Concerns of CropLife America Regarding the Application and Use of the U.S. EPA’s Toxicity Reference Database
Environ Health Perspect. doi:10.1289/ehp.0900951 available via http://dx.doi.org [Online 25 September 2009]
Referencing: Profiling Chemicals Based on Chronic Toxicity Results from the U.S. EPA ToxRef Database
In a recent article in EHP, Martin et al. (2009) reported classifying the relative toxicity of chemicals using the U.S. EPA’s (U.S. Environmental Protection Agency) Toxicity Reference Database (ToxRefDB). The authors profiled results from in vivo chronic toxicity/carcinogenicity studies across 310 chemicals currently contained within ToxRefDB. This database has been suggested to be a model for development of predictive signatures of toxicity and for validation of the U.S. EPA’s ToxCast research program (Martin et al. 2009). Although the goals of the U.S. EPA program are worthy of our support because they promote both the prediction of response for chemicals with unknown activity and the avoidance of unnecessary testing in animals, CropLife America has several concerns regarding the application and use of ToxRefDB, as described by Martin et al.
First, we at CropLife America understand that ToxRefDB is not intended for risk assessment purposes. However, in their Table 3, Martin et al. (2009) present a list of 109 chemical compounds according to a “relative potency” grading system (using a scale based on lowest-effect dose levels/end points from chronic toxicity studies) and whether or not tumors occurred according to multigenders/multisites/multispecies. Thus, the summary presented in Table 3 represents a hazard ranking system based on relative potency. Such systems are used as tools by some regulatory bodies to make decisions (e.g., the European Union, the State of California under Proposition 65). As a result, it is possible, and even likely, that the data in Table 3 could be used to support regulatory action based solely on this relative potency ranking, which is outside the context of the formal risk assessment process. Even a cursory review of the chemicals listed in Table 3 reveals the presence of many currently registered food-use pesticides that have not been found to pose any unacceptable cancer risk. Therefore, additional care should be taken in the future with regard to any potential rankings using ToxRefDB analyses.
Second, it is problematic that some data entries for chemicals listed in Table 3 (Martin et al. 2009) demonstrate an absence of available information. For example, we checked the accuracy of the Table 3 entry of “N” indicating “not assessed (no study available).” This entry appeared for 12 chemicals (pesticides) that denoted a lack of multispecies carcinogenicity data. In six cases (i.e., pyraclostrobin, dichlorvos, alachlor, captan, maneb, and propargite) the U.S. EPA website of Reregistration Eligibility Decision (RED) documents (U.S. EPA 2009) indicates that, contrary to information presented in Martin et al.’s Table 3, multispecies carcinogenicity studies are available. This inconsistency involving readily available information from RED documents and from data evaluation records (DERs; used primarily by the ToxRefDB) should be addressed to ensure future consistency and completeness of the data. This additional check of existing information by the ToxRefDB is especially important given the statement by Martin et al. (2009) in their abstract that “these data are now accessible and mineable within ToxRefDB and are serving as a primary source of validation for U.S. EPA’s ToxCast research program in predictive toxicology.” Any validation work performed with an incomplete database would be questionable.
Third, we would prefer greater transparency when analyzing “cancer datasets” involving grouping of nonneoplastic proliferative lesions with preneoplastic lesions/neoplastic lesions. Because this type of grouping of nonneoplastic proliferative lesions with neoplasia is not standard evaluation practice (Williams et al. 2008), we at Crop Life America would prefer future ToxRefDB interpretation to identify specific terminology used with regard to scoring system(s) of end point progression schema [such as used by Martin et al. (2009) in their Figure 3A]. Identification of specific terminology and key events for nonneoplastic proliferative lesions and preneoplastic lesions would increase transparency for future publications. Martin et al. stated in their “Results” that they used their method to increase species concordance, which in turn, probably increased the relative power of the statistical analysis. However, it is well known that hyperplastic lesions, for instance, do not always progress to tumors (Klaunig and Kamendulis 2007). By grouping nonneoplastic proliferative lesions with neoplasia, Martin et al. may have increased species concordance and statistical power but may have failed to fully consider the biological plausibility and/or consequences of the grouping. Moreover, the use of this controversial application in the interpretation of the analyses presented by Martin et al. casts some doubt on their validity.
Finally, our last concern involves implementation of results from in vivo testing, which Martin et al. (2009) compared with results of in vitro testing. The authors failed to discuss the issue of chemical activation and detoxification. It is a general principle of toxicology that toxicity of chemicals can be directly dependent on metabolism (Kemper et al. 2008). Metabolic pathways exist in intact animals but not in isolated cells. Therefore, both pharmacokinetics and metabolism are important biological components of the toxicity profile of any chemical. It is not clear that the current analyses using the ToxRefDB (Martin et al. 2009) took this into consideration.
In conclusion, based on our four concerns given above, we hope that the authors will address these points to increase the degree of clarity and consistency of interpretation of analyses using the ToxRefDB.
E.J. is employed by a trade association whose members manufacture and use chemicals in ToxRefDB.
Erik Janus
Science & Regulatory Affairs
CropLife America
Washington, DC
E-mail: EJanus@croplifeamerica.org
References
Kemper RA, Hayes JR, Bogdanffy MS. 2008. Metabolism: a determinant of toxicity. In: Principles and Methods of Toxicology (Hayes AW, ed). 5th ed. Boca Raton, FL:CRC Press, 103–178.
Klaunig JE, Kamendulis LM. 2007. Chemical carcinogenesis. In: Casarett & Doull’s Toxicology: The Basic Science of Poisons (Klaassen CD, ed). 7th ed. New York:McGraw-Hill, 329–380.
Martin MT, Judson RS, Reif DM, Kavlock RJ, Dix DJ. 2009. Profiling chemicals based on chronic toxicity results from the U.S. EPA ToxRef Database. Environ Health Perspect 117:392–399.
U.S. EPA (U.S. Environmental Protection Agency). 2009. Pesticide Reregistration Status. Available: http://www.epa.gov/oppsrrd1/reregistration/status.htm [accessed 11 September 2009].
Williams GM, Iatropoulos MJ, Enzmann HG. 2008. Principles of testing for carcinogenic activity. In: Principles and Methods of Toxicology, (Hayes AW, ed). 5th ed. Boca Raton, FL:CRC Press, 1265–1316.
U.S. EPA’s Toxicity Reference Database: Martin and Dix Respond
Environ Health Perspect. doi:10.1289/ehp.0900951R available via http://dx.doi.org [Online 25 September 2009]
We appreciate the letter from Janus of CropLife America commenting on that group’s assessment of the database and our article (Martin et al. 2009a) from its perspective as an agriculture and pest-management trade organization. We also appreciate the CropLife America’s continued interest in the U.S. EPA’s (U.S. Environmental Protection Agency) ToxRefDB and ToxCast research programs, including the review of much of the data entered into ToxRefDB. However, Janus’s comments do not address the ToxRefDB applications presented in our article, but instead create hypothetical uses of the database and reported data.
For example, in Table 3 of our article (Martin et al. 2009a), we presented multigender, multisite, and multispecies rodent tumorigens in order to provide data in a systematic and computable format for predictive toxicity models incorporating potency values. In contrast, Janus and CropLife America refer to a hypothetical regulatory application of this same animal tumorigenicity data in a ranking system never suggested in our article.
The U.S. EPA has gone to great lengths to make ToxRefDB and its development as transparent as possible. Three manuscripts and data sets have been published to date (Knudsen et al. 2009; Martin et al. 2009a, 2009b), and the standardized vocabulary and a version of the database are available on the ToxRefDB website (U.S. EPA 2008b). We will continue to make every effort to publicly release information from ToxRefDB as it continues to develop.
We recognize the complexity of pathologic progression to cancer. The end point progression scheme we presented (Martin et al. 2009a) included aggregation of proliferative, preneoplastic, and neoplastic lesions for the development of predictive signatures from in vitro data coming from the ToxCast research program (U.S. EPA 2008a). This approach is not controversial in the context of predictive toxicology research and is supported by the literature (Cohen and Arnold 2008; Hanahan and Weinberg 2000).
We agree that it is important to incorporate pharmacokinetics and metabolism, including chemical detoxification and activation, into predictive toxicology efforts. However, this issue is outside the scope of our article (Martin et al. 2009a) and is being addressed in other aspects of the ToxCast research program.
Two additional papers on multigenerational reproductive and prenatal developmental toxicity studies in ToxRefDB have been recently published (Knudsen et al. 2009; Martin et al. 2009b), again with the primary goal of providing diverse end points for predictive modeling as part of the ToxCast research program (Dix et al. 2007). Of toxicity end points in ToxRefDB, we are using only those of sufficient quality for predictive modeling, and we are taking care to distinguish between missing versus negative data.
We view ToxRefDB as a valuable resource to the scientific community and one in which the U.S. EPA, stakeholders, and other interested parties can work together to ensure the success of ToxRefDB and the larger ToxCast effort.
The authors declare they have no competing financial interests.
Matthew T. Martin
David J. Dix
National Center for Computational Toxicology
Office of Research & Development
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina
E-mail: Martin.Matt@epamail.epa.gov
This response does not necessarily reflect official U.S. EPA policy.
References
Cohen SM, Arnold LL. 2008. Cell proliferation and carcinoenesis. J Toxicol Pathol 21:1–7.
Dix DJ, Houck KA, Martin MT, Richard AM, Setzer RW, Kavlock RJ. 2007. The ToxCast program for prioritizing toxicity testing of environmental chemicals. Toxicol Sci 95:5–12.
Hanahan D, Weinberg RA. 2000. The hallmarks of cancer. Cell 100:57–70.
Knudsen TB, Martin MT, Kavlock RJ, Judson RS, Dix DJ, Singh AV. 2009. Profiling the activity of environmental chemicals in prenatal developmental toxicity studies using the U.S. EPA’s ToxRefDB. Reprod Toxicol 28(2):209–219; doi:10.1016/j.reprotox.2009.03.016 [Online 10 April 2009].
Martin MT, Judson RS, Reif DM, Kavlock RJ, Dix DJ. 2009a. Profiling chemicals based on chronic toxicity results from the U.S. EPA ToxRef Database. Environ Health Perspect 117:392–399.
Martin MT, Kavlock RJ, Rotroff D, Corum D, Judson RS, Dix DJ. 2009b. Profiling the reproductive toxicity of chemicals from multigeneration studies in the Toxicity Reference Database (ToxRefDB). Toxicol Sci 110(1):181–190; doi:10.1093/toxsci/kfp080 [Online 10 April 2009].
U.S. EPA (U.S. Environmental Protection Agency). 2008a. ToxCast Program. Available: http://www.epa.gov/ncct/toxcast/ [accessed 29 May 2009].
U.S. EPA (U.S. Environmental Protection Agency). 2008b. ToxRefDB Program. Available: http://www.epa.gov/ncct/toxrefdb/ [accessed 29 May 2009].
