- Email: [email protected]
Exposome science for public health protection and innovation
S12
Abstracts / Toxicology Letters 238S (2015) S12–S14
Invited sessions Keynotes - EUROTOX/SOT Debate - Hot Topic K-1 Systems medicine, microbiomes and personalised healthcare J. Nicholson
HESI CITE Lecture K-2 Phylotoxicology: Breaking the artificial divide between human- and eco-toxicology J. Colbourne 1,∗ , M. Viant 1 , J. Shaw 1,2 1
Imperial College London, London, United Kingdom
University of Birmingham, Birmingham, United Kingdom Indiana University, School of Public and Environmental Affairs, Bloomington, United States
The complex gene–environment interactions that create individual and population disease risks are also responsible for the expression of metabolic phenotypes in different body compartments and fluids. Thus metabolic phenotyping offers an important window on systemic activity and responses to drugs and toxins. Advanced spectroscopic and multivariate statistical methods can be employed to help characterize personalised profiles, disease processes, toxic mechanisms and responses to therapy (Nicholson and Lindon, 2008). We have developed new scalable and translatable strategies for “phenotyping the patient journey” (Nicholson et al., 2012) using top-down systems biology tools that capitalize on the use of metabolic datasets (Clayton et al., 2006) for diagnostic and prognostic biomarker generation to aid clinical decision-making at point-of-care. These have been shown to be of value in the development of prognostic marker models for both clinical efficacy and drug toxicity in cancer patients. Such approaches, including those for near real-time applications as in surgery, molecular pathology, oncology and critical-care, can be extremely sensitive for the detection of diagnostic and prognostic biomarkers in a variety conditions (Balog et al., 2013; Veselkov et al., 2014). These methods also provide a powerful adjunct to conventional procedures for disease assessment that are required for future developments in “precision medicine” including understanding of the symbiotic influences on patient state (Mirnezami et al., 2012). Finally, the “Metabolome Wide Association Study” (Holmes et al., 2008) concept provides powerful new tool to generate disease risk biomarkers (e.g. for cancer or cardiometabolic diseases) from epidemiological sample collections. Such population risk models can also link to individual patient healthcare models thus closing the personal and public healthcare modelling triangle. The ultimate challenge is to take complex validated data sets and models on human biology and to visualise these in engaging formats and forms that clinically actionable in an ever changing background of human health.
Toxicology is traditionally pursued by two distinct research communities that either focus on human health or environmental health concerns. This division is arguably counter-productive, by splitting research and policy attention away from a common goal to understand how chemicals and advanced materials adversely impact biological processes and how to best manage their potential health risks. The need to break this artificial divide has never been greater, by virtue of bold steps taken by EU lawmakers at legislating the need to assess the human toxicity of all chemicals sold in Europe (REACH) and at achieving “good chemical status” for all European freshwater ecosystems (Water Framework Directive). This has spurred science to provide a comprehensive and cost-effective solution to implement effectively these two ground-breaking EU policy directives. The proposed solution is Phylogenetic Toxicology, which applies high-throughput toxicity testing with data-rich genomics assays applied to 3R compliant model species representing animal biology. These include biomedical and ecologically relevant organisms that altogether can deliver experimentally derived predictions of a chemical’s modes of actions and key events in the etiology of illness or injury. This solution to chemical risk assessment incorporates an important discovery made within the past 10 years in studies of the functional elements in animal genomes; a significant suite of elements and their functional associations for growth, maintenance and reproduction is shared among animals (including humans) representing over 60% of transcribed and epigenetically modified genomes. This crucial finding is reinvigorating the use of experimental, scientifically and legally accepted alternative model species for understanding the human condition and ecological challenges. This finding also provides a proven platform for the necessarily big and transformative set of experiments that combine genomics, metabolomics, evolutionary theory, bioinformatics and toxicology to meet the regulatory challenges of today and tomorrow. This talk is delivered on behalf of the Consortium for Environmental Omics and Toxicology.
References
http://dx.doi.org/10.1016/j.toxlet.2015.08.090
2
Nicholson, J.K., Lindon, J.C., 2008. Nature 455, 1054–1056. Nicholson, J.K., et al., 2012. Nature 491, 384–392. Clayton, T.A., et al., 2006. Nature 440, 1073–1077. Balog, J., et al., 2013. Sci. Transl. Med. 5 (194), 194ra93. Veselkov, K.A., et al., 2014. PNAS, http://dx.doi.org/10.1073/pnas Mirnezami, R., Nicholson, J.K., Darzi, A., 2012. N. Engl. J. Med. 366 (6), 489–491. Holmes, E., et al., 2008. Nature 453, 396–400.
Keynote Lecture Bo Holmstedt Memorial Fund K-3 Exposome science for public health protection and innovation
http://dx.doi.org/10.1016/j.toxlet.2015.08.074 D. Sarigiannis Aristotle University of Thessaloniki, Chemical Engineering, Thessaloniki, Greece The exposome represents the totality of exposures from conception onwards, encompassing the exogenous and endogenous exposures and modifiable risk factors that predispose to and predict diseases throughout a person’s life span. Unraveling it will
Abstracts / Toxicology Letters 238S (2015) S12–S14
help us understand the intricate web of relationships between environmental exposures, lifestyle, genetics and disease. It is thus expected to contribute significantly to the determination of causal associations between environmental factors and human health taking into account genetic susceptibility. Bringing this vision into reality poses significant challenges in terms of untangling the complex biological networks that regulate body’s response to external stressors and analyzing the large datasets generated from the use of high throughput analytical platforms (-omics). Exposome research will try to reverse the “nature versus nurture” paradigm and define one characterised by complex and dynamic interactions between DNA sequence, epigenetic DNA modifications, gene expression and environmental factors that all combine to influence disease phenotypes. The approach outlined in this lecture brings together environmental, socio-economic, exposure, biomarker and health effect data; it further includes all computational procedures necessary for applying advanced bioinformatics coupling advanced data mining with biological and exposure modeling so as to ensure that environmental exposure-health associations are studied comprehensively. The overall methodology is being verified in population studies across Europe, tackling various levels of environmental exposure, age windows and gender-related exposure, socio-economic and genetic variability. Untangling the exposome will: (a) make public health and environmental policies more cost effective (b) stimulate innovation in ubiquitous sensing, high dimensional biology and big data analytics (c) promote transdisciplinary education to create environmental health scientists who would be science “integrators” and “translators” into precision disease prevention. The lecture will highlight the main aspects of exposome science, the importance of the Global Exposome Initiative and discuss the best ways in which European toxicologists and health risk scientists can contribute to its success. http://dx.doi.org/10.1016/j.toxlet.2015.08.154 Keynote Lecture K-4 Challenges for a full replacement of animal models to assess immunotoxicty E. Corsini Università degli Studi di Milano, Dipartimento di Chimica, Milan, Italy The immune system can be the target of many chemicals, with potentially severe adverse effects on the host’s health. Over the last two decades, little has changed in practice of immunotoxicity testing for regulatory purposes, especially for immunosuppression, and autoimmunity is still a challenge. At the same time, however, several in vitro approaches have been developed for the identification of contact allergens, which are currently under discussion at the OECD level and should be soon adopted for routine testing. While these methods are useful for hazard identification, currently it is not possible to rank chemicals for their sensitizing potency, an issue and challenge that is important for a full safety assessment. In vitro alternative approaches might offer an opportunity to screen for problematic substances and prioritizing them for in vivo testing. New approaches emerge from mapping of pathways of immunotoxicity. Increasingly, the contribution of inflammatory and infectious components to the adverse outcome pathways of chemicals for various hazards are recognized, urging to include these tests for proinflammatory and immunomodulatory properties into integrated testing strategies. http://dx.doi.org/10.1016/j.toxlet.2015.08.156
S13
EUROTOX/SOT Debate D In Vitro Alternatives are Ready to be Implemented and Relied Upon for Human Safety Testing G. Daston 1,∗ , M. Whelan 2,∗ 1 Procter & Gamble, Victor Mills Society Research Fellow, Cincinnati, United States 2 European Commission Joint Research Centre, EURL ECVAM, Ispra, Italy
Each year the EUROTOX and SOT Annual Meetings include a debate that continues a tradition that originated in the early 1990s in which leading toxicologists advocate opposing sides of an issue of significant toxicological importance. This year, our debaters will address the proposition: In vitro alternatives are ready to be implemented and relied upon for human safety testing. In vitro and other non-animal test methods have been under development for many years as possible replacements for animal testing as the basis for human safety risk assessment. The need for these methods is acute, both because of legislative pressure, such as the European Union’s Cosmetics Regulation which forbids the use of ingredients tested in animals after March 2013, and because of the growing discrepancy between the number of chemicals being introduced into commerce and the ability to thoroughly evaluate their toxicity in animals. Despite these pressures, implementation of alternative methods has been slow, both because of the rigorous validation process required to qualify them as replacements and because of the difficulties in modeling all relevant aspects of pharmacokinetics and pharmacodynamics that are present in the intact organism. Still, scientists and regulators continue to look for applications for alternative methods that will be reliable and withstand criticism. Some of these include the use of read-across to support safety assessment for groups of related chemicals, or high-throughput screening such as the ToxCast program to prioritize large numbers of chemicals for further testing. The debaters will discuss the state of the science of alternative methods and whether they can be relied upon for supporting human safety assessments. Regardless of framework differences and personal convictions, each scientific debate delegate will present relevant evidence and compelling scientific arguments to persuade and appeal to the response of the audience in order to obtain the approval or refusal of the motion. In addition to being a featured session at the SOT Annual Meeting in San Diego, California, this debate also takes place (with the debaters taking the reverse positions) in Porto, Portugal during the 51st Congress of the European Societies of Toxicology. http://dx.doi.org/10.1016/j.toxlet.2015.08.158
Abstracts / Toxicology Letters 238S (2015) S12–S14
Invited sessions Keynotes - EUROTOX/SOT Debate - Hot Topic K-1 Systems medicine, microbiomes and personalised healthcare J. Nicholson
HESI CITE Lecture K-2 Phylotoxicology: Breaking the artificial divide between human- and eco-toxicology J. Colbourne 1,∗ , M. Viant 1 , J. Shaw 1,2 1
Imperial College London, London, United Kingdom
University of Birmingham, Birmingham, United Kingdom Indiana University, School of Public and Environmental Affairs, Bloomington, United States
The complex gene–environment interactions that create individual and population disease risks are also responsible for the expression of metabolic phenotypes in different body compartments and fluids. Thus metabolic phenotyping offers an important window on systemic activity and responses to drugs and toxins. Advanced spectroscopic and multivariate statistical methods can be employed to help characterize personalised profiles, disease processes, toxic mechanisms and responses to therapy (Nicholson and Lindon, 2008). We have developed new scalable and translatable strategies for “phenotyping the patient journey” (Nicholson et al., 2012) using top-down systems biology tools that capitalize on the use of metabolic datasets (Clayton et al., 2006) for diagnostic and prognostic biomarker generation to aid clinical decision-making at point-of-care. These have been shown to be of value in the development of prognostic marker models for both clinical efficacy and drug toxicity in cancer patients. Such approaches, including those for near real-time applications as in surgery, molecular pathology, oncology and critical-care, can be extremely sensitive for the detection of diagnostic and prognostic biomarkers in a variety conditions (Balog et al., 2013; Veselkov et al., 2014). These methods also provide a powerful adjunct to conventional procedures for disease assessment that are required for future developments in “precision medicine” including understanding of the symbiotic influences on patient state (Mirnezami et al., 2012). Finally, the “Metabolome Wide Association Study” (Holmes et al., 2008) concept provides powerful new tool to generate disease risk biomarkers (e.g. for cancer or cardiometabolic diseases) from epidemiological sample collections. Such population risk models can also link to individual patient healthcare models thus closing the personal and public healthcare modelling triangle. The ultimate challenge is to take complex validated data sets and models on human biology and to visualise these in engaging formats and forms that clinically actionable in an ever changing background of human health.
Toxicology is traditionally pursued by two distinct research communities that either focus on human health or environmental health concerns. This division is arguably counter-productive, by splitting research and policy attention away from a common goal to understand how chemicals and advanced materials adversely impact biological processes and how to best manage their potential health risks. The need to break this artificial divide has never been greater, by virtue of bold steps taken by EU lawmakers at legislating the need to assess the human toxicity of all chemicals sold in Europe (REACH) and at achieving “good chemical status” for all European freshwater ecosystems (Water Framework Directive). This has spurred science to provide a comprehensive and cost-effective solution to implement effectively these two ground-breaking EU policy directives. The proposed solution is Phylogenetic Toxicology, which applies high-throughput toxicity testing with data-rich genomics assays applied to 3R compliant model species representing animal biology. These include biomedical and ecologically relevant organisms that altogether can deliver experimentally derived predictions of a chemical’s modes of actions and key events in the etiology of illness or injury. This solution to chemical risk assessment incorporates an important discovery made within the past 10 years in studies of the functional elements in animal genomes; a significant suite of elements and their functional associations for growth, maintenance and reproduction is shared among animals (including humans) representing over 60% of transcribed and epigenetically modified genomes. This crucial finding is reinvigorating the use of experimental, scientifically and legally accepted alternative model species for understanding the human condition and ecological challenges. This finding also provides a proven platform for the necessarily big and transformative set of experiments that combine genomics, metabolomics, evolutionary theory, bioinformatics and toxicology to meet the regulatory challenges of today and tomorrow. This talk is delivered on behalf of the Consortium for Environmental Omics and Toxicology.
References
http://dx.doi.org/10.1016/j.toxlet.2015.08.090
2
Nicholson, J.K., Lindon, J.C., 2008. Nature 455, 1054–1056. Nicholson, J.K., et al., 2012. Nature 491, 384–392. Clayton, T.A., et al., 2006. Nature 440, 1073–1077. Balog, J., et al., 2013. Sci. Transl. Med. 5 (194), 194ra93. Veselkov, K.A., et al., 2014. PNAS, http://dx.doi.org/10.1073/pnas Mirnezami, R., Nicholson, J.K., Darzi, A., 2012. N. Engl. J. Med. 366 (6), 489–491. Holmes, E., et al., 2008. Nature 453, 396–400.
Keynote Lecture Bo Holmstedt Memorial Fund K-3 Exposome science for public health protection and innovation
http://dx.doi.org/10.1016/j.toxlet.2015.08.074 D. Sarigiannis Aristotle University of Thessaloniki, Chemical Engineering, Thessaloniki, Greece The exposome represents the totality of exposures from conception onwards, encompassing the exogenous and endogenous exposures and modifiable risk factors that predispose to and predict diseases throughout a person’s life span. Unraveling it will
Abstracts / Toxicology Letters 238S (2015) S12–S14
help us understand the intricate web of relationships between environmental exposures, lifestyle, genetics and disease. It is thus expected to contribute significantly to the determination of causal associations between environmental factors and human health taking into account genetic susceptibility. Bringing this vision into reality poses significant challenges in terms of untangling the complex biological networks that regulate body’s response to external stressors and analyzing the large datasets generated from the use of high throughput analytical platforms (-omics). Exposome research will try to reverse the “nature versus nurture” paradigm and define one characterised by complex and dynamic interactions between DNA sequence, epigenetic DNA modifications, gene expression and environmental factors that all combine to influence disease phenotypes. The approach outlined in this lecture brings together environmental, socio-economic, exposure, biomarker and health effect data; it further includes all computational procedures necessary for applying advanced bioinformatics coupling advanced data mining with biological and exposure modeling so as to ensure that environmental exposure-health associations are studied comprehensively. The overall methodology is being verified in population studies across Europe, tackling various levels of environmental exposure, age windows and gender-related exposure, socio-economic and genetic variability. Untangling the exposome will: (a) make public health and environmental policies more cost effective (b) stimulate innovation in ubiquitous sensing, high dimensional biology and big data analytics (c) promote transdisciplinary education to create environmental health scientists who would be science “integrators” and “translators” into precision disease prevention. The lecture will highlight the main aspects of exposome science, the importance of the Global Exposome Initiative and discuss the best ways in which European toxicologists and health risk scientists can contribute to its success. http://dx.doi.org/10.1016/j.toxlet.2015.08.154 Keynote Lecture K-4 Challenges for a full replacement of animal models to assess immunotoxicty E. Corsini Università degli Studi di Milano, Dipartimento di Chimica, Milan, Italy The immune system can be the target of many chemicals, with potentially severe adverse effects on the host’s health. Over the last two decades, little has changed in practice of immunotoxicity testing for regulatory purposes, especially for immunosuppression, and autoimmunity is still a challenge. At the same time, however, several in vitro approaches have been developed for the identification of contact allergens, which are currently under discussion at the OECD level and should be soon adopted for routine testing. While these methods are useful for hazard identification, currently it is not possible to rank chemicals for their sensitizing potency, an issue and challenge that is important for a full safety assessment. In vitro alternative approaches might offer an opportunity to screen for problematic substances and prioritizing them for in vivo testing. New approaches emerge from mapping of pathways of immunotoxicity. Increasingly, the contribution of inflammatory and infectious components to the adverse outcome pathways of chemicals for various hazards are recognized, urging to include these tests for proinflammatory and immunomodulatory properties into integrated testing strategies. http://dx.doi.org/10.1016/j.toxlet.2015.08.156
S13
EUROTOX/SOT Debate D In Vitro Alternatives are Ready to be Implemented and Relied Upon for Human Safety Testing G. Daston 1,∗ , M. Whelan 2,∗ 1 Procter & Gamble, Victor Mills Society Research Fellow, Cincinnati, United States 2 European Commission Joint Research Centre, EURL ECVAM, Ispra, Italy
Each year the EUROTOX and SOT Annual Meetings include a debate that continues a tradition that originated in the early 1990s in which leading toxicologists advocate opposing sides of an issue of significant toxicological importance. This year, our debaters will address the proposition: In vitro alternatives are ready to be implemented and relied upon for human safety testing. In vitro and other non-animal test methods have been under development for many years as possible replacements for animal testing as the basis for human safety risk assessment. The need for these methods is acute, both because of legislative pressure, such as the European Union’s Cosmetics Regulation which forbids the use of ingredients tested in animals after March 2013, and because of the growing discrepancy between the number of chemicals being introduced into commerce and the ability to thoroughly evaluate their toxicity in animals. Despite these pressures, implementation of alternative methods has been slow, both because of the rigorous validation process required to qualify them as replacements and because of the difficulties in modeling all relevant aspects of pharmacokinetics and pharmacodynamics that are present in the intact organism. Still, scientists and regulators continue to look for applications for alternative methods that will be reliable and withstand criticism. Some of these include the use of read-across to support safety assessment for groups of related chemicals, or high-throughput screening such as the ToxCast program to prioritize large numbers of chemicals for further testing. The debaters will discuss the state of the science of alternative methods and whether they can be relied upon for supporting human safety assessments. Regardless of framework differences and personal convictions, each scientific debate delegate will present relevant evidence and compelling scientific arguments to persuade and appeal to the response of the audience in order to obtain the approval or refusal of the motion. In addition to being a featured session at the SOT Annual Meeting in San Diego, California, this debate also takes place (with the debaters taking the reverse positions) in Porto, Portugal during the 51st Congress of the European Societies of Toxicology. http://dx.doi.org/10.1016/j.toxlet.2015.08.158