Can mode of action predict mixture toxicity for risk assessment?

Borgert, Christopher J.; Quill, Terry F.; McCarty, L.S.; Mason, Ann M.

doi:10.1016/j.taap.2004.05.005

Cited by 134 publications

(77 citation statements)

References 36 publications

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“…Mechanism of action has been defined as ''a complete and detailed understanding of each and every step in the sequence of events that leads to a toxic outcome'' [6], which includes detailed knowledge of the causal and temporal relationships among all the steps leading to a specific effect [7]. In contrast, mode of action has been defined as ''a common set of biochemical, physiological, or behavioral responses that characterize an adverse biological response where major, but not necessarily all, linkages between a direct initiating event and an adverse outcome are understood'' [6,7]. In practice, however, the term mechanism of action is often used to describe just a portion of the biological response lying between an initiating event and adverse outcome, whereas the term mode of action is commonly defined by an outcome or initiating event but is rarely anchored to both.…”

Section: Definition Of Adverse Outcome Pathwaysmentioning

confidence: 99%

Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment

Ankley

Bennett

Erickson

et al. 2009

Enviro Toxic and Chemistry

2,110

1,240

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Ecological risk assessors face increasing demands to assess more chemicals, with greater speed and accuracy, and to do so using fewer resources and experimental animals. New approaches in biological and computational sciences may be able to generate mechanistic information that could help in meeting these challenges. However, to use mechanistic data to support chemical assessments, there is a need for effective translation of this information into endpoints meaningful to ecological risk-effects on survival, development, and reproduction in individual organisms and, by extension, impacts on populations. Here we discuss a framework designed for this purpose, the adverse outcome pathway (AOP). An AOP is a conceptual construct that portrays existing knowledge concerning the linkage between a direct molecular initiating event and an adverse outcome at a biological level of organization relevant to risk assessment. The practical utility of AOPs for ecological risk assessment of chemicals is illustrated using five case examples. The examples demonstrate how the AOP concept can focus toxicity testing in terms of species and endpoint selection, enhance across-chemical extrapolation, and support prediction of mixture effects. The examples also show how AOPs facilitate use of molecular or biochemical endpoints (sometimes referred to as biomarkers) for forecasting chemical impacts on individuals and populations. In the concluding sections of the paper, we discuss how AOPs can help to guide research that supports chemical risk assessments and advocate for the incorporation of this approach into a broader systems biology framework.

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Section: Definition Of Adverse Outcome Pathwaysmentioning

confidence: 99%

Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment

Ankley

Bennett

Erickson

et al. 2009

Enviro Toxic and Chemistry

2,110

1,240

View full text Add to dashboard Cite

show abstract

“…Because extensive information regarding both pharmacodynamics and pharmacokinetics is needed to actually judge the similarity of the mode of action of two or more chemicals [23], the preference of IA above CA based on the known or assumed mode of action has been questioned [23][24][25][26]. The classification of similar and dissimilar modes of action as applied in the present study relates to the pesticidal mode of action of the a.s., hence to the specific toxicity towards the target organisms based on the known molecular target and the development of cross-resistances in target organisms.…”

Section: Similarity In the Mode Of Actionmentioning

confidence: 99%

Predicting the aquatic toxicity of commercial pesticide mixtures

Coors

Frische

2011

Environ Sci Eur

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Background: Previous studies reported on a large (> 80%) compliance between the observed toxicity of pesticide mixtures and their toxicity as predicted by the concept of concentration addition (CA). The present study extents these findings to commercially sold and frequently applied pesticide mixtures by investigating whether the aquatic toxicity of 66 herbicidal and 53 fungicidal combination products, i.e., authorized plant protection products that contain two or more active substances, can reliably be predicted by CA. Results: In more than 50% of cases, the predicted and observed mixture toxicity deviated by less than factor 2. An indication for a synergistic interaction was only detected with regard to algal growth inhibition for mixtures of fungicides that inhibit different enzymes of ergosterol biosynthesis. The greatest degree of compliance between prediction and observation was found for the acute toxicity of fungicidal products towards Daphnia and fish, while the greatest degree of underestimation of product toxicity occurred for the acute toxicity of herbicidal products towards Daphnia and fish. Using the lowest available toxicity measures within taxonomic groups as the most conservative approach resulted in a bias towards overestimation of product toxicity, but did not eliminate cases of considerable underestimation of product toxicity. Conclusions:The results suggest that the CA concept can be applied to predict the aquatic toxicity of commercial pesticide mixtures using the heterogeneous data typically available in a risk assessment context for a number of clearly identified combinations of test species and pesticide types with reasonably small uncertainty.

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“…Two of the most common problems in risk assessment concern the extrapolation of data (usually from relatively high levels of exposure as used in laboratory studies to much lower, real-life exposures) (Douglas 2009) and the grouping of toxic or similar substances into classes in order to facilitate their joint regulation (meaning faster and less resourceintensive regulatory decisions) (Cranor 2011;Borgert et al 2004). In other words, researchers in risk assessment have to decide which model of data extrapolation to adopt (for instance, with or without a threshold 11 ), or how to usefully group substances (applying different, even conflicting criteria).…”

Section: Controversy and Mechanistic Information In Risk Assessmentmentioning

confidence: 99%

Mechanistic Information as Evidence in Decision-Oriented Science

2015

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Mechanistic information is used in the field of risk assessment in order to clarify two controversial methodological issues, the selection of inference guides and the definition of standards of evidence. In this paper we present an analysis of the concept of mechanistic information in risk assessment by recurring to previous philosophical analyses of mechanistic explanation. Our conclusion is that the conceptual analysis of mechanistic explanation facilitates a better characterization of the concept of mechanistic information. However, it also shows that the use of this kind of information in risk assessment is heavily influenced by pragmatic factors, which have not been sufficiently taken into account in philosophical analysis. Mechanistic models are like hypothesis that have to be validated empirically. Due to their dependence on the standards of evidence, they are subject to the same pragmatic factors. Therefore, recurring to mechanistic information does not lead to closure of the methodological controversies in risk assessment.

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Can mode of action predict mixture toxicity for risk assessment?

Cited by 134 publications

References 36 publications

Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment

Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment

Predicting the aquatic toxicity of commercial pesticide mixtures

Mechanistic Information as Evidence in Decision-Oriented Science

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