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

Russell Thomas.  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 The data from Tier 2 assessments are used to generate Provisional Peer Reviewed Toxicity Values (PPRTVs) which are unpublished Integrated Risk Information System (IRIS)-like assessments that the agency uses to set clean up and exposure levels for lower priority chemicals.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 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, during the analysis and interpretation of the data collected to date, it became apparent that estimating the point-of-departure for developmental and reproductive toxicity endpoints would provide bigger economic and animal savings than estimating the point-of-departure for standard chronic toxicity endpoints.

In 2012 and 2013, additional chemicals will be tested in short-term and subchronic in vivo genomic studies. A total of approximately 8 chemicals will be analyzed per year. Each chemical will be administered in a six point dose response and animals will be sacrificed at 2 weeks and 13 weeks post exposure. Both traditional histology and transcriptomic measurements will be performed on each chemical. Points-of-departure will be estimated for both the pathological and transcriptional changes and the results compared. The 16 chemicals have not been selected yet, but will include a mix of chemicals that act via different mechanisms and will include chemicals that do not induce adverse histological responses.

In 2014, proof-of-concept studies will be performed to evaluate the feasibility of estimating the point-of-departure for developmental and reproductive toxicity endpoints. For the proof-of-concept studies, approximately 6 chemicals will be evaluated in the OECD 421 Reproductive and Developmental Toxicity Screening Protocol. Each chemical will be administered in a six point dose response. Both traditional histology and transcriptomic measurements will be performed on each chemical. Points-of-departure will be estimated for both the pathological and transcriptional changes and the results compared.

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. The 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.

Keywords

transcriptomics, risk assessment, dose-response, NexGen risk assessment

Project Start and End Dates

January 2010 – December 2014

Project ID

MTH1002-01

Peer-reviewed Publication(s)

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. (In Press).

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. (In
Press).

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. (In
External Peer Review).

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 (In Press).

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. Toxicological Sciences 120(1):194-205.

Other Publication(s)

None to date.

Abstract Revision Date

January 2012

*This abstract was prepared by the principal investigator for the project.

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