History of the National Academies of Sciences, Engineering, and Medicine's Institute for Laboratory Animal Research.

The Institute for Laboratory Animal Research (ILAR) was created within the National Academies of Sciences, Engineering, and Medicine (National Academies) in 1953 when biomedical research using animals was in its infancy in terms of quantity, quality, complexity, sophistication, and care. Over the intervening 69 years, ILAR has witnessed unprecedented growth, followed by unprecedented decline, and then regrowth in usage of specific species and models and an overall shift in experimental burden away from larger to smaller species (ie, mice, fish, and rats). ILAR has contributed much to the evolution of necessary research using animals and animal models for the benefit of humans, animals, and the environment and to the development and implementation of humane principles and standards for care and use of research animals.

Fit for Purpose Assessment: A New Direction for IACUCs.

The organization and function of the institutional animal care and use committee (IACUC) is the key component of government regulation and oversight of necessary scientific research using live animals and of AAALAC - International accreditation of animal care and use programs in the United States. The regulations, roles, and responsibilities of IACUCs have evolved since their inception 35 years ago from a limited focus on animal welfare and specific animal procedures to embracing scientific quality, data reproducibility and translation, and animal welfare as inextricably interdependent and critical components of generation of new scientific knowledge and medical treatments. A current challenge for IACUCs is in evaluating whether benefits to be derived (eg, new knowledge or treatments) justify any unavoidable pain, stress, or injury associated with proposed research protocols, because the former are long-term and at best speculative outcomes, whereas the latter are immediate and tangible for the study animals.

A Brief History of Use of Animals in Biomedical Research and Perspective on Non-Animal Alternatives.

Animals have been closely observed by humans for at least 17 000 years to gain critical knowledge for human and later animal survival. Routine scientific observations of animals as human surrogates began in the late 19th century driven by increases in new compounds resulting from synthetic chemistry and requiring characterization for potential therapeutic utility and safety. Statistics collected by the United States Department of Agriculture's Animal and Plant Health Inspection Service and United Kingdom Home Office show that animal usage in biomedical research and teaching activities peaked after the mid-20th century and thereafter fell precipitously until the early 21st century, when annual increases (in the UK) were again observed, this time driven by expansion of genetically modified animal technologies.

Perspectives on using a multiplex human kidney safety biomarker panel to detect cisplatin-induced tubular toxicity in male and female Cynomolgus monkeys.

Multiplex biomarker panel assays would enable early de-risking of discovery compound related kidney safety liabilities. The objective of this study was to evaluate the usefulness of the Myriad RBM Human KidneyMAP (Multi-Analyte Profile)® v.1.

Scientific Knowledge and Technology, Animal Experimentation, and Pharmaceutical Development.

Human discovery of pharmacologically active substances is arguably the oldest of the biomedical sciences with origins >3500 years ago. Since ancient times, four major transformations have dramatically impacted pharmaceutical development, each driven by advances in scientific knowledge, technology, and/or regulation: (1) anesthesia, analgesia, and antisepsis; (2) medicinal chemistry; (3) regulatory toxicology; and (4) targeted drug discovery. Animal experimentation in pharmaceutical development is a modern phenomenon dating from the 20th century and enabling several of the four transformations.

A defense of 'risk-benefit' terminology.

The longstanding concept of risk-benefit analysis is an established and familiar practice among animal research programs. It is generally preferred by researchers and statisticians and this term is used throughout the Guide for the Care and Use of Laboratory Animals. However, the term 'harm-benefit analysis' has recently come into use, particularly in the accreditation process for animal research programs.

A Historical View and Vision into the Future of the Field of Safety Pharmacology.

Professor Gerhard Zbinden recognized in the 1970s that the standards of the day for testing new candidate drugs in preclinical toxicity studies failed to identify acute pharmacodynamic adverse events that had the potential to harm participants in clinical trials. From his vision emerged the field of safety pharmacology, formally defined in the International Conference on Harmonization (ICH) S7A guidelines as "those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above." Initially, evaluations of small-molecule pharmacodynamic safety utilized efficacy models and were an ancillary responsibility of discovery scientists.

A Standard of Knowledge for the Professional Practice of Toxicology.

Background: Employers, courts, and the general public judge the credibility of professionals based on credentials such as academic degrees, publications, memberships in professional organizations, board certifications, and professional registrations. However, the relevance and merit of these credentials can be difficult to determine objectively. Board certification can be a reliable indicator of proficiency if the certifying organization demonstrates, through regularly scheduled independent review, that its processes meet established standards and when a certificate holder is required to periodically demonstrate command of a body of knowledge that is essential to current professional practice.

A peripherally restricted P2Y receptor antagonist altered rat tumor incidences with no human relevance: Mode of action consistent with dopamine agonism.

Background: Ticagrelor is an orally available, direct acting and reversible P2Y receptor antagonist approved for treatment of acute coronary syndrome. The objectives of these studies were to (1) evaluate the Ticagrelor 2-year rat carcinogenicity bioassay data; (2) investigate potential mode of action (MOA) and (3) interpret human relevance.

Methods: The following studies were done (1) rat two-year carcinogenicity study in male and female rats, (2) and genotoxicity assays, (3) quantitative whole body autoradiography (QWBA; male and female rats), (4) pharmacological profiling for more than 300 assays, and (5) ovariectomized rat assay.

Pharmaceutical toxicology: designing studies to reduce animal use, while maximizing human translation.

Evaluation of the safety of new chemicals and pharmaceuticals requires the combination of information from various sources (e.g. in vitro, in silico and in vivo) to provide an assessment of risk to human health and the environment.

Renal biomarker changes associated with hyaline droplet nephropathy in rats are time and potentially compound dependent.

Alpha 2u-globulin mediated hyaline droplet nephropathy (HDN) is a male rat specific lesion induced when a compound or metabolite binds to alpha 2u-globulin. The objective of this study was to investigate if the newer and more sensitive renal biomarkers would be altered with HDN as well as be able to distinguish between HDN and oxidative stress-induced kidney injury. Rats were dosed orally for 7 days to determine (1) if HDN (induced by 2-propanol or D-limonene) altered the newer renal biomarkers and not BUN or creatinine, (2) if renal biomarkers could distinguish between HDN and oxidative stress-induced kidney injury (induced by potassium bromate), (3) sensitivity of HDN-induced renal biomarker changes relative to D-limonene dose, and (4) reversibility of HDN and renal biomarkers, using vehicle or 300 mg/kg/day D-limonene with 7 days of dosing and necropsies scheduled over the period of Days 8-85.

Inhibition of oestradiol-induced prolactin release in a dual-cannulated ovariectomized rat model by carmoxirole, a peripherally restricted dopamine agonist.

Centrally acting dopamine agonists (e.g. bromocriptine) and dopamine transport inhibitors (e.

Safety pharmacology in 2010 and beyond: survey of significant events of the past 10 years and a roadmap to the immediate-, intermediate- and long-term future in recognition of the tenth anniversary of the Safety Pharmacology Society.

In recognition of the tenth anniversary of the Safety Pharmacology Society (SPS), this review summarizes the significant events of the past 10years that have led to the birth, growth and evolution the SPS and presents a roadmap to the immediate-, intermediate- and long-term future of the SPS. The review discusses (i) the rationale for an optimal non-clinical Safety Pharmacology testing, (ii) the evolution of Safety Pharmacology over the last decade, (iii) its impact on drug discovery and development, (iv) the merits of adopting an integrated risk assessment approach, (v) the translation of non-clinical findings to humans and finally (vi) the future challenges and opportunities facing this discipline. Such challenges include the emergence of new molecular targets and new approaches to treat diseases, the rapid development of science and technologies, the growing regulatory concerns and associated number of guidance documents, and the need to train and educate the next generation of safety pharmacologist.

In vivo and in vitro liver and gill EROD activity in rainbow trout (Oncorhynchus mykiss) exposed to the beta-blocker propranolol.

The conservation of common physiological systems across vertebrate classes suggests the potential for certain pharmaceuticals, which have been detected in surface waters, to produce biological effects in nontarget vertebrates such as fish. However, previous studies assessing the effects of such compounds in fish have not taken into account the potential for metabolism and elimination. This study aimed to assess if propranolol, a β-adrenergic receptor antagonist or β-blocker, could modulate EROD activity (indicative of CYP1A activity) in rainbow trout (Oncorhynchus mykiss) gills and liver.

The value of repeating studies and multiple controls: replicated 28-day growth studies of rainbow trout exposed to clofibric acid.

Two studies to examine the effect of waterborne clofibric acid (CA) on growth-rate and condition of rainbow trout were conducted using accepted regulatory tests (Organisation for Economic Co-operation and Development [OECD] 215). The first study (in 2005) showed significant reductions after 21 d of exposure (21-d growth lowest-observed-effect concentration [LOEC] = 0.1 µg/L, 21-d condition LOEC = 0.

Using data from drug discovery and development to aid the aquatic environmental risk assessment of human pharmaceuticals: concepts, considerations, and challenges.

Over recent years, human pharmaceuticals have been detected in the aquatic environment. This, combined with the fact that many are (by design) biologically active compounds, has raised concern about potential impacts in wildlife species. This concern was realized with two high-profile cases of unforeseen environmental impact (i.

Uptake of propranolol, a cardiovascular pharmaceutical, from water into fish plasma and its effects on growth and organ biometry.

Pharmaceuticals in the environment (PIE) are of importance since these compounds are designed to affect biological receptors/enzymes that are often conserved across vertebrate families. Across-species extrapolation of these therapeutic targets suggests potential for impacting amphibia and fish in the aquatic environment. Due to the scarcity of relevant ecotoxicological data, the long-tem impact of PIE remains a research question.

Drugs effects on ventricular repolarization: a critical evaluation of the strengths and weaknesses of current methodologies and regulatory practices.

A growing number of drugs and drug combinations inhibit cardiac potassium ion conductance and ventricular repolarization, and increase cardiac APD, QT interval, and risk of potentially fatal TdP. The past decade has seen an explosion of research advances into the mechanism of action underpinning these observations, and an unprecedented level of collaboration between academia, industry, and regulatory authorities to define effective strategies for accurate prediction of increased TdP risk (if any) in humans, based upon nonclinical and/or clinical endpoints. Because the incidence of TdP is so very low, even for drugs for which the association is known, the risk can only be assessed based upon surrogate markers (signals) in in vitro and in vivo non-clinical studies as well as in clinical trials.

Evaluation and applications of radiotelemetry in small laboratory animals.

Radiotelemetry is the "state of the art" for monitoring physiological functions in awake and freely moving laboratory animals, while minimizing stress artifacts. For researchers, especially those in the fields of pharmacology and toxicology, the technique provides a valuable tool for defining the physiological and pathophysiological consequences derived from advances molecular, cellular, and tissue biology and in predicting the effectiveness and safety of new compounds in humans. There is ample evidence that radiotelemetry systems for measuring physiological functions has been sufficiently validated.

Safety pharmacology and risk assessment.

Evaluation of experimental drugs in animals for effects on critical organ systems allows identification of functional signals of efficacy and safety that can be subsequently monitored in human clinical trials. The International Conference on Harmonization (ICH), 'Guidelines on Safety Pharmacology', finalized in 2000, defined critical organ systems (cardiovascular, respiratory and central nervous system) and functions to be evaluated, and points to consider for study design and conduct. The new Safety Pharmacology guidelines recognise that while in vitro studies of molecular targets (enzymes, receptors, ion channels, etc.