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Environ Health Perspect. 2009 October; 117(10): A432–A433.
PMCID: PMC2897211

U.S. EPA’s Toxicity Reference Database: Martin and Dix Respond

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 multi-gender, 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 prolifera tive, 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.


  • Cohen SM, Arnold LL. Cell proliferation and carcinoenesis. J Toxicol Pathol. 2008;21:1–7.
  • Dix DJ, Houck KA, Martin MT, Richard AM, Setzer RW, Kavlock RJ. The ToxCast program for prioritizing toxicity testing of environmental chemicals. Toxicol Sci. 2007;95:5–12. [PubMed]
  • Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70. [PubMed]
  • Knudsen TB, Martin MT, Kavlock RJ, Judson RS, Dix DJ, Singh AV. Profiling the activity of environmental chemicals in prenatal developmental toxicity studies using the U.S. EPA’s ToxRefDB. Reprod Toxicol. 2009;28(2):209–219. doi: 10.1016/j.reprotox.2009.03.016. [Online 10 April 2009] [PubMed] [Cross Ref]
  • Martin MT, Judson RS, Reif DM, Kavlock RJ, Dix DJ. Profiling chemicals based on chronic toxicity results from the U.S. EPA ToxRef Database. Environ Health Perspect. 2009a;117:392–399. [PMC free article] [PubMed]
  • Martin MT, Kavlock RJ, Rotroff D, Corum D, Judson RS, Dix DJ. Profiling the reproductive toxicity of chemicals from multigeneration studies in the Toxicity Reference Database (ToxRefDB) Toxicol Sci. 2009b;110(1):181–190. doi: 10.1093/toxsci/kfp080. [Online 10 April 2009] [PubMed] [Cross Ref]
  • U.S EPA (U.S. Environmental Protection Agency) ToxCast Program. 2008a. [[accessed 29 May 2009]]. Available:
  • U.S EPA (U.S. Environmental Protection Agency) ToxRefDB Program. 2008b. [[accessed 29 May 2009]]. Available:

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