Correspondence/Rebuttal Cite This: Environ. Sci. Technol. XXXX, XXX, XXX-XXX
pubs.acs.org/est
Comment on “Mode of Action (MOA) Assignment Classifications for Ecotoxicology: An Evaluation of Approaches”
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recent paper by Kienzler et al.1 concludes that, in order to apply the concept of mode of action (MoA) broadly in regulatory ecotoxicology, MoA classification schemes need to be harmonized. Their conclusion is based on an attempt “...to critically evaluate available MoA classification methodologies, ... compare the various approaches, and evaluate their utility and limitations...” Unfortunately, terminological confusion between the general definition of mode of action (MoA) and specific definitions for various types of MoA used in extant classification schemes thwarted their objectives. Terminological confusion starts with the first three sentences (S1, S2, S3) of the third paragraph of the Introduction. S1 states that “MOA is an operational term that has been loosely defined in both human health and ecotoxicology as a functional change at the cellular level, in contrast to the mechanism of action or molecular initiating event.” S3, however, posits a contradictory definition: “Generally, MOA describes key events at various levels of biological organization, starting with cellular interaction and leading to functional and/or anatomical changes.”1 Although they correctly note that “[t]he definitions of MOA used are unique to each of the classification schemes investigated...”1 the authors seem not to recognize that, before MoA schemes can be evaluated, this fundamental confusion must be resolved regarding the level of mechanistic detail that differentiates a mode of action from a mechanism of action (MeA). By ignoring the need for a consistent general MoA definition and description of how the “unique” MoA specific definitions differ among classification schemes, the authors forfeited the ability to evaluate whether the schemes examined are based on general toxicity or on MoA. The oversight negatively affected their analysis in three important ways. First, the authors compare apples to oranges. For example, the Verhaar et al. (1992) framework is widely used in regulatory toxicity activities, but it cannot be considered a MoA-based classification scheme since its five classes do not represent different MoA; i.e., groups with a similar, but not identical, MeA. Historically, much was made of the difference between neutral and polar narcotics, hence the two narcosis categories (Class 1 and Class 2) proposed by Verhaar 25 years ago, and the third (Ester Narcosis; see Table 11) of a similar vintage. Although the MoA/MeA for narcosis is still incompletely resolved, the differences may be more related to internal partitioning variability and/or bioavailability issues than toxicological potency differences. Thus, only one narcosis class may be needed. It remains unclear if it is a mode or mechanism of action; a single MoA currently appears as the best option. Looking at Table 1,1 it can be seen that unspecific reactive category (Class 3) lumps together several different chemical reactions that modify or denature various macromolecules in different ways. Although each might be a specific MeA, at the least, they represent separate MoAs. In the specific mechanism MoA group (Class 4), the corresponding groupings identified in the non-Verhaar MoA schemes actually represent different MoAs or MeAs. Certainly they cannot be considered to be a © XXXX American Chemical Society
single MoA class as specified by Verhaar. Finally, the Class 5 grouping is neither a MoA nor a MeA classification; rather, it is place-keeping category for unknown modes/mechanisms of toxic action. Second, the authors relate these confused concepts of MoA and MeA to AOPs, which is mentioned in S2 and is continued in the discussion section of the paper where it is suggested that MoA classification may be useful in adverse outcome pathway (AOP) development by grouping compounds “... acting by a specific mechanism.”1 This is consistent with a common view that MoA and AOP are very similar, if not identical, e.g., “Mode of action is conceptually identical to the more recent term of “adverse outcome pathway” (AOP)...”2 However, “An individual AOP, composed of a single sequence of KEs and KERs, is a pragmatic unit of AOP development and evaluation”.3 Yet, in AOP Principle 3, “branching”,3 as might be found in an MoA (a group of similar, not identical mechanisms of action), is specifically excluded. This nullifies equating AOP with MoA. Thus, according to the MoA/MeA definitions noted earlier, AOPs appear to have much more in common with MeA. Third, lack of clarity regarding the first two points contributes to a mistaken statement of the fundamental problem: “However, MOA classification has never been standardized in ecotoxicology, and a comprehensive comparison of classification tools and approaches has never been reported.”1 Unfortunately, this is misleading on the first point and incorrect on the second. MoA has been well-defined for some time. In 1999, Schlosser and Bogdanffy4 outlined general definitions for MoA and the related concept of mechanism of action (MeA): “A ‘mode of action’ is a category or class of toxic mechanisms for which the major (but not all) biochemical steps are understood. The ‘mechanism of action’ for a chemical, on the other hand, is a complete and detailed understanding of each and every step in the sequence of events that leads to a toxic outcome.” This has been further reviewed, evaluated, and discussed.5−7 What is still missing are detailed operational, technical definitions of “mode” and “mechanism” sufficient to allow reliable identification of groups of “similar” MeA and justify categorization into different MoA classes. As for the second point, this was discussed in a comprehensive 2006 review of a large number of toxicity classification schemes that noted, among other things, no useful, scientifically sound MoA classification scheme was currently available and a broadly applicable, generally accepted scheme addressing modes/ mechanisms of toxic action spanning the full range of biological levels of organization, from biochemical through whole organisms to ecosystems, was needed to enable advances in regulatory risk assessment.6 While we agree entirely with Kienzler et al.1 regarding the need to harmonize MoA classifications schemes for use in regulatory ecotoxicology, and also human toxicology, their
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DOI: 10.1021/acs.est.7b04967 Environ. Sci. Technol. XXXX, XXX, XXX−XXX
Environmental Science & Technology
Correspondence/Rebuttal
inadequate discernment of the underlying problem and insufficient use of prior knowledge has led them to conclude what has been widely known for more than a decade: currently available MoA classification schemes vary widely, are currently inadequate for quantitative, toxicologically sound regulatory purposes, and, for progress to be made in regulatory ecotoxicity and risk assessment, “Development of comprehensive classification schemes for modes/mechanisms of toxic action and mechanisms of interaction is needed...”6 We trust that the above explanation will prevent confusion and misdirection from inhibiting much-needed progress on this vital toxicological problem.
Lynn S. McCarty*,† Christopher J. Borgert‡ †
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L.S. McCarty Scientific Research & Consulting, Newmarket, ON L3X 3E2, Canada ‡ Applied Pharmacology and Toxicology, Inc., Gainesville, Florida 32605, United States
AUTHOR INFORMATION
Corresponding Author
*Phone: 905 953-9342. E-mail:
[email protected]. ORCID
Lynn S. McCarty: 0000-0002-4095-4699 Notes
The authors declare no competing financial interest.
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REFERENCES
(1) Kienzler, A.; Barron, M. G.; Belanger, S. E.; Beasley, A.; Embry, M. R. Mode of Action (MOA) Assignment Classifications for Ecotoxicology: An Evaluation of Approaches. Environ. Sci. Technol. 2017, 51 (17), 10203−10211. (2) Meek, M. E.; Boobis, A.; Cote, I.; Dellarco, V.; Fotakis, G.; Munn, S.; Seed, J.; Vickers, C. New developments in the evolution and application of the WHO/IPCS framework on mode of action/species concordance analysis. J. Appl. Toxicol. 2014, 34, 1−18. (3) Villeneuve, D. L.; Crump, D.; Garcia-Reyero, N.; Hecker, M.; Hutchinson, T. H.; LaLone, C. A.; Landesmann, B.; Lettieri, T.; Munn, S.; Nepelska, M.; Ottinger, M. A.; Vergauwen, L.; Whelan, M. Adverse outcome pathway (AOP) development I: strategies and principles. Toxicol. Sci. 2014, 142, 312−320. (4) Schlosser, P. M.; Bogdanffy, M. S. Determining modes of action for biologically based risk assessments. Regul. Toxicol. Pharmacol. 1999, 30, 75−79. (5) Borgert, C. J.; Quill, T. F.; McCarty, L. S.; Mason, A. M. Can mode of action predict mixture toxicity for risk assessment? Toxicol. Appl. Pharmacol. 2004, 201, 85−96. (6) McCarty, L. S.; Borgert, C. J. Review of the toxicity of chemical mixtures: theory, policy, and regulatory practice. Regul. Toxicol. Pharmacol. 2006, 45, 119−143. (7) Guyton, K. Z.; Barone, S.; Brown, R. C.; Euling, S. Y.; Jinot, J.; Makris, S. Mode of action Frameworks: A critical analysis. J. Toxicol. Environ. Health, Part B 2008, 11, 16−31.
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DOI: 10.1021/acs.est.7b04967 Environ. Sci. Technol. XXXX, XXX, XXX−XXX
