Prescription drug safe storage practices in Arizona tribal communities.

This paper provides an overview of an opioid poisoning prevention pilot project conducted in several American Indian/Alaskan Native communities using an applied public health approach. The intent of the project was to identify a prescription medication safeguarding option for use in the home environment. The authors engaged the target population to obtain their buy-in to select an intervention that was acceptable and appropriate for their needs. Focus groups and key informant interviews conducted in several tribal communities resulted in the selection of a heavy-duty, lockable storage box as the intervention. Through community-based partnerships, 55 boxes were installed in participating households. Along with the box, participants also received education on safe medication storage and disposal. At baseline, only 1% of the participants reported storing their medication securely. During a 60-day follow-up visit, 95% of the observed boxes were being used to store medications. Also at baseline, 31% of the participants reported a history of lost or stolen medications. There were no reported lost or stolen medications during the 60-day project period among the participants. During the follow-up visits, project staff also found the boxes being used to store other items valuable to the participants. Reportedly, having their medication and other valuables secured in one location provided a heightened feeling of security. Since the completion of this pilot project, several organisations and entities have replicated it in their communities.

A primer on systematic reviews in toxicology.

Systematic reviews, pioneered in the clinical field, provide a transparent, methodologically rigorous and reproducible means of summarizing the available evidence on a precisely framed research question. Having matured to a well-established approach in many research fields, systematic reviews are receiving increasing attention as a potential tool for answering toxicological questions. In the larger framework of evidence-based toxicology, the advantages and obstacles of, as well as the approaches for, adapting and adopting systematic reviews to toxicology are still being explored. To provide the toxicology community with a starting point for conducting or understanding systematic reviews, we herein summarized available guidance documents from various fields of application. We have elaborated on the systematic review process by breaking it down into ten steps, starting with planning the project, framing the question, and writing and publishing the protocol, and concluding with interpretation and reporting. In addition, we have identified the specific methodological challenges of toxicological questions and have summarized how these can be addressed. Ultimately, this primer is intended to stimulate scientific discussions of the identified issues to fuel the development of toxicology-specific methodology and to encourage the application of systematic review methodology to toxicological issues.

Evidence-Based Toxicology.

Evidence-based toxicology (EBT) was introduced independently by two groups in 2005, in the context of toxicological risk assessment and causation as well as based on parallels between the evaluation of test methods in toxicology and evidence-based assessment of diagnostics tests in medicine. The role model of evidence-based medicine (EBM) motivated both proposals and guided the evolution of EBT, whereas especially systematic reviews and evidence quality assessment attract considerable attention in toxicology.Regarding test assessment, in the search of solutions for various problems related to validation, such as the imperfectness of the reference standard or the challenge to comprehensively evaluate tests, the field of Diagnostic Test Assessment (DTA) was identified as a potential resource. DTA being an EBM discipline, test method assessment/validation therefore became one of the main drivers spurring the development of EBT.In the context of pathway-based toxicology, EBT approaches, given their objectivity, transparency and consistency, have been proposed to be used for carrying out a (retrospective) mechanistic validation.In summary, implementation of more evidence-based approaches may provide the tools necessary to adapt the assessment/validation of toxicological test methods and testing strategies to face the challenges of toxicology in the twenty first century.

60 Years of the 3Rs symposium: Lessons learned and the road ahead.

When The Principles of Humane Experimental Technique was published in 1959, authors William Russell and Rex Burch had a modest goal: to make researchers think about what they were doing in the laboratory - and to do it more humanely. Sixty years later, their groundbreaking book was celebrated for inspiring a revolution in science and launching a new field: The 3Rs of alternatives to animal experimentation. On November 22, 2019, some pioneering and leading scientists and researchers in the field gathered at the Johns Hopkins Bloomberg School of Public Health in Bal-timore for the 60 Years of the 3Rs Symposium: Lessons Learned and the Road Ahead. The event was sponsored by the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), the Foundation for Chemistry Research and Initiatives, the Alternative Research & Development Foundation (ARDF), the American Cleaning Institute (ACI), the International Fragrance Association (IFRA), the Institute for In Vitro Sciences (IIVS), John "Jack" R. Fowle III, and the Society of Toxicology (SoT). Fourteen pres-entations shared the history behind the groundbreaking publication, international efforts to achieve its aims, stumbling blocks to progress, as well as remarkable achievements. The day was a tribute to Russell and Burch, and a testament to what is possible when people from many walks of life - science, government, and industry - work toward a common goal.

William Russell and Rex Burch published their book The Principles of Humane Experimental Technique in 1959. The book encouraged researchers to replace animal experiments where it was possible, to refine experiments with animals in order to reduce their suffering, and to reduce the number of animals that had to be used for experiments to the minimum. Sixty years later, a group of pioneering and leading scientists and researchers in the field gathered to share how the publi­cation came about and how the vision inspired international collaborations and successes on many different levels including new laws. The paper includes an overview of important milestones in the history of alternatives to animal experimentation.

Community-based medication disposal pilot initiative in southwest tribal communities.

BACKGROUND: Misuse and abuse of prescription drugs including opioids has been a driving force behind the drug overdose epidemic plaguing communities across the USA for more than two decades. Medication accumulation in the home environment can contribute to this issue. However, research on proper disposal in rural communities is limited. For this project, an applied public health approach was used to raise awareness and improve prescription drug disposal practices by pilot testing prescription drug disposal systems in participating communities. METHODS: A community-based disposal project was facilitated with assistance from community partners. The project centered on distribution of drug deactivation bags in homes and medication drop boxes at multiple healthcare facilities. RESULTS: The team distributed 215 drug deactivation bags to 162 community households resulting in destruction of 8011 pills, 8 medicated dermal patches and 777 mL of liquid medication. A total of 4684 pounds of medication were collected and disposed of through healthcare facility drop boxes. CONCLUSION: The strategies identified are scalable and easy to replicate to meet any community's needs in reducing potential challenges of medication diversion.

A Systematic Review to Compare Chemical Hazard Predictions of the Zebrafish Embryotoxicity Test With Mammalian Prenatal Developmental Toxicity.

Originally developed to inform the acute toxicity of chemicals on fish, the zebrafish embryotoxicity test (ZET) has also been proposed for assessing the prenatal developmental toxicity of chemicals, potentially replacing mammalian studies. Although extensively evaluated in primary studies, a comprehensive review summarizing the available evidence for the ZET's capacity is lacking. Therefore, we conducted a systematic review of how well the presence or absence of exposure-related findings in the ZET predicts prenatal development toxicity in studies with rats and rabbits. A two-tiered systematic review of the developmental toxicity literature was performed, a review of the ZET literature was followed by one of the mammalian literature. Data were extracted using DistillerSR, and study validity was assessed with an amended SYRCLE's risk-of-bias tool. Extracted data were analyzed for each species and substance, which provided the basis for comparing the 2 test methods. Although limited by the number of 24 included chemicals, our results suggest that the ZET has potential to identify chemicals that are mammalian prenatal developmental toxicants, with a tendency for overprediction. Furthermore, our analysis confirmed the need for further standardization of the ZET. In addition, we identified contextual and methodological challenges in the application of systematic review approaches to toxicological questions. One key to overcoming these challenges is a transition to more comprehensive and transparent planning, conduct and reporting of toxicological studies. The first step toward bringing about this change is to create broad awareness in the toxicological community of the need for and benefits of more evidence-based approaches.

An animal protection perspective on 21st century toxicology.

The Humane Society of the United States (HSUS) strongly endorses the vision for the future of toxicity testing proposed in the 2007 National Research Council report Toxicity Testing in the 21st Century. Although crafted primarily with the aim of better assessing the public health risks from chemical exposures, the vision would have a major impact on advancing both alternative testing methods and animal welfare. Consequently, The HSUS seeks to have the vision implemented expeditiously. The HSUS is pleased that the report has elicited considerable discussion and debate and garnered a certain level of approval and applaud current implementation efforts. However, these efforts do not fully capture the vision and strategy outlined by the NRC. The HSUS believes that the timely implementation of the NRC vision warrants a large-scale "Human Toxicology Project" akin to the Human Genome Project of the late 20th century. The HSUS spearheaded the formation of the Human Toxicology Project Consortium to help marshal the necessary will, funding, and research for this effort. Our sister organization, the Humane Society International, is embarking on a related effort with European partners. The HSUS cofounded a website, AltTox.org, devoted exclusively to the scientific and policy issues central to advancing nonanimal methods of toxicity testing. The NRC report has provided a unified framework by which to systematically incorporate the fruits of modern biology and technology into hazard identification and risk assessment, to the betterment not only of toxicity testing and public health, but also of animal protection.

Toxicity testing in the 21st century: a vision and a strategy.

With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.

Personal reflections on Russell and Burch, FRAME, and the HSUS.

The coincidence of anniversaries associated with the publication of William Russell and Rex Burch's The Principles of Humane Experimental Technique, the founding of the Fund for the Replacement of Animals in Medical Experiments (FRAME), and the establishment of the collaboration between FRAME and the University of Nottingham, provides an opportunity to reflect on Russell and Burch's legacy and how it was carried forward by FRAME. The Principles, published in 1959, was the pioneering work in what later became the alternatives or Three Rs field of replacement, reduction, and refinement of animal use. Such was the book's initial and undeserved obscurity, however, that FRAME, following its founding in 1969, pioneered a similar approach independently of Russell and Burch's work. The Humane Society of the United States (HSUS) was also an early champion of the alternatives framework, and through the establishment of the Russell and Burch Award, helped unite Russell and Burch with what had emerged as the alternatives community. Thanks largely to FRAME, Russell and Burch were able to participate in Three Rs activity before their deaths. They lived long enough to see their ideas take hold, but not long enough to see the emerging revolution currently under way in toxicity testing, toward the use of non-animal methods.

Beyond the 3Rs: Expanding the use of human-relevant replacement methods in biomedical research.

This year marks the 60th anniversary of Russell and Burch's pioneering book, The Principles of Humane Experimental Technique. Their 3Rs framework has helped to inspire humane and scientific progress in experimental technique. However, it is time to update its strategic application. The 21st century has already seen the development of promising, high-tech non-animal models, such as organs-on-a-chip and computational approaches that, in our view, will replace animals as the default option in biomedical experimentation. How fast this transition will take place will depend on the pace at which these new models are optimized to reflect the biology of humans, rather than that of non-human animals. While the new methods are likely to reshape all areas in which animals are currently used in science, we particularly encourage their application in biomedical research, which accounts for the bulk of animals used. We call for the pursuit of a three-prong strategy that focuses on (1) advancing non-animal methods as replacements of animal experiments, (2) applying them to biomedical research, and (3) improving their relevance to human biology. As academics and scientists, we feel that educational efforts targeted at young scientists in training will be an effective and sustainable way to advance this vision. Our strategy may not promise an imminent end to the use of animals in science, but it will bring us closer to an era in which the 3Rs are increasingly perceived as a solution to a receding problem. Russell and Burch themselves surely would have welcomed these positive changes.

Adaptation of the Systematic Review Framework to the Assessment of Toxicological Test Methods: Challenges and Lessons Learned With the Zebrafish Embryotoxicity Test.

Systematic review methodology is a means of addressing specific questions through structured, consistent, and transparent examinations of the relevant scientific evidence. This methodology has been used to advantage in clinical medicine, and is being adapted for use in other disciplines. Although some applications to toxicology have been explored, especially for hazard identification, the present preparatory study is, to our knowledge, the first attempt to adapt it to the assessment of toxicological test methods. As our test case, we chose the zebrafish embryotoxicity test (ZET) for developmental toxicity and its mammalian counterpart, the standard mammalian prenatal development toxicity study, focusing the review on how well the ZET predicts the presence or absence of chemical-induced prenatal developmental toxicity observed in mammalian studies. An interdisciplinary team prepared a systematic review protocol and adjusted it throughout this piloting phase, where needed. The final protocol was registered and will guide the main study (systematic review), which will execute the protocol to comprehensively answer the review question. The goal of this preparatory study was to translate systematic review methodology to the assessment of toxicological test method performance. Consequently, it focused on the methodological issues encountered, whereas the main study will report substantive findings. These relate to numerous systematic review steps, but primarily to searching and selecting the evidence. Applying the lessons learned to these challenges can improve not only our main study, but may also be helpful to others seeking to use systematic review methodology to compare toxicological test methods. We conclude with a series of recommendations that, if adopted, would help improve the quality of the published literature, and make conducting systematic reviews of toxicological studies faster and easier over time.

Evidence for the outcomes and impact of clinical pharmacy: context of UK hospital pharmacy practice.

OBJECTIVES: The role of clinical pharmacists in hospitals has evolved and continues to expand. In the UK, outside of a few national policy drivers, there are no agreed priorities, measures or defined outcomes for hospital clinical pharmacy (CP). This paper aims to (1) highlight the need to identify and prioritise specific CP roles, responsibilities and practices that will bring the greatest benefit to patients and health systems and (2) describe systematic weaknesses in current research methodologies for evaluating CP services and propose a different approach. METHOD: Published reviews of CP services are discussed using the Economic, Clinical and Humanistic Outcomes framework. Recurring themes regarding study methodologies, measurements and outcomes are used to highlight current weaknesses in studies evaluating CP. RESULTS: Published studies aiming to demonstrate the economic, clinical or humanistic outcomes of CP often suffer from poor research design and inconsistencies in interventions, measurements and outcomes. This has caused difficulties in drawing meaningful conclusions regarding CP's definitive contribution to patient outcomes. CONCLUSION: There is a need for more research work in National Health Service (NHS) hospitals, employing a different paradigm to address some of the weaknesses of existing research on CP practice. We propose a mixed-methods approach, including qualitative research designs, and with emphasis on cost-consequence analyses for economic evaluations. This approach will provide more meaningful data to inform policy and demonstrate the contribution of hospital CP activities to patient care and the NHS.

Report of the Working Group on Animal Distress in the Laboratory.

Finding ways to minimize pain and distress in research animals is a continuing goal in the laboratory animal research field. Pain and distress, however, are not synonymous, and measures that alleviate one may not affect the other. Here, the authors provide a summary of a meeting held in February 2004 that focused on distress in laboratory animals. They discuss the difficulties associated with defining 'distress,' propose methods to aid in recognizing and alleviating distressful conditions, and provide recommendations for animal research conduct and oversight that would minimize distress experienced by laboratory animals.

Guidance on assessing the methodological and reporting quality of toxicologically relevant studies: A scoping review.

Assessments of methodological and reporting quality are critical to adequately judging the credibility of a study's conclusions and to gauging its potential reproducibility. To aid those seeking to assess the methodological or reporting quality of studies relevant to toxicology, we conducted a scoping review of the available guidance with respect to four types of studies: in vivo and in vitro, (quantitative) structure-activity relationships ([Q]SARs), physico-chemical, and human observational studies. Our aims were to identify the available guidance in this diverse literature, briefly summarize each document, and distill the common elements of these documents for each study type. In general, we found considerable guidance for in vivo and human studies, but only one paper addressed in vitro studies exclusively. The guidance for (Q)SAR studies and physico-chemical studies was scant but authoritative. There was substantial overlap across guidance documents in the proposed criteria for both methodological and reporting quality. Some guidance documents address toxicology research directly, whereas others address preclinical research generally or clinical research and therefore may not be fully applicable to the toxicology context without some translation. Another challenge is the degree to which assessments of methodological quality in toxicology should focus on risk of bias - as in clinical medicine and healthcare - or be broadened to include other quality measures, such as confirming the identity of test substances prior to exposure. Our review is intended primarily for those in toxicology and risk assessment seeking an entry point into the extensive and diverse literature on methodological and reporting quality applicable to their work.

The Emergence of Systematic Review in Toxicology.

The Evidence-based Toxicology Collaboration hosted a workshop on "The Emergence of Systematic Review and Related Evidence-based Approaches in Toxicology," on November 21, 2014 in Baltimore, Maryland. The workshop featured speakers from agencies and organizations applying systematic review approaches to questions in toxicology, speakers with experience in conducting systematic reviews in medicine and healthcare, and stakeholders in industry, government, academia, and non-governmental organizations. Based on the workshop presentations and discussion, here we address the state of systematic review methods in toxicology, historical antecedents in both medicine and toxicology, challenges to the translation of systematic review from medicine to toxicology, and thoughts on the way forward. We conclude with a recommendation that as various agencies and organizations adapt systematic review methods, they continue to work together to ensure that there is a harmonized process for how the basic elements of systematic review methods are applied in toxicology.

Possibilities for refinement and reduction: future improvements within regulatory testing.

Approaches and challenges to refining and reducing animal use in regulatory testing are reviewed. Regulatory testing accounts for the majority of animals reported in the most painful and/or distressful categories in the United States and Canada. Refinements in testing, including the use of humane endpoints, are of increasing concern. Traditional approaches to reduction (e.g., improving experimental design) are being supplemented with complementary approaches, such as the use of tier testing to eliminate some chemicals prior to in vivo testing. Technological advances in telemetry and noninvasive techniques will help decrease either the demand for animals in testing or animal suffering. Further decreases in animal use will stem from international harmonization and coordination of testing programs. Progress in refinement and reduction faces a variety of broad challenges, including limited funding for research. In the specific area of refinement, a key challenge is the issue of distress (as distinct from pain). In the area of reduction, the practice of using unjustifiably high numbers of animals from small species (e.g., rodents) should be challenged. One case study of the use of carbon dioxide as a euthanasia agent illustrates the need for further analysis and research. Notwithstanding the complexities and challenges, the potential for refinement and reduction in regulatory testing is encouraging.

The HSUS's Pain and Distress Initiative: overview and update.

The Humane Society of the United States (HSUS) publicly launched its Pain and Distress Initiative in 2000, to encourage greater attention to the prevention and alleviation of pain and distress in research animals. The initiative's ultimate goal is the phasing out of all significant pain and distress in animal research by 2020. There have been several developments to date. A survey conducted for The HSUS revealed that Americans strongly oppose the use of animals in experiments that cause them to suffer. The HSUS has begun producing a newsletter, The Pain & Distress Report, distributed periodically to over 2000 Institutional Animal Care and Use Committees, scientists and regulators. In 2000, the US Department of Agriculture issued a proposal to upgrade the regulation and reporting of pain and distress. We have challenged the leading research institutions over their under-reporting of unrelieved pain and distress in animals. We have written a comprehensive critique of CO2 euthanasia, arguing that it causes avoidable pain and distress in animals. The National Institutes of Health has issued new guidance on CO2 euthanasia. These developments lay the groundwork for a sustained effort to eliminate animal suffering in research.