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April 26, 2011

U.S. Environmental Protection Agency, Headquarters Procurement Operations Division, (3803R)
Response Due Date: Tuesday, May 17, 2011, COB

Posted Date: 26 April 2011


Response Date: 6 May 2011


The Environmental Protection Agency, under the procedures set forth in FAR Part 13, Simplified Acquisition, intends to issue a sole source purchase order to Dr. Kenneth Ramos of the University of Louisville, for a review of the existing outline and the document on evaluating the molecular mechanisms of environmental injury and the genetic and epigenetic basis of PAH-induced disease. Additional explanation of the tasks involved and the justification for the sole source award are set forth below. Notwithstanding our intent to award on a sole source basis, any one believing it has the expertise to perform these tasks should send a technical capability statement to dawson.paul@epa.gov before the response date set forth above.




The overall goal of this project is to develop a systems biology approach for assessing human health risks of PAHs. This prototype will examine the utility of toxicogenomic data (i.e., transcriptomics, proteomics, and metabolomics) for assessing the relative cancer potency of polycyclic aromatic hydrocarbons (PAHs). This work will build on a recent review of the mechanisms of PAH induced cancer and analyses of recently published human studies regarding the metabolism, genotoxicity, gene expression profiles, and carcinogenicity (EPA, 2010), as well as older work (EPA, 2002). The effort will comprise review of a series of analyses on the gene expression data. This effort will extend review of identified key regulatory pathways and integrated genetic and environmental modulators to define disease associated targets knowledge of biological pathways of disease ( Teneng et al. 2011, Kumar 2010, Montoya-Durango et al. 2010 , Rouchka et al. 2010, Tithof et al. 2010, Gohlke et al. 2009; Thomas et al. 2009) . Specifically, the review will focus on identified: 1) the adverse effects of PAHs exposures on pathways and mechanisms relevant to carcinogenicity; 2) factors that make specific PAHs of greater or lessor concern for public health, i.e., variability between species and variability within the human population; 3) environmental co-exposures and co-morbid conditions likely to impact the toxicity and carcinogenicity; and 4) quantitative approaches to estimate the low-dose human health risks of PAH exposures.


When toxicity data on a complex mixture of concern or on a sufficiently similar mixture are unavailable, PAH cancer risk assessment is conducted using a relative potency factor (RPF) approach. The RPF approach uses benzo(a)pyrene as the indicator compound and estimates the relative potency of other unsubstituted PAHs using traditional in vivo cancer bioassay data. The reliance on in vivo cancer bioassay data limits the current RPF approach to a small number of PAHs (<30 compounds). Toxicogenomic studies that identify a relationship between specific toxicity pathways and cancer potency may be used to extend and improve upon the RPF approach.


PAHs are carcinogenic compounds and ubiquitous environmental contaminant. Primary sources of exposure include fixed industrial sources, emissions from burning coal and oil, mobile emissions from cars and trucks and cigarette smoke that are found in the environment as complex mixtures (EPA 2010) .

Recently, toxicogenomic studies have proven useful for discriminating among compounds with different effects (carcinogen vs. noncarcinogen; genotoxic carcinogens vs. nongenotoxic carcinogen). For example, Van Delft et al. (2005, 2004) showed that class discrimination models of microarray data could be used to discriminate between genotoxic and nongenotoxic carcinogens. In a series of studies by Ellinger-Ziegelbauer et al. (2009, 2005), a strong DNA damage response at the gene expression level suggested direct DNA modification, whereas increased expression of genes involved in cell cycle progression was characteristic of indirect-acting agents. Staal et al. (2007a, 2006) demonstrated the use of clustering techniques applied to microarray data from human HepG2 cells to discriminate between PAHs of low and high carcinogenic potency. As part of a QSAR effort, Wan et al. (2008) used hierarchical clustering of gene expression data to explore similarities between low molecular weight PAHs with different structural features. In addition, gene expression data on simple mixtures of PAHs have been compared with expression profiles for individual compounds to evaluate both similarity and issues of interaction (Staal et al., 2008, 2007b; Wan et al., 2008).


These studies have begun to provide “proof of concept” that toxicogenomic techniques may be valuable tools for grouping PAHs by mode of action (MOA) and/or potency and possibly for predicting the MOA and/or potency of untested PAHs or even mixtures of PAHs. Some toxicogenomic techniques are especially well-suited to this effort (e.g., microarray data) because (1) they do not presuppose knowledge of all possible MOAs, and thereby allow for the identification of new putative MOAs; and (2) the multivariate, widely focused nature of the data lends itself well to robust evaluations of similarity and differences among PAHs and/or PAH mixtures.




Dr. Kenneth Ramos is uniquely qualified to perform the work described in this project. Dr. Ramos is a Professor in the Division of Environmental Health Sciences, Department of Biochemistry and Molecular Biology , University of Louisville Health Sciences Center, KY . Dr. Ramos is a leading expert in the study of molecular mechanisms of environmental injury and genetic and epigenetic determinants of environmental disease. A major thrust in his laboratory is the study of mammalian retro-elements and endogenous retroviral-like sequences. He has been invited to give lectures at various institutions. He is a member of many societies including Society of Toxicology, American Association for the Advancement of Science, and American Society for Biochemistry and Molecular Biology. Dr. Ramos is a recipient of several grants including NIEHS, ATSDR, NSF and trained many pre- and post-doctoral students. Dr. Ramos has published over 140 peer-reviewed publications, 72 book chapters, review articles and editorials and presented over 200 abstracts at national and international professional society meetings.


Dr. Ramos is a demonstrated expert in the field, but it is his leadership and participation in the national efforts and dialogues to advance the field of molecular biology in risk assessment that uniquely qualify him to work on this project. This unique experience is illustrated by his membership on the National Academy of Sciences (NAS) Committee on Emerging Issues and Data on Environmental Contaminants, which produced “Communicating Toxicogenomics Information to Non-Experts Workshop Summary” (2005). He was a leader, originator and presenter of the first attempted case study for PAHs at the NAS “Validation of Toxicogenomics Technologies: Workshop” (2007). He was also a key panelist, speaker on use of omics in PAH risk assessments at the NAS “Toxicity Pathways-Based Assessment Workshop”. Furthermore, Dr. Ramos was a key participant at the “EPA's NexGen workshop” (2010). It is this consistent, outstanding service as an advisor to the NAS and the nation that uniquely qualifies him to conduct this project.

This work will build from a recent EPA-sponsored project on the carcinogenic mechanisms of PAHs and a related workshop in which Dr. Ramos was a key participant. In addition, the current work will extend from the recent research, analyses and reviews of PAHs performed by Dr. Ramos' laboratory ( Teneng et al., 2011; Kumar et al., 2010; Rouchka et al., 2010; Tithof et al. 2010; Montoya-Durango and Ramos, 2010 ) . In all, Dr. Ramos' recognized expertise, his extensive past research experience, and his current active research work regarding PAH carcinogenicity will be invaluable to the conduct of the current project.




The effort will focus on review of the existing outline and the document on evaluating the molecular mechanisms of environmental injury and the genetic and epigenetic basis of PAH-induced disease. Specific steps will include the consideration and review of the outline and the document that will be provided to the contractor. The document will include (1) identified pathways specific to cancer subtypes associated with PAH exposure; (2) identified pathways associated with benzo[a]pyrene exposure at various doses and exposure durations; (3) identified pathways associated with exposure at various PAH mixtures; (4) comparison of pathways from steps 1-3 above; (5) comparison of test systems used in above studies and appropriateness of each for use in risk assessment. The contractor shall also suggest future research to establish an association between toxicogenomic endpoints and cancer bioassay data for PAH mixtures. The contractor shall address the qualification of the analyses in his reviews and include questions such as, key issues, decision points, data set characterization, and qualification of the analytical processes, as applicable.


The Contractor shall provide the EPA Project Officer with the following task/deliverables based on the below schedule of deliverables or sooner. All the deliverables must be provided in electronic format (and in a hardcopy).


Deliverables Anticipated Completion Dates

Task 1 Teleconference calls Within 2 weeks of the date of award; Bimonthly thereafter

Task 2 Review of outline of analysis plan Within 6 weeks of the date of award

Task 3 Review of draft analysis report Within 4 months of date of award

Task 4 Review revision of analysis report Within 5 months of date of award

Task 5 Coauthor final report Within 8 months of date of award

Task 6 Participate in conference Within 8 months of data of award


Ellinger-Ziegelbauer H, Stuart B, Wahle B, Bomann W, Ahr HJ. (2005) Comparison of the expression profiles induced by genotoxic and nongenotoxic carcinogens in rat liver. Mutat Res 575: 61–84.

Ellinger-Ziegelbauer H, Aubrecht J, Kleinjans JC, Ahr HJ. (2009) Application of toxicogenomics to study mechanisms of genotoxicity and carcinogenicity. Toxicol Lett 186: 36–44.

Gohlke JM, Thomas R, Zhang Y, Rosenstein MC, Davis AP, Murphy C, Becker KG, Mattingly CJ, Portier CJ (2009). Genetic and environmental pathways to complex diseases. BMC Syst Biol 3: 46.

Kumar M, Lu Z, Takwi AA, Chen W, Callander NS, Ramos KS , Young KH, Li Y. (2011) Negative regulation of the tumor suppressor p53 gene by microRNAs. Oncogene. 30(7): 843-53.   Montoya-Durango DE, Ramos KS . (2010) L1 retrotransposon and retinoblastoma: molecular linkages between epigenetics and cancer. Curr Mol Med. 10(5):511-21.   Rouchka E, Montoya-Durango DE, Stribinskis V, Ramos KS , Kalbfleisch T. (2010) Assessment of genetic variation for the LINE-1 retrotransposon from next generation sequence data. BMC Bioinformatics. 11 (Suppl 9):S12.

Staal YC, van Herwijnen MH, van Schooten FJ, van Delft JH. (2006) Modulation of gene expression and DNA adduct formation in HepG2 cells by polycyclic aromatic hydrocarbons with different carcinogenic potencies. Carcinogenesis 27(3):646–655.

Staal YC, Hebels DG, van Herwijnen MH Gottschalk RW, van Schooten FJ, van Delft JH. (2007a) Binary PAH mixtures cause additive or antagonistic effects on gene expression but synergistic effects on DNA adduct formation. Carcinogenesis 28(12):2632–2640.

Staal YC, van Herwijnen MH, Pushparajah DS, Umachandran M, Ioannides C, van Schooten FJ, van Delft JHM (2007b) Modulation of gene expression and DNA-adduct formation in precision-cut liver slices exposed to polycyclic aromatic hydrocarbons of different carcinogenic potency. Mutagenesis 22(1):55–62.

Staal YC, Pushparajah DS, van Herwijnen MH, Gottschalk RW, Maas LM, Ioannides C, van Schooten FJ, van Delft JH. (2008) Interactions between polycyclic aromatic hydrocarbons in binary mixtures: effects on gene expression and DNA adduct formation in precision-cut rat liver slices. Mutagenesis 23(6):491–499.

Teneng I, Montoya-Durango DE, Quertermous JL, Lacy ME, Ramos KS . (2011) Reactivation of L1 retrotransposon by benzo(a)pyrene involves complex genetic and epigenetic regulation. Epigenetics 6(3).   Tithof PK, Richards SM, Elgayyar MA, Menn FM, Vulava VM, McKay L, Sanseverino J, Sayler G, Tucker DE, Leslie CC, Lu KP, Ramos KS .(2010) Activation of group IVC phospholipase A(2) by polycyclic aromatic hydrocarbons induces apoptosis of human coronary artery endothelial cells. Arch Toxicol. Dec 4 [Epub ahead of print].

Thomas R, Gohlke JM, Stopper GF, Parham FM, Portier CJ (2009). Choosing the right path: enhancement of biologically relevant sets of genes or proteins using pathway structure. Genome Biol 10(4): R44.

U.S. EPA. Development of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) Mixtures (External Review Draft). U.S. Environmental Protection Agency, Washington, DC, EPA/635/R-08/012A, 2010.

U.S. EPA. Peer Consultation Workshop on Approaches to Polycyclic Aromatic Hydrocarbon (PAH) Health Assessment. U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Washington Office, Washington, DC, EPA/635/R-02/005, 2002

van Delft JH, van Agen E, van Breda SG, Herwijnen MH, Staal YC, Kleinjans JC (2004) Discrimination of genotoxic from non-genotoxic carcinogens by gene expression profiling. Carcinogenesis 25(7):1265–1276.

van Delft JH, van Agen E, van Breda SG, Herwijnen MH, Staal YC, Kleinjans JC. (2005) Comparison of supervised clustering methods to discriminate genotoxic from non-genotoxic carcinogens by gene expression profiling. Mutat Res 575(1-2):17–33.

Wan B, Yarbrough JW, Schultz TW (2008) Structure-related clustering of gene expression fingerprints of THP-1 cells exposed to smaller polycyclic aromatic hydrocarbons. SAR QSAR Environ Res 19(3–4):351–373.

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