Green Toxicology: a strategy for sustainable chemical and material development

Green Toxicology refers to the application of predictive toxicology in the sustainable development and production of new less harmful materials and chemicals, subsequently reducing waste and exposure. Built upon the foundation of “Green Chemistry” and “Green Engineering”, “Green Toxicology” aims to shape future manufacturing processes and safe synthesis of chemicals in terms of environmental and human health impacts. Being an integral part of Green Chemistry, the principles of Green Toxicology amplify the role of health-related aspects for the benefit of consumers and the environment, in addition to being economical for manufacturing companies. Due to the costly development and preparation of new materials and chemicals for market entry, it is no longer practical to ignore the safety and environmental status of new products during product development stages. However, this is only possible if toxicologists and chemists work together early on in the development of materials and chemicals to utilize safe design strategies and innovative in vitro and in silico tools. This paper discusses some of the most relevant aspects, advances and limitations of the emergence of Green Toxicology from the perspective of different industry and research groups. The integration of new testing methods and strategies in product development, testing and regulation stages are presented with examples of the application of in silico, omics and in vitro methods. Other tools for Green Toxicology, including the reduction of animal testing, alternative test methods, and read-across approaches are also discussed.

[1]  Andreas Künkel,et al.  Ecoflex® and Ecovio®: Biodegradable, Performance-Enabling Plastics , 2011 .

[2]  Roland Buesen,et al.  A testing strategy for the identification of mammalian, systemic endocrine disruptors with particular focus on steroids. , 2012, Regulatory toxicology and pharmacology : RTP.

[3]  Wojciech Zareba,et al.  Ambient fine particulate air pollution triggers ST-elevation myocardial infarction, but not non-ST elevation myocardial infarction: a case-crossover study , 2014, Particle and Fibre Toxicology.

[4]  Daniel L Villeneuve,et al.  Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment , 2010, Environmental toxicology and chemistry.

[5]  Alexander Star,et al.  Biodegradation of single-walled carbon nanotubes through enzymatic catalysis. , 2008, Nano letters.

[6]  Gerberick Frank,et al.  The intra- and inter-laboratory reproducibility and predictivity of the KeratinoSens assay to predict skin sensitizers in vitro: results of a ring-study in five laboratories. , 2011, Toxicology in vitro : an international journal published in association with BIBRA.

[7]  Paul T Anastas,et al.  Origins, current status, and future challenges of green chemistry. , 2002, Accounts of chemical research.

[8]  Nicholas D. Anastas.  1. Green Toxicology , 2012 .

[9]  John D. Hayler,et al.  Key green chemistry research areas—a perspective from pharmaceutical manufacturers , 2007 .

[10]  Eugenia Valsami-Jones,et al.  A strategy for grouping of nanomaterials based on key physico-chemical descriptors as a basis for safer-by-design NMs , 2014 .

[11]  Thomas Hartung,et al.  Integrated Testing Strategies (ITS) for safety assessment. , 2015, ALTEX.

[12]  Robert Landsiedel,et al.  Applicability of in vitro tests for skin irritation and corrosion to regulatory classification schemes: substantiating test strategies with data from routine studies. , 2012, Regulatory toxicology and pharmacology : RTP.

[13]  David M. Reif,et al.  Toxicity Testing in the 21st Century Beyond Environmental Chemicals , 2018, ALTEX.

[14]  Sergio Martinoia,et al.  A multi‐laboratory evaluation of microelectrode array‐based measurements of neural network activity for acute neurotoxicity testing , 2017, Neurotoxicology.

[15]  Robert Landsiedel,et al.  Erratum to "Applicability of in vitro tests for skin irritation and corrosion to regulatory classification schemes: substantiating test strategies with data from routine studies" [Regul. Toxicol. Pharmacol. (2012) 402-414]. , 2013, Regulatory toxicology and pharmacology : RTP.

[16]  Robert Landsiedel,et al.  Non-animal test methods for predicting skin sensitization potentials , 2012, Archives of Toxicology.

[17]  Thomas Steger-Hartmann,et al.  Incorporation of in silico biodegradability screening in early drug development—a feasible approach? , 2011, Environmental science and pollution research international.

[18]  Wei Zhang,et al.  Green techniques for organic synthesis and medicinal chemistry , 2012 .

[19]  Robert Landsiedel,et al.  In-house Validation of the EpiOcular™ Eye Irritation Test and its Combination with the Bovine Corneal Opacity and Permeability Test for the Assessment of Ocular Irritation , 2011, Alternatives to laboratory animals : ATLA.

[20]  Thomas Hartung,et al.  Pathways of Toxicity. , 2014, ALTEX.

[21]  Miroslav Machala,et al.  Global gene expression changes in human embryonic lung fibroblasts induced by organic extracts from respirable air particles , 2012, Particle and Fibre Toxicology.

[22]  Judith Klein-Seetharaman,et al.  Carbon nanotubes degraded by neutrophil myeloperoxidase induce less pulmonary inflammation. , 2010, Nature nanotechnology.

[23]  Paul J Hergenrother,et al.  Glucose conjugation for the specific targeting and treatment of cancer. , 2013, Chemical science.

[24]  OECD GUIDELINE FOR THE TESTING OF CHEMICALS In Vitro Skin Sensitisation : human Cell Line Activation Test ( h-CLAT ) , 2017 .

[25]  Hequn Li,et al.  Use of the ES-D3 cell differentiation assay, combined with the BeWo transport model, to predict relative in vivo developmental toxicity of antifungal compounds. , 2015, Toxicology in vitro : an international journal published in association with BIBRA.

[26]  Thomas Hartung,et al.  Food for thought ... on alternative methods for nanoparticle safety testing. , 2010, ALTEX.

[27]  Steve Peers,et al.  The EU Charter of Fundamental Rights , 2014 .

[28]  Read-Across Assessment Framework (RAAF) , 2017 .

[29]  Klaus Kümmerer,et al.  Sustainable from the very beginning: rational design of molecules by life cycle engineering as an important approach for green pharmacy and green chemistry , 2007 .

[30]  Antonio Marcomini,et al.  Grouping and Read-Across Approaches for Risk Assessment of Nanomaterials , 2015, International journal of environmental research and public health.

[31]  Nicole Kleinstreuer,et al.  Supporting read-across using biological data. , 2016, ALTEX.

[32]  Sebastian Hoffmann,et al.  Food for thought ... on in silico methods in toxicology. , 2009, ALTEX.

[33]  Jong Hwan Sung,et al.  Using physiologically-based pharmacokinetic-guided “body-on-a-chip” systems to predict mammalian response to drug and chemical exposure , 2014, Experimental biology and medicine.

[34]  Ord Us Epa.  Toxicity ForeCaster (ToxCast™) Data , 2015 .

[35]  Daniel P. Russo,et al.  Global Analysis of Publicly Available Safety Data for 9,801 Substances Registered under REACH from 2008–2014 , 2016, ALTEX.

[36]  H. Spielmann,et al.  The embryonic stem cell test (EST), an in vitro embryotoxicity test using two permanent mouse cell lines : 3T3 fibroblasts and embryonic stem cells , 1997 .

[37]  Sharon Munn,et al.  Adverse outcome pathway (AOP) development I: strategies and principles. , 2014, Toxicological sciences : an official journal of the Society of Toxicology.

[38]  Steffen Foss Hansen,et al.  Nanotechnology — early lessons from early warnings , 2013 .

[39]  Markus Schulz,et al.  Refinement and Reduction of Acute Oral Toxicity Testing: A Critical Review of the Use of Cytotoxicity Data , 2011, Alternatives to laboratory animals : ATLA.

[40]  DRAFT REVISED,et al.  OECD GUIDELINE FOR THE TESTING OF CHEMICALS , 2010 .

[41]  Alexandra Maertens,et al.  Analysis of Publically Available Skin Sensitization Data from REACH Registrations 2008–2014 , 2016, ALTEX.

[42]  Thomas Steger-Hartmann,et al.  Trace analysis of the antineoplastics ifosfamide and cyclophosphamide in sewage water by twostep solid-phase extraction and gas chromatography-mass spectrometry , 1996 .

[43]  Reinhard Kreiling,et al.  A decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping). , 2015, Regulatory toxicology and pharmacology : RTP.

[44]  Hywel Morgan,et al.  NeuroChip: A Microfluidic Electrophysiological Device for Genetic and Chemical Biology Screening of Caenorhabditis elegans Adult and Larvae , 2013, PloS one.

[45]  Andrea E M Seiler,et al.  The validated embryonic stem cell test to predict embryotoxicity in vitro , 2011, Nature Protocols.

[46]  Martyn Poliakoff,et al.  The 24 Principles of Green Engineering and Green Chemistry: “IMPROVEMENTS PRODUCTIVELY” , 2008 .

[47]  J. W. Frost,et al.  Synthesis of Gallic Acid and Pyrogallol from Glucose: Replacing Natural Product Isolation with Microbial Catalysis , 2000 .

[48]  Cheryl A Murphy,et al.  Adverse outcome pathways and ecological risk assessment: Bridging to population‐level effects , 2011, Environmental toxicology and chemistry.

[49]  J. Sina,et al.  Bovine corneal opacity and permeability test: an in vitro assay of ocular irritancy. , 1992, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[50]  OECD GUIDELINE FOR THE TESTING OF CHEMICALS , 2016 .

[51]  J. Farman,et al.  Late lessons from early warnings: the precautionary principle 1896-2000 , 2002 .

[52]  Steve Peers,et al.  The EU Charter of Fundamental Rights: a commentary , 2014 .

[53]  Hao Zhu,et al.  Analysis of Draize Eye Irritation Testing and its Prediction by Mining Publicly Available 2008–2014 REACH Data , 2016, ALTEX.

[54]  도신 마우리치오,et al.  Biodegradable aliphatic-aromatic polyesters , 2006 .

[55]  J. G. Hengstler,et al.  Alternative methods to safety studies in experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH) , 2008, Archives of Toxicology.

[56]  Craig A Poland,et al.  Length-dependent pleural inflammation and parietal pleural responses after deposition of carbon nanotubes in the pulmonary airspaces of mice , 2012, Nanotoxicology.

[57]  Zuang Valerie,et al.  Alternative methods for regulatory toxicology – a state-of-the-art review , 2014 .

[58]  Hiroshi Itagaki,et al.  A Comparative Evaluation of In Vitro Skin Sensitisation Tests: The Human Cell-line Activation Test (h-CLAT) versus the Local Lymph Node Assay (LLNA) , 2010, Alternatives to laboratory animals : ATLA.

[59]  Test No. 438: Isolated Chicken Eye Test Method for Identifying i) Chemicals Inducing Serious Eye Damage and ii) Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage , 2018, OECD Guidelines for the Testing of Chemicals, Section 4.

[60]  P. Grandjean,et al.  Late lessons from early warnings: science, precaution, innovation , 2013 .

[61]  Richard A Becker,et al.  Read-across approaches--misconceptions, promises and challenges ahead. , 2014, ALTEX.

[62]  Christoph Studer,et al.  Sameness: The regulatory crux with nanomaterial identity and grouping schemes for hazard assessment. , 2015, Regulatory toxicology and pharmacology : RTP.

[63]  Antonio Novellino,et al.  Feasibility Assessment of Micro-Electrode Chip Assay as a Method of Detecting Neurotoxicity in vitro , 2011, Front. Neuroeng..

[64]  Petra S Kern,et al.  Assessing skin sensitization hazard in mice and men using non-animal test methods. , 2015, Regulatory toxicology and pharmacology : RTP.

[65]  Test Guideline No. 431 In Vitro Skin Corrosion: Reconstructed Human Epidermis (RhE)Test Method , 2016 .

[66]  Robert Landsiedel,et al.  LuSens: a keratinocyte based ARE reporter gene assay for use in integrated testing strategies for skin sensitization hazard identification. , 2014, Toxicology in vitro : an international journal published in association with BIBRA.

[67]  Paul Anastas,et al.  Green chemistry: principles and practice. , 2010, Chemical Society reviews.

[68]  Lang Tran,et al.  ITS-NANO - Prioritising nanosafety research to develop a stakeholder driven intelligent testing strategy , 2014, Particle and Fibre Toxicology.

[69]  Thomas Hartung,et al.  Chemical regulators have overreached , 2009, Nature.

[70]  Andrew Stirling,et al.  MTBE in petrol as a substitute for lead , 2002 .

[71]  David J. C. Constable,et al.  Perspective on Solvent Use in the Pharmaceutical Industry , 2007 .

[72]  Rachael M. Crist,et al.  Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity , 2012, Particle and Fibre Toxicology.

[73]  TG 442C.  OECD GUIDELINE FOR THE TESTING OF CHEMICALS In Chemico Skin Sensitisation : Direct Peptide Reactivity Assay ( DPRA ) , 2015 .

[74]  Robert Landsiedel,et al.  Linking energy metabolism to dysfunctions in mitochondrial respiration--a metabolomics in vitro approach. , 2011, Toxicology letters.

[75]  Julie B. Zimmerman,et al.  Green Chemistry and Green Engineering: A Framework for Sustainable Technology Development , 2011 .

[76]  T. Hartung.  Toxicology for the twenty-first century , 2009, Nature.

[77]  Thomas Steger-Hartmann,et al.  Investigations into the environmental fate and effects of iopromide (ultravist), a widely used iodinated X-ray contrast medium. , 2002, Water research.

[78]  Tatsuhiko Yamada,et al.  Multi-walled carbon nanotube induces nitrative DNA damage in human lung epithelial cells via HMGB1-RAGE interaction and Toll-like receptor 9 activation , 2016, Particle and Fibre Toxicology.

[79]  Alexandra Maertens,et al.  Green toxicology. , 2014, ALTEX.

[80]  Aldert Piersma,et al.  The ECVAM International Validation Study on In Vitro Embryotoxicity Tests: Results of the Definitive Phase and Evaluation of Prediction Models , 2002, Alternatives to laboratory animals : ATLA.

[81]  R Jelinek,et al.  Use of chick embryo in screening for embryotoxicity. , 1982, Teratogenesis, carcinogenesis, and mutagenesis.

[82]  Magnus Løfstedt,et al.  Guidance Document on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption , 2012 .

[83]  Joshua A. Harrill,et al.  In Vitro Assessment of Developmental Neurotoxicity: Use of Microelectrode Arrays to Measure Functional Changes in Neuronal Network Ontogeny1 , 2010, Front. Neuroeng..

[84]  Denis Lacombe,et al.  Glufosfamide: can we improve the process of anticancer agent development? , 2012, Expert opinion on investigational drugs.

[85]  Andrew Worth,et al.  Applying Adverse Outcome Pathways (AOPs) to support Integrated Approaches to Testing and Assessment (IATA). , 2014, Regulatory toxicology and pharmacology : RTP.

[86]  John Blacker,et al.  Pharmaceutical process development : current chemical and engineering challenges , 2011 .

[87]  Thomas Hartung,et al.  Alternative in vitro assays in nanomaterial toxicology. , 2011, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[88]  T Steger-Hartmann,et al.  Environmental risk assessment for the widely used iodinated X-ray contrast agent iopromide (Ultravist). , 1999, Ecotoxicology and environmental safety.

[89]  John W. Frost,et al.  SHIKIMIC ACID AND QUINIC ACID : REPLACING ISOLATION FROM PLANT SOURCES WITH RECOMBINANT MICROBIAL BIOCATALYSIS , 1999 .

[90]  Sebastian Hoffmann,et al.  Intra- and inter-laboratory reproducibility and accuracy of the LuSens assay: A reporter gene-cell line to detect keratinocyte activation by skin sensitizers. , 2016, Toxicology in vitro : an international journal published in association with BIBRA.

[91]  Thomas Steger-Hartmann.  In Silico Toxicology – Current Approaches and Future Perspectives to Predict Toxic Effects with Computational Tools , 2014 .

[92]  Valentina Siracusa,et al.  Biodegradable polymers for food packaging: a review , 2008 .

[93]  M. Plummer,et al.  International agency for research on cancer. , 2020, Archives of pathology.

[94]  Alexandra Maertens,et al.  t4 report: Toward Good Read-Across Practice (GRAP) Guidance , 2016, ALTEX.

[95]  Thomas Hartung,et al.  Green toxicology. , 2014, ALTEX.

[96]  Stephan Wagner,et al.  Spot the difference: engineered and natural nanoparticles in the environment--release, behavior, and fate. , 2014, Angewandte Chemie.

[97]  D. Herrmann,et al.  Synthetic Biodegradable Polymers , 2016 .

[98]  Peter Morfeld,et al.  Response to the Reply on behalf of the ‘Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area’ (MAK Commission) by Andrea Hartwig Karlsruhe Institute of Technology (KIT) , 2015, Particle and Fibre Toxicology.

[99]  Hasan Demir,et al.  Principles of Green Chemistry , 2019, Green Chemistry in Scientific Literature.

[100]  TG 442D.  OECD GUIDELINE FOR THE TESTING OF CHEMICALS In Vitro Skin Sensitisation: ARE-Nrf2 Luciferase Test Method , 2000 .

[101]  D. Ingber,et al.  From 3D cell culture to organs-on-chips. , 2011, Trends in cell biology.

[102]  Thomas Hartung,et al.  Making big sense from big data in toxicology by read-across. , 2016, ALTEX.

[103]  J. W. Frost,et al.  Environmentally compatible synthesis of catechol from D-glucose , 1995 .

[104]  Lewis Looper,et al.  Executive Agency for Health and Consumers , 2014 .

[105]  Richard A. Becker,et al.  Food for Thought ... Read-Across Approaches – Misconceptions , Promises and Challenges Ahead , 2014 .

[106]  Thomas Hartung,et al.  Re-evaluation of animal numbers and costs for in vivo tests to accomplish REACH legislation requirements for chemicals - a report by the transatlantic think tank for toxicology (t(4)). , 2009, ALTEX.

[107]  Reinhard Kreiling,et al.  Case studies putting the decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping) into practice. , 2016, Regulatory toxicology and pharmacology : RTP.

[108]  Thomas Braunbeck,et al.  Zebrafish (Danio rerio) embryos as a model for testing proteratogens. , 2011, Toxicology.

[109]  Alexandra Maertens,et al.  Analysis of Public Oral Toxicity Data from REACH Registrations 2008–2014 , 2016, ALTEX.

[110]  R. Müller,et al.  Biodegradable Aliphatic-Aromatic Polyesters: “Ecoflex®” , 2002 .

[111]  B. van Ravenzwaay,et al.  The use of metabolomics for the discovery of new biomarkers of effect. , 2007, Toxicology letters.

[112]  Will Watson.  Pharmaceutical Process Development: Current Chemical and Engineering Challenges , 2012 .

[113]  K Kümmerer,et al.  Biodegradability of antineoplastic compounds in screening tests: influence of glucosidation and of stereochemistry. , 2000, Chemosphere.