The Experts below are selected from a list of 2199 Experts worldwide ranked by ideXlab platform
Roland Solecki - One of the best experts on this subject based on the ideXlab platform.
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Update of the DevTox data database for harmonized risk assessment and alternative methodologies in Developmental Toxicology: Report of the 9th Berlin Workshop on Developmental Toxicity.
Reproductive Toxicology, 2019Co-Authors: Roland Solecki, Martina Rauch, Jochen Buschmann, Rupert Kellner, A. Gall, Olena Kucheryavenko, Anne Schmitt, Nathalie DelrueAbstract:Representatives of applied science (e.g. governmental organizations, academia, and industry) met to discuss the progress towards a harmonized human health risk assessment in Developmental Toxicology of plant protection products, biocidal products, and other environmental chemicals at the 9th Berlin Workshop on Developmental Toxicity held in September 2018. Within the focus of the scientific discussion were the future of in-vitro methods for Developmental and reproductive Toxicology, the potential relevance of alternative species in testing of Developmental effects, and risk and hazard assessment of Developmental and endocrine effects. Furthermore, the need for a harmonized terminology for classification of anomalies in laboratory animals in Developmental toxicity studies aiming for human health risk assessment was determined. Here, the DevTox database was identified as an extremely valuable tool. Overall, the participants agreed that still one of the biggest challenges for testing Developmental toxicity in the 21st century is the development of animal-free test strategies and alternatives to animal testing that could provide human-relevant information in a rapid, efficient, and mechanistically informative manner.
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Continuing harmonization of terminology and innovations for methodologies in Developmental Toxicology: Report of the 8th Berlin Workshop on Developmental Toxicity, 14-16 May 2014
Reproductive Toxicology, 2015Co-Authors: Roland Solecki, Martina Rauch, Andrea Gall, Ruth Clark, Verena Heinrich, Haidong Kan, Antje Fuchs, Jochen Buschmann, Rupert Kellner, Thomas B KnudsenAbstract:This article is a report of the 8th Berlin Workshop on Developmental Toxicity held in May 2014. The main aim of the workshop was the continuing harmonization of terminology and innovations for methodologies used in the assessment of embryo- and fetotoxic findings. The following main topics were discussed: harmonized categorization of external, skeletal, visceral and materno-fetal findings into malformations, variations and grey zone anomalies, aspects of Developmental anomalies in humans and laboratory animals, and innovations for new methodologies in Developmental Toxicology. The application of Version 2 terminology in the DevTox database was considered as a useful improvement in the categorization of Developmental anomalies. Participants concluded that initiation of a project for comparative assessments of Developmental anomalies in humans and laboratory animals could support regulatory risk assessment and university-based training. Improvement of new methodological approaches for alternatives to animal testing should be triggered for a better understanding of Developmental outcomes.
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Harmonization of description and classification of fetal observations: achievements and problems still unresolved: report of the 7th Workshop on the Terminology in Developmental Toxicology Berlin, 4-6 May 2011.
Reproductive Toxicology, 2013Co-Authors: Roland Solecki, Ruth Clark, Antje Fuchs, Jochen Buschmann, Brigitte Bergmann, Heinrich Bürgin, Stephane Barbellion, Laura Comotto, Ali S. Faqi, Ralph GerspachAbstract:This article summarizes the 7th Workshop on the Terminology in Developmental Toxicology held in Berlin, May 4-6, 2011. The series of Berlin Workshops has been mainly concerned with the harmonization of terminology and classification of fetal anomalies in Developmental toxicity studies. The main topics of the 7th Workshop were knowledge on the fate of anomalies after birth, use of Version 2 terminology for maternal-fetal observations and non-routinely used species, reclassification of " grey zone" anomalies and categorization of fetal observations for human health risk assessment.The paucity of data on health consequences of the postnatal permanence of fetal anomalies is relevant and further studies are needed. The Version 2 terminology is an important step forward and the terms listed in this glossary are considered also to be appropriate for most observations in non-routinely used species.Continuation of the Berlin Workshops was recommended. Topics suggested for the next Workshop were grouping of fetal observations for reporting and statistical analysis. © 2012 Elsevier Inc.
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Harmonization of terminology in Developmental Toxicology: the quest for a more precise description and a harmonized classification of fetal observations.
Reproductive Toxicology, 2009Co-Authors: Francisco José Roma Paumgartten, Martina Rauch, Ruth Clark, Jochen Buschmann, Roland Solecki, Konstanze Grote, Ibrahim ChahoudAbstract:Harmonization of terminology in Developmental Toxicology is a prerequisite to ensure a better risk assessment of chemicals. As part of an international effort of the International Programme on Chemical Safety (IPCS) to harmonize terminology in Developmental Toxicology, workshops have taken place in Berlin since 1995. This publication reports the main outcomes of the Fifth and Sixth Berlin Workshops held in 2005 and 2007, respectively. The objective of the Fifth workshop was to discuss a draft international proposal for updating the glossary of descriptive terms for fetal abnormalities put forward by Wise et al. [Wise LD, et al. Terminology of Developmental abnormalities in common laboratory mammals (version 1). Teratology 1997;55:249-92]. The participants were asked to classify the new external, visceral and skeletal observations included within this new version 2 of Terminology of Developmental Abnormalities in common Laboratory Mammals according to the two-category scheme (malformation and variation) agreed at previous Berlin workshops. The discussions held during the Sixth Workshop were mainly focused on the causes of uncertainty and low agreement regarding classification of some fetal observations as malformations or variations. Lack of precision in descriptive terms and insufficient knowledge of the postnatal consequences of fetal observations had been identified as major causes of uncertainty and lower agreement among evaluators regarding the classification of "grey zone anomalies", i.e. abnormalities that do not fit readily into one of the two categories (malformation or variation). Imprecise anatomical terms, observation terms that are too broad, lack of information on severity and the use of different terms for the same change or different severities of the same change, were found to be the main reasons that descriptive terms are often not sufficiently precise to allow accurate classification of findings. It was agreed that provision of additional information, including sub-location within the affected structure, more detailed description of the nature of the change, in conjunction with presentation of photographs wherever possible, and a grading for severity would make descriptive terms more precise, thereby reducing misclassifications. A better knowledge of the adversity and postnatal consequences of fetal observations was considered as the key issue for achieving a substantial reduction in the number of misclassifications and grey zone anomalies. The urgent need for additional research along this line as a prerequisite for a better risk assessment was emphasized by the participants.
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Harmonization of rat fetal external and visceral terminology and classification. Report of the Fourth Workshop on the Terminology in Developmental Toxicology, Berlin, 18-20 April 2002.
Reproductive Toxicology, 2003Co-Authors: Roland Solecki, Ruth Clark, Jochen Buschmann, Alice M. Druga, Brigitte Bergmann, Heinrich Bürgin, E.a.j. Van Duijnhoven, Martine Duverger, James Edwards, Hannelore FreudenbergerAbstract:This article is a report on the Fourth Berlin Workshop on Terminology in Developmental Toxicology, which was held in April 2002. The workshop is part of an international project in the field of harmonization of terminology in Developmental Toxicology supported by IPCS. The goal of the Harmonization Project is to ensure better chemical risk assessment. The aim of this Fourth Workshop was to discuss the results of a previously conducted survey on classification of external and visceral anomalies, which are listed in the international glossary, developed under the auspices of IFTS (1997 glossary). The discussions among experts from research institutions, regulatory agencies, and industries were mainly focussed on terms for which there was disagreement and/or uncertainties and the possible reasons. For the illustration of "gray-zone" anomalies, pictures were provided by the participants, which constituted the basis for detailed discussions.There was high agreement that most of the external anomalies (>66%) should be classified as malformations. The few external anomalies for which there was low agreement to classify as a malformation were discussed in detail. None of the external findings, which had in the survey a high agreement, were categorized as a variation.A high agreement regarding the classification of approximately one-third of visceral anomalies was achieved with 34 and 2% being described as malformation and variation, respectively. Most of the visceral findings had low agreement indices and there appeared to be several reasons for this. Thus, the response, 'Not known/not used in the laboratory' (N) was often given. A couple of reasons for difficulties in the classification of an anomaly were that it is only rarely seen upon fetal examination or tends to be species specific. Furthermore, the classification of some anomalies as malformation or variation will remain vague as the decision must be made on a case-by-case basis. Factors affecting the decision include: the availability of appropriate historical control data, description of the grading and severity, whether the anomaly occurs in isolation or whether there is a relationship with an abnormal process, and finally, if the change represents an irreversible one, affecting human and/or animal health. It was concluded that a severity grading, supported by pictures of the anomaly, would be especially helpful to classify certain changes as malformation or as variation. Several of the soft tissue changes were considered likely to be the consequence of functional disorders and thus not strictly Developmental anomalies. The possibility to describe a finding as 'Not Malformation' (Unclassified) was agreed upon. As a general conclusion it was emphasized that the observation of a permanent structural change should be considered to be a warning of possible consequences to humans, even when there is no apparent adverse effect on health and survival in adult animals of the species under investigation. Therefore, research is needed to further investigate postnatal consequences. Future collaboration in the field of reproductive and Developmental Toxicology should aim to further develop and implement a harmonized approach to the interpretation of study data. Therefore, this terminology work will continue in close cooperation with the IPCS Harmonization Project. A Steering Group should be established to facilitate the implementation of harmonized terminology into daily scientific work and its regulatory application
Jochen Buschmann - One of the best experts on this subject based on the ideXlab platform.
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Update of the DevTox data database for harmonized risk assessment and alternative methodologies in Developmental Toxicology: Report of the 9th Berlin Workshop on Developmental Toxicity.
Reproductive Toxicology, 2019Co-Authors: Roland Solecki, Martina Rauch, Jochen Buschmann, Rupert Kellner, A. Gall, Olena Kucheryavenko, Anne Schmitt, Nathalie DelrueAbstract:Representatives of applied science (e.g. governmental organizations, academia, and industry) met to discuss the progress towards a harmonized human health risk assessment in Developmental Toxicology of plant protection products, biocidal products, and other environmental chemicals at the 9th Berlin Workshop on Developmental Toxicity held in September 2018. Within the focus of the scientific discussion were the future of in-vitro methods for Developmental and reproductive Toxicology, the potential relevance of alternative species in testing of Developmental effects, and risk and hazard assessment of Developmental and endocrine effects. Furthermore, the need for a harmonized terminology for classification of anomalies in laboratory animals in Developmental toxicity studies aiming for human health risk assessment was determined. Here, the DevTox database was identified as an extremely valuable tool. Overall, the participants agreed that still one of the biggest challenges for testing Developmental toxicity in the 21st century is the development of animal-free test strategies and alternatives to animal testing that could provide human-relevant information in a rapid, efficient, and mechanistically informative manner.
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Continuing harmonization of terminology and innovations for methodologies in Developmental Toxicology: Report of the 8th Berlin Workshop on Developmental Toxicity, 14-16 May 2014
Reproductive Toxicology, 2015Co-Authors: Roland Solecki, Martina Rauch, Andrea Gall, Ruth Clark, Verena Heinrich, Haidong Kan, Antje Fuchs, Jochen Buschmann, Rupert Kellner, Thomas B KnudsenAbstract:This article is a report of the 8th Berlin Workshop on Developmental Toxicity held in May 2014. The main aim of the workshop was the continuing harmonization of terminology and innovations for methodologies used in the assessment of embryo- and fetotoxic findings. The following main topics were discussed: harmonized categorization of external, skeletal, visceral and materno-fetal findings into malformations, variations and grey zone anomalies, aspects of Developmental anomalies in humans and laboratory animals, and innovations for new methodologies in Developmental Toxicology. The application of Version 2 terminology in the DevTox database was considered as a useful improvement in the categorization of Developmental anomalies. Participants concluded that initiation of a project for comparative assessments of Developmental anomalies in humans and laboratory animals could support regulatory risk assessment and university-based training. Improvement of new methodological approaches for alternatives to animal testing should be triggered for a better understanding of Developmental outcomes.
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Harmonization of description and classification of fetal observations: achievements and problems still unresolved: report of the 7th Workshop on the Terminology in Developmental Toxicology Berlin, 4-6 May 2011.
Reproductive Toxicology, 2013Co-Authors: Roland Solecki, Ruth Clark, Antje Fuchs, Jochen Buschmann, Brigitte Bergmann, Heinrich Bürgin, Stephane Barbellion, Laura Comotto, Ali S. Faqi, Ralph GerspachAbstract:This article summarizes the 7th Workshop on the Terminology in Developmental Toxicology held in Berlin, May 4-6, 2011. The series of Berlin Workshops has been mainly concerned with the harmonization of terminology and classification of fetal anomalies in Developmental toxicity studies. The main topics of the 7th Workshop were knowledge on the fate of anomalies after birth, use of Version 2 terminology for maternal-fetal observations and non-routinely used species, reclassification of " grey zone" anomalies and categorization of fetal observations for human health risk assessment.The paucity of data on health consequences of the postnatal permanence of fetal anomalies is relevant and further studies are needed. The Version 2 terminology is an important step forward and the terms listed in this glossary are considered also to be appropriate for most observations in non-routinely used species.Continuation of the Berlin Workshops was recommended. Topics suggested for the next Workshop were grouping of fetal observations for reporting and statistical analysis. © 2012 Elsevier Inc.
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Harmonization of terminology in Developmental Toxicology: the quest for a more precise description and a harmonized classification of fetal observations.
Reproductive Toxicology, 2009Co-Authors: Francisco José Roma Paumgartten, Martina Rauch, Ruth Clark, Jochen Buschmann, Roland Solecki, Konstanze Grote, Ibrahim ChahoudAbstract:Harmonization of terminology in Developmental Toxicology is a prerequisite to ensure a better risk assessment of chemicals. As part of an international effort of the International Programme on Chemical Safety (IPCS) to harmonize terminology in Developmental Toxicology, workshops have taken place in Berlin since 1995. This publication reports the main outcomes of the Fifth and Sixth Berlin Workshops held in 2005 and 2007, respectively. The objective of the Fifth workshop was to discuss a draft international proposal for updating the glossary of descriptive terms for fetal abnormalities put forward by Wise et al. [Wise LD, et al. Terminology of Developmental abnormalities in common laboratory mammals (version 1). Teratology 1997;55:249-92]. The participants were asked to classify the new external, visceral and skeletal observations included within this new version 2 of Terminology of Developmental Abnormalities in common Laboratory Mammals according to the two-category scheme (malformation and variation) agreed at previous Berlin workshops. The discussions held during the Sixth Workshop were mainly focused on the causes of uncertainty and low agreement regarding classification of some fetal observations as malformations or variations. Lack of precision in descriptive terms and insufficient knowledge of the postnatal consequences of fetal observations had been identified as major causes of uncertainty and lower agreement among evaluators regarding the classification of "grey zone anomalies", i.e. abnormalities that do not fit readily into one of the two categories (malformation or variation). Imprecise anatomical terms, observation terms that are too broad, lack of information on severity and the use of different terms for the same change or different severities of the same change, were found to be the main reasons that descriptive terms are often not sufficiently precise to allow accurate classification of findings. It was agreed that provision of additional information, including sub-location within the affected structure, more detailed description of the nature of the change, in conjunction with presentation of photographs wherever possible, and a grading for severity would make descriptive terms more precise, thereby reducing misclassifications. A better knowledge of the adversity and postnatal consequences of fetal observations was considered as the key issue for achieving a substantial reduction in the number of misclassifications and grey zone anomalies. The urgent need for additional research along this line as a prerequisite for a better risk assessment was emphasized by the participants.
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Harmonization of rat fetal external and visceral terminology and classification. Report of the Fourth Workshop on the Terminology in Developmental Toxicology, Berlin, 18-20 April 2002.
Reproductive Toxicology, 2003Co-Authors: Roland Solecki, Ruth Clark, Jochen Buschmann, Alice M. Druga, Brigitte Bergmann, Heinrich Bürgin, E.a.j. Van Duijnhoven, Martine Duverger, James Edwards, Hannelore FreudenbergerAbstract:This article is a report on the Fourth Berlin Workshop on Terminology in Developmental Toxicology, which was held in April 2002. The workshop is part of an international project in the field of harmonization of terminology in Developmental Toxicology supported by IPCS. The goal of the Harmonization Project is to ensure better chemical risk assessment. The aim of this Fourth Workshop was to discuss the results of a previously conducted survey on classification of external and visceral anomalies, which are listed in the international glossary, developed under the auspices of IFTS (1997 glossary). The discussions among experts from research institutions, regulatory agencies, and industries were mainly focussed on terms for which there was disagreement and/or uncertainties and the possible reasons. For the illustration of "gray-zone" anomalies, pictures were provided by the participants, which constituted the basis for detailed discussions.There was high agreement that most of the external anomalies (>66%) should be classified as malformations. The few external anomalies for which there was low agreement to classify as a malformation were discussed in detail. None of the external findings, which had in the survey a high agreement, were categorized as a variation.A high agreement regarding the classification of approximately one-third of visceral anomalies was achieved with 34 and 2% being described as malformation and variation, respectively. Most of the visceral findings had low agreement indices and there appeared to be several reasons for this. Thus, the response, 'Not known/not used in the laboratory' (N) was often given. A couple of reasons for difficulties in the classification of an anomaly were that it is only rarely seen upon fetal examination or tends to be species specific. Furthermore, the classification of some anomalies as malformation or variation will remain vague as the decision must be made on a case-by-case basis. Factors affecting the decision include: the availability of appropriate historical control data, description of the grading and severity, whether the anomaly occurs in isolation or whether there is a relationship with an abnormal process, and finally, if the change represents an irreversible one, affecting human and/or animal health. It was concluded that a severity grading, supported by pictures of the anomaly, would be especially helpful to classify certain changes as malformation or as variation. Several of the soft tissue changes were considered likely to be the consequence of functional disorders and thus not strictly Developmental anomalies. The possibility to describe a finding as 'Not Malformation' (Unclassified) was agreed upon. As a general conclusion it was emphasized that the observation of a permanent structural change should be considered to be a warning of possible consequences to humans, even when there is no apparent adverse effect on health and survival in adult animals of the species under investigation. Therefore, research is needed to further investigate postnatal consequences. Future collaboration in the field of reproductive and Developmental Toxicology should aim to further develop and implement a harmonized approach to the interpretation of study data. Therefore, this terminology work will continue in close cooperation with the IPCS Harmonization Project. A Steering Group should be established to facilitate the implementation of harmonized terminology into daily scientific work and its regulatory application
Ruth Clark - One of the best experts on this subject based on the ideXlab platform.
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Continuing harmonization of terminology and innovations for methodologies in Developmental Toxicology: Report of the 8th Berlin Workshop on Developmental Toxicity, 14-16 May 2014
Reproductive Toxicology, 2015Co-Authors: Roland Solecki, Martina Rauch, Andrea Gall, Ruth Clark, Verena Heinrich, Haidong Kan, Antje Fuchs, Jochen Buschmann, Rupert Kellner, Thomas B KnudsenAbstract:This article is a report of the 8th Berlin Workshop on Developmental Toxicity held in May 2014. The main aim of the workshop was the continuing harmonization of terminology and innovations for methodologies used in the assessment of embryo- and fetotoxic findings. The following main topics were discussed: harmonized categorization of external, skeletal, visceral and materno-fetal findings into malformations, variations and grey zone anomalies, aspects of Developmental anomalies in humans and laboratory animals, and innovations for new methodologies in Developmental Toxicology. The application of Version 2 terminology in the DevTox database was considered as a useful improvement in the categorization of Developmental anomalies. Participants concluded that initiation of a project for comparative assessments of Developmental anomalies in humans and laboratory animals could support regulatory risk assessment and university-based training. Improvement of new methodological approaches for alternatives to animal testing should be triggered for a better understanding of Developmental outcomes.
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Harmonization of description and classification of fetal observations: achievements and problems still unresolved: report of the 7th Workshop on the Terminology in Developmental Toxicology Berlin, 4-6 May 2011.
Reproductive Toxicology, 2013Co-Authors: Roland Solecki, Ruth Clark, Antje Fuchs, Jochen Buschmann, Brigitte Bergmann, Heinrich Bürgin, Stephane Barbellion, Laura Comotto, Ali S. Faqi, Ralph GerspachAbstract:This article summarizes the 7th Workshop on the Terminology in Developmental Toxicology held in Berlin, May 4-6, 2011. The series of Berlin Workshops has been mainly concerned with the harmonization of terminology and classification of fetal anomalies in Developmental toxicity studies. The main topics of the 7th Workshop were knowledge on the fate of anomalies after birth, use of Version 2 terminology for maternal-fetal observations and non-routinely used species, reclassification of " grey zone" anomalies and categorization of fetal observations for human health risk assessment.The paucity of data on health consequences of the postnatal permanence of fetal anomalies is relevant and further studies are needed. The Version 2 terminology is an important step forward and the terms listed in this glossary are considered also to be appropriate for most observations in non-routinely used species.Continuation of the Berlin Workshops was recommended. Topics suggested for the next Workshop were grouping of fetal observations for reporting and statistical analysis. © 2012 Elsevier Inc.
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Harmonization of terminology in Developmental Toxicology: the quest for a more precise description and a harmonized classification of fetal observations.
Reproductive Toxicology, 2009Co-Authors: Francisco José Roma Paumgartten, Martina Rauch, Ruth Clark, Jochen Buschmann, Roland Solecki, Konstanze Grote, Ibrahim ChahoudAbstract:Harmonization of terminology in Developmental Toxicology is a prerequisite to ensure a better risk assessment of chemicals. As part of an international effort of the International Programme on Chemical Safety (IPCS) to harmonize terminology in Developmental Toxicology, workshops have taken place in Berlin since 1995. This publication reports the main outcomes of the Fifth and Sixth Berlin Workshops held in 2005 and 2007, respectively. The objective of the Fifth workshop was to discuss a draft international proposal for updating the glossary of descriptive terms for fetal abnormalities put forward by Wise et al. [Wise LD, et al. Terminology of Developmental abnormalities in common laboratory mammals (version 1). Teratology 1997;55:249-92]. The participants were asked to classify the new external, visceral and skeletal observations included within this new version 2 of Terminology of Developmental Abnormalities in common Laboratory Mammals according to the two-category scheme (malformation and variation) agreed at previous Berlin workshops. The discussions held during the Sixth Workshop were mainly focused on the causes of uncertainty and low agreement regarding classification of some fetal observations as malformations or variations. Lack of precision in descriptive terms and insufficient knowledge of the postnatal consequences of fetal observations had been identified as major causes of uncertainty and lower agreement among evaluators regarding the classification of "grey zone anomalies", i.e. abnormalities that do not fit readily into one of the two categories (malformation or variation). Imprecise anatomical terms, observation terms that are too broad, lack of information on severity and the use of different terms for the same change or different severities of the same change, were found to be the main reasons that descriptive terms are often not sufficiently precise to allow accurate classification of findings. It was agreed that provision of additional information, including sub-location within the affected structure, more detailed description of the nature of the change, in conjunction with presentation of photographs wherever possible, and a grading for severity would make descriptive terms more precise, thereby reducing misclassifications. A better knowledge of the adversity and postnatal consequences of fetal observations was considered as the key issue for achieving a substantial reduction in the number of misclassifications and grey zone anomalies. The urgent need for additional research along this line as a prerequisite for a better risk assessment was emphasized by the participants.
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Harmonization of rat fetal external and visceral terminology and classification. Report of the Fourth Workshop on the Terminology in Developmental Toxicology, Berlin, 18-20 April 2002.
Reproductive Toxicology, 2003Co-Authors: Roland Solecki, Ruth Clark, Jochen Buschmann, Alice M. Druga, Brigitte Bergmann, Heinrich Bürgin, E.a.j. Van Duijnhoven, Martine Duverger, James Edwards, Hannelore FreudenbergerAbstract:This article is a report on the Fourth Berlin Workshop on Terminology in Developmental Toxicology, which was held in April 2002. The workshop is part of an international project in the field of harmonization of terminology in Developmental Toxicology supported by IPCS. The goal of the Harmonization Project is to ensure better chemical risk assessment. The aim of this Fourth Workshop was to discuss the results of a previously conducted survey on classification of external and visceral anomalies, which are listed in the international glossary, developed under the auspices of IFTS (1997 glossary). The discussions among experts from research institutions, regulatory agencies, and industries were mainly focussed on terms for which there was disagreement and/or uncertainties and the possible reasons. For the illustration of "gray-zone" anomalies, pictures were provided by the participants, which constituted the basis for detailed discussions.There was high agreement that most of the external anomalies (>66%) should be classified as malformations. The few external anomalies for which there was low agreement to classify as a malformation were discussed in detail. None of the external findings, which had in the survey a high agreement, were categorized as a variation.A high agreement regarding the classification of approximately one-third of visceral anomalies was achieved with 34 and 2% being described as malformation and variation, respectively. Most of the visceral findings had low agreement indices and there appeared to be several reasons for this. Thus, the response, 'Not known/not used in the laboratory' (N) was often given. A couple of reasons for difficulties in the classification of an anomaly were that it is only rarely seen upon fetal examination or tends to be species specific. Furthermore, the classification of some anomalies as malformation or variation will remain vague as the decision must be made on a case-by-case basis. Factors affecting the decision include: the availability of appropriate historical control data, description of the grading and severity, whether the anomaly occurs in isolation or whether there is a relationship with an abnormal process, and finally, if the change represents an irreversible one, affecting human and/or animal health. It was concluded that a severity grading, supported by pictures of the anomaly, would be especially helpful to classify certain changes as malformation or as variation. Several of the soft tissue changes were considered likely to be the consequence of functional disorders and thus not strictly Developmental anomalies. The possibility to describe a finding as 'Not Malformation' (Unclassified) was agreed upon. As a general conclusion it was emphasized that the observation of a permanent structural change should be considered to be a warning of possible consequences to humans, even when there is no apparent adverse effect on health and survival in adult animals of the species under investigation. Therefore, research is needed to further investigate postnatal consequences. Future collaboration in the field of reproductive and Developmental Toxicology should aim to further develop and implement a harmonized approach to the interpretation of study data. Therefore, this terminology work will continue in close cooperation with the IPCS Harmonization Project. A Steering Group should be established to facilitate the implementation of harmonized terminology into daily scientific work and its regulatory application
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Conference Proceedings Harmonization of rat fetal external and visceral terminology and classification Report of the Fourth Workshop on the Terminology in Developmental Toxicology, Berlin, 18-20 April 2002
2003Co-Authors: Roland Solecki, Ruth Clark, Jochen Buschmann, Brigitte Bergmann, Heinrich Bürgin, Martine Duverger, James Edwards, Hannelore Freudenberger, Alice Druga, Pierre GuittinAbstract:AbstractThis article is a report on the Fourth Berlin Workshop on Terminology in Developmental Toxicology, which was held in April 2002. Theworkshop is part of an international project in the field of harmonization of terminology in Developmental Toxicology supported by IPCS.The goal of the Harmonization Project is to ensure better chemical risk assessment. The aim of this Fourth Workshop was to discuss theresults of a previously conducted survey on classification of external and visceral anomalies, which are listed in the international glossary,developed under the auspices of IFTS (1997 glossary). The discussions among experts from research institutions, regulatory agencies,and industries were mainly focussed on terms for which there was disagreement and/or uncertainties and the possible reasons. For theillustration of “gray-zone” anomalies, pictures were provided by the participants, which constituted the basis for detailed discussions.There was high agreement that most of the external anomalies (>66%) should be classified as malformations. The few external anomaliesfor which there was low agreement to classify as a malformation were discussed in detail. None of the external findings, which had in thesurvey a high agreement, were categorized as a variation.A high agreement regarding the classification of approximately one-third of visceral anomalies was achieved with 34 and 2% beingdescribed as malformation and variation, respectively. Most of the visceral findings had low agreement indices and there appeared to beseveral reasons for this. Thus, the response, ‘Not known/not used in the laboratory’ (N) was often given. A couple of reasons for difficultiesin the classification of an anomaly were that it is only rarely seen upon fetal examination or tends to be species specific. Furthermore,the classification of some anomalies as malformation or variation will remain vague as the decision must be made on a case-by-casebasis. Factors affecting the decision include: the availability of appropriate historical control data, description of the grading and severity,whether the anomaly occurs in isolation or whether there is a relationship with an abnormal process, and finally, if the change representsan irreversible one, affecting human and/or animal health. It was concluded that a severity grading, supported by pictures of the anomaly,would be especially helpful to classify certain changes as malformation or as variation. Several of the soft tissue changes were consideredlikely to be the consequence of functional disorders and thus not strictly Developmental anomalies. The possibility to describe a findingas ‘Not Malformation’ (Unclassified) was agreed upon. As a general conclusion it was emphasized that the observation of a permanentstructural change should be considered to be a warning of possible consequences to humans, even when there is no apparent adverse effecton health and survival in adult animals of the species under investigation. Therefore, research is needed to further investigate postnatalconsequences. Future collaboration in the field of reproductive and Developmental Toxicology should aim to further develop and implementa harmonized approach to the interpretation of study data. Therefore, this terminology work will continue in close cooperation with theIPCS Harmonization Project. A Steering Group should be established to facilitate the implementation of harmonized terminology intodaily scientific work and its regulatory application.
Cindy X Zhang - One of the best experts on this subject based on the ideXlab platform.
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In Vitro Developmental Toxicology Screens: A Report on the Progress of the Methodology and Future Applications
Chemical Research in Toxicology, 2016Co-Authors: Cindy X Zhang, Jonathan S Ball, Julie Panzica-kelly, Karen Augustine-rauchAbstract:There has been increasing focus on generation and assessment of in vitro Developmental Toxicology models for assessing teratogenic liability of chemicals. The driver for this focus has been to find reliable in vitro assays that will reduce or replace the use of in vivo tests for assessing teratogenicity. Such efforts may be eventually applied in testing pharmaceutical agents where a Developmental Toxicology assay or battery of assays may be incorporated into regulatory testing to replace one of the two species currently used in teratogenic assessment. Such assays may be eventually applied in testing a broader spectrum of chemicals, supporting efforts aligned with Tox21 strategies and responding to REACH legislation. This review describes the Developmental Toxicology assays that are of focus in these assessments: rodent whole embryo culture, zebrafish embryo assays, and embryonic stem cell assays. Progress on assay development as well as future directions of how these assays are envisioned to be applied for broader safety testing of chemicals are discussed. Altogether, the Developmental model systems described in this review provide rich biological systems that can be utilized in better understanding teratogenic mechanisms of action of chemotypes and are promising in providing proactive safety assessment related to Developmental toxicity. Continual advancements in refining/optimizing these in vitro assays are anticipated to provide a robust data set to provide thoughtful assessment of how whole animal teratogenicity evaluations can be reduced/refined in the future.
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in vitro Developmental Toxicology screens a report on the progress of the methodology and future applications
Chemical Research in Toxicology, 2016Co-Authors: Cindy X Zhang, Jonathan S Ball, Julie Panzicakelly, Karen AugustinerauchAbstract:There has been increasing focus on generation and assessment of in vitro Developmental Toxicology models for assessing teratogenic liability of chemicals. The driver for this focus has been to find reliable in vitro assays that will reduce or replace the use of in vivo tests for assessing teratogenicity. Such efforts may be eventually applied in testing pharmaceutical agents where a Developmental Toxicology assay or battery of assays may be incorporated into regulatory testing to replace one of the two species currently used in teratogenic assessment. Such assays may be eventually applied in testing a broader spectrum of chemicals, supporting efforts aligned with Tox21 strategies and responding to REACH legislation. This review describes the Developmental Toxicology assays that are of focus in these assessments: rodent whole embryo culture, zebrafish embryo assays, and embryonic stem cell assays. Progress on assay development as well as future directions of how these assays are envisioned to be applied fo...
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A Developmental Toxicology Assay Platform for Screening Teratogenic Liability of Pharmaceutical Compounds.
Birth Defects Research Part B: Developmental and Reproductive Toxicology, 2016Co-Authors: Karen Augustine-rauch, Cindy X Zhang, Julieta M. Panzica-kellyAbstract:Increasing need for proactive safety optimization of pharmaceutical compounds has led to generation and/or refinement of in vitro Developmental Toxicology assays. Our laboratory has developed three in vitro Developmental Toxicology assays to assess teratogenic liability of pharmaceutical compounds. These assays included a mouse molecular embryonic stem cell assay (MESCA), a dechorionated zebrafish embryo culture (ZEC) assay, and a streamlined rat whole embryo culture (rWEC) assay. Individually, the assays presented good (73-82%) predictivity. However, it remains to be determined whether combining or tiering the assays could enhance performance. Seventy-three compounds representing a broad spectrum of pharmaceutical targets and chemistry were evaluated across the assays to generate testing strategies that optimized performance. The MESCA and ZEC assays were found to have two limitations: compound solubility and frequent misclassification of compounds with H1 receptor or GABAnergic activity. The streamlined rWEC assay was found to be a cost-effective stand-alone assay for supporting poorly soluble compounds and/or ones with H1 or GABAnergic activity. For all other compounds, a tiering strategy using the MESCA and ZEC assays additionally optimized throughput, cost, and minimized animal use. The tiered strategy resulted in improved performance achieving 88% overall predictivity and was comparable with 89% overall predictivity achieved with frequency analysis (final teratogenic classification made from most frequent teratogenic classification from each individual assay). Furthermore there were 21 compounds in the test set characterized as definitive or suspect human teratogens and the multiassay approach achieved 95 and 91% correct classification using the tiered or frequency screening approach, respectively.
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fishing for teratogens a consortium effort for a harmonized zebrafish Developmental Toxicology assay
Toxicological Sciences, 2014Co-Authors: Jonathan S Ball, Cindy X Zhang, Julie Panzicakelly, Donald B Stedman, Jedd M Hillegass, Aleasha Coburn, Brian P Enright, Belen Tornesi, Hamid R Amouzadeh, Malcolm J HetheridgeAbstract:: A consortium of biopharmaceutical companies previously developed an optimized Zebrafish Developmental toxicity assay (ZEDTA) where chorionated embryos were exposed to non-proprietary test compounds from 5 to 6 h post fertilization and assessed for morphological integrity at 5 days post fertilization. With the original 20 test compounds, this achieved an overall predictive value for teratogenicity of 88% of mammalian in vivo outcome [Gustafson, A. L., Stedman, D. B., Ball, J., Hillegass, J. M., Flood, A., Zhang, C. X., Panzica-Kelly, J., Cao, J., Coburn, A., Enright, B. P., et al. (2012). Interlaboratory assessment of a harmonized Zebrafish Developmental Toxicology assay-Progress report on phase I. Reprod. Toxicol. 33, 155-164]. In the second phase of this project, 38 proprietary pharmaceutical compounds from four consortium members were evaluated in two laboratories using the optimized method using either pond-derived or cultivated-strain wild-type Zebrafish embryos at concentrations up to 100μM. Embryo uptake of all compounds was assessed using liquid chromatography-tandem mass spectrometry. Twenty eight of 38 compounds had a confirmed embryo uptake of >5%, and with these compounds the ZEDTA achieved an overall predictive value of 82% and 65% at the two respective laboratories. When low-uptake compounds (≤ 5%) were retested with logarithmic concentrations up to 1000μM, the overall predictivity across all 38 compounds was 79% and 62% respectively, with the first laboratory achieving 74% sensitivity (teratogen detection) and 82% specificity (non-teratogen detection) and the second laboratory achieving 63% sensitivity (teratogen detection) and 62% specificity (non-teratogen detection). Subsequent data analyses showed that technical differences rather than strain differences were the primary contributor to interlaboratory differences in predictivity. Based on these results, the ZEDTA harmonized methodology is currently being used for compound assessment at lead optimization stage of development by 4/5 of the consortium companies.
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Zebrafish Embryo Developmental Toxicology Assay
Methods in Molecular Biology, 2012Co-Authors: Julieta M. Panzica-kelly, Cindy X Zhang, Karen Augustine-rauchAbstract:A promising in vitro zebrafish Developmental Toxicology assay was generated to test compounds for their teratogenic potential. The assay's predictivity is approximately 87% in AB strain fish (Brannen KC et al., Birth Defects Res B Dev Reprod Toxicol 89:66-77, 2010). The procedure entails exposing dechorionated gastrulation-stage embryos to a range of compound concentrations for 5 days throughout embryonic and larva development. The larvae are evaluated for viability in order to identify an LC25 (the compound concentration in which 25% lethality is observed) and morphological anomalies using a numerical score system to identify the NOAEL (no observed adverse effect level). These values are used to calculate the teratogenic index (LC25/NOAEL ratio) of each compound. If the teratogenic index is equal to or greater than 10 then the compound is classified as a teratogen, and if the ratio is less than 10 then the compound is classified as a nonteratogen (Brannen KC et al., Birth Defects Res B Dev Reprod Toxicol 89:66-77, 2010).
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In Vitro Developmental Toxicology Screens: A Report on the Progress of the Methodology and Future Applications
Chemical Research in Toxicology, 2016Co-Authors: Cindy X Zhang, Jonathan S Ball, Julie Panzica-kelly, Karen Augustine-rauchAbstract:There has been increasing focus on generation and assessment of in vitro Developmental Toxicology models for assessing teratogenic liability of chemicals. The driver for this focus has been to find reliable in vitro assays that will reduce or replace the use of in vivo tests for assessing teratogenicity. Such efforts may be eventually applied in testing pharmaceutical agents where a Developmental Toxicology assay or battery of assays may be incorporated into regulatory testing to replace one of the two species currently used in teratogenic assessment. Such assays may be eventually applied in testing a broader spectrum of chemicals, supporting efforts aligned with Tox21 strategies and responding to REACH legislation. This review describes the Developmental Toxicology assays that are of focus in these assessments: rodent whole embryo culture, zebrafish embryo assays, and embryonic stem cell assays. Progress on assay development as well as future directions of how these assays are envisioned to be applied for broader safety testing of chemicals are discussed. Altogether, the Developmental model systems described in this review provide rich biological systems that can be utilized in better understanding teratogenic mechanisms of action of chemotypes and are promising in providing proactive safety assessment related to Developmental toxicity. Continual advancements in refining/optimizing these in vitro assays are anticipated to provide a robust data set to provide thoughtful assessment of how whole animal teratogenicity evaluations can be reduced/refined in the future.
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in vitro Developmental Toxicology screens a report on the progress of the methodology and future applications
Chemical Research in Toxicology, 2016Co-Authors: Cindy X Zhang, Jonathan S Ball, Julie Panzicakelly, Karen AugustinerauchAbstract:There has been increasing focus on generation and assessment of in vitro Developmental Toxicology models for assessing teratogenic liability of chemicals. The driver for this focus has been to find reliable in vitro assays that will reduce or replace the use of in vivo tests for assessing teratogenicity. Such efforts may be eventually applied in testing pharmaceutical agents where a Developmental Toxicology assay or battery of assays may be incorporated into regulatory testing to replace one of the two species currently used in teratogenic assessment. Such assays may be eventually applied in testing a broader spectrum of chemicals, supporting efforts aligned with Tox21 strategies and responding to REACH legislation. This review describes the Developmental Toxicology assays that are of focus in these assessments: rodent whole embryo culture, zebrafish embryo assays, and embryonic stem cell assays. Progress on assay development as well as future directions of how these assays are envisioned to be applied fo...
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fishing for teratogens a consortium effort for a harmonized zebrafish Developmental Toxicology assay
Toxicological Sciences, 2014Co-Authors: Jonathan S Ball, Cindy X Zhang, Julie Panzicakelly, Donald B Stedman, Jedd M Hillegass, Aleasha Coburn, Brian P Enright, Belen Tornesi, Hamid R Amouzadeh, Malcolm J HetheridgeAbstract:: A consortium of biopharmaceutical companies previously developed an optimized Zebrafish Developmental toxicity assay (ZEDTA) where chorionated embryos were exposed to non-proprietary test compounds from 5 to 6 h post fertilization and assessed for morphological integrity at 5 days post fertilization. With the original 20 test compounds, this achieved an overall predictive value for teratogenicity of 88% of mammalian in vivo outcome [Gustafson, A. L., Stedman, D. B., Ball, J., Hillegass, J. M., Flood, A., Zhang, C. X., Panzica-Kelly, J., Cao, J., Coburn, A., Enright, B. P., et al. (2012). Interlaboratory assessment of a harmonized Zebrafish Developmental Toxicology assay-Progress report on phase I. Reprod. Toxicol. 33, 155-164]. In the second phase of this project, 38 proprietary pharmaceutical compounds from four consortium members were evaluated in two laboratories using the optimized method using either pond-derived or cultivated-strain wild-type Zebrafish embryos at concentrations up to 100μM. Embryo uptake of all compounds was assessed using liquid chromatography-tandem mass spectrometry. Twenty eight of 38 compounds had a confirmed embryo uptake of >5%, and with these compounds the ZEDTA achieved an overall predictive value of 82% and 65% at the two respective laboratories. When low-uptake compounds (≤ 5%) were retested with logarithmic concentrations up to 1000μM, the overall predictivity across all 38 compounds was 79% and 62% respectively, with the first laboratory achieving 74% sensitivity (teratogen detection) and 82% specificity (non-teratogen detection) and the second laboratory achieving 63% sensitivity (teratogen detection) and 62% specificity (non-teratogen detection). Subsequent data analyses showed that technical differences rather than strain differences were the primary contributor to interlaboratory differences in predictivity. Based on these results, the ZEDTA harmonized methodology is currently being used for compound assessment at lead optimization stage of development by 4/5 of the consortium companies.