The emerging discipline of evidence-based toxicology (EBT) is a process for transparently, consistently, and objectively assessing available scientific evidence in order to answer questions in toxicology, the study of the adverse effects of chemical, physical, or biological agents on living organisms and the environment, including the prevention and amelioration of such adverse effects. EBT has the potential to address concerns in the toxicological community about the limitations of current approaches to assessing the state of the science. These include concerns related to transparency in decision making, synthesis of different types of evidence, and the assessment of bias and credibility. The evidence-based methods and approaches now being introduced to toxicology are widely used in medicine, which is the basis for their nomenclature. The need to improve the performance assessment of toxicological test methods was the main impetus for translating these tools to toxicology. The U.S. National Research Council (NRC) concurs that new means of assessment are needed to keep pace with recent advances in the development of toxicological test methods. These new test methods capitalize on the recent advances in biochemistry and molecular biology that have enhanced scientists' understanding of the nature and mechanisms underlying how chemicals cause adverse effects, and the tests have the potential to be much quicker and less expensive than the tests traditionally used to evaluate toxicity.
Contents
- Background
- Process and progress
- Defining characteristics of evidence based toxicology
- Regulatory decision making
- Evaluating effects of environmental exposures
- Causation
- Clinical toxicology
- 21st century toxicology
- Limitations and challenges
- References
EBT can be applied to literature reviews of chemical effects, as well as test method performance. Historically, authors of reviews assessing the results of toxicological studies have searched, selected, and weighed the scientific evidence in a non-systematic and non-transparent way. Due to their narrative nature, these reviews tend to be subjective, are potentially biased and cannot be reproduced. Two examples highlighting these deficiencies are the cancer risk assessment of two persistent, organic pollutants, polychlorinated biphenyls (PCBs) and trichloroethylene. Narrative reviews of PCBs published within a year of each other came to different conclusions about the cancer risk posed by these chemicals. Similarly, 27 different risk assessments of trichloroethylene have come to substantially different conclusions. A key tool used in evidence-based medicine that holds promise for EBT is the systematic review, which is a highly structured approach to reviewing and synthesizing the scientific literature while limiting bias. The steps to carrying out a systematic review include framing the question to be addressed; appraising and deciding how relevant studies will be identified and retrieved; determining if any studies need to be excluded from the analysis; and deciding how the included studies will be appraised in terms of their quality and risk of bias. Ultimately the data will be synthesized across studies, often by a meta-analysis. Typically, a protocol of how the review will be conducted is prepared ahead of time and is often peer reviewed.
Scientists have made progress in their efforts to apply systematic reviews to evaluate the evidence for associations between environmental toxicants and human health risks. To date, researchers have shown that important elements of the systematic review methodology established in evidence-based medicine can be adopted into EBT with little change, and a limited number of such studies have been attempted. For example, an EBT-style systematic review responds to concerns in the pharmaceutical industry regarding why drug candidates recommended by animal studies have unexpectedly failed by identifying instruments that may ameliorate the problem. Researchers using systematic reviews to address toxicological concerns include a group of scientists from government, industry, and academia in North America and European Union (EU) who have joined forces to promote evidence-based approaches to toxicology through the nonprofit Evidence-based Toxicology Collaboration (EBTC). The EBT is applying systematic reviews to toxicological methods. This is just one of the avenues that the EBTC's members are researching to help toxicologists improve health protection and safety assurance.
Background
The evidence-based approach was first conceived as a means to standardize the practice of medicine. Evidence-based medicine (EBM) was launched three decades ago. Its rise as a distinct discipline is generally credited to the work and advocacy of Scottish epidemiologist Archie Cochrane. The Cochrane Collaboration named in his honor was launched at Oxford University in 1993 to promote evidence-based reviews of clinical medical literature. More recently, EBM expanded to encompass evidence-based health care (EBHC).
EBM/HC involves the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. Prior to EBM's launch in the 1980s, medical decisions about diagnosis, prevention, treatment or harm were often made without a rigorous evaluation of the alternatives. Research in the 1970s and 1980s showed that different physicians regularly recommended different treatments and tests for patients with ailments that were essentially the same, and that large proportions of procedures being performed by physicians were considered inappropriate by the standards of medical experts. EBM/HC supporters stress that evidence always has been important to the practice of medicine. Rather, EBM/HC enhances how evidence is used through a structured way of transparently assessing it in an unbiased manner. EBT's supporters make a similar argument.
The idea of applying the evidence-based approach honed in medicine to toxicology has been percolating for two decades, with proponents in both medicine and toxicology. Three research papers published in 2005 and 2006 catalyzed what eventually became known as EBT by suggesting that EBM's established tools and concepts might serve as a prototype of evidence-based decision-making and thus help toxicological practice to come to more consistent and transparent decisions based solely on the external scientific evidence available.
Several factors suggest that current approaches for assessing toxicological methods need to be enhanced or replaced, with EBT perhaps providing the needed solutions. New methods are oriented more to human biology than animal biology, as well as their emphasis on suites of tests versus one-to-one replacements requiring evidence-based approaches to appropriately assess reelavance and to provide transparent and consistent means for data integration. Other motivations for EBT include the reality that toxicology largely relies on tests that have changed little despite scientific and technological progress. As a consequence, safety assessments which directly impact on our health and our environment are largely based on tests of unknown relevance and reliability. To be effective and relevant, safety assessments in toxicology depend on progress in basic scientific research and should be systematically reviewed allowing constant adaptation to advances in knowledge.
Process and progress
The First International Forum Toward Evidence-Based Toxicology was held in Como, Italy in 2007. The forum was organised by the European Commission in close collaboration with scientists active in toxicology, life sciences, biostatistics, modelling, and medicine. It was attended by 170 scientists from more than 25 European, American, and Asian countries. The goal was to explore the available concepts of EBT, and to launch an initiative to formally implement evidence-based assessment methods in toxicology.
The starting point for the discussions were two research papers suggesting that the tools and concepts established in evidence-based medicine could serve as a prototype of evidence-based decision-making for evaluating toxicological data. Apparent fundamental differences between medicine and toxicology were carefully considered during these discussions. Forum participants attempted to bridge both disciplines in order to make use of the accrued wisdom embodied in EBM/HC and apply them to produce EBT. The participants of the forum agreed upon ten defining characteristics of EBT.
Defining characteristics of evidence-based toxicology
The proceedings of this forum were published as a special issue in Human & Experimental Toxicology. EBT's proponents include experts in EBM, public health, and toxicology who believe that EBT can help toxicologists to better serve the goals of health protection and safety assurance. They argue that EBT's methodologies for the collecting, appraising, and pooling evidence help can ensure that all available information on a given topic is evaluated in a transparent and unbiased manner. They contend that EBT's concept of the systematic review could prove particularly helpful for the standardization and quality assurance of novel methodologies for evaluating toxicity, as well as their formal validation. In this regard, EBT may prove particularly useful for validating newer in vitro, “21st century” toxicology tools. EBT can also help scientists integrate new toxicological test methods into test strategies being implemented across the globe. In 2010, a group of EBT supporters joined together to convene a workshop titled “21st Century Validation for 21st Century Tools.” The workshop was held in Baltimore, and its session on the potential for evidence-based approaches to assess the performance of the new generation of non-animal test methods inspired the formation of the Evidence-Based Toxicology Collaboration (EBTC). The EBTC was officially launched in the U.S. in March 2011 at a Society of Toxicology conference. The EBTC's EU branch was officially opened during the 2012 Eurotox conference.
Regulatory decision-making
Some scientists and policymakers would like EBT to help them combine information from various sources. Regulators often designate one study as “the lead study,” then use later studies as additional information. Many perceive this as unsatisfying, but objective approaches to combine study results are lacking. The EBM concept of the systematic review has promise for this application. Ellen Silbergeld of Johns Hopkins University has produced structured reviews that can serve as forerunners for this approach.
Evaluating effects of environmental exposures
The U.S. National Toxicology Program's Office of Health Assessment and Translation (OHAT) is using EBT-style principles to conduct systematic reviews via several case studies. The first two case studies evaluate the evidence regarding the association of (1) bisphenol A (BPA) exposure with obesity and (2) perflurooctanoic acid (PFOA) or perfluorooctane sulfonate (PFOS) exposure with immunotoxicity.
The scientists involved in reviewing the association between exposure to BPA and obesity believe it to be the first systematic review on this topic, and they note that obesity has not been addressed as a health outcome in other safety evaluations of BPA. Their goal is to develop hazard identification conclusions regarding whether exposure to BPA is associated with overweight/obesity in humans based on integrating evidence from human, animal, and mechanistic studies. The approach that OHAT is using seems especially appropriate for substances with substantial yet conflicting literature, and hence the need for a systematic review to sort out a somewhat confusing situation, according to public comments on the proposal.
Causation
An alternative approach to EBT focuses on causation. It addresses the challenge of tracing a health effect back to a toxicant, such as lung cancer to smoking. This approach is similar to legal arguments Some experts believe that this approach could raise the standards for how to prove causation, and thereby increase the difficulty involved in banning toxic substances.
Clinical toxicology
Practitioners of clinical toxicology, which is concerned with the treatment of patients known to be exposed to toxic substances, are also beginning to use an EBM-style approach., Guidance documents based on this approach have already been published.
21st century toxicology
The National Research Council's (NRC) landmark 2007 publication, Toxicity Testing in the 21st Century, has also been an impetus for EBT. The study, which was sponsored by the federal Environmental Protection Agency, observed that recent advances in systems biology, testing in cells and tissues, and related scientific fields offer the potential to fundamentally change the way chemicals are tested for risks they may pose to humans. At present, toxicology largely relies on toxicity tests that have changed little despite scientific and technological progress.
The approach proposed in the NRC report takes advantage of rapidly evolving scientific understanding of how genes, proteins, and small molecules interact to maintain normal cell function and how some of these interactions can be perturbed in ways that could lead to health problems. Specifically, the new testing approach would focus on toxicity pathways—cellular pathways that, when sufficiently perturbed, are expected to lead to adverse health effects. In addition to being faster and less expensive than conventional toxicology tests, many scientists believe that new pathway-based tests using human cells and cell lines will provide results that do a better job of predicting how exposure to lower doses of chemicals may affect humans. The new tests may help researchers to speed the evaluation of the very large number of substances whose potential toxicity has yet to be adequately assessed., In addition to providing new tools for assessing test method performance, especially as the focus shifts from animal to human biology, EBT gives scientists a method for comparatively evaluating the results gleaned from new means of investigating the effects of chemical exposure, and for communicating the results of such evaluations to both other scientists and the public.
The scientists who have banded together to create the EBTC believe that EBT can help enable toxicology to handle new challenges by synthesizing available data in ways that are transparent, objective, and systematic. Upcoming challenges that may benefit from this approach include new substances, such as materials developed using nanotechnology; new health concern focuses, such as immunotoxicity; and new methods for evaluating toxicity being developed in a range of fields including molecular biology, analytical chemistry, and computer modelling.
Limitations and challenges
Some of the challenges to implementing EBT arise because of the differences between toxicology and medicine and health care. The main focus of EBM is on a single type of study—randomized, controlled clinical trials, which are a direct measure of the effectiveness of the health care intervention under scrutiny. In contrast, toxicology employs a variety of different kinds of studies, including epidemiological studies of people, as well as whole animal in vivo tests and in vitro cell-based tests, which are models of the situation in people. This methodological heterogeneity complicates evidence integration and introduces the issue of relevance – how relevant is a given in vivo or in vitro model to the human situation? Adding to the difficulty is the reality that a lot of toxicological evidence, more so than in medicine and health care, is not readily accessible in the literature.
For these and other reasons, one cannot simply pull EBM approaches off the shelf and apply them to EBT. They need to be adapted with care and with a full appreciation of the differences between medicine/health care and toxicology. Adapting evidence-based approaches for toxicology requires considerable work, and the EBTC's members and others are investigating how they can be implemented to further the goal of improving health protection and safety assurance.