மாசு ஜர்னல்

Abstract

Whole genome sequencing (WGS) of human tumours has revealed distinct patterns of mutation that hint at the causative origins of cancer. The Catalogue of Somatic Mutations in Cancer (COSMIC) is a global resource for information on somatic mutations in human cancer and currently lists 30 distinct mutational signatures. Some signatures are correlated with known environmental exposures, but the causative origins of many signatures remain unknown. We have developed an experimental approach using human induced pluripotent stem (iPS) cells to define mutational signatures of environmental carcinogens by WGS. Treatment conditions (e.g. concentration) for WGS were optimized by assessing cytotoxicity, DNA damage response signaling and the formation of premutagenic DNA adducts. After WGS, a ubiquitous background mutational signature was extracted in all clones showing similarities with COSMIC Signature 18 which has been reported in other cultured human cells. Specific signatures were identified in human iPS cells, following exposure to benzo[a]pyrene (BaP), simulated sunlight aristolochic acid I (AAI) and aflatoxin B1 (AFB1), revealing characteristic mutation pattern for each carcinogen that were highly similar to COSMIC signatures of mutations found in tumors of individuals who were exposed to the agent of interest: predominantly G to T mutations for BaP were linked to COSMIC Signature 4; C to T for simulated sunlight was linked to COSMIC Signature 7; A to T for AAI was linked to COSMIC Signature 22; and G to T for AFB1 was linked to COSMIC Signature 24. Thus, human cell-based systems and WGS can be used to study the genome as a record of environmental exposure. Recent Publications 1. Long A S, Wills J W, Krolak D, Guo M, Dertinger S D, et al. (2018) Benchmark dose analyses of multiple genetic toxicity endpoints permit robust, cross-tissue comparisons of MutaMouse responses to orally delivered benzo[a]pyrene. Arch. Toxicol. 92(2):967???982. 2. White P A, Douglas G R, Phillips D H and Arlt V M (2017) Quantitative relationships between lacZ mutant frequency and DNA adduct frequency in Muta???Mouse tissues and cultured cells exposed to 3-nitrobenzanthrone. Mutagenesis 32(2):299??? 312. 3. Kucab J E, Zwart E P, van Steeg H, Luijten M, Schmeiser H H, et al. (2016) TP53 and lacZ mutagenesis induced by 3-nitrobenzanthrone in Xpa-deficient human TP53 knock-in mouse embryo fibroblasts. DNA Repair 39:21???33. 4. Nik-Zainal S, Kucab J E, Morganella S, Glodzik D, Alexandrov L B, et al. (2015) The genome as a record of environmental exposure. Mutagenesis 30(6):763???70. 5. Kucab J E, van Steeg H, Luijten M, Schmeiser H H, White PA, et al. (2015) TP53 mutations induced by BPDE in Xpa-WT and Xpa-Null human TP53 knock-in (Hupki) mouse embryo fibroblasts. Mutat. Res. 773:48???62. There are many ways by which to define "environmental" carcinogens. Here the epithet "environmental" is taken to cover any unwanted, environmentally derived chemicals that enter the human body via food, drink or air and that have been shown to cause, or are suspected of causing, cancer in humans and/or experimental animals. As a further qualification, only man-made materials will be considered, with the exception of radon. The definition includes environmental contaminants in' food but excludes food additives and natural ingredients. Mytotoxins, passive smoking and occupational carcinogens will not be dealt with because they are discussed elsewhere in this book. Furthermore, the effects of chlorofluorocarbons on stratospheric ozone levels, and thus indirectly on ultraviolet radiation and skin cancer, are beyond the scope of this chapter. Environmental carcinogens are discussed here by chemical group rather than by source of exposure. However, in the context of each chemical the different sources of exposure are presented, and quantitative data will be given when feasible. Before individual chemicals are considered, the fate of chemicals in the environment, classification of carcinogens, variation in the populations exposed and principles of risk estimation will be discussed. Environmental carcinogenesis is a very wide field covering environmental hygiene, human exposure assessment, carcinogenic properties of chemicals and some degree of risk assessment. For this reason several sources have been consulted in preparing this chapter. The World Health Organization has published valuable reference material in this area such as Guidelines for Drinking-Water Quality (WHO 1984a), Air Quality Guidelines (WHO 1987a) and Environmental Health Criteria on a number of compounds; the Environmental Protection Agency of the United States of America (U.S.EPA) has assessed human exposure to and risks from a variety of environmental carcinogens, and many of these risk estimates are quoted here. The Monographs series of the International Agency for Research on Cancer offers authoritative, qualitative assessments on the carcinogenic properties of chemicals and data on the occurrence of these chemicals in the environment; furthermore, the periodicals Environmental Carcinogenesis Reviews and Environmental Health Perspectives are invaluable sources of reference data in the areas to be covered in this chapter. Sampling and analytical techniques in environmental hygiene have developed considerably during the past 2 decades. The accuracy of the methods has improved, and sensitivities have increased by orders of magnitude for some measurements. The older results thus need to be treated with due caution. The greatest problem is, however, the Climate Change & environmental toxicology 4 october . 2018 Volume 4ï?· Issue 3 paucity of measurements. Rarely are representative measurements available, even for one subpopulation that cover all the possible sources of exposure. This being the case, extrapolations even to a national level may be tenuous and extrapolations to a global level are sheer guesswork. There are many ways by which to define “environmental” carcinogens. Here the epithet “environmental” is taken to cover any unwanted, environmentally derived chemicals that enter the human body via food, drink or air and that have been shown to cause, or are suspected of causing, cancer in humans and/or experimental animals. As a further qualification, only manmade materials will be considered, with the exception of radon. The definition includes environmental contaminants in food but excludes food additives and natural ingredients. Mycotoxins, passive smoking and occupational carcinogens will not be dealt with because they are discussed elsewhere in this book. Furthermore, the effects of chlorofluorocarbons on stratospheric ozone levels, and thus indirectly on ultraviolet radiation and skin cancer, are beyond the scope of this chapter.

Abstract

Statement of the Problem: Interventions for development, sustainability, and/or climate change adaptation have a history of ambiguous outcomes and outright failures. How can interventions, and especially those that involve government, research and stakeholders, including local residents, result in sustainable outcomes that persist beyond the intervention, and move towards climate change behaviour-change in the practice of all participants? Methodology & Theoretical Orientation: The underpinning methodology is transdisciplinary (TD). Critical realism provides a theoretical foundation for discerning causal mechanisms in complex systems using the full range of disciplinary enquiry. The concept of complex social-ecological systems (CSES) provides a lens to forefront the role adaptation and feed-back. Expansive learning provides the mechanisms to guide processes of co-learning and the co-development of knowledge. Strategic adaptive management provides practical on-the-ground steps for stakeholders to participate in an adaptation process. The governance system in each particular CSES provides the contextual possibility of a process that will persist. Participatory governance brings the vitality and relevance of civil society. Eight case studies to probe the challenging question of whether painstaking on-the-ground trust??? Building; activating participatory governance processes; and engaging in reflexive praxis, can catalyse change towards climate change adaption, specifically focusing on water scarcity. Conclusion & Significance: The selected approach is slow, with many pitfalls. There are not many examples of unequivocal success. However, we can demonstrate learning, begin to understand failure more deeply, and most importantly share???Narratives of hope? Pace of progress and the difficulty of persevering. These???Narratives of hope??? Are the landmarks to encourage perseverance until a bigger body of evidence emerges and principles of practice are refined? We have enough examples of participatory governance being a key lever for ongoing change towards climate change adaptation to suggest it is worth persevering. The approach is easy to criticize??? Especially in terms of the pace of progress and the difficulty of persevering with these processes. These???Narratives of hope??? Are the landmarks to encourage perseverance until a bigger body of evidence emerges and principles of practice are refined? Recent Publications 1. Palmer C G, Biggs R and Cumming G S (2015) Applied research for enhancing human well-being and environmental stewardship: using complexity thinking in Southern Africa. Ecology and Society 20(1):53. 2. Lang D J, Wiek A, Bermann M, Stauffacher M, Martens P, et al. (2012) Transdisciplinary research in sustainability science: practice, principles, and challenges. Sustainability Science 7(5):25???43. 3. Folke C (2006) Resilience: the emergence of a perspective for social-ecological systems analyses. Even after introducing significant measures to reduce greenhouse gas (GHG) emissions, some additional degree of climate change is unavoidable and will have significant economic, social and environmental impacts on Canadian communities. To reduce the negative impacts of this change and to take advantage of new opportunities presented, Canadians will need to adapt. Photo courtesy of Agriculture and Agro-Food Canada Climate change adaptation refers to actions that reduce the negative impact of climate change, while taking advantage of potential new opportunities. It involves adjusting policies and actions because of observed or expected changes in climate. Adaptation can be reactive, occurring in response to climate impacts, or anticipatory, occurring before impacts of climate change are observed. In most circumstances, anticipatory adaptations will result in lower long-term costs and be more effective than reactive adaptations. Adaptation is not a new concept: Canadians have developed many approaches to effectively deal with the extremely variable climate. For example, communities in the Prairie Provinces have been designed to withstand extreme differences in seasonal temperatures. Nevertheless, the amount and rate of future climate change will pose some new challenges. The fact that science now allows communities to anticipate a range of potential climate conditions, and therefore take action before the worst impacts are incurred, makes adaptation to future climate change different from how Canadians have adapted historically. Photo courtesy of Jerry Mouland +Adaptation (responding to climate impacts) and mitigation (reducing GHG emissions) are necessary complements in addressing climate change. The fourth assessment report of the Intergovernmental Panel on Climate Change states that while neither adaptation nor mitigation actions alone can prevent significant climate change impacts, taken together they can significantly reduce risks. Mitigation is necessary to reduce the rate and magnitude of climate change, while adaptation is essential to reduce the damages from climate change that cannot be avoided. Single policies and measures can be designed to help tackle both mitigation and adaptation. For example, as the climate changes, a projected higher frequency and intensity of rain storms may increase storm water runoff and the potential for localised flooding in urban areas. Planting street trees is an initiative that municipalities can implement to both reduce storm water runoff (adaptation) and increase carbon storage (mitigation). In other cases, there may be conflicts between adaptation and mitigation goals that can only be addressed in a broader context of community priorities and risk tolerance. For example, increased use of air conditioning can be considered an adaptive measure because it reduces human health problems during heat waves, which are projected to become more frequent in future. However, air conditioning is energy intensive and, depending on the source of the electricity, is likely to increase carbon dioxide emissions. Therefore, in deciding which adaptation action is most appropriate for a particular situation, attention must be paid to its implications for adaptation and mitigation, as well as its cost, efficacy and acceptance by the public. The Earth’s climate is changing. Some of this change is due to natural variations that have been taking place for millions of years, but increasingly, human activities that release heat-trapping gases into the atmosphere are warming the planet by contributing to the “greenhouse effect.”Climate Change & environmental toxicology 4 october . 2018 Volume 4ï?· Issue 3 The Intergovernmental Panel on Climate Change concludes that the best estimate for global average surface air warming over the current century ranges from 1.8°C to 4.0°C (IPCC 2007). This rate of temperature change is without precedent in at least the last 10 000 years. Consequently, historical climate no longer provides an accurate gauge for future climate conditions.

Abstract 

Human culture and food security rely on the ecosystem services provided by historic patterns of biodiversity. We therefore need to understand the factors that determine where species can and cannot live, and the impact of both natural and anthropogenic variation. Such predictions require an understanding of the mechanisms underlying species range limits, and how they are linked to climate. The Southern Ocean offers a???Natural laboratory??? For testing the evolutionary and physiological capacity of species in response to their environment. Its isolation has resulted in high levels of endemism and the lack of indigenous humans means that the environment is close to pristine. It is a constantly cold ocean but with large seasonal variation in light levels, primary productivity and ph. Animals living in the Southern Ocean have several physiological adaptations for life in the cold, including natural antifreeze, increased mitochondrial densities and the ability to grow to a large size. Life in the extreme cold has also resulted in a reduced ability to cope with warming. The activity limits for limpets and clams are only 1 to 2�C above current maximum summer temperatures. Comparisons of long-term oceanographic and reproductive data-sets have shown that one of the strongest signals affecting internal variability in reproduction is El Ni�o, which causes dramatic changes in the coastal system. In addition to this understanding, the Western Antarctic Peninsula has been one of the fastest warming regions, resulting in massive changes in the cryosphere. The reduction in the duration of winter sea ice, an increase in energy transfer from the atmosphere and the increase in iceberg scour has resulted in dramatic changes in benthic communities. Findings from the Antarctic have taught us much about the evolution of physiological capacity and the evolution of marine communities across latitudes. Recent Publications 1. Ashton G V, Morley S A, Barnes D K A, Clark M S and Peck L S (2017) Warming by 1�C drives species and assemblage level responses in Antarctica???s marine shallows. Current Biology 27(17):2698???2705. 2. Watson S A, Morley S A and Peck L S (2017) Latitudinal trends in shell production cost from the tropics to the poles Science Advances 3(9):e1701362. 3. Morley S A, Nguyen K D, Peck L S, Lai C-H and Tan K S (2017) Can acclimation of thermal tolerance, in adults and across generations, act as a buffer against climate change in tropical marine ectotherms? J Therm. Biol. 68:195???199. 4. Morley S A, Suckling C S, Clark M S, Cross E L and Peck L S (2016) Long term effects of altered pH and temperature on the feeding energetics of the Antarctic sea urchin, Ste echinus neumayeri. Biodiversity 17:34???45. 5. Morley S A Chien-Hsian L, Clarke A, Tan K S, Thorne M A S and Peck L S (2014) Limpet feeding rate and the consistency of physiological response to temperature. J Comp Physiol. 184:563???570. Ambient temperature is very likely the most important environmental factor determining the distribution and diversity of life in the oceans. Hence, climate change is expected to alter marine biodiversity on a global scale. Here we review observed and predicted effects of climate change on the diversity of marine species. Overall, an increasing number of studies demonstrate that effects of climate change on marine biodiversity are already apparent from local to global scales. So far, long-term fish and plankton monitoring data have provided the most compelling evidence for climate-driven changes in species distribution and diversity, but studies involving other groups such as corals, seaweeds and mammals are increasing. As a general pattern, tropical regions often experience a loss of species due to elevated heat stress, whereas temperate regions increase in diversity, as species migrate poleward. Net increases in diversity are also expected in the Polar Regions, but so far there are few observations to support this. Complex patterns of change can emerge where ocean warming is accompanied by the effects of sea level rise, acidification, habitat change, changes in ocean circulation, stratification and other aspects of global change. From a management perspective, the conservation of biological diversity will provide insurance and resilience in the face of rapid global change. Cumulative impacts of exploitation, habitat destruction and other threats to biodiversity need to be minimized to maintain the adaptive capacity of marine ecosystems in the present and coming centuries. This might be particularly pressing in tropical regions and developing countries, which will face exceptional socioeconomic and climate-related pressures, as well as in the Polar Regions, which are faced with a multitude of emerging pressures. The ocean makes up 71% of the planet and provides many services to human communities from mitigating weather extremes to generating the oxygen we breathe, from producing the food we eat to storing the excess carbon dioxide we generate. However, the effects of increasing greenhouse gas emissions threaten coastal and marine ecosystems through changes in ocean temperature and melting of ice, which in turn affect ocean currents, weather patterns, and sea level. And, because the carbon sink capacity of the ocean has been exceeded, we are also seeing the ocean’s chemistry change because of our carbon emissions. In fact, mankind has increased the acidity of our ocean by 30% over the past two centuries. (This is covered in our Research Page on Ocean Acidification). The ocean and climate are inextricably linked. The ocean plays a fundamental role in mitigating climate change by serving as a major heat and carbon sink. The ocean also bears the brunt of climate change, as evidenced by changes in temperature, currents and sea level rise, all of which affect the health of marine species, nearshore and deep ocean ecosystems. As concerns about climate change increase, the interrelationship between the ocean and climate change must be Climate Change & environmental toxicology 4 october . 2018 Volume 4ï?· Issue 3 recognized, understood, and incorporated into governmental policies. Since the Industrial Revolution, the amount of carbon dioxide in our atmosphere has increased by over 35%, primarily from the burning of fossil fuels. Ocean waters, ocean animals, and ocean habitats all help the ocean absorb a significant portion of the carbon dioxide emissions from human activities. The global ocean is already experiencing the significant impact of climate change and its accompanying effects. They include air and water temperature warming, seasonal shifts in species, coral bleaching, sea level rise, coastal inundation, coastal erosion, harmful algal blooms, hypoxic (or dead) zones, new marine diseases, loss of marine mammals, changes in levels of precipitation, and fishery declines. In addition, we can expect more extreme weather events (droughts, floods, storms), which affect habitats and species alike. To protect our valuable marine ecosystems, we must act. The overall solution to climate change is to significantly reduce the emission of greenhouse gases. The most recent international agreement to address climate change, the Paris Agreement, entered into force in 2016. Meeting the targets of the Paris Agreement will require action at international, national, local and community levels around the world. Additionally, blue carbon may provide a method for the longterm sequestration and storage of carbon. “Blue Carbon” is the carbon dioxide captured by the world’s ocean and coastal ecosystems. This carbon is stored in the form of biomass and sediments from mangroves, tidal marshes, and seagrass meadows. More information about Blue Carbon can be found here.

Abstract Since the start of the industrial revolution, society has become increasingly reliant on the use of chemicals, including pesticides, pharmaceuticals, plasticizers and personal care products, to name a few. In 2016, European chemical sales alone were valued at 507 billion Euros, with 80,000 chemicals reported to be in common use worldwide. Alongside the many benefits of chemicals to society, concerns about the impacts of certain chemicals to both human and wildlife health, including the so-called???Endocrine disrupting chemicals??? Is a topic of increasing concern? Since the term???Endocrine disruptor??? Was coined in 1991, extensive research into the effects of various chemicals, and chemical mixtures, on human and wildlife health has been conducted globally. More than 1,300 studies have suggested connections between endocrinedisrupting chemical (EDC) exposure and serious health conditions such as infertility, diabetes, obesity, hormone-related cancers and neurological disorders in humans. The range of endocrine targets captured by regulatory tests is expanding rapidly, and new mechanistic insights, such as epigenetic mechanisms of chemicalinduced disease, continue to challenge the regulatory frameworks designed to protect society and the environment. Difficulties still exist in balancing the trade-offs between the benefits of chemicals to society at point of use with the burden of proof needed to demonstrate the adverse consequences of the same chemicals once they are allowed to disperse in the environment. When dealing with such complexity, is it possible to achieve a vision of a sustainable society where chemicals are managed carefully throughout their lifecycle and where people benefit from their use and thrive within nature???S limits? What strategies and insights can sustainability science offer to help society balance the Toxic -Eco system? Recent Publications 1. Kaur S, Jobling S, Jones CS, Noble LR, Routledge EJ, Lockyer AE (2015) The Nuclear Receptors of Biomphalaria globate and Lottie gigantean: Implications for Developing New Model Organisms. PLOS One 10(4): UNSP e0121259. 2. Bannister R, Beresford N, Granger DW, Pounds NA, Rand-Weaver M, White R, Jobling S, Routledge EJ (2013) No substantial changes in estragon receptor and estragon-related receptor orthologue gene transcription in Marisa cornuarietis exposed to estrogenic chemicals. Aquatic Toxicology 140: 19-26. 3. Routledge EJ, White R, Parker MG, Somper JP (2000) Differential effects of xenoestrogens on coactivator recruitment by estragon receptor (ER) alpha and ER beta. Journal of Biological Chemistry 275(46): 35986-35993. 4. Routledge EJ, Parker J, Odom J, Ashby J, Somper JP (1998) some alkyl hydroxyl benzoate preservatives (parabens) are estrogenic. Toxicology and Applied Pharmacology 153(1): 12-19. 5. Routledge EJ & Somper JP (1996) Estrogenic activity of surfactants and some of their degradation products assessed using a recombinant yeast screen. Environmental Toxicology and Chemistry 15(3): 241-248. Synthetic (manufactured) chemicals are a part of everyday life – they are everywhere and in everything. They can enter the environment through consumer use or industrial processes. Once in the Abstract Since the start of the industrial revolution, society has become increasingly reliant on the use of chemicals, including pesticides, pharmaceuticals, plasticizers and personal care products, to name a few. In 2016, European chemical sales alone were valued at 507 billion Euros, with 80,000 chemicals reported to be in common use worldwide. Alongside the many benefits of chemicals to society, concerns about the impacts of certain chemicals to both human and wildlife health, including the so-called???Endocrine disrupting chemicals??? Is a topic of increasing concern? Since the term???Endocrine disruptor??? Was coined in 1991, extensive research into the effects of various chemicals, and chemical mixtures, on human and wildlife health has been conducted globally. More than 1,300 studies have suggested connections between endocrinedisrupting chemical (EDC) exposure and serious health conditions such as infertility, diabetes, obesity, hormone-related cancers and neurological disorders in humans. The range of endocrine targets captured by regulatory tests is expanding rapidly, and new mechanistic insights, such as epigenetic mechanisms of chemicalinduced disease, continue to challenge the regulatory frameworks designed to protect society and the environment. Difficulties still exist in balancing the trade-offs between the benefits of chemicals to society at point of use with the burden of proof needed to demonstrate the adverse consequences of the same chemicals once they are allowed to disperse in the environment. When dealing with such complexity, is it possible to achieve a vision of a sustainable society where chemicals are managed carefully throughout their lifecycle and where people benefit from their use and thrive within nature???S limits? What strategies and insights can sustainability science offer to help society balance the Toxic -Eco system? Recent Publications 1. Kaur S, Jobling S, Jones CS, Noble LR, Routledge EJ, Lockyer AE (2015) The Nuclear Receptors of Biomphalaria globate and Lottie gigantean: Implications for Developing New Model Organisms. PLOS One 10(4): UNSP e0121259. 2. Bannister R, Beresford N, Granger DW, Pounds NA, Rand-Weaver M, White R, Jobling S, Routledge EJ (2013) No substantial changes in estragon receptor and estragon-related receptor orthologue gene transcription in Marisa cornuarietis exposed to estrogenic chemicals. Aquatic Toxicology 140: 19-26. 3. Routledge EJ, White R, Parker MG, Somper JP (2000) Differential effects of xenoestrogens on coactivator recruitment by estragon receptor (ER) alpha and ER beta. Journal of Biological Chemistry 275(46): 35986-35993. 4. Routledge EJ, Parker J, Odom J, Ashby J, Somper JP (1998) some alkyl hydroxyl benzoate preservatives (parabens) are estrogenic. Toxicology and Applied Pharmacology 153(1): 12-19. 5. Routledge EJ & Somper JP (1996) Estrogenic activity of surfactants and some of their degradation products assessed using a recombinant yeast screen. Environmental Toxicology and Chemistry 15(3): 241-248. Synthetic (manufactured) chemicals are a part of everyday life – they are everywhere and in everything. They can enter the environment through consumer use or industrial processes. Once in the Abstract Since the start of the industrial revolution, society has become increasingly reliant on the use of chemicals, including pesticides, pharmaceuticals, plasticizers and personal care products, to name a few. In 2016, European chemical sales alone were valued at 507 billion Euros, with 80,000 chemicals reported to be in common use worldwide. Alongside the many benefits of chemicals to society, concerns about the impacts of certain chemicals to both human and wildlife health, including the so-called???Endocrine disrupting chemicals??? Is a topic of increasing concern? Since the term???Endocrine disruptor??? Was coined in 1991, extensive research into the effects of various chemicals, and chemical mixtures, on human and wildlife health has been conducted globally. More than 1,300 studies have suggested connections between endocrinedisrupting chemical (EDC) exposure and serious health conditions such as infertility, diabetes, obesity, hormone-related cancers and neurological disorders in humans. The range of endocrine targets captured by regulatory tests is expanding rapidly, and new mechanistic insights, such as epigenetic mechanisms of chemicalinduced disease, continue to challenge the regulatory frameworks designed to protect society and the environment. Difficulties still exist in balancing the trade-offs between the benefits of chemicals to society at point of use with the burden of proof needed to demonstrate the adverse consequences of the same chemicals once they are allowed to disperse in the environment. When dealing with such complexity, is it possible to achieve a vision of a sustainable society where chemicals are managed carefully throughout their lifecycle and where people benefit from their use and thrive within nature???S limits? What strategies and insights can sustainability science offer to help society balance the Toxic -Eco system? Recent Publications 1. Kaur S, Jobling S, Jones CS, Noble LR, Routledge EJ, Lockyer AE (2015) The Nuclear Receptors of Biomphalaria globate and Lottie gigantean: Implications for Developing New Model Organisms. PLOS One 10(4): UNSP e0121259. 2. Bannister R, Beresford N, Granger DW, Pounds NA, Rand-Weaver M, White R, Jobling S, Routledge EJ (2013) No substantial changes in estragon receptor and estragon-related receptor orthologue gene transcription in Marisa cornuarietis exposed to estrogenic chemicals. Aquatic Toxicology 140: 19-26. 3. Routledge EJ, White R, Parker MG, Somper JP (2000) Differential effects of xenoestrogens on coactivator recruitment by estragon receptor (ER) alpha and ER beta. Journal of Biological Chemistry 275(46): 35986-35993. 4. Routledge EJ, Parker J, Odom J, Ashby J, Somper JP (1998) some alkyl hydroxyl benzoate preservatives (parabens) are estrogenic. Toxicology and Applied Pharmacology 153(1): 12-19. 5. Routledge EJ & Somper JP (1996) Estrogenic activity of surfactants and some of their degradation products assessed using a recombinant yeast screen. Environmental Toxicology and Chemistry 15(3): 241-248. Synthetic (manufactured) chemicals are a part of everyday life – they are everywhere and in everything. They can enter the environment through consumer use or industrial processes. Once in the Abstract Since the start of the industrial revolution, society has become increasingly reliant on the use of chemicals, including pesticides, pharmaceuticals, plasticizers and personal care products, to name a few. In 2016, European chemical sales alone were valued at 507 billion Euros, with 80,000 chemicals reported to be in common use worldwide. Alongside the many benefits of chemicals to society, concerns about the impacts of certain chemicals to both human and wildlife health, including the so-called???Endocrine disrupting chemicals??? Is a topic of increasing concern? Since the term???Endocrine disruptor??? Was coined in 1991, extensive research into the effects of various chemicals, and chemical mixtures, on human and wildlife health has been conducted globally. More than 1,300 studies have suggested connections between endocrinedisrupting chemical (EDC) exposure and serious health conditions such as infertility, diabetes, obesity, hormone-related cancers and neurological disorders in humans. The range of endocrine targets captured by regulatory tests is expanding rapidly, and new mechanistic insights, such as epigenetic mechanisms of chemicalinduced disease, continue to challenge the regulatory frameworks designed to protect society and the environment. Difficulties still exist in balancing the trade-offs between the benefits of chemicals to society at point of use with the burden of proof needed to demonstrate the adverse consequences of the same chemicals once they are allowed to disperse in the environment. When dealing with such complexity, is it possible to achieve a vision of a sustainable society where chemicals are managed carefully throughout their lifecycle and where people benefit from their use and thrive within nature???S limits? What strategies and insights can sustainability science offer to help society balance the Toxic -Eco system? Recent Publications 1. Kaur S, Jobling S, Jones CS, Noble LR, Routledge EJ, Lockyer AE (2015) The Nuclear Receptors of Biomphalaria globate and Lottie gigantean: Implications for Developing New Model Organisms. PLOS One 10(4): UNSP e0121259. 2. Bannister R, Beresford N, Granger DW, Pounds NA, Rand-Weaver M, White R, Jobling S, Routledge EJ (2013) No substantial changes in estragon receptor and estragon-related receptor orthologue gene transcription in Marisa cornuarietis exposed to estrogenic chemicals. Aquatic Toxicology 140: 19-26. 3. Routledge EJ, White R, Parker MG, Somper JP (2000) Differential effects of xenoestrogens on coactivator recruitment by estragon receptor (ER) alpha and ER beta. Journal of Biological Chemistry 275(46): 35986-35993. 4. Routledge EJ, Parker J, Odom J, Ashby J, Somper JP (1998) some alkyl hydroxyl benzoate preservatives (parabens) are estrogenic. Toxicology and Applied Pharmacology 153(1): 12-19. 5. Routledge EJ & Somper JP (1996) Estrogenic activity of surfactants and some of their degradation products assessed using a recombinant yeast screen. Environmental Toxicology and Chemistry 15(3): 241-248. Synthetic (manufactured) chemicals are a part of everyday life – they are everywhere and in everything. They can enter the environment through consumer use or industrial processes. Once in the Environment, some end up in our bodies, in wild flora and fauna, or in the atmosphere, potentially driving climate change. Chemicals production and consumption is set to double by 2030, from a $5 trillion industry globally in 2017, with production set to increase, mainly in emerging economies. If chemicals production is doubled, chemical pollution must not double as a consequence – rather we should aim to significantly reduce it from current levels. Current international attempts at the massive undertaking of addressing chemical pollution are not working. For the world to solve the major environmental and health challenges we face, there must be a sustainable chemicals revolution. We can only achieve this through senior-level engagement with the chemical sciences community through an authoritative, intergovernmental sciencepolicy interface. Early in 2020, we engaged with scientists in our community to develop our vision for a chemicals strategy, relevant to any nation in principle. We identified four pillars on which any chemicals strategy has to be based: education, innovation, circular economy and regulation. National governments must invest in these areas and create a responsible framework of action for chemicals management.

Abstract Statement of the Problem: In accordance with 3Rs, alternative models are required to replace standard neurotoxicity testing. High content, high-throughput tools are needed considering specific features of nervous system (NS) functioning to identify neurotoxic vs. cytotoxic effects. By considering intercellular communication through transmitters and transmitter sensors (receptors), and collective behaviour of neuron network as relevant NS functional features, the purpose of this study is to develop tools providing neuron-specific endpoints. Methodology & Theoretical Orientation: A multi-disciplinary electrophysiological, neurochemical and immune cyto chemical approach, combining electrical activity recording of neuron network (on engineered micro-electrode arrays (MEAs) equipped with 60 electrodes onto which cerebrocortical neurons were cultured; data analysis through a home-made software and measurement of transmitter release was used to assess network maturation and to detect effectiveness of neuroactive/neurotoxic substances. Findings: During network development, maturation of glutamatergic/GABAergic neuron networks, target for relevant neurotoxicity mechanisms (excitotoxicity) and drugs classes, was observed. In mature networks, synaptic connectivity was related to activation of glutamatergic pathways, and the system behaved as a sensitive sensor of glutamatergic transmission functioning. Activation or blockade of NMDA/AMPA receptors, or blockade of glutamate transporters, induced firing and bursting activity variations related to the effects on transmitter release. Also, the network sensed the fine transmission variations involved in synapse plasticity: the collective network behaviour and glutamate release were controlled by NMDA-dependent NO-cGMP pathway, as indicated by its pharmacological manipulation (NO synthase/guanylyl cyclase inhibitors, NO donors/8Br-cGMP). By presenting examples of network activity modulation by neuroactive substances (glutamate/GABA receptor agonists/antagonists) and by known neurotoxic ants (e.g., demonic acid, chlorpyrifos Oxon), and ineffectiveness of molecules not exhibiting acute neurotoxic effects, we report evidence that MEAs-coupled neuron networks can represent an integrated approach for neurotoxicity testing based on functional neuron specific endpoints. They might provide an effective in vitro alternative tool for evaluating substance neurotoxicity, also providing a mechanistic approach. Recent Publications 1. Frega M, Pasquale V, Tedesco M, Marcoli M, Contestabile A, et al. (2012) cortical cultures coupled to microelectrode arrays: a novel approach to perform in vitro excitotoxicity testing. Neurotoxicol Teratol 34:116???127. 2. Marcoli M, Agnati L F, Benedetti F, Genedani S, Guidolin D, et al. (2015) On the role of the extracellular space on the holistic behaviour of the brain. Rev Neurosci 26(5):489???506. 3. Fuxe J, Agnati L F, Marcoli M and Borroto-Escuela D (2015) Volume transmission in central dopamine and noradrenaline neurons ant its astroglial target. Neurochem Res 40(12):2600???14. 4. Cervetto C, Vergani L, Passalacqua M, Ragazzoni M, Venturini A, et al. (2016) Astrocyte-dependent vulnerability to excitotoxicity in spermine oxidase overexpressing mouse. Neuromolecular Med 18:50???68. 5. Pietropaoli S, Leonetti A, Cervetto C, Venturini A, Mastrantonio R, et al. (2018) Glutamate excitotoxicity linked to spermine oxidase overexpression. Mol Neurobiol. 55(9):7259???7270. Diseases of environmental origin result from exposures to synthetic and naturally occurring chemical toxicants encountered in the environment, ingested with foods, or administered as pharmaceutical agents. They are, by definition, preventable: they can be prevented by eliminating or reducing exposures to toxicants. The fundamental purpose of testing chemical substances for neurotoxicity is to prevent disease by identifying toxic hazards before humans are exposed. That approach to disease prevention is termed "primary prevention." In contrast, "secondary prevention" consists of the early detection of disease or dysfunction in exposed persons and populations followed by prevention of additional exposure. (Secondary prevention of neurotoxic effects in humans. In the most effective approach to primary prevention of neurotoxic disease of environmental origin, a potential hazard is identified through premarket testing of new chemicals before they are released into commerce and the environment. Identifying potential neurotoxicity caused by the use of illicit substances of abuse or by the consumption of foods that contain naturally occurring toxins is less likely. Disease is prevented by restricting or banning the use of chemicals found to be neurotoxic or by instituting engineering controls and imposing the use of protective devices at points of environmental release. Each year, 1,200–1,500 new substances are considered for premarket review by the Environmental Protection Agency (EPA) (Reiter, 1980), and several hundred compounds are added to the 70,000 distinct chemicals and the more than 4 million mixtures, formulations, and blends already in commerce. The proportion of the new chemicals that could be neurotoxic if exposure were sufficient is not known (NRC, 1984) and cannot be estimated on the basis of existing information. However, of the 588 chemicals used in substantial quantities by American industry in 1982 and judged to be of toxicology.