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Rebuttal
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
38, 336–338 (1997)
LETTERS TO THE EDITOR Editor’s Comment
The article ‘‘Influence of the Energy Relationships of Organic Compounds on Toxicity to the Cladoceran Daphnia magna and the Fish Pimephales promelas,’’ authored by Giulio P. Genoni, recently appeared in Vol. 36 of Ecotoxicology and Environmental Safety. This information was questioned by T. Wayne Schultz. In such cases we offer the authors an opportunity to present a rebuttal and then both views are published simultaneously. In these rare instances, it is the further policy of the editors of EES not to allow a continuing dialogue, and the matter ends with this presentation. What follows, then, is Dr. Schultz’s comments and the rebuttal by Dr. Genoni. Frederick Coulston Editor
To the Editor: Recently, I had the opportunity to read the article by Dr. Giulio P. Genoni titled ‘‘Influence of the Energy Relationship of Organic Compounds on Toxicity to the Cladoceran Daphnia magna and the Fish Pimephales promelas’’ that appeared in Vol. 36 of Ecotoxicology and Environmental Safety, where he proposes to use the energy of chemical formation as a predictor of acute toxic potency. I take issue with Dr. Genoni’s conclusion that ‘‘correlations between transformity and toxicity may prove to be an important generalization in ecotoxicology that contributes a conceptual framework for making cross-class comparisons of the toxicity of . . . compounds.’’ I feel the study is flawed and, therefore, the conclusion unsubstantiated. The flaws rest on the facts that: (1) The energy of formation is not related to mode or mechanism of toxic action. (2) The energy of formation is not related to potency within a mode or mechanism. (3) The chemicals used in the present analyses are, in large part, of the same mode of action, nonpolar narcosis. I will direct my specific comments to the fathead minnow data because the minnow has been more thoroughly studied, but the same argument can be made for the water-flea data. Disregarding the ‘‘others’’ category, six chemical classes as defined by the author remain. Four (i.e., alkanes, alkenes, benzenes, and biphenyls) of the six remaining contain chemicals that elicit their toxic response via baseline nonpolar narcosis (i.e., nonreactive and nonionic). Moreover, 9 of the 11 alcohols (i.e., nonchloro-substituted derivatives) are classic nonpolar 336 0147-6513/97 $25.00 Copyright © 1997 by Academic Press All rights of reproduction in any form reserved.
narcotics. The commonly cited investigations of Ko¨nemann (1981), Veith et al. (1983), and McKim et al. (1987) describe this fact. The two chloroalcohols, although of similar ‘‘class,’’ probably act by a specific molecular mechanism, indirectacting SN2 electrophilicity, not nonpolar narcosis. Members of the sixth class described by Dr. Genoni, the phenols, are not baseline toxicants (Schultz et al., 1986). Phenols are a well-studied class. While members of this group of chemicals elicit several modes and mechanisms of toxic action (Cronin and Schultz, 1996), the derivatives examined in the study act via either polar narcosis or weak acid respiratory uncoupling depending on the number of halo-substitutions (Schultz et al., 1986; McKim et al., 1987; Veith and Broderius, 1987; Bradbury et al., 1989; Cajina-Quezada and Schultz, 1990). Fathead minnow acute toxicities for the three modes of action, nonpolar narcosis, polar narcosis, and weak acid respiratory uncoupling, have each been modeled by a unique hydrophobic-dependent (i.e., 1-octanol/water partition coefficient) structure–toxicity relationship also suggesting separate modes of action (see Bearden and Schultz, 1997). Recently, Veith and Mekenyan (1993) presented a response– surface approach based on hydrophobicity and electrophilicity dependent on model toxicity. This surface approach models across chemical classes as well as modes and mechanisms of action. This decade of progress in structure–activity modeling seems to have been ignored in this study by Dr. Genoni. Additionally, it is of interest to note that the transformity class-based approach proposed by Dr. Genoni is further refuted by chemicals used in his study. From the traditional structure–
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LETTERS TO THE EDITOR
toxicity viewpoint, the chloroalcohols model by neither the chloroalkane nor the alcohol class. In conclusion, Dr. Genoni’s study in large part focuses on chemicals of one mode of action, nonpolar narcotics. It is well documented that the toxic potency of such neutral organics is modeled with very high predictability by hydrophobicity regardless of chemical class. Within a congeneric series (e.g., chlorobenzenes and chlorophenols), the heat of formation is inversely related to hydrophobicity. The latter relationship is the basis for the marginal dependencies shown by Dr. Genoni. REFERENCES Bearden, A. P., and Schultz, T. W. (1997). Structure–activity relationships for Pimephales and Tetrahymena: A mechanism of action approach. Environ. Toxicol. Chem. 16, 1311–1317. Bradbury, S. P., Henry, T. R., Niemi, G. J., Carlson, R. W., and Snarski, V. M. (1989). Use of respiratory-cardiovascular responses of rainbow trout (Salmo gairdneri) in identifying acute toxicity syndromes in fish. Polar narcotics. Environ. Toxicol. Chem. 8, 247–261. Cajina-Quezada, M., and Schultz, T. W. (1990). Structure–toxicity relationships for selected weak acid respiratory uncouplers. Aquat. Toxicol. 17, 239–252. Cronin, M. T. D., and Schultz, T. W. (1996). Structure–toxicity relationships for phenols to Tetrahymena pyriformis. Chemosphere 32, 1453– 1468. Ko¨nemann, H. (1981). Quantitative structure–activity relationships in fish toxicity studies. I. Relationship for 50 industrial pollutants. Toxicology 19, 209–221. McKim, J. M., Schmieder, P. K., Carlson, R. W., Hunt, E. P., and Niemi, G. J. (1987). Use of respiratory-cardiovascular responses of rainbow trout (Salmo gairdneri) in identifying acute toxicity syndromes in fish. I. Pentachlorophenol, 2,4-dinitrophenol, tricaine methanesulfonate and 1-octanol. Environ. Toxicol. Chem. 6, 295–312. Schultz, T. W., Holcombe, G. W., and Phipps, G. L. (1986). Relationships of quantitative structure–activity to comparative toxicity of selected phenols in the Pimephales promelas and Tetrahymena pyriformis test systems. Ecotoxicol. Environ. Saf. 12, 146–153. Veith, G. D., and Broderius, S. J. (1987). Structure–toxicity relationships for industrial chemicals causing Type (II) narcosis syndrome. In QSAR in Environmental Toxicology-II (K. L. E. Kaiser, Ed.), pp. 385–391. D. Reidel Publishing Co., Dordrecht, The Netherlands. Veith, G. D., Call, D. J., and Brooke, L. T. (1983). Structure–toxicity relationships for the fathead minnow, Pimephales promelas: Narcotic industrial chemicals. Can. J. Fish Aquat. Sci. 40, 743–748. Veith, G. D., and Mekenyan, O. G. (1993). A QSAR approach for estimating the aquatic toxicity of soft electrophiles {QSAR for soft electrophiles}. Quant. Struct.-Act. Relation. 12, 349–256.
T. Wayne Schultz Department of Animal Science University of Tennessee College of Veterinary Medicine Knoxville, Tennessee 37996 ARTICLE NO. ES971592
Rebuttal To the Editor: The article addressed by Dr. Schultz’s comment and the related articles (Genoni and Montague, 1995; Genoni, 1997a,b,c) actually make the point that a unifying principle in ecotoxicology might be derivable from the hierarchy theory in systems science. Hierarchy theory (Odum, 1983, 1996) builds on thermodynamics and investigates interactions in dissipative systems in terms of their energy relationships. As noted by Dr. Schultz, I proposed to use transformity as a predictor of toxicity. Transformity is the relative energy input required to sustain one unit of energy flow in a transformation process (Odum, 1983, 1996). In this article I pointed out that it is difficult to obtain a good estimate of transformity and I used Gibbs energy of formation as a crude estimate of transformity. I abundantly addressed the limitations of Gibbs free energy of formation as an estimate of transformity for a substance. Briefly, it underestimates transformity, because it accounts neither for the energy needed to transport a substance to the site of interaction nor for the activation energy involved in each transformation step. It is a problem that we do not have at present better estimates of transformity. Making better estimates presumably will be a difficult, though manageable, task. Because of the paucity of available data, this correlation analysis could not be done on a larger set of chemicals, though I did find 70 organic chemicals for which ecotoxicity data on two test organisms as well as estimates of Gibbs energy of formation were available. These included, albeit in unequal proportions, chemicals of several modes of action. This data set seemed to me to offer at least a first insight. Given the existing uncertainties, I adorned my articles with numerous caveats. I presented the conclusions as being to a large extent speculative and as a suggestion for further research. Dr. Schultz may have misunderstood me and taken my conclusions as implying solid evidence. Dr. Schultz is correct in noting that there has been steady progress in the field of QSARs for explaining and predicting toxicity and that, lately, models that apply even across classes of organic compounds have been developed. At this stage of development, the model that compares the transformity of compounds and their toxicity cannot, and does not intend to, compete with the existing models of QSARs. The regression equations may not convey much meaning at this stage and therefore I did not report them in the article. Rather, this model should be understood as a line of research that might complement QSAR research. It is a first step in a new direction. As first steps are prone to be, it is imperfect. Yet it may suggest some exciting possibilities for the search of unifying principles in ecotoxicology. REFERENCES Genoni, G. P., and Montague, C. L. (1995). Influence of the energy relationships of trophic levels and of elements on bioaccumulation. Ecotox. Environ. Saf. 30, 203–218.
338
LETTERS TO THE EDITOR
Genoni, G. P. (1997a). Influence of the energy relationships of organic compounds on toxicity to the cladoceran Daphnia magna and the fish Pimephales promelas. Ecotox. Environ. Saf. 36, 27–37. Genoni, G. P. (1997b). Influence of the energy relationships of organic compounds on their specificity towards aquatic organisms. Ecotox. Environ. Saf. 36, 99–108. Genoni, G. P. (1997c). Towards a conceptual synthesis in ecotoxicology. Oikos 80, 96–106.
Odum, H. T. (1983). Systems Ecology: An Introduction. Wiley, New York. Odum, H. T. (1996). ‘‘Environmental Accounting. Energy and Environmental Decision Making.’’ Wiley, New York.
Giulio P. Genoni Department of Hydrobiology and Limnology Swiss Federal Institute for Environmental Science and Technology CH-8600 Duebendorf, Switzerland ARTICLE NO. ES971610
38, 336–338 (1997)
LETTERS TO THE EDITOR Editor’s Comment
The article ‘‘Influence of the Energy Relationships of Organic Compounds on Toxicity to the Cladoceran Daphnia magna and the Fish Pimephales promelas,’’ authored by Giulio P. Genoni, recently appeared in Vol. 36 of Ecotoxicology and Environmental Safety. This information was questioned by T. Wayne Schultz. In such cases we offer the authors an opportunity to present a rebuttal and then both views are published simultaneously. In these rare instances, it is the further policy of the editors of EES not to allow a continuing dialogue, and the matter ends with this presentation. What follows, then, is Dr. Schultz’s comments and the rebuttal by Dr. Genoni. Frederick Coulston Editor
To the Editor: Recently, I had the opportunity to read the article by Dr. Giulio P. Genoni titled ‘‘Influence of the Energy Relationship of Organic Compounds on Toxicity to the Cladoceran Daphnia magna and the Fish Pimephales promelas’’ that appeared in Vol. 36 of Ecotoxicology and Environmental Safety, where he proposes to use the energy of chemical formation as a predictor of acute toxic potency. I take issue with Dr. Genoni’s conclusion that ‘‘correlations between transformity and toxicity may prove to be an important generalization in ecotoxicology that contributes a conceptual framework for making cross-class comparisons of the toxicity of . . . compounds.’’ I feel the study is flawed and, therefore, the conclusion unsubstantiated. The flaws rest on the facts that: (1) The energy of formation is not related to mode or mechanism of toxic action. (2) The energy of formation is not related to potency within a mode or mechanism. (3) The chemicals used in the present analyses are, in large part, of the same mode of action, nonpolar narcosis. I will direct my specific comments to the fathead minnow data because the minnow has been more thoroughly studied, but the same argument can be made for the water-flea data. Disregarding the ‘‘others’’ category, six chemical classes as defined by the author remain. Four (i.e., alkanes, alkenes, benzenes, and biphenyls) of the six remaining contain chemicals that elicit their toxic response via baseline nonpolar narcosis (i.e., nonreactive and nonionic). Moreover, 9 of the 11 alcohols (i.e., nonchloro-substituted derivatives) are classic nonpolar 336 0147-6513/97 $25.00 Copyright © 1997 by Academic Press All rights of reproduction in any form reserved.
narcotics. The commonly cited investigations of Ko¨nemann (1981), Veith et al. (1983), and McKim et al. (1987) describe this fact. The two chloroalcohols, although of similar ‘‘class,’’ probably act by a specific molecular mechanism, indirectacting SN2 electrophilicity, not nonpolar narcosis. Members of the sixth class described by Dr. Genoni, the phenols, are not baseline toxicants (Schultz et al., 1986). Phenols are a well-studied class. While members of this group of chemicals elicit several modes and mechanisms of toxic action (Cronin and Schultz, 1996), the derivatives examined in the study act via either polar narcosis or weak acid respiratory uncoupling depending on the number of halo-substitutions (Schultz et al., 1986; McKim et al., 1987; Veith and Broderius, 1987; Bradbury et al., 1989; Cajina-Quezada and Schultz, 1990). Fathead minnow acute toxicities for the three modes of action, nonpolar narcosis, polar narcosis, and weak acid respiratory uncoupling, have each been modeled by a unique hydrophobic-dependent (i.e., 1-octanol/water partition coefficient) structure–toxicity relationship also suggesting separate modes of action (see Bearden and Schultz, 1997). Recently, Veith and Mekenyan (1993) presented a response– surface approach based on hydrophobicity and electrophilicity dependent on model toxicity. This surface approach models across chemical classes as well as modes and mechanisms of action. This decade of progress in structure–activity modeling seems to have been ignored in this study by Dr. Genoni. Additionally, it is of interest to note that the transformity class-based approach proposed by Dr. Genoni is further refuted by chemicals used in his study. From the traditional structure–
337
LETTERS TO THE EDITOR
toxicity viewpoint, the chloroalcohols model by neither the chloroalkane nor the alcohol class. In conclusion, Dr. Genoni’s study in large part focuses on chemicals of one mode of action, nonpolar narcotics. It is well documented that the toxic potency of such neutral organics is modeled with very high predictability by hydrophobicity regardless of chemical class. Within a congeneric series (e.g., chlorobenzenes and chlorophenols), the heat of formation is inversely related to hydrophobicity. The latter relationship is the basis for the marginal dependencies shown by Dr. Genoni. REFERENCES Bearden, A. P., and Schultz, T. W. (1997). Structure–activity relationships for Pimephales and Tetrahymena: A mechanism of action approach. Environ. Toxicol. Chem. 16, 1311–1317. Bradbury, S. P., Henry, T. R., Niemi, G. J., Carlson, R. W., and Snarski, V. M. (1989). Use of respiratory-cardiovascular responses of rainbow trout (Salmo gairdneri) in identifying acute toxicity syndromes in fish. Polar narcotics. Environ. Toxicol. Chem. 8, 247–261. Cajina-Quezada, M., and Schultz, T. W. (1990). Structure–toxicity relationships for selected weak acid respiratory uncouplers. Aquat. Toxicol. 17, 239–252. Cronin, M. T. D., and Schultz, T. W. (1996). Structure–toxicity relationships for phenols to Tetrahymena pyriformis. Chemosphere 32, 1453– 1468. Ko¨nemann, H. (1981). Quantitative structure–activity relationships in fish toxicity studies. I. Relationship for 50 industrial pollutants. Toxicology 19, 209–221. McKim, J. M., Schmieder, P. K., Carlson, R. W., Hunt, E. P., and Niemi, G. J. (1987). Use of respiratory-cardiovascular responses of rainbow trout (Salmo gairdneri) in identifying acute toxicity syndromes in fish. I. Pentachlorophenol, 2,4-dinitrophenol, tricaine methanesulfonate and 1-octanol. Environ. Toxicol. Chem. 6, 295–312. Schultz, T. W., Holcombe, G. W., and Phipps, G. L. (1986). Relationships of quantitative structure–activity to comparative toxicity of selected phenols in the Pimephales promelas and Tetrahymena pyriformis test systems. Ecotoxicol. Environ. Saf. 12, 146–153. Veith, G. D., and Broderius, S. J. (1987). Structure–toxicity relationships for industrial chemicals causing Type (II) narcosis syndrome. In QSAR in Environmental Toxicology-II (K. L. E. Kaiser, Ed.), pp. 385–391. D. Reidel Publishing Co., Dordrecht, The Netherlands. Veith, G. D., Call, D. J., and Brooke, L. T. (1983). Structure–toxicity relationships for the fathead minnow, Pimephales promelas: Narcotic industrial chemicals. Can. J. Fish Aquat. Sci. 40, 743–748. Veith, G. D., and Mekenyan, O. G. (1993). A QSAR approach for estimating the aquatic toxicity of soft electrophiles {QSAR for soft electrophiles}. Quant. Struct.-Act. Relation. 12, 349–256.
T. Wayne Schultz Department of Animal Science University of Tennessee College of Veterinary Medicine Knoxville, Tennessee 37996 ARTICLE NO. ES971592
Rebuttal To the Editor: The article addressed by Dr. Schultz’s comment and the related articles (Genoni and Montague, 1995; Genoni, 1997a,b,c) actually make the point that a unifying principle in ecotoxicology might be derivable from the hierarchy theory in systems science. Hierarchy theory (Odum, 1983, 1996) builds on thermodynamics and investigates interactions in dissipative systems in terms of their energy relationships. As noted by Dr. Schultz, I proposed to use transformity as a predictor of toxicity. Transformity is the relative energy input required to sustain one unit of energy flow in a transformation process (Odum, 1983, 1996). In this article I pointed out that it is difficult to obtain a good estimate of transformity and I used Gibbs energy of formation as a crude estimate of transformity. I abundantly addressed the limitations of Gibbs free energy of formation as an estimate of transformity for a substance. Briefly, it underestimates transformity, because it accounts neither for the energy needed to transport a substance to the site of interaction nor for the activation energy involved in each transformation step. It is a problem that we do not have at present better estimates of transformity. Making better estimates presumably will be a difficult, though manageable, task. Because of the paucity of available data, this correlation analysis could not be done on a larger set of chemicals, though I did find 70 organic chemicals for which ecotoxicity data on two test organisms as well as estimates of Gibbs energy of formation were available. These included, albeit in unequal proportions, chemicals of several modes of action. This data set seemed to me to offer at least a first insight. Given the existing uncertainties, I adorned my articles with numerous caveats. I presented the conclusions as being to a large extent speculative and as a suggestion for further research. Dr. Schultz may have misunderstood me and taken my conclusions as implying solid evidence. Dr. Schultz is correct in noting that there has been steady progress in the field of QSARs for explaining and predicting toxicity and that, lately, models that apply even across classes of organic compounds have been developed. At this stage of development, the model that compares the transformity of compounds and their toxicity cannot, and does not intend to, compete with the existing models of QSARs. The regression equations may not convey much meaning at this stage and therefore I did not report them in the article. Rather, this model should be understood as a line of research that might complement QSAR research. It is a first step in a new direction. As first steps are prone to be, it is imperfect. Yet it may suggest some exciting possibilities for the search of unifying principles in ecotoxicology. REFERENCES Genoni, G. P., and Montague, C. L. (1995). Influence of the energy relationships of trophic levels and of elements on bioaccumulation. Ecotox. Environ. Saf. 30, 203–218.
338
LETTERS TO THE EDITOR
Genoni, G. P. (1997a). Influence of the energy relationships of organic compounds on toxicity to the cladoceran Daphnia magna and the fish Pimephales promelas. Ecotox. Environ. Saf. 36, 27–37. Genoni, G. P. (1997b). Influence of the energy relationships of organic compounds on their specificity towards aquatic organisms. Ecotox. Environ. Saf. 36, 99–108. Genoni, G. P. (1997c). Towards a conceptual synthesis in ecotoxicology. Oikos 80, 96–106.
Odum, H. T. (1983). Systems Ecology: An Introduction. Wiley, New York. Odum, H. T. (1996). ‘‘Environmental Accounting. Energy and Environmental Decision Making.’’ Wiley, New York.
Giulio P. Genoni Department of Hydrobiology and Limnology Swiss Federal Institute for Environmental Science and Technology CH-8600 Duebendorf, Switzerland ARTICLE NO. ES971610