S10 Abstracts / Toxicology Letters 229S (2014) S4–S21

Symposia 5: Application of AOP/MOA-based approaches inchemical risk assessment

PS4.1-O1Evolution of mode of action/adverse outcomepathway analyses

M.E. (Bette) Meek

University of Ottawa, Ottawa, Canada

The World Health Organization/International Programme onChemical Safety (IPCS) mode of action/human relevance (MOA/HR)framework has been updated to reflect evolving experience inits application and to incorporate recent developments in toxic-ity testing and predictive modeling at different levels of biologicalorganization. The modified framework is incorporated within aniterative roadmap, encouraging continuous refinement of prob-lem formulation and mode of action based (integrated) testing andassessment strategies.

The framework can be used as originally envisaged, wherethe outcome of chemical exposure is known, or in hypothesizingpotential effects resulting from exposure, based on information onputative key events in established modes of action from appro-priate in vitro or in silico systems and other evidence. The updateincludes illustration of MOA analysis in various case examples suchas prioritizing substances for further testing, the development ofmore efficient testing strategies and addressing read-across for pri-ority setting and combined exposures.

Weight of evidence considerations for hypothesized MOAs havebeen developed additionally in the update and more recentlyevolved as a basis to contribute to the revision of guidance andelectronic tools for an international knowledge base on adverseoutcome pathways (AOPs) being developed for an initiative of theOrganization for Economic Cooperation and Development (OECD).

http://dx.doi.org/10.1016/j.toxlet.2014.06.063

PS4.1-O2AOP strategy: shaping the future for humanhealth and environmental risk assessment

Maurice Whelan

European Commission Joint Research Centre,Institute for Health andConsumer Protection, Ispra, Italy

The aim of AOP strategy is to provide an effective and efficientmeans to gather, integrate and curate mechanistic toxicologicalknowledge in order to make it available in a readily usable formto a wide range of actors in the risk assessment domain. Use-casesof suitably packaged knowledge are many, including the ratio-nale design of Integrated Approaches to Testing and Assessment(IATA), reinforcing chemical categories and read-across, the devel-opment of computational predictive toxicology tools, extrapolationacross species or life-stages, and the framing weight-of-evidenceanalysis in chemical assessment. The desire to make better use ofmechanistic-based reasoning in the risk assessment of chemicalshas been around for decades and there are numerous practitionersthat have successfully demonstrated the feasibility and effective-ness of bring toxicological knowledge to bear in decision-making.However widespread transitioning to a truly knowledge-basedparadigm for human health and environmental risk assessment hasbeen severely impeded by the fact that the collective knowledgeon toxicology is highly dispersed, primarily between hundreds ofthousands of articles in the scientific literature. Thus mining and

application of mechanistic knowledge for the purposes of chem-ical testing and assessment remains a rather specialist disciplineapplied in an ad hoc manner. The primary goal therefore of theAOP Development Program of the OECD is to provide a scientifi-cally sound yet practical framework for the harvesting, curation anddissemination of toxicological knowledge of relevance to the riskassessment community, and to support the international rollout ofthis framework with a suite of knowledge-management guidanceand tools.

http://dx.doi.org/10.1016/j.toxlet.2014.06.064

PS4.1-O3Bradford Hill criteria still needed: Applicationsto MoA elucidation, low dose evaluation andadverse outcome pathway

David Rouquié

Bayer CropScience, Sophia Antipolis, France

Data obtained in Mode of Action (MoA) investigations based onthe framework developed by the IPCS/WHO are increasingly gener-ated to support the submission of phytopharmaceutical dossiers toregulatory authorities. The framework follows a scientific approachwhich favors a more transparent evaluation of the MoA leadingto adverse effects induced by chemicals in laboratory animals andthe relevance of these effects to humans. These principles are nowbeing also applied to the on-going OECD initiative aiming at compil-ing known Adverse Outcome Pathways (AOP). In this presentation,two case studies will be presented one describing the elucidation ofthe MoA for a thyroid carcinogen in the mouse and a second describ-ing the application of MoA investigations to the characterization oflow dose effect of a reference endocrine disruptor in the rat. More-over, as suggested by a recent ECETOC task force, a proposal for aninternational database of known MoA obtained in laboratory ani-mals using data rich chemicals will be presented and its potentialto facilitate the regulatory acceptance of the toxicity pathway andAOP concepts will be discussed.

http://dx.doi.org/10.1016/j.toxlet.2014.06.065

PS4.1-O4Applying the skin sensitisation AOP to humanhealth risk assessment

Gavin Maxwell ∗, Richard Cubberley, Seraya Dhadra, NicholaGellatly, Sandrine Jacquoilleot, Craig Moore, Ruth Pendlington,Juliette Pickles, Ouarda Saib, David Sheffield, Richard Stark, VickiSummerfield, Cameron MacKay

Safety and Environmental Assurance Centre (SEAC), Unilever,Sharnbrook, Bedfordshire, UK

Mechanistic understanding of the key events that drive skin sen-sitisation has recently been documented as an AOP and a range ofdata integration approaches have been proposed to characterisesensitiser potential or potency using non-animal test method data.Despite this progress our ability to combine these non-animal haz-ard data with exposure information to inform risk assessmentdecisions (i.e. to establish a safe level of human exposure for asensitising chemical) remains a key gap. Our aim is to apply ourmechanistic understanding of skin sensitisation to improve ourability to make risk assessment decisions. Central to our approachis mathematical modelling of the response and evaluation of modeloutput against available clinical data on sensitisation.

Abstracts / Toxicology Letters 229S (2014) S4–S21 S11

Our current model outputs naïve CD8+ T cell activation as a sur-rogate measure for sensitisation induction in humans. Ordinarydifferential equations are used to model key events of the AOP:skin penetration (chemical diffusion and partitioning), haptenationof protein nucleophiles and antigen processing and presentationby skin dendritic cells. Biological parameters are taken from theimmunological literature with human data used where possible.Bioavailability and chemical-specific parameters are derived frombespoke in vitro experiments and from sensitiser-specific literature.The model has been used to simulate a study published in 1983 byFriedmann et al. in which 132 healthy volunteers were exposed toone of five doses of the contact allergen 2,4-dinitrochlorobenzene.Comparison is made between simulation results and this clinicaldata. Clinical research and additional modelling is currently under-way to inform future model development.

http://dx.doi.org/10.1016/j.toxlet.2014.06.066

PS4.1-O5Conclusions and discussion

Alan Boobis

Imperial College London, London, UK

The mode of action (MOA) and adverse outcome pathway (AOP)concepts had their origins in ecotoxicology and in mammalian-based risk assessment, respectively. However, there has beensubstantial convergence of the approaches for human health riskassessment and in this respect an AOP is essentially indistinguish-able from a MOA for a toxic effect. Establishment of a MOA/AOPrequires identification of necessary and measurable key events,including the molecular initiating event if possible, the use ofweight of evidence based on modified Bradford Hill considerationsfor evaluation of key events, the rigorous exclusion of alternativepathways, the biological linkage of key events to an adverse out-come and the systematic qualitative and quantitative comparisonof key events in model systems with those in humans, as appro-priate. The MOA/AOP approach is seeing increasing application forboth cancer and non-cancer endpoints, the quantitative informa-tion obtained on key events being invaluable in dose-responseassessment for human risk. International initiatives are under-way to agree the core information necessary to establish a robustMOA/AOP, and for the creation of a central repository of suchMOAs/AOPs. MOAs/AOPs are proving invaluable in the design ofnew evaluation methods and as a bridge to systems approaches torisk assessment. A key challenge is the use of information obtainedusing non-animal methods (computational and in vitro) to con-struct MOAs/AOPs that are reliably predictive of adverse effects invivo.

http://dx.doi.org/10.1016/j.toxlet.2014.06.067

Symposia 6 – Nanotoxicology/nanosafety

PS4.2-O1Understanding the basis of pulmonary toxicityof high aspect respirable particles

Craig Poland

Institute of Occupational Medicine, Edinburgh, UK

Fibres developed for industrial purposes have long since engen-dered an air of suspicion as to the potential long term healtheffects should inadvertent exposure occur and this is due to the

long term legacy of asbestos use. Whilst this has been the case fornumerous fibres which have been developed such as man-madevitreous fibres, silicon carbide, and para-aramid; more recentlysuch concerns have focused on the risks of fibrous nanomateri-als. Comparative toxicological analyses of different types of fibreshave identified key physicochemical properties which can affectthe propensity of a fibre to pose a respiratory hazard. Here wepresent these properties and how they may be mitigated to reducethe toxicity of fibrous nano-materials based on evidence from car-bon nanotubes, titanium dioxide nanowires as well as other fibrousnanomaterials to produce materials that are inherently safer forworkers and consumers.

Whilst attention has focused on nano-fibres due to theirmorphological similarity to other hazardous fibres, many of theproperties that dictate fibre pathogenicity are relevant to othernon-fibrous nanomaterials. Of these properties, a low aerodynamicdiameter is crucial for the respirability of particulates but as hasbeen shown for fibres, a low aerodynamic diameter can be com-patible with a high aspect ratio as can be seen with platelet-likeparticles such as graphene. This raises concerns that new highaspect (i.e. physically large) particles that possess a low enoughaerodynamic diameter to allow alveolar deposition may presentmany of the risks to respiratory health seen with pathogenicfibres.

http://dx.doi.org/10.1016/j.toxlet.2014.06.069

PS4.2-O2“Safe-by-design” and “toxic-by design”, twoapproaches for design of novel functionalnanomaterials

Angela Ivask 1, Katre Juganson 1, Olesja Bondarenko 1,Meeri Visnapuu 2, Kaja Kasemets 1,∗, Anne Kahru 1

1 National Institute of Chemical Phyiscs and Biophysics, Tallinn,Estonia, 2 Institute of Physics, University of Tartu, Tartu, Estonia

Nanotechnologies have big expectations in almost everyindustrial domain, from energy production to medicine orfood. According to US Project on Emerging Nanotechnologies(http://www.nanotechproject.org/consumerproducts) and DanishNanodatabase (http://nanodb.dk/) there are more than one thou-sand nanomaterial-containing consumer products available onthe market today. The great expectations for nanotechnology arebased on novel properties that materials assume at the nanoscale(1–100 nm) due to increased relative surface area and resultingsurface reactivity. However, the novel physico-chemical proper-ties those are responsible for technological breakthroughs couldalso lead to increased bioavailability and toxicity of engineerednanomaterials. Therefore, for sustainable development of nan-otechnologies it is important to harmonize developments inmaterial science and safety studies. In this paper, we discuss hownanomaterials′ physico-chemical properties influence their biolog-ical effects and how to use these knowledge for “safe-by design”and “toxic-by-design” in nanotechnology. The latter is of particularimportance as about 30% of nanomaterials are developed for e.g.,antimicrobial applications in hygiene or medical products whiletheir safety to humans need to be assured. We illustrate the “safe-bydesign” and “toxic-by-design” approaches for silver, titanium- andzinc oxide nanomaterials with our own results and data from theliterature. In addition, a biological tool-box, a suite of in vitro meth-ods using various test bacteria and mammalian cells for targetedtesting of functional nanomaterials will be presented. Financialsupport from Estonian Research Council projects IUT-23, ETF8561,