The role of chemistry in developing understanding of adverse outcome pathways and their application in risk assessment

The Adverse Outcome Pathway (AOP) conceptual framework has been presented as a logical sequence of events or processes within biological systems which can be used to understand adverse effects and refine the current risk assessment practice. This approach shifts the risk assessment focus from traditional apical endpoints to the development of a mechanistic understanding of a chemicals effect at a molecular and cellular level. In order to obtain this level of detail, chemistry in all its disciplines has a key role to play. Measurement techniques will be important in understanding chemical characterisation, free concentration and exposure at the site of interest. Such measurements will be vital in developing structure-based toxicological alerts and informing predictive models. This paper explores the areas where chemistry will be influential in the development of AOPs.

[1]  Robert J. Kavlock The future of toxicity testing—The NRC vision and the EPA's ToxCast program national center for computational toxicology , 2009 .

[2]  Menghang Xia,et al.  Mechanism-based testing strategy using in vitro approaches for identification of thyroid hormone disrupting chemicals. , 2013, Toxicology in vitro : an international journal published in association with BIBRA.

[3]  C. Russom,et al.  Predicting modes of toxic action from chemical structure: Acute toxicity in the fathead minnow (Pimephales promelas) , 1997 .

[4]  Frank Gerberick,et al.  Nothing is perfect, not even the local lymph node assay: a commentary and the implications for REACH , 2009, Contact dermatitis.

[5]  Melvin E. Andersen,et al.  Physiologically Based Pharmacokinetic Modeling : Science and Applications , 2005 .

[6]  J. Blake,et al.  On the Connection between Chemical Constitution and Physiological Action , 1886, Nature.

[7]  M T D Cronin,et al.  A review of the electrophilic reaction chemistry involved in covalent protein binding relevant to toxicity , 2011, Critical reviews in toxicology.

[8]  David W. Roberts,et al.  A Minireview of Available Skin Sensitization (Q)SARs/Expert Systems , 2008 .

[9]  M. Cronin,et al.  Pitfalls in QSAR , 2003 .

[10]  A. C. Brown,et al.  V.—On the Connection between Chemical Constitution and Physiological Action. Part. I.—On the Physiological Action of the Salts of the Ammonium Bases, derived from Strychnia, Brucia, Thebaia, Codeia, Morphia, and Nicotia , 1870, Transactions of the Royal Society of Edinburgh.

[11]  J. Hermens,et al.  Classifying environmental pollutants , 1992 .

[12]  Bas J Blaauboer,et al.  The use of biomarkers of toxicity for integrating in vitro hazard estimates into risk assessment for humans. , 2012, ALTEX.

[13]  Yuri Dancik,et al.  Design and performance of a spreadsheet-based model for estimating bioavailability of chemicals from dermal exposure. , 2013, Advanced drug delivery reviews.

[14]  D. Dixon,et al.  Methodology for demonstrating and measuring the photocytotoxicity of fluoranthene to fish cells in culture. , 1997, Toxicology in vitro : an international journal published in association with BIBRA.

[15]  Rolf Altenburger,et al.  Physicochemical substance properties as indicators for unreliable exposure in microplate-based bioassays. , 2007, Chemosphere.

[16]  M. E. Hahn,et al.  Serum alters the uptake and relative potencies of halogenated aromatic hydrocarbons in cell culture bioassays. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[17]  Hasso Seibert,et al.  Impact of protein binding on the availability and cytotoxic potency of organochlorine pesticides and chlorophenols in vitro. , 2002, Toxicology.

[18]  A. Natsch,et al.  Use of in vitro testing to identify an unexpected skin sensitizing impurity in a commercial product: a case study. , 2010, Toxicology in vitro : an international journal published in association with BIBRA.

[19]  J. Pawliszyn,et al.  Evolution of solid-phase microextraction technology. , 2000, Journal of chromatography. A.

[20]  G Patlewicz,et al.  Global (Q)SARs for skin sensitisation–assessment against OECD principles , 2007, SAR and QSAR in environmental research.

[21]  Minne B Heringa,et al.  Toward more useful in vitro toxicity data with measured free concentrations. , 2004, Environmental science & technology.

[22]  H Seibert,et al.  Factors influencing nominal effective concentrations of chemical compounds in vitro: medium protein concentration. , 2002, Toxicology in vitro : an international journal published in association with BIBRA.

[23]  Ivan Rusyn,et al.  In vitro models for liver toxicity testing. , 2013, Toxicology research.

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

[25]  Judith C. Madden,et al.  In silico toxicology : principles and applications , 2010 .

[26]  Kannan Krishnan,et al.  Cutting Edge PBPK Models and Analyses: Providing the Basis for Future Modeling Efforts and Bridges to Emerging Toxicology Paradigms , 2012, Journal of toxicology.

[27]  J B Houston,et al.  The Integrated Use of Alternative Methods in Toxicological Risk Evaluation , 1999, Alternatives to laboratory animals : ATLA.

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

[29]  Valérie Zuang,et al.  Alternative (non-animal) methods for cosmetics testing: current status and future prospects—2010 , 2011, Archives of Toxicology.

[30]  Andrew P Worth,et al.  Report of the Workshop on the Validation of QSARs and Other Computational Prediction Models , 2004, Alternatives to laboratory animals : ATLA.

[31]  R Kroes,et al.  The threshold of toxicological concern concept in risk assessment. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[32]  S. Ulrich Solid-phase microextraction in biomedical analysis. , 2000, Journal of chromatography. A.

[33]  Cameron MacKay,et al.  Determining epidermal disposition kinetics for use in an integrated nonanimal approach to skin sensitization risk assessment. , 2011, Toxicological sciences : an official journal of the Society of Toxicology.

[34]  B Ekwall,et al.  Overview of the Final MEIC Results: II. The In Vitro--In Vivo Evaluation, Including the Selection of a Practical Battery of Cell Tests for Prediction of Acute Lethal Blood Concentrations in Humans. , 1999, Toxicology in vitro : an international journal published in association with BIBRA.

[35]  Uwe Marx,et al.  ‘Human-on-a-chip’ Developments: A Translational Cutting-edge Alternative to Systemic Safety Assessment and Efficiency Evaluation of Substances in Laboratory Animals and Man? , 2012, Alternatives to laboratory animals : ATLA.

[36]  Harvey J Clewell,et al.  Quantitative in vitro to in vivo extrapolation of cell-based toxicity assay results , 2012, Critical reviews in toxicology.

[37]  R. Altenburger,et al.  How to deal with lipophilic and volatile organic substances in microtiter plate assays , 2008 .

[38]  Bas J Blaauboer,et al.  Biokinetic Modeling and in Vitro–in Vivo Extrapolations , 2010, Journal of toxicology and environmental health. Part B, Critical reviews.

[39]  K. Krishnan,et al.  QSARs for PBPK modelling of environmental contaminants , 2011, SAR and QSAR in environmental research.

[40]  S. Bradbury,et al.  Quantitative structure-activity relationships and ecological risk assessment: an overview of predictive aquatic toxicology research. , 1995, Toxicology letters.

[41]  J. Bailar,et al.  Toxicity Testing in the 21st Century: A Vision and a Strategy , 2010, Journal of toxicology and environmental health. Part B, Critical reviews.

[42]  Bas J Blaauboer,et al.  Quantifying processes determining the free concentration of phenanthrene in Basal cytotoxicity assays. , 2012, Chemical research in toxicology.