Application of Genomics in Chemical Risk Assessment – An NCEA-Hamner Collaboration

Barbara Wetmore. The Hamner Institutes for Health Sciences

There is an effort within the National Center for Environmental Assessment (NCEA) of the U.S. Environmental Protection Agency (EPA) to “modernize” the way risk assessments are performed. The new effort has been called “NexGen” risk assessment methodology and has been broken down into three tiers based on the type and extent of data collected on the chemical. A Tier 1 assessment is based primarily on in vitro high-throughput screening (HTS) data as collected in the ToxCast program. A Tier 2 assessment has both in vitro HTS data and a limited amount of in vivo data. The data from Tier 2 assessments are used to generate Provisional Peer Reviewed Toxicity Values (PPRTVs) which are unpublished Integrated Risk Information System (IRIS)-like assessments that the agency uses to set clean up and exposure levels for lower priority chemicals. Finally, a Tier 3 assessment is a full IRIS risk assessment for high priority chemicals.

From 2009 – 2011, NCEA collaborated with the Hamner Institutes for Health Sciences (Hamner) to evaluate the use of in vivo genomic data for performing Tier 2 assessments. This collaboration included a series of studies that have demonstrated a high correlation between pathological effects of chemicals and transcriptional responses. The correlation appeared stable over time and suggests that transcriptional points-of-departure could be used as a surrogate in a chemical risk assessment. However, more chemicals need to be examined to confirm the correlation and provide a convincing dataset that will withstand scientific scrutiny. In addition, it is unknown whether transcriptional changes need to be measured in the target tissue or whether a limited number of “sentinel” tissues could be evaluated.

In 2012, three additional chemicals were tested in short-term and subchronic in vivo genomic studies. Each chemical was administered in a six-point dose response and animals were sacrificed at 2 weeks and 13 weeks post exposure. Both traditional histology and transcriptomic measurements were performed on each chemical. Analysis of the data is currently underway. Apart from the additional chemicals, both the lungs and livers from archived studies were also analyzed using gene expression microarrays. These tissues were chosen as potential “sentinel” tissues due to their roles as “portals of entry” for inhalation and oral exposures. The transcriptional points-of-departure from these sentinel tissues will be compared with the pathological points-of-departure in the target tissue.

In 2013, studies were proposed to apply the short-term in vivo genomic studies to chemicals in the PPRTV system that have limited or no toxicological data. These studies will be a demonstration of the applicability of the approach for the NexGen effort. Dr. R.S. Thomas, the previous principal investigator for this project, has moved from the Hamner to the EPA’s National Center for Computational Toxicology (NCCT). This has led to a temporary suspension of this effort. Tentative plans are in place to continue this collaboration with NCCT and NCEA at a future time.

Implications: The NexGen effort within EPA has set out to change the way risk assessments are performed by tailoring the scope and depth of a risk assessment to the type of information that is needed or available for a chemical. EPA plans to incorporate information from new technologies to assess potential risks from data poor chemicals. This change in the risk assessment paradigm provides an opportunity to collaborate with the Agency on the application of transcriptional dose-response data in risk assessment. The incorporation of new technologies, such as transcriptomics, would allow reference values to be estimated more economically while also using fewer animals and at shorter time scales than currently possible.

Key words: transcriptomics, risk assessment, dose-response, NexGen risk assessment

Project start and end dates: January 2010 – December 2014

Peer-reviewed publication(s):

Thomas, R.S., Wesselkamper, S.C., Wang, N.C.Y., Zhao, Q.J., Petersen, D.D., Lambert, J.C., Cote, I., Yang, L., Healy, E., Black, M.B., Clewell, H.J., Allen, B.C., and Andersen, M.E. (2013). Temporal concordance between apical and transcriptional points-of-departure for chemical risk assessment. Toxicol Sci 134(1):180-194.

Dodd, D.E., Layko, D.K., Cantwell, K.E., Willson, G.A., and Thomas, R.S. (2013). Subchronic toxicity evaluation of potassium bromate in Fischer 344 rats. Environ. Toxicol Pharmacol 36(3):1227-34.

Dodd, D.E., Pluta, L.J., Sochaski, M.A., Wall, H.G., and Thomas, R.S. (2012). Subchronic hepatotoxicity evaluation of hydroazobenzene in Fischer 344 rats. Int J Toxicol 31(6):564-571.

Dodd, D.E., Pluta, L.J., Sochaski, M.A., Funk, K.A., and Thomas, R.S. (2012). Subchronic urinary bladder toxicity evaluation of N-Nitrosodiphenylamine in Fischer 344 rats. J Appl Toxicol 33(5):383-389.

Dodd, D.E., Pluta, L.J., Sochaski, M.A., Banas, D.A., and Thomas, R.S. (2012). Subchronic hepatotoxicity evaluation of bromobenzene in Fischer 344 rats. J Appl Toxicol 33(5):370-377.

Dodd, D.E., Pluta, L.J., Sochaski, M.A., Funk, K.A., and Thomas, R.S. (2012). Subchronic thyroid toxicity evaluation of 4,4’-methylenebis(N,N’-dimethyl)aniline in Fischer 344 rats. J Toxicol Env Hlth Part A 75(11):637-648.

Dodd, D.E., Pluta, L.J., Sochaski, M.A., Banas, D.A., and Thomas, R.S. (2012). Subchronic hepatotoxicity evaluation of 2,3,4,6-tetrachlorophenol in Sprague Dawley rats. J Toxicol 2012:376246.

Thomas, R.S., Clewell, H.J., Allen, B.C., Yang, L., Healy, E., and Andersen, M.E. (2012). Integrating pathway-based transcriptomic data into quantitative chemical risk assessment: A five chemical case study. Mut Res 746(2):135-143.

Dodd, D.E., Pluta, L.J., Sochaski, M.A., Funk, K.A., and Thomas, R.S. (2012). Subchronic hepatotoxicity evaluation of 1,2,4-tribromobenzene in Sprague-Dawley rats. Int J Toxicol 31(3):250-6.

Thomas, R.S., Clewell, H.J., Allen, B.C., Wesselkamper, S.C., Wang, N.C.Y., Lambert, J.C., Hess- Wilson, J.K., Zhao, Q. J., and Andersen, M.E. (2011). Application of transcriptional benchmark dose values in quantitative cancer and noncancer risk assessment. Toxicol Sci 120(1):194-205.

Other publication(s): None to date.

Abstract revision date: July 2014