Evidence-based toxicology: A comprehensive framework for causation

Northwestern University, Evanston, Illinois, United States
Human & Experimental Toxicology (Impact Factor: 1.75). 05/2005; 24(4):161-201. DOI: 10.1191/0960327105ht517oa
Source: PubMed


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. Many believe that a similar set of characteristics, popularly called the ‘Hill Criteria’, make it possible, if knowledge is robust, to infer causation from only observational (nonexperimental) studies, where allocation of test subjects or items is not under the control of the investigator.

    • "One group working on evidence-based toxicology in The Navigation Guide already embeds COI as an item in its risk of bias assessment (Woodruff and Sutton 2014). Toxicology also has a history of service to private interests, which indicates a particu lar need to evaluate sources of funding as related not only to study bias but also claims of evidence-based practices from interested stakeholders and their consultants (Ashford et al. 2002;Denison 2014;EBTC 2015;Guzelian et al. 2005;Pearce et al. 2015;ToxStrategies 2015). The case of the Klimisch Score is paradigmatic: It was proposed by industry scientists of BASF and has been widely adopted by regulators, despite its lack of validation or relevance to any systematic assessment of the quality of the studies (Klimisch et al. 1997). "
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    ABSTRACT: The most essential goal of medicine and public health is to prevent harm [primum non nocere]. This goal is only fully achieved with primary prevention, which requires us to identify and prevent harms prior to human exposure through research and testing that does not involve human subjects. For that reason, public health policies place considerable reliance on nonhuman toxicological studies. But toxicology as a field has often not produced efficient and timely evidence for decision making in public health. In response to this, the US National Research Council called for the adoption of evidence-based methods and systematic reviews in regulatory decision making. EPA, FDA and the European Food Safety Agency have recently endorsed these methods in their assessments of safety and risk. In this article we summarize challenges and problems in current practices in toxicology as applied to decision making. We compare these practices with the principles and methods utilized in evidence based medicine and healthcare, with emphasis on the record of the Cochrane Collaboration. We propose a stepwise strategy to support the development, validation, and application of evidence based toxicology (EBT). We discuss current progresses in this field produced by the Office of Health Assessment and Translation of the National Toxicology Program (OHAT) and Navigation Guide works. We propose that adherence to the Cochrane principles is a fundamental prerequisite for the development and implementation of EBT. The adoption of evidence based principles and methods will enhance the validity, transparency, efficiency and acceptance of toxicological evidence, with benefits in terms of reducing delays and costs for all stakeholders (researchers, consumers, regulators, industry).
    No preview · Article · Jun 2015 · Environmental Health Perspectives
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    • "Uncertainty arises from study limitations regarding internal validity, including exposure assessment, confounding and other potential sources of bias, and external validity or generalization from study populations to the populations for which risk assessments are conducted (Guzelian et al. 2005; Hertz-Picciotto 1995; Lash et al. 2009; Levy 2008; Maldonado 2008; Persad and Cooper 2008). Further, point estimates can be inaccurate because of internal validity issues and since confidence intervals only focus on the potential for random error. "
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    ABSTRACT: Background: There is a recognized need to improve the application of epidemiologic data in human health risk assessment especially for understanding and characterizing risks from environmental and occupational exposures. Although there is uncertainty associated with the results of most epidemiologic studies, techniques exist to characterize uncertainty that can be applied to improve weight-of-evidence evaluations and risk characterization efforts. Methods: This report derives from a Health and Environmental Sciences Institute (HESI) workshop held in Research Triangle Park, North Carolina, to discuss the utility of using epidemiologic data in risk assessments, including the use of advanced analytic methods to address sources of uncertainty. Epidemiologists, toxicologists, and risk assessors from academia, government, and industry convened to discuss uncertainty, exposure assessment, and application of analytic methods to address these challenges. Synthesis: Several recommendations emerged to help improve the utility of epidemiologic data in risk assessment. For example, improved characterization of uncertainty is needed to allow risk assessors to quantitatively assess potential sources of bias. Data are needed to facilitate this quantitative analysis, and interdisciplinary approaches will help ensure that sufficient information is collected for a thorough uncertainty evaluation. Advanced analytic methods and tools such as directed acyclic graphs (DAGs) and Bayesian statistical techniques can provide important insights and support interpretation of epidemiologic data. Conclusions: The discussions and recommendations from this workshop demonstrate that there are practical steps that the scientific community can adopt to strengthen epidemiologic data for decision making.
    Full-text · Article · Jul 2014 · Environmental Health Perspectives
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    • "The translation of evidence-based approaches from medicine to toxicology is already underway, at least at the conceptual level, but this process is only a decade old and still in the formative stage. Guzelian et al. (2005) coined the phrase " evidencebased toxicology " (EBT) and noted its promise in assessing the evidence that specific chemicals cause specific health effects in humans. Around the same time, Hoffmann and Hartung (2005) noted the potential value in translating evidence-based assessments of diagnostic measures in medicine to assessments of test methods in toxicology. "
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    ABSTRACT: The Evidence-based Toxicology Collaboration (EBTC) was established recently to translate evidence-basedapproaches from medicine and health care to toxicology in an organized and sustained effort. The EBTC held a workshop on "Evidence-based Toxicology for the 21st Century: Opportunities and Challenges" in Research Triangle Park, North Carolina, USA on January 24-25, 2012. The presentations largely reflected two EBTC priorities: to apply evidence-based methods to assessing the performance of emerging pathwaybased testing methods consistent with the 2007 National Research Council report on "Toxicity Testing in the 21st Century" as well as to adopt a governance structure and work processes to move that effort forward. The workshop served to clarify evidence-based approaches and to provide food for thought on substantive and administrative activities for the EBTC. Priority activities include conducting pilot studies to demonstrate the value of evidence-based approaches to toxicology, as well as conducting educational outreach on these approaches.
    Full-text · Article · Jan 2013 · ALTEX: Alternativen zu Tierexperimenten
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