Correspondence/Rebuttal pubs.acs.org/est
Comment on “Application of the Activity Framework for Assessing Aquatic Ecotoxicology Data for Organic Chemicals” We offer the following comments to the paper of Thomas et al.1. The authors apply the activity concept to experimental data of nonspecific toxicity. The goal is to identify a systematic relationship that would then help to predict toxic effects for untested chemicals. However, it appears to us that the suggested approach is a step backward in our process understanding and chemical risk management rather than a step forward. (1) The authors find that acute nonpolar narcosis (MoA 1) occurs within an activity range of anarcosis: 0.01 to 0.1. If this relatively narrow range was to hold for MoA 1 chemicals in general, then it would allow to predict the aqueous concentration of MoA 1 chemical i at which ). narcosis occurs in equilibrium situations (Cnarcosis iw cos is Cinar = w
ainarcosis γi w ·Vw
(1)
where γi w and Vw are the activity coefficient of i in water and the molar volume of water, respectively. Over two decades, it has been increasingly recognized that acute narcosis occurs for any chemical i when a fixed membrane concentration of ca. 100 mmol per L of membrane is reached, irrespective of the polarity of the as, chemicals.2,3 This threshold allows to identify Cnarcosis iw cos is Cinar = w
100mmol/Lm K i m,w
(2)
where Kim,w is the membrane/water partition coefficient. This constant toxic membrane concentration (CTMC) concept is not equivalent to the constant activity approach. Activities would only be linearly related to membrane concentrations for various chemicals if their activity coefficients in membranes were the same, or, less abstract, if their intermolecular interactions in their pure liquid state would obey the same relation to their interactions in membranes, which is not the case. Figure 1 shows that the CTMC approach narrows down the range of the experimental data from Thomas et al.4 for both MoA 1 and 2 chemicals and for different organisms more than the activity approach does, with only one exception (MoA 1, algae). Additionally, the CTMC approach places MoA 1 and 2 chemicals more or less in the same range of membrane concentrations for all organisms, whereas the activity approach does not. (2) There are also many practical advantages of the CTMC approach over the activity approach. The activity of a chemical in water can be calculated from its water concentration and its activity coefficient in water. The activity coefficient in water is calculated from its subcooled liquid vapor pressure and its water/air partition constant, which may often not be available. Thomas et al., therefore, revert to water solubilities © XXXX American Chemical Society
Figure 1. Activity and equilibrium membrane concentration at toxic effects. Toxicity data are from Thomas et al.4 The bars indicate the mean and standard deviations of log-transformed data. Kim,w used was estimated by a PP-LFER.5
instead of activity coefficients in water. It follows from theory, though, that activity coefficients can only be related to solubilitites of chemicals if their activity coefficient stays constant from infinite dilution up to saturation concentration. Water miscible chemicals are an extreme example where this is not the case. As a remedy the authors assign a water solubility of 55.5 mol/ L to these chemicals, which is the molar solubility of
A
DOI: 10.1021/acs.est.5b05534 Environ. Sci. Technol. XXXX, XXX, XXX−XXX
Environmental Science & Technology
Correspondence/Rebuttal
applied to MoA 1 and 2 chemicals and even organic ions. We do not see that the activity approach could provide any significant information regarding toxicity evaluation that the CTMC approach cannot.
water in itself. Such an arbitrarily chosen value does not serve as a valid estimate for their activity coefficients and must not be interpreted in terms of toxicity. For partially ionizable chemicals, the experimental water solubility is also not useful because it does not represent the partition behavior of the neutral species alone. For many sparingly soluble chemicals, for which water solubility could indeed be used to calculate the activity coefficient in water, other problems arise: water solubility is often quite difficult to measure accurately. In addition, for compounds whose pure form is a solid at room temperature, a correction of the measured solubility to that of the subcooled liquid is needed. The method suggested by Thomas et al. based on a constant entropy of fusion of 56 J/(mol K) for all chemicals can be quite inaccurate.6 If no experimental solubility data are available, then one has to revert to predictive methods. However, the prediction of solubilities is generally more challenging than that of partition coefficients, because there is no common reference (i.e., each chemical is referenced to its own pure liquid state). Particularly for solid chemicals, the crystal structure, which is not easy to model, plays a role in the solubility. A model to directly predict subcooled liquid solubilities would have a problem with calibration data, because there is no directly measured data for solid chemicals. The Kim,w value needed for the CTMC approach is often easier to measure than water solubility (although Kim,w measurements for highly hydrophobic chemicals could be equally challenging); it works for all chemicals no matter whether they are solid, water miscible, or ionizable. And there are various methods that allow to predict Kim,w.5,7 Even just Kow can approximate Kim,w of diverse neutral chemicals fairly well.5 (3) Surfactants and all chemicals that form micelles or aggregates in water are difficult to handle with the activity concept. Moreover, the concept can principally not be applied to the toxicity of organic ions, because they do not exist as a pure liquid phase. Ions do, however, make up a large fraction of those chemicals that have to be assessed by regulators and they do partition to membranes. Available data suggest that they exert narcosis and that their effect is correlated to their Kim,w values.8 A predictive method of Kim,w for organic ions based on molecular structure is available.7 (4) It is a misconception that organic chemicals must spontaneously precipitate when their aqueous concentration exceeds the solubility of the pure solid. Correct is that precipitation will occur at this threshold if a pure solid phase of the chemical already exists in the system. In the absence of the pure phase or a suitable nucleus, spontaneous precipitation will not occur until a very high degree of oversaturation is reached because the accidental encounter of a few molecules of the solute at a time can still not provide the cohesive energy that is needed to form a stable pure phase. It is thus dangerous to assume that chemicals whose aqueous solubility is below the effective aqueous concentration might never exert toxic effects. Supersaturation ratios up to 50 have been reported for various pharmaceuticals.9 In conclusion, we find that the CTMC approach has many practical advantages over the activity approach and it can be
Kai-Uwe Goss*,† Satoshi Endo‡ †
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Helmholtz Centre for Environmental Research- UFZ, Permoserstr. 15, 04318 Leipzig, Germany ‡ Osaka City University, Urban Research Plaza & Graduate School of Engineering, Sugimoto 3-3-138, Sumiyoshi-ku, 558-8585 Osaka, Japan
AUTHOR INFORMATION
Corresponding Author
*Phone: ++49 341 235 1411; e-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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REFERENCES
(1) Thomas, P.; Dawick, J.; Lampi, M.; Lemaire, P.; Presow, S.; van Egmond, R.; Arnot, J. A.; Mackay, D.; Mayer, P.; Galay Burgos, M. Application of the Activity Framework for Assessing Aquatic Ecotoxicology Data for Organic Chemicals. Environ. Sci. Technol. 2015, 49 (20), 12289−12296. (2) Van Wezel, A.; Opperhuizen, A. Narcosis due to environmentalpollutants in aquatic organisms - residue-based toxicity, mechanisms, and membrane burdens. Crit. Rev. Toxicol. 1995, 25 (3), 255−279. (3) Escher, B. I.; Hermens, J. L. M. Modes of action in ecotoxicology: Their role in body burdens, species sensitivity, QSARs, and mixture effects. Environ. Sci. Technol. 2002, 36 (20), 4201−4217. (4) Thomas, P.; Dawick, J.; Lampi, M.; Lemaire, P.; Presow, S.; Van Egmond, R.; Galay Burgos, M. Activity-Based Relationships for Aquatic Ecotoxicology Data: Use of the Activity Approach to Strengthen MoA Predictions; ECETOC Technical Report No. 120; European Centre for Ecotoxicology and Toxicology of Chemicals: Brussels, Belgium, 2013; ISSN-0773-8072-120 (print). (5) Endo, S.; Escher, B. I.; Goss, K. U. Capacities of Membrane Lipids to Accumulate neutral Organic Chemicals. Environ. Sci. Technol. 2011, 45, 5912−5921. (6) Van Noort, P. C. M. Fugacity ratio estimations for high-melting rigid aromatic compounds. Chemosphere 2004, 56 (1), 7−12. (7) Bittermann, K.; Spycher, S.; Endo, S.; Pohler, L.; Huniar, U.; Goss, K.-U.; Klamt, A. Prediction of phospholipid-water partition coefficients of ionic organic chemicals using the mechanistic model COSMOmic. J. Phys. Chem. B 2014, 118 (51), 14833−14842. (8) Escher, B. I.; Eggen, R. I. L.; Schreiber, U.; Schreiber, Z.; Vye, E.; Wisner, B.; Schwarzenbach, R. P. Baseline toxicity (narcosis) of organic chemicals determined by in vitro membrane potential measurements in energy-transducing membranes. Environ. Sci. Technol. 2002, 36 (9), 1971−1979. (9) Box, K. J.; Comer, J. E. A. Using Measured pK(a), LogP and Solubility to Investigate Supersaturation and Predict BCS Class. Curr. Drug Metab. 2008, 9 (9), 869−878.
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DOI: 10.1021/acs.est.5b05534 Environ. Sci. Technol. XXXX, XXX, XXX−XXX
