SCOPE NOTE Drug safety includes adverse events, immunogenicity, cardiotoxicity, hepatotoxicity, neurotoxicity, nephrotoxicity, toxicology, Phase IV/pharmacovigilance post marketing surveillance, preclinical drug safety.

Related glossaries include Biomarkers   Clinical trials   Pharmacogenomics   Regulatory

adverse drug event ADE:  Recently, another more inclusive term, Adverse Drug Event (ADE) has come into use. According to Bates et al, the term ADE, defined as an injury resulting from medical intervention related to a drug, is preferred since it is more comprehensive and clinically significant than the ADR. (JAMA 1995;274:29- 34). Saeed A Khan, "Drug Interaction or Adverse Drug Reaction? Confusing Terms", British Medical Journal 10 July, 1998  http://www.bmj.com/rapid-response/2011/10/27/drug-interaction-or-adverse-drug-reaction-confusing-terms
Related terms: adverse drug reaction ADR, drug interaction. See also pharmacovigilance, post-marketing surveillance 

adverse effect: Change in biochemistry, physiology, growth, development morphology, behavior, or lifespan of an organism which results in impairment of functional capacity or impairment of capacity to compensate for additional stress or increase in susceptibility to other environmental influences. Change in biochemistry, physiology, growth, development morphology, behavior, or lifespan of an organism which results in impairment of functional capacity or impairment of capacity to compensate for additional stress or increase in susceptibility to other environmental influences.  IUPAC Toxicology

adverse event terminology, Norman GoldFarb 2012 Journal of Clinical Research Best Practices http://firstclinical.com/journal/2012/1207_Adverse.pdf 

adverse drug reaction ADR:  ADRs may include drug interactions as one of many causes but the reverse is not true. The reader is cautioned regarding usage of drug reaction terms as multiple nearly- similar terms of varying granularity abound. .. "An adverse reaction to a drug has been defined as any noxious or unintended reaction to a drug that is administered in standard doses by the proper route for the purpose of prophylaxis, diagnosis, or treatment(2). However, WHO's original definition of ADR excluded therapeutic failures, intentional and accidental poisoning and drug abuse, as well as adverse events due to medication errors such as drug administration or non- compliance(1) ... Due to non- uniform usage of these terms, it is sometimes difficult to compare various studies and derive incidence rates, etc. for ADRs, and Drug Interactions. Saeed A Khan, "Drug Interaction or Adverse Drug Reaction? Confusing Terms", British Medical Journal 10 July, 1998 http://bmj.com/cgi/eletters/316/7149/1930

We define an adverse drug reaction as "an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product." Such reactions are currently reported by use of WHO's Adverse Reaction Terminology, which will eventually become a subset of the International Classification of Diseases. Adverse drug reactions are classified into six types (with mnemonics): dose-related (Augmented), non-dose-related (Bizarre), dose-related and time-related (Chronic), time-related (Delayed), withdrawal (End of use), and failure of therapy (Failure).  Edwards, IR; Aronson JK,  Adverse Drug Reactions, Definitions, Diagnosis and Management, Lancet 356(9237): 1255- 1259, 2000 Oct 7

Wikipedia http://en.wikipedia.org/wiki/Adverse_drug_reaction   Related terms: adverse drug event ADE, drug interaction  

Ames test: This test for genotoxicity, developed in the 1970s, determines the reversion of a mutant his gene in Salmonella typhimurium when exposed to a genotoxic agent that causes base changes affecting the mutant gene.

antedrugs: The antedrug concept was introduced by Lee and Soliman in 1982 in designing potent, yet safer locally active anti-inflammatory steroids. Antedrug  is defined as an active synthetic derivative that is designed to undergo biotransformation to the readily excretable inactive form upon entry in the systemic circulation, thus  minimizing systemic side effects and increasing the therapeutic indices  MO Khan et al   Antedrugs: an approach to safer drugs, Current Med Chem 2005;12(19): 2227-2239

biochemical toxicology: Of particular interest [to the Journal of Biochemical and Molecular toxicology] are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology. Journal of Biochemical and Molecular Toxicology, Wiley Periodicals http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1099-0461/homepage/ProductInformation.html 

cardiotoxicity: At least 50 companies have a claimed product or service relevant to cardiotoxicity screening, of which 29 have some clear focus on proarrhythmic cardiotoxicity or ion channel screening. ... Ion currents across a cardiac myocyte cell membrane cause a sequence of voltage changes known as the action potential, which is the basis of the heartbeat.  Drug-mediated interference with one or more of the ion channels that give rise to the action potential may cause potentially lethal arrhythmias. This could be brought about by direct binding of drug to ion channel proteins, or by indirect interference with ion channel function. The clinical outcome of drug-ion channel interactions could be potentiated by a variety of predisposing factors, such as concurrent disease, medication, genetic variations, age, and gender. Insight Pharma Reports, Cardiotoxicity issues, technologies and solutions for the future, 2008 

Cardiotoxicity is one of the major forms of toxicity seen in drugs and it accounts for most drug recalls and delays experienced in regulatory approvals. While improvements in experimental and clinical trial design have helped with better detection of cardiac toxicity in drug candidates, the problem still persists and often goes unnoticed until the compound is further along in development or has reached the market. 

computational toxicology: Tens of thousands of chemicals are currently in use, and hundreds more are introduced every year. Because current chemical testing is expensive and time consuming, only a small fraction of chemicals have been evaluated fully for potential human health effects.  EPA’s National Center for Computational Toxicology is working to figure out how to change the current approach used to evaluate the safety of chemicals. NCCT researchers integrate advances in biology, biotechnology, chemistry, and computer science to identify important biological processes that may be disrupted by the chemicals. http://www.epa.gov/ncct/comptoxfactsheet.html 

drug metabolites: Guidance for Industry, Safety testing of drug metabolites, FDA, 2008 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079266.pdf 

drug safety: Improving products’ effective clinical safety will increase the industry’s fundamental value proposition to patients, healthcare providers, payors and regulators. The program will focus on pharmacovigilance program implementation and specific strategies and approaches to creating true value from a peri- and post-approval drug safety program. Drug safety programs and monitoring and the approach of this conference are not to look at safety in the silos of early-phase safety or post-approval safety but to view safety holistically, across the lifecycle, especially at the transition from approval to broader use in the marketplace.  Narrower terms: pharmacovigilance, Phase IV, post approval drug safety, preclinical drug safety

Drug Safety & Availability, FDA  http://www.fda.gov/Drugs/DrugSafety/default.htm  Information for consumers and health professionals on new drug warnings and other safety information, drug label changes, and shortages of medically necessary drug products.


CDER Drug Safety Priorities, FDA 2017 https://www.fda.gov/downloads/Drugs/DrugSafety/UCM605229.pdf

EMA: European Medicines Agency http://www.ema.europa.eu/ema/  Was EMEA.

ecotoxicogenomics: Understanding the biological effects of exposures to chemicals in the environment relies on classical methods and emerging technologies in the areas of genomics, proteomics, and metabonomics. Linkages between the historical and newer toxicological tools are currently being developed in order to predict and assess risk. Being able to classify chemicals and other stressors based on effects they have at the molecular, tissue, and organismal levels helps define a systems biology approach to development of streamlined, cost-effective, and comprehensive testing approaches for evaluating environmental hazards. AL Miracle, GT Ankley, Ecotoxicogenomics: linkages between exposure and effects in assessing risks of aquatic contaminants to fish. Reprod Toxicol 19(3): 321- 326, Jan- Feb 2005 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15686867&query_hl=23

ecotoxicology:  To facilitate the application of chemistry in ecotoxicology, there is a need for a glossary addressing the terms in ecotoxicology essential for communication between the disciplines. This project will create such a glossary, reflecting IUPAC's concern about the impact of chemicals on health and the environment. It will also complement the previous projects which resulted in glossaries in toxicology and toxicokinetics. IUPAC, Glossary of terms used in ecotoxicology media.iupac.org/publications/pac/2009/pdf/8105x0829.pdf
Wikipedia http://en.wikipedia.org/wiki/Ecotoxicology  

ED 50:  Abbreviation for median effective dose. 

endocrine disruptors:  chemicals that can interfere with endocrine (or hormone) systems at certain doses. These disruptions can cause cancerous tumors, birth defects, and other developmental disorders.[1] Any system in the body controlled by hormones can be derailed by hormone disruptors. Specifically, endocrine disruptors may be associated with the development of learning disabilities, severe attention deficit disorder, cognitive and brain development problems; deformations of the body (including limbs); breast cancer, prostate cancer, thyroid and other cancers; sexual development problems such as feminizing of males or masculinizing effects on females, etc.[2]

Recently the Endocrine Society released a statement on endocrine-disrupting chemicals (EDCs) specifically listing obesity, diabetes, female reproduction, male reproduction, hormone-sensitive cancers in females, prostate cancer in males, thyroid, and neurodevelopment and neuroendocrine systems as being affected biological aspects of being exposed to EDCs.[3] The critical period of development for most organisms is between the transition from a fertilized egg into a fully formed infant. As the cells begin to grow and differentiate, there are critical balances of hormones and protein changes that must occur. Therefore, a dose of disrupting chemicals may do substantial damage to a developing fetus. The same dose may not significantly affect adult mothers. Wikipedia accessed 2018 Nov 19 https://en.wikipedia.org/wiki/Endocrine_disruptor 

evidence based toxicology: This paper identifies deficiencies in some current practices of causation and risk evaluation by toxicologists and formulates an evidence-based solution. The practice of toxicology focuses on adverse health events caused by physical or chemical agents. Some relations between agents and events are identified risks, meaning unwanted events known to occur at some frequency. However, other relations that are only possibilities--not known to occur (and may never be realized) --also are sometimes called risks and are even expressed quantitatively. The seemingly slight differences in connotation among various uses of the word 'risk' conceal deeply philosophic differences in the epistemology of harm. We label as 'nomological possibilities' (not as risks) all predictions of harm that are known not to be physically or logically impossible. Some of these nomological possibilities are known to be causal. We term them 'epistemic'. Epistemic possibilities are risks. The remaining nomological possibilities are called 'uncertainties'. Distinguishing risks (epistemic relationships) from among all nomological possibilities requires knowledge of causation. Causality becomes knowable when scientific experiments demonstrate, in a strong, consistent (repeatable), specific, dose-dependent, coherent, temporal and predictive manner that a change in a stimulus determines an asymmetric, directional change in the effect.  Evidence-based toxicology: a comprehensive framework for causation, Guzelian PS, Victoroff MS, Halmes NC, James RC, Guzelian CP., Hum Exp Toxicol. 2005 Apr;24(4): 161-201 

FDA: Every day the Food and Drug Administration (FDA) works to balance expeditious access to drugs with concerns for safety, consonant with its mission to protect and advance the public health. The task is all the more complex given the vast diversity of patients and how they respond to drugs, the conditions being treated, and the range of pharmaceutical products and supplements patients use. Reviewers in the Center for Drug Evaluation and Research (CDER) at the FDA must weigh the information available about a drug’s risk and benefit, make decisions in the context of scientific uncertainty, and integrate emerging information bearing on a drug’s risk-benefit profile throughout the lifecycle of a drug, from drug discovery to the end of its useful life. These processes may have life-or-death consequences for individual patients, and for drugs that are widely used, they may also affect entire segments of the population.  Future of Drug Safety: Promoting and Protecting the Health of the Public, National Academies Press, 2007 http://books.nap.edu/openbook.php?record_id=11750&page=1 

good pharmacovigilance practice:  EMA http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000345.jsp

hepatotoxicity: Wikipedia http://en.wikipedia.org/wiki/Hepatotoxicity   

idiosyncratic drug reactions, also known as type B reactions, are drug reactions that occur rarely and unpredictably amongst the population. This is not to be mistaken with idiopathic, which implies that the cause is not known. They frequently occur with exposure to new drugs, as they have not been fully tested and the full range of possible side-effects have not been discovered; they may also be listed as an adverse drug reaction with a drug, but are extremely rare. Wikipedia accessed August 12, 2018 https://en.wikipedia.org/wiki/Idiosyncratic_drug_reaction

idiosyncratic toxicity: The primary role of Phase IV post marketing surveillance is to detect rare or idiosyncratic adverse events that do not manifest in the population sizes common to clinical trials ... While clinical forecasting is aimed at predicting safety and efficacy early in the drug development process, rare or idiosyncratic toxicities can only be detected in Phase IV.  There, Phase IV serves as a very important safety net, to catch problems that could not be predicted.  Insight Pharma Reports, Bayesian Forecasting of Phase III Outcomes: The Next Wave in Predictive Tools, June 2007   

Few drug development surprises can be as devastating as toxicity problems that only show up under a combination of conditions as idiosyncratic toxicity. Because of the role of variations in human drug metabolizing enzymes there may only be subtle (or no) evidence of such problems during pre-clinical safety studies. Such problems are also unlikely to show up in all but the largest clinical trials, but if the side effects are serious, it can result in product withdrawal.   

immunogenicity: is the ability of a particular substance, such as an antigen or epitope, to provoke an immune response in the body of a human or animal. In other words, immunogenicity is the ability to induce a humoral and/or cell-mediated immune responses. https://en.wikipedia.org/wiki/Immunogenicity  accessed 2017 Oct 16

Immunogenicity Assessment and Regulatory Approval of Biologics Achieving Assay Quality and Clinical Success of Novel Biologics APRIL 10-11, 2019 BOSTON MA Immunogenicity has always been a critical safety concern, especially when many biotherapeutics are becoming increasingly complex. Understanding and controlling immunogenicity-related risks are essential in the development of biotherapeutics to ensure meeting the regulatory requirements. The 12^th Annual Immunogenicity Assessment and Regulatory Approval of Biologics conference brings industry, regulatory and scientific experts together to share best practices in assessing immunogenicity of novel biologics along with biosimilar products. The session will also discuss the challenges and solutions for addressing new regulatory guidelines in assay development and validation for cell and gene therapies. http://www.pegsummit.com/Immunogenicity/

Immunogenicity Case Studies and Clinical Management Interpretation and Understanding of Immunogenicity Data in Clinical Settings APRIL 8-9, 2019 BOSTON MA As the immunogenicity field is moving forward, closing the gap between clinicians and assay developers is essential in the success of biologic development and accelerates the adoption of new biologic therapies in patient treatments. This year, CHI’s Immunogenicity Case Studies and Clinical Management conference will focus on new case studies of novel biologics and emphasize on closing this gap by providing multiple viewpoints from clinicians, technology developers and regulators on how to use immunogenicity data in clinical settings.  http://www.pegsummit.com/Immunogenicity-Mitigation/

immunoinformatics: the application of informatics techniques to molecules of the immune system. One of the key goals of immunoinformatics is the development of computer aided vaccine design (CAVD), or computational vaccinology, and its application to the search for new vaccines. Key to solving this challenge is the prediction of immunogenicity, be that at the level of epitope, subunit vaccine or attenuated pathogen. Flower DR, Doytchinova IA Immunoinformatics and the prediction of immunogenicity Appl Bioinformatics. 2002;1(4):167-176  http://www.ncbi.nlm.nih.gov/pubmed/15130835 .

immunotoxicology: The primary objective of this “Glossary of Terms Used in Immunotoxicology” is to give clear definitions for those who contribute to studies relevant to immunotoxicology but are not themselves immunologists. This applies especially to chemists who need to understand the literature of immunology without recourse to a multiplicity of other glossaries or dictionaries. The glossary includes terms related to basic and clinical immunology insofar as they are necessary for a self-contained document, and particularly terms related to diagnosing, measuring, and understanding effects of substances on the immune system. The glossary consists of about 1200 terms as primary alphabetical entries, and Annexes of common abbreviations, examples of chemicals with known effects on the immune system, autoantibodies in autoimmune disease, and therapeutic agents used in autoimmune disease and cancer. IUPAC mmunotoxicology recommendations, 2012  https://www.iupac.org/publications/pac/84/5/1113/

LD 50:  The dose of a substance that will kill half (50%) of the treated test animals when given as a single dose.  A measure of acute toxicity. Chemical Hygiene Glossary of Terms, Environment, Health & Safety Lab, Lawrence Berkeley National Laboratory, US

Lead Optimization for Drug Metabolism & Safety Tools and Strategies for Predicting, Evaluating and Building Safety into Drug Design APRIL 12, 2019 San Diego CA The more chemists know about how the structure of a compound can possibly impact its drug-like properties, the faster they can optimize it for drug development. Lead compounds in drug discovery need to be optimized for both efficacy and safety. Unfortunately, some of the adverse events related to drug metabolism, clearance, and drug-drug interactions (DDI) do not surface until much later in drug development. This unique one-day symposium on Lead Optimization for Drug Metabolism & Safety will bring together experts from chemistry, ADME, DMPK and pharmacology to talk about some of the factors that must be considered early in lead optimization, particularly for addressing safety concerns. https://www.drugdiscoverychemistry.com/lead-optimization/

metabolite: A compound derived from the parent drug through Phase I and/or Phase II metabolic pathways, Glossary,  Guidance for Industry, Safety testing of drug metabolites, FDA, 2016 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079266.pdf 

Any intermediate or product resulting from metabolism. IUPAC  International Union of Pure and Applied Chemistry, Glossary for Chemists of terms used in biotechnology. Recommendations, Pure & Applied Chemistry 64 (1): 143-168, 1992  See also Metabolic Profiling

molecular toxicology:  The scope [of the Journal of Biochemical and Molecular Toxicology] includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, activation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology. Journal of Biochemical and Molecular Toxicology, Wiley Periodicals http://www3.interscience.wiley.com/cgi-bin/jabout/38998/ProductInformation.html

nanotoxicology: Nanotoxicology invites contributions addressing research relating to the potential for human and environmental exposure, hazard and risk associated with the use and development of nano-structured materials. In this context, the term nano-structured materials has a broad definition, including ‘materials with at least one dimension in the nanometer size range’. These nanomaterials range from nanoparticles and nanomedicines, to nano-surfaces of larger materials and composite materials. The range of nanomaterials in use and under development is extremely diverse, so this journal includes a range of materials generated for purposeful delivery into the body (food, medicines, diagnostics and prosthetics), to consumer products (e.g. paints, cosmetics, electronics and clothing), and particles designed for environmental applications (e.g. remediation). It is the nano-size range if these materials which unifies them and defines the scope of Nanotoxicology.  While the term ‘toxicology’ indicates risk, the journal Nanotoxicology also aims to encompass studies that enhance safety during the production, use and disposal of nanomaterials. Well-controlled studies demonstrating a lack of exposure, hazard or risk associated with nanomaterials, or studies aiming to improve biocompatibility are welcomed and encouraged, as such studies will lead to an advancement of nanotechnology. Furthermore, many nanoparticles are developed with the intention to improve human health (e.g. antimicrobial agents), and again, such articles are encouraged. In order to promote quality. Aims and Scope, Nanotoxicology, Taylor & Francis  http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=inan20
Wikipedia http://en.wikipedia.org/wiki/Nanotoxicology 

nephrotoxicity: toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on renal function. There are various forms,^[1] and some drugs may affect renal function in more than one way. Nephrotoxins are substances displaying nephrotoxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the decreased renal function (e.g., heparin). Wikipedia accessed 2018 Aug 20 https://en.wikipedia.org/wiki/Nephrotoxicity

neurotoxicity: a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system.[1] It occurs when exposure to substance – specifically, a neurotoxin – alters the normal activity of the nervous system in such a way as to cause permanent or reversible damage to nervous tissue.[1] This can eventually disrupt or even kill neurons, which are cells that transmit and process signals in the brain and other parts of the nervous system.  … The term neurotoxicity implies the involvement of a neurotoxin; however, the term neurotoxic may be used more loosely to describe states that are known to cause physical brain damage, but where no specific neurotoxin has been identified. Wikipedia accessed 2018 Nov 10 https://en.wikipedia.org/wiki/Neurotoxicity the need for totally or partially replacing the animal toxicity assays with shorter-term, animal-free toxicological methods has become more and more compelling in the recent decades. In the field of drug design, one primary need is the early recognition of potentially toxic molecules. In fact, attrition due to nonclinical safety represents a major issue for the productivity of pharmaceutical research and development [1Blomme EAG, Will Y. Toxicology strategies for drug discovery: present and future. Chem Res Toxicol. 2016;29:473–504.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]]. In other fields, new regulatory policies (e.g. registration, evaluation, authorization and restriction of chemical substances and cosmetics) tend to drastically reduce the use of animals.

As a consequence, there are considerable opportunities to accept ‘alternative’ approaches, both in silico (e.g. quantitative structure–activity relationships [QSAR]) and in vitro. This research is extremely active and has generated a large variety of approaches and proposals [2Worth A, Barroso J, Bremer S, et al. Alternative methods for regulatory toxicology – a state-of-the-art review. Ispra: European Commission. JRC Science and Policy Reports; 2014. [Google Scholar]]. Particularly relevant are large-scale funded programs, like the European Union projects safety evaluation ultimately replacing animal testing and EU-ToxRisk [3Daneshian M, Kamp H, Hengstler JG, et al. Highlight report: launch of a large integrated European in vitro toxicology project: EU-ToxRisk. Arch Toxicol. 2016;90:1021–1024.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]] and the US Environmental Protection Agency ToxCast project [4Kavlock RJ, Austin CP, Tice RR. Toxicity testing in the 21st century: implications for human health risk assessment. Risk Anal. 2009;29:485–487.[Crossref], [PubMed], [Web of Science ®] Emerging trends in technologies include new in vitro screening assays, transcriptomics, stem cells, engineered microscale physiological systems, 3D organotypic culture models, and small model organisms (such as zebra fish and Caenorhabditis elegans). A great emphasis is being given to in-depth explorations of the mechanisms of toxicological action: the rationale is to identify the key events in the toxicity pathways and then devise new in vitro tests that could specifically measure those events. The ToxCast/Tox21 project [4Kavlock RJ, Austin CP, Tice RR. Toxicity testing in the 21st century: implications for human health risk assessment. Risk Anal. 2009;29:485–487.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]] and the Adverse Outcome Pathway (AOP) concept and related activities [2Worth A, Barroso J, Bremer S, et al. Alternative methods for regulatory toxicology – a state-of-the-art review. Ispra: European Commission. JRC Science and Policy Reports; 2014. [Google Scholar],5Ankley GT, Bennett RS, Erickson RJ, et al. Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem. 2011;29:730–741.[Crossref], [Web of Science ®], [Google Scholar]] are examples of this new impetus. Another challenge is to develop tools for integrating multiple types of data from diverse experimental systems into unified risk assessment paradigms. Romualdo Benigni (2016) Predictive toxicology today: the transition from biological knowledge to practicable models, Expert Opinion on Drug Metabolism & Toxicology, 12:9, 989-992, DOI: 10.1080/17425255.2016.1206889 https://www.tandfonline.com/doi/full/10.1080/17425255.2016.1206889