The developing embryo presents a moving target in which windows of sensitivity open and close with time, and mechanisms of action evolve and return to silence in a time- and location-dependent fashion in the embryo. Logically, complete coverage of embryogenesis as to toxicity pathways cannot be expected from single reductionist in vitro assays. Combined approaches need to be developed, in which complementary in vitro assays are integrated in tiered and battery strategies that can be applied case by case for individual chemicals. The entry point of an individual compound into actual testing can depend on pre-existing information such as physico-chemical properties, structure-activity relationships, and anticipated kinetic and metabolic characteristics. Integral coverage of embryotoxicity modes of action can be derived using an ontology framework. This provides a network approach interconnecting the realm of adverse outcome pathways and homeostatic mechanisms into a single model for quantitative hazard and risk assessment. The network can be analyzed for critical key events at the molecular or cellular level that may mediate adverse outcomes. This analysis can guide the development and selection of dedicated in vitro and in silico tools to monitor compound effects in a quantitative fashion. Feeding these quantitative effect patterns into the ontology-based model mediates prediction of adverse effects at the level of the organism. Such IATA need to be established based on sufficiently detailed knowledge of underlying biology and physiology, and of
Introduction: Preterm birth is an important health care issue affecting about 8% of births and has major consequences to the newborn infant. Neurodevelopment of the preterm infant is the paramount long-term outcome. Completion of normal brain development in the preterm infant may not be achieved due to inability to provide the conditions required for normal brain development or due to acquired damage to the susceptible premature brain. Increased survival of the most immature infants has prevented reduction of many of the severe morbidities associated with prematurity. Methods: Preterm infants are a heterogeneous population that are at risk for complications related to prematurity. Late preterm infants born at 34–36 weeks represent the vast majority of preterm infants. Very low birth weight infants (VLBW) (birth weight ≤ 1500 gram) represent 1% of all infants born, however are responsible for most of the mortality and major morbidity associated with prematurity. Outcomes related to prematurity are provided. Possible interventions to improve outcomes of infants born prematurely are discussed. Results: Late preterm infants are mainly at risk for short-term adverse outcomes such as neonatal intensive care unit admission, transient respiratory problems and jaundice. However, there is increasing recognition that this population is also at increased risk for neurodevelopmental abnormalities. VLBW infants are at risk for preterm morbidities including bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia,
Integrated approaches to testing and assessment (IATA) in developmental toxicology Aldert H. Piersma
Abstracts / Reproductive Toxicology 72 (2017) 15–21
the toxicity pathways within the physiology, and of the critical key events therein that need monitoring, and of the availability of sufficient alternative assays to cover those critical key events in a quantitative fashion. An essential part of the interpretation in the IATA in terms of risk assessment is the quantitative extrapolation from in vitro to in vivo exposure levels (qivive). It follows that it is clearly an immense challenge to make this approach work. However, components of each of these aspects have already been worked out as proof of principle. Further expansion and integration is needed for a full coverage of toxicity pathways in the innovative approach. Fine-tuning the model to the human situation will generate a mechanistically based integral model for toxicity prediction for man, which has the advantage of avoiding the animal model and the classical black box approach of considering adverse effects at the level of the organism only. This will enhance the relevance of testing for human risk assessment and enable a much more informative and reliable mechanism-based risk assessment for man. Developmental toxicity, with its moving target of the embryo-fetus, provides specific challenges for such an approach, and requires serious investments. In addition to the necessary transition to mode of action based toxicological risk assessment, the high pressure on animal use in developmental toxicology warrants specific attention in this field.
high-throughput screening and high-content screening (HTS/HCS) data, and web-based chemistry dashboards. For example, the ToxCast/Tox21 program has provided HTS/HCS data on thousands of chemicals and hundreds of in vitro assays that include biochemical assays, reporter cell lines, and zebrafish developmental toxicity. Newer assays derive from pluripotent stem cell platforms (mouse, human) in the near-term with microscale organotypic culture models and engineered microphysiological systems on the horizon. Vast collections of HTS/HCS data and chemistry information, in combination with AOPs, can flip the emphasis from descriptive end-points to mechanistic chemical-biological interactions. Translating local interactions into quantitative predictions of developmental toxicity is challenged by the complex cellular dynamics in an embryo (cell signaling, migration, proliferation, apoptosis, differential adhesion, matrix remodeling, etc.). Mechanistic modeling through computational embryology can help navigate this complexity. Steady progress has been made with multicellular agent-based models (ABMs) that recapitulate morphogenetic drivers for somitogenesis, urethrogenesis, palatogenesis, and other events. Computational systems models such as these offer a novel heuristic approach to reconstruct tissue dynamics from the bottom-up, cell-by-cell and interaction-by-interaction. Individually, they simulate emergent phenotypes and can be used to predict adverse outcomes or cybermorphs that bring an AOP to life. Collectively, they form an integrative platform or ‘virtual embryo’ that represents the spatial and temporal diversity of morphological development for predictive DART. This abstract does not reflect US EPA policy.
Preterm birth – Epidemiology, consequences and possible interventions
http://dx.doi.org/10.1016/j.reprotox.2017.06.079
Gil Klinger 1,2,3
http://dx.doi.org/10.1016/j.reprotox.2017.06.080
1
Center for Health Protection, National Institute for Public Health and the Environment RIVM, Bilthoven, The Netherlands
Neonatal Intensive Care Unit, Tel Aviv University, Tel Aviv, Israel 2 Schneider Children’s Medical Center of Israel and Beilinson Teratology Information Service, Tel Aviv University, Tel Aviv, Israel 3 Rabin Medical Center, Petah Tikva, Israel and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Developmental toxicology is an area of particular challenges when it comes to innovative animal-free approaches. The developing embryo presents a moving target in which windows of sensitivity open and close with time, and mechanisms of action evolve and return to silence in a time- and location-dependent fashion in the embryo. Logically, complete coverage of embryogenesis as to toxicity pathways cannot be expected from single reductionist in vitro assays. Combined approaches need to be developed, in which complementary in vitro assays are integrated in tiered and battery strategies that can be applied case by case for individual chemicals. The entry point of an individual compound into actual testing can depend on pre-existing information such as physico-chemical properties, structure-activity relationships, and anticipated kinetic and metabolic characteristics. Integral coverage of embryotoxicity modes of action can be derived using an ontology framework. This provides a network approach interconnecting the realm of adverse outcome pathways and homeostatic mechanisms into a single model for quantitative hazard and risk assessment. The network can be analyzed for critical key events at the molecular or cellular level that may mediate adverse outcomes. This analysis can guide the development and selection of dedicated in vitro and in silico tools to monitor compound effects in a quantitative fashion. Feeding these quantitative effect patterns into the ontology-based model mediates prediction of adverse effects at the level of the organism. Such IATA need to be established based on sufficiently detailed knowledge of underlying biology and physiology, and of
Introduction: Preterm birth is an important health care issue affecting about 8% of births and has major consequences to the newborn infant. Neurodevelopment of the preterm infant is the paramount long-term outcome. Completion of normal brain development in the preterm infant may not be achieved due to inability to provide the conditions required for normal brain development or due to acquired damage to the susceptible premature brain. Increased survival of the most immature infants has prevented reduction of many of the severe morbidities associated with prematurity. Methods: Preterm infants are a heterogeneous population that are at risk for complications related to prematurity. Late preterm infants born at 34–36 weeks represent the vast majority of preterm infants. Very low birth weight infants (VLBW) (birth weight ≤ 1500 gram) represent 1% of all infants born, however are responsible for most of the mortality and major morbidity associated with prematurity. Outcomes related to prematurity are provided. Possible interventions to improve outcomes of infants born prematurely are discussed. Results: Late preterm infants are mainly at risk for short-term adverse outcomes such as neonatal intensive care unit admission, transient respiratory problems and jaundice. However, there is increasing recognition that this population is also at increased risk for neurodevelopmental abnormalities. VLBW infants are at risk for preterm morbidities including bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia,
Integrated approaches to testing and assessment (IATA) in developmental toxicology Aldert H. Piersma