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									U.S. ENVIRONMENTAL PROTECTION AGENCY
1.   Date:                                  February 22, 2011
2.   Program Office:                        ORD/NCEA
3.   Project Identification:                Benzene NexGen Project
4.   Description of Project:                See Statement of Work
5.   Period of Performance:                 Up to one year after date of award
6.   Type of Purchase Order:                Firm Fixed Price (inclusive of travel costs and fees)

BACKGROUND
The overall goal of this project is to develop a systems biology approach for assessing human
health risks of benzene. This work will build on a recent review of the mechanisms of benzene-
induced acute myelogenous leukemia (AML) and will entail review and analyses of recently
published human studies regarding the metabolism, hematotoxicity, gene expression profiles,
and leukemogenicity of benzene (Bi et al. 2010; Goldstein 2010; Khalade et al. 2010; McHale et
al. 2010b; Rappaport et al. 2010; Smith 2010; Vlaanderen et al. 2010; Zhang et al. 2010). The
modeling effort will comprise a series of analyses on the gene expression data (McHale et al.
2010b), comparisons to hematological and chromosome aberration data, and dose-response
modeling of leukemia data (Vlaanderen et al. 2010). This effort will extend analyses identifying
key regulatory pathways and integrating genetic and environmental modulators to define disease
associated targets knowledge of biological pathways of disease (Gohlke et al. 2009; Thomas et
al. 2009). Specifically, the data analysis will focus on identifying: 1) the adverse effects of
benzene at low exposures on pathways and mechanisms relevant to hematotoxicity and
leukemia; 2) susceptible populations; 3) environmental co-exposures and co-morbid conditions
likely to impact the toxicity and carcinogenicity of benzene; and 4) quantitative approaches to
estimate the low-dose human health risks of benzene exposure.

Benzene is a ubiquitous environmental contaminant. Primary sources of exposure include fixed
industrial sources, emissions from burning coal and oil, fuel evaporation from gasoline filling
stations, mobile emissions from cars and trucks and cigarette smoke (from active and passive
smoking) (Weisel 2010). Benzene has been identified in at least 1000 of the 1684 hazardous
National Priority List waste sites (HazDat, 2006).

Cancer health effects. The EPA’s IRIS database lists benzene as a known human carcinogen
(causing leukemia) by all routes of exposure. The first report of the association of occupational
benzene exposure and hematopoietic diseases was published more than 100 years ago.
Numerous reports have confirmed the association of occupational benzene exposure with
leukemia (reviewed in (Smith 2010)). A substantial number of subsequent epidemiologic studies
have provided estimates of the relationship between work exposures to benzene and leukemia
risk. A recent systematic review and meta-analysis provided consistent evidence that workplace
benzene exposures increase leukemia risk with a dose-response pattern (Khalade et al. 2010). In
addition to AML, some evidence of an increase in chronic lymphocytic leukemia (CLL) was
seen.




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Data discussed in the EPA IRIS assessment suggest that genetic abnormalities occur at low
exposure in humans, and the formation of toxic metabolites plateaus above 25 ppm (80,000
μg/m3). More recent data on benzene adducts in humans, published after the most recent IRIS
assessment, suggest that the enzymes involved in benzene metabolism start to saturate at
exposure levels as low as 1 ppm. These data highlight the importance of ambient exposure
levels and their contribution to benzene-related adducts. This is consistent with recent
epidemiological data which also suggest a supralinear exposure-response relationship and which
"[extend] evidence for hematopoietic cancer risks to levels substantially lower than had
previously been established" (Hayes et al. 1997; Hayes et al. 2001; Lan et al. 2004). These data
are from the largest cohort study done to date with individual worker exposure estimates.

Non-cancer health effects. A number of adverse noncancer health effects, including blood
disorders such as preleukemia and aplastic anemia, have also been associated with exposure to
benzene (Aksoy 1989); (Goldstein 1988). People with long-term occupational exposure to
benzene have experienced harmful effects on the blood-forming tissues, especially in the bone
marrow. These effects can disrupt normal blood production and suppress the production of
important blood components, such as red and white blood cells and blood platelets, leading to
anemia (a reduction in the number of red blood cells), leukopenia (a reduction in the number of
white blood cells), and thrombocytopenia (a reduction in the number of blood platelets, thus
reducing the ability of blood to clot). Chronic inhalation exposure to benzene in humans and
animals results in pancytopenia, a condition characterized by decreased numbers of circulating
erythrocytes (red blood cells), leukocytes (white blood cells), and thrombocytes (blood platelets).
Individuals that develop pancytopenia and have continued exposure to benzene may develop
aplastic anemia, whereas others exhibit both pancytopenia and bone marrow hyperplasia
(excessive cell formation), a condition that may indicate a preleukemic state. The most sensitive
noncancer effect observed in humans, based on current data, is the depression of the absolute
lymphocyte and/or granulocyte count in blood (Qu et al. 2002; Lan et al. 2004).

Reports in the medical literature of benzene’s hematotoxic effects in humans provide data
suggesting a wide range of hematological endpoints that are triggered at occupational exposures
of less than 5 ppm (about 16 mg/m3) and, more significantly, at air exposure levels of 1 ppm
(about 3 mg/m3) or less among genetically or otherwise susceptible populations. These studies
had large sample sizes and extensive individual exposure monitoring.

Susceptible (and/or vulnerable) populations. Children may represent a subpopulation at
increased risk from benzene exposure, due to factors that could increase their susceptibility.
Children may have a higher unit body weight exposure because of their heightened activity
patterns which can increase their exposures, as well as different ventilation tidal volumes and
frequencies, factors that influence uptake. This could entail a greater risk of leukemia and other
toxic effects to children if they are exposed to benzene at similar levels as adults. There is
limited information from two studies regarding an increased risk to children whose parents have
been occupationally exposed to benzene. Data from animal studies have shown benzene
exposures result in damage to the hematopoietic (blood cell formation) system during
development. Also, key changes related to the development of childhood leukemia occur in the
developing fetus. Several studies have reported that genetic changes related to eventual

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leukemia development occur before birth. For example, there is one study of genetic changes in
twins who developed T cell leukemia at 9 years of age. An association between traffic volume,
residential proximity to busy roads and occurrence of childhood leukemia has also been
identified in some studies, while others show no association.

Biomarker Approach to Risk Assessment
Mechanistic information can aid in reaching conclusions about the chemical causation of cancer
(Goldstein 2010). This is evident in the hazard identification approach used by US EPA, IARC
and NTP in classifying a chemical as a known human carcinogen. These approaches allow for
the use of mechanistic information to raise concern about the human carcinogenic potential of a
chemical for which strong, but less than conclusive, epidemiologic evidence is available.
Mechanistic analyses can also inform selection of early disease biomarkers for use in estimating
cancer and non-cancer risk at low exposures.

Chronic animal toxicity studies are unlikely to be informative of the carcinogenic effects of
benzene at low doses since no accepted animal model of benzene-induced leukemia exists at the
present time, and low dose studies would require a prohibitively large number of animals.
Biologically based dose–response models can incorporate data on biological processes at the
cellular and molecular level to link external exposure to an adverse effect risk but have not
improved the reliability of quantitative predictions of low-dose human risk due to challenges of
dose- and species extrapolation (Crump et al. 2010). In such circumstances where traditional
epidemiology and toxicology are of limited value it has been proposed that non-tumor data such
as biological markers (biomarkers) be employed in the risk assessment process (Albertini et al.
2003).

Benzene has multiple mechanisms of action (Hartwig 2010; Zhang et al. 2010) that may
contribute to leukemia development, with investigations focused primarily in the following
areas:

    (1) Oxidative stress from reactive oxygen species generated by redox cycling;
    (2) Chromosome alterations including translocations, deletions, and aneuploidy;
    (3) Topoisomerase II inhibition (Mondrala et al. 2010);
    (4) Protein damage to tubulin, and histones; and
    (5) Immune system dysfunction (TNF-α, INF-γ, AhR, etc.).

Studies to date have provided evidence for multiple potential mechanisms, however these studies
are limited by the available research tools that analyze only one or a few, a priori selected genes,
pathways or metabolites at a time. A systems biology approach can interrogate all potential
mechanisms by which benzene exposure contributes to disease, through the application of
unbiased omic-based technologies in an integrated manner.


STATEMENT OF WORK
The tasks shall comprise a series of analyses on the gene expression data (McHale et al. 2010b),
and comparisons to hematological and chromosome aberration data generated by the biomarker

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project. The effort will then perform dose-response modeling of the leukemia data published by
Vlaanderen (Vlaanderen et al. 2010).

Specific steps will include:

   1. Statistically model the dose-response for all (>3000) genes significantly altered by
      benzene exposure and determine the cluster patterns of different gene sets;
   2. Statistically model the dose-response for benzene of genes in the AML Kegg pathway;
   3. Statistically model the dose-response of other biologically relevant pathways;
   4. Phenotypically anchor by comparison to hematological parameters that have already
      been measured;
   5. Compare the modeling results to dose-response data for chromosome aberrations; and
   6. Compare the modeling results to dose-response data for gene expression, hematological
      changes and chromosome aberrations to the flexible meta-regression analyses presented
      in Vlaanderen et al. 2010.

Additionally the contractor shall, prior to initiating the above steps, prepare a Quality Assurance
Project Plan (QAPP) according to guidance provided in EPA Requirements for Quality
Assurance Project Plans (EPA QA/R-5, EPA/240/B-01/003, U.S. Environmental Protection
Agency, Office of Environmental Information, Washington, DC, March 2001, reissued May 31,
2006) to ensure that environmental and related data collected, compiled, and/or generated for this
project are complete, accurate, and of the type, quantity, and quality required for their intended
use. The contractor shall conduct work in conformance with the procedures detailed in the QAPP
that is prepared specifically for this project. Work can begin after the QAPP has been accepted
and approved by an EPA Quality Manager. Additional guidance is available at:
http://www.epa.gov/QUALITY/qapps.html or go to the QAPP template attachment to this SOW.

The Contractor shall provide the EPA Project Officer with the following task/deliverables based
on the below schedule of deliverables or sooner. All deliverables are to be provided in electronic
format.

       Deliverables                                   Anticipated Completion Dates

       Task 1 QAPP (Quality Assurance                Within 1 week of the date of award
              Project Plan)

       Task 2 Teleconference calls                   Within 2 weeks of the date of award, and
                                                     bimonthly thereafter

       Task 3 Outline of analysis plan               Within 6 weeks of the date of award

       Task 4 Draft analysis report                  Within 4 months of date of award

       Task 5 Revision of analysis report in         Within 5 months of date of award
              response to EPA PO comments

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       Task 5 Presentation of analysis to EPA        Within 6 months of date of award


MANAGEMENT CONTROLS
The following management controls are adequate to ensure that Agency officials remain
accountable and retain control over the contractor's product. In summary, this contract will
utilize these management controls to assure that the proposed contractor services will not place
EPA in a vulnerable position and will ensure that Government policy is not being created by or
unduly influenced by contractors, and that contractor employee will not be assumed to be EPA
employee. The project officer is responsible for assuring compliance.

       1. All work will be off-site. The contractor will take care to ensure that it has no
          conflict of interest in the performance of this work. The contractor is responsible for
          identifying any known or apparent conflict of interest in reporting it to the Project
          Officer for resolution.

       2. The Project Officer will monitor the deliverable schedule and review the deliverables
          to ensure that the content and quality are responsive to the requirements of the SOW.
          Under this fixed price vehicle, the Project Officer may not provide technical direction
          to the Contractor which would have the effect of changing the deliverable schedule,
          adding or deleting items required under the contract, changing deliverable due dates,
          deleting or substantially changing the content of a deliverable. Any problems with
          deliverables or the contract schedule will be addressed to the Contractor only through
          the Contracting Officer. Technical communication between the project officer and
          contractor for the purpose of clarification or preliminary advisement of issues or
          problems is permissible.

       3. The Contractor will submit all drafts and final deliverables to the Project Officer.
          These documents will be secured per records control management protocols.

       4. The contractor shall clearly identify itself as an EPA contractor when acting in
          fulfillment of this contract. No decision-making activities relating to Agency policy,
          enforcement or future contracting will take place if the contractor is present. If the
          contractor has a need to meet with Federal employees onsite, then the Contractor
          personnel shall visibly wear identification in performance of this contract while on-
          site which will be issued by the Government upon arrival to the Federal facility.

       5. EPA shall be mentioned as the funding source, with appropriate and standard EPA
          disclaimers, for all subsequent articles and publications that arise as a result of the
          work products of this contract, its result and products, and subsequent work stemming
          from these products after the contract is completed.




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