Evidence-based toxicology: a comprehensive framework for causation

@article{citeulike:938206, abstract = {This paper identifies deficiencies in some current practices of causation and risk evaluation by toxicologists and formulates an evidence-based solution. Some relations between physical or chemical agents and adverse health events known to occur at some frequency are identified risks. 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. 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 (and possibly observational studies) 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. In medicine, evaluation of causal relationships has been dominated by Authority-based opinions, expressed by experts (or consensus groups of experts) relying on their education, training, experience, wisdom, prestige, intuition, skill, and improvisation. In response, Evidence-based medicine (EBM) was developed, to make a conscientious, explicit, and judicious use of current best evidence. EBM employs a structured, 'transparent' protocol for carrying out a deliberate, objective, unbiased, and systematic review of the evidence about a formally framed question. Recent studies have disclosed that toxicologists (individually or in expert groups), not unlike their medical counterparts prior to EBM, show distressing variations in their biases with regard to data selection, data interpretation, and data evaluation when performing reviews for causation analyses. Moreover, toxicologists often fail to acknowledge explicitly (particularly in regulatory and policy making arenas) when shortcomings in the evidence necessitate reliance upon Authority-based opinions, rather then Evidence-based conclusions (Guzelian and Guzelian. 2004. Authority-based explanation. Science. 303:1468-1469). Accordingly, for answering questions about general and specific causation, we have constructed a framework for Evidence-based toxicology (EBT), derived from the accepted principles of EBM and expressed succinctly as three stages, comprising 12 total steps. These are: 1) Collecting and evaluating the relevant data (Source, Exposure, Dose, Diagnosis); 2) Collecting and evaluating the relevant knowledge (Frame the question, Assemble the relevant (delimited) literature, Assess and critique the literature); 3) Joining data with knowledge to arrive at a conclusion (General causation - answer to the framed question, Dose-response, Timing, Alternative cause, Coherence). The second of these stages (which amounts to an analysis of general causation), is addressed by an EBM-styled approach (adapted for the infrequent availability of human experimental studies in environmental toxicology). This involves assembling literature (through documented algorithms for database queries), excluding irrelevancies by use of delimiters as filters, and ranking and rating the remaining articles for strength of study design and for quality of execution gauged by application of either a ready-made quality assessment instrument or a custom designed checklist or scale. The results of this systematic review (including a structured review of relevant animal and in vitro studies) are then themselves systematically used to determine which causation criteria are fulfilled. Toxicology is maturing from a derivative science largely devoted to routinized performance and interpretation of safety tests, to a discipline deeply enmeshed in the remarkable advances in biochemistry and molecular biology to better understanding the nature and mechanism of adverse effects caused by chemicals. It is time for toxicologists, like scientists in other fields, to formalize a method for differentiating settled toxicological knowledge of risk from mere nomological possibility, and for communicating their conclusions to other scientists and the public. It is time for evidence-based toxicology.}, author = {Guzelian, Philip S. }, citeulike-article-id = {938206}, keywords = {ebt, evidence-based, toxicology}, month = {April}, pages = {161--201}, posted-at = {2006-11-09 19:10:46}, priority = {0}, title = {Evidence-based toxicology: a comprehensive framework for causation}, url = {http://www.ingentaconnect.com/content/sage/het/2005/00000024/00000004/art00001} }

TY - JOUR ID - citeulike:938206 L3 - citeulike-article-id:938206 TI - Evidence-based toxicology: a comprehensive framework for causation SP - 161 EP - 201 N2 - This paper identifies deficiencies in some current practices of causation and risk evaluation by toxicologists and formulates an evidence-based solution. Some relations between physical or chemical agents and adverse health events known to occur at some frequency are identified risks. 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. 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 (and possibly observational studies) 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. In medicine, evaluation of causal relationships has been dominated by Authority-based opinions, expressed by experts (or consensus groups of experts) relying on their education, training, experience, wisdom, prestige, intuition, skill, and improvisation. In response, Evidence-based medicine (EBM) was developed, to make a conscientious, explicit, and judicious use of current best evidence. EBM employs a structured, 'transparent' protocol for carrying out a deliberate, objective, unbiased, and systematic review of the evidence about a formally framed question. Recent studies have disclosed that toxicologists (individually or in expert groups), not unlike their medical counterparts prior to EBM, show distressing variations in their biases with regard to data selection, data interpretation, and data evaluation when performing reviews for causation analyses. Moreover, toxicologists often fail to acknowledge explicitly (particularly in regulatory and policy making arenas) when shortcomings in the evidence necessitate reliance upon Authority-based opinions, rather then Evidence-based conclusions (Guzelian and Guzelian. 2004. Authority-based explanation. Science. 303:1468-1469). Accordingly, for answering questions about general and specific causation, we have constructed a framework for Evidence-based toxicology (EBT), derived from the accepted principles of EBM and expressed succinctly as three stages, comprising 12 total steps. These are: 1) Collecting and evaluating the relevant data (Source, Exposure, Dose, Diagnosis); 2) Collecting and evaluating the relevant knowledge (Frame the question, Assemble the relevant (delimited) literature, Assess and critique the literature); 3) Joining data with knowledge to arrive at a conclusion (General causation - answer to the framed question, Dose-response, Timing, Alternative cause, Coherence). The second of these stages (which amounts to an analysis of general causation), is addressed by an EBM-styled approach (adapted for the infrequent availability of human experimental studies in environmental toxicology). This involves assembling literature (through documented algorithms for database queries), excluding irrelevancies by use of delimiters as filters, and ranking and rating the remaining articles for strength of study design and for quality of execution gauged by application of either a ready-made quality assessment instrument or a custom designed checklist or scale. The results of this systematic review (including a structured review of relevant animal and in vitro studies) are then themselves systematically used to determine which causation criteria are fulfilled. Toxicology is maturing from a derivative science largely devoted to routinized performance and interpretation of safety tests, to a discipline deeply enmeshed in the remarkable advances in biochemistry and molecular biology to better understanding the nature and mechanism of adverse effects caused by chemicals. It is time for toxicologists, like scientists in other fields, to formalize a method for differentiating settled toxicological knowledge of risk from mere nomological possibility, and for communicating their conclusions to other scientists and the public. It is time for evidence-based toxicology. KW - ebt KW - evidence-based KW - toxicology AU - Guzelian, Philip UR - http://www.ingentaconnect.com/content/sage/het/2005/00000024/00000004/art00001 ER -