**PERFORMANCE WORK STATEMENT**

**PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK)**

**MODELING TECHNICAL SUPPORT**

1.  **INTRODUCTION**

In general, the U.S. EPA conducts human health risk assessments to
provide citizens and regulators with information about pollutants or
naturally occurring compounds that are linked to health problems. The
questions addressed by risk assessments include what types of health
problems are caused by substances in the environment, how likely is it
that people will experience problems when exposed at different levels,
and how severe this harm likely to be. The answers to these questions
provide decision makers with the scientific information they need to
make informed decisions about actions that may be taken to protect human
health.

As part of this goal, the Agency conducts quantitative characterizations
of a chemical's dose-response relationship for adverse effects following
human exposure, and derive reference values for "safe"[^1] levels of
exposure that are used to protect the public health. Often, the database
needed to conduct this quantitative characterization may be inadequate
or incomplete, and default adjustment factors have been developed to
accommodate data deficiencies such as when only animal dose-response
data are available, and one must extrapolate the animal dose-response to
an estimate of the human dose-response relationship. There are, however,
many data gaps that are not addressed by default factors. Moreover, the
default adjustment factors are in part empirically or policy based, and
do not account for all of the available chemical-specific toxicokinetic
or toxicodynamic data that might improve the accuracy of reference
values.

Physiologically-based pharmacokinetic (PBPK) models provide a chemical-
specific quantitative characterization of a chemical's toxicokinetics,
and if adequately developed and tested, have the potential to replace
default factors when estimating internal dose in different species
(i.e., test animals and humans) resulting from a variety of exposure
regimens. As such, PBPK models are increasingly being used in the
derivation of reference values either to replace the less
chemical-specific default adjustment factors (e.g., for interspecies
extrapolation and intraspecies variability) or to bridge data gaps where
no default factors exist (e.g., route-to-route extrapolation;
less-than-lifetime exposure duration extrapolation).

The purpose of this EPA-wide PBPK Contract is to provide technical
support for the Agency's evaluation, modification, and application of
PBPK models to derive health-based reference values. The work on
individual task orders might also involve developing and/or evaluating
technical concepts, methods, or information technologies (e.g.,
databases, model archives, web-based search and retrieval) that would
enhance the use of PBPK model in health assessments.

This contract will be managed out of Cincinnati, OH by a designated lead
in EPA's National Homeland Security Research Center (NHSRC). However,
other EPA Research Centers, Laboratories, and Program Offices may also
access this contract for similar technical support (see list in Appendix
A) may also access this contract for similar technical support.

The programs and research areas listed in Appendix A are not intended to
be all inclusive or unchanging over the life of the contract, and new or
different programs may be included as the Agency's priorities change
over time.

2.  **TYPES OF TECHNICAL SUPPORT**

Each task order from EPA will identify the purpose/objective of the work
requested. For each specific area of interest, the Agency may request
any or all of the following types of support in individual task orders:

A.  Provide support for an initial evaluation of available
    pharmacokinetic (PK) and PBPK models that may have potential use in
    an assessment for a specified chemical.

B.  Detailed evaluation of a model, recommendations for further model
    development or modifications that are needed to meet a specific use,
    and estimate of the level of effort needed to conduct the additional
    work.

C.  Further develop or modify models specified for specific uses in an
    assessment.

D.  Develop information resources that support model development, or
    maintain and further elaborate existing resources.

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3.  **INITIAL PBPK MODEL SCOPING AND EVALUATION**

At the beginning of a human health risk assessment development cycle for
any given chemical, an initial determination (or scoping) is needed to
identify available pharmacokinetic (PK) or PBPK models for the chemical
of interest, the adequacy and appropriateness of the model(s) for
potential use in the assessment, and what, if any, additional work might
be needed to modify a model for a specific use.

Examples of topics and issues that are addressed in the initial scoping
include the following:

-   What is known about the toxicokinetics of the chemical of interest?

-   What PK or PBPK model(s) are available for the chemical of interest,
    and what level of QA/QC have they undergone (e.g., peer review
    publication, regulatory agency review, etc.)?

-   What are likely sensitive endpoints for the chemical under review,
    and what are the test species, exposure regimens, and route of
    exposure from the initial identification of critical studies?

-   Are identified models parameterized for the relevant test species
    (and/or humans), and for the potential route(s) of exposure that are
    relevant to humans?

-   Is the model code and supporting documentation readily available,
    and can it be made public (i.e., this relates to requirements for
    transparency?

-   How extensively has the model been used and/or evaluated, what were
    the outcomes, and what documentation is available to review?

-   Is further model development needed for each potential use in the
    assessment?

-   What are the estimated time and people resources needed for full
    retrieval of model documentation, for evaluation, and for suggested
    modifications of the model for use in the assessment?

In general, the Contractor shall conduct an initial survey of the
literature (see Appendix B) to identify the extent and nature of the
toxicokinetic data and hazardous effects data for specified chemicals,
as well as available PK/PBPK models that have potential applications in
the assessment. This work is not intended to be a full search and
retrieval of all relevant studies, rather a broad overview of the
literature sufficient to make an initial determination of the key
features of the kinetics relative to the most sensitive endpoint(s) for
hazardous effects, and an initial identification of potential candidates
for the critical studies (and in particular, the species and strain of
test animals) that could be used for derivation of a reference value.
This information will then support prioritization and selection of any
available PBPK models for a more detailed model evaluation.

4.  **DETAILED PBPK MODEL EVALUATION**

Selected models will be further evaluated for quality and
appropriateness for specific uses. The broad criteria presented in Clark
et al. (2004)[^2] and Chiu et al. (2007)[^3] should be used to evaluate
the overall quality of the model, and specific chemical toxicokinetic
hazardous effects data used to evaluate the appropriateness of the model
for potential use in the assessment. This evaluation will include model
runs in the appropriate software (as specified by EPA) to reproduce
published results, and to assure that the model code and computer
implementation support model analysis and use. The evaluation may also
include sensitivity analysis, and more specialized analyses (e.g., Monte
Carlo, Bayesian) to duplicate previous results or to evaluate the model
structure or parameter values. This work will also include organizing
and formatting the model code, supporting documentation, and data for
entry into a model archive maintained at EPA (details on the format
requirements will be provided).

Based on the model evaluation results, the Contractor will identify
which PBPK models are currently sufficient for specific uses in each
assessment, and if not sufficient, what further development or needed
modifications would be needed for specific uses in the assessment, along
with an estimated level of effort to conduct that work.

5.  **DEVELOPMENT/MODIFICATION OF A PBPK MODEL**

Based on review of the evaluation reports, EPA will identify specific
models for application or for further development. The Contractor shall
assist EPA in this work that could include additional literature and
data compilation, modifications to the model structure, recalibrating
and testing of the model against new data (or combinations of new and
previous data), and application of the model for specific use in an
assessment.

The Contractor may also be asked to evaluate and support the use of
quantitative structure-activity relationship (QSAR) models in the
estimation of PBPK model parameters where chemical specific parameter
values are not available, and a QSAR approach would further support the
use of a PBPK model in the derivation of a reference value.

6.  **PBPK MODEL INFORMATION RESOURCES**

The use of PBPK models in risk assessment remains a relatively new
approach, and there is need for readily accessible and high quality
resources to support model evaluations and development. Critical
information resources that are being or have been developed at EPA
include: 1) a compilation of frequently used physiological parameter
values (e.g., tissue volumes, blood flows, respiratory rates) and
chemical specific toxicokinetic parameter values (e.g., enzyme activity,
absorption, partitioning) in human and nonhuman test species/strains for
both the general population and for sensitive subpopulations (e.g.,
early life, aged, pregnant); 2) an archive of PK/PBPK models that have
been or are being used in the development of health hazard assessments,
including the supporting documentation and data used to develop and test
the model; 3) an annotated bibliography of key PBPK model references to
support efficient identification and retrieval of needed data; and 4) a
glossary of PBPK model terms.

The Contractor shall support the maintenance and further elaboration of
these resources and develop any additional resources that EPA determines
will facilitate the development, evaluation, or use of PK and PBPK
models in human risk assessment. The Agency will provide the Contractor
with recently completed or on-going EPA sponsored databases of
physiological parameters, and any documentation EPA has for models that
have been or are currently being considered for use in an assessment.
The Contractor shall identify and retrieve new physiological and
chemical specific parameter value compilations (in hardcopy and/or
electronic database format) to add to the database, and any new models
(and supporting documentation) to further populate the model archive.

Concurrent with the search and retrieval of parameter databases and
models, the Contractor shall compile and annotate new model references
from the peer reviewed literature or other reputable sources to add to
EPA's annotated bibliography of PBPK model references and to further
augment the glossary of terms.

7.  **GENERAL REQUIREMENTS**

In support of each specific task order, the Contractor shall perform the
activities listed below, where applicable. The Contractor shall provide
expertise in PBPK model development, evaluation, and use in risk
assessments; toxicology and derivation of reference values; and
information science (i.e., search, retrieval, review, quality control,
and organization of information). Each task order issued under this
contract will require a quality assurance project plan (QAPP) that will
be subject to EPA approval. The Contractor shall not perform any work
under this contract until the QAPP is reviewed and approved.

The Contractor must address in the QAPP how secondary data will be
considered. Secondary data is defined as the use of environmental or
health data that was developed for a different purpose. This includes
data used from citations found in the literature (*See* Appendix C: QA
Requirements for Use of Secondary Data).

**Appendix A: Information on Participating EPA Organizations**

[The Integrated Risk Information System (IRIS) Program -- National
Center for Environmental Assessment (NCEA)]{.underline}

The Integrated Risk Information System (IRIS) is an EPA database
containing Agency consensus scientific positions on potential adverse
human health effects that may result from chronic (or lifetime) exposure
to chemicals in the environment. IRIS currently provides information on
over 500 specific chemical substances and the potential adverse health
effects that may result from a chemical exposure.

IRIS contains both qualitative and quantitative summaries of
chemical-specific health information in support of hazard identification
and dose-response evaluation, two steps in the overall risk assessment
process. IRIS assessments address reference doses for non-cancer health
effects resulting from an oral exposure (RfD) or from an inhalation
exposure (RfC), as well as values for the risk of cancer following
either an oral or inhalation exposure. Combined with information that
specifies the kind and extent of exposure to environmental contaminants,
the health hazard information in IRIS may be used to evaluate the
potential health risks to the public from those exposures.

[The Provisional Advisory Levels (PALs) Program - National Homeland
Security Research Center (NHSRC)]{.underline}

Health-based provisional advisory levels (PALs) are threshold exposure
limits for the general public. They can be applied for national
emergency programs and community planning in the event of terrorist
incidents or natural disasters. In addition, they are applicable for
establishing criteria for re-entry into buildings and reuse of drinking
water. PALs have been developed for a few substances based on route- and
duration- specific point of departure (POD) data, such as NOAELs,
LOAELs, or the benchmark dose (BMD). However, for a number of chemicals
of interest, the availability of such information is very limited. In
such data-poor situations, appropriately developed Quantitative
Structure-Activity Relationship (QSAR) models may be applied to evaluate
the biochemical properties of the putative toxin, and appropriately
developed Physiologically-Based Pharmacokinetic (PBPK) models may be
used to conduct route-to-route, species, and/or exposure duration
extrapolations, as well as support estimates of intra-individual human
variability in a scientifically-sound manner.

[The Acute Exposure Guideline Levels (AEGLs) Program -- Office of
Pollution Prevention and Toxics (OPPT)]{.underline}

EPA participates in a collaborative effort of the public and private
sectors worldwide to develop acute exposure guideline levels, or AEGLs,
which are intended to describe the risk to humans resulting from
once-in-a-lifetime, or rare, exposure to airborne chemicals. Acute
exposures are single, non-repetitive exposures for not more than 8 hrs.
AEGLs are developed to help both national and local authorities, as well
as private companies, deal with emergencies involving spills, or other
catastrophic exposures.

[Hazard, Exposure, and Risk Assessment Activities - Office of Science
and Technology (OST) /Office of Water (OW)]{.underline}

The Office of Water conducts a variety of hazard, exposure, and risk
assessments to support the regulatory initiatives of the Office of
Groundwater/Drinking Water (OGW/DW). These assessments are conducted,
primarily, by the Health and Ecological Criteria Division (HECD) of the
Office of Science and Technology (OST). Prominent among the products of
these assessments are Health Effects Support Documents (HESDs), Health
Advisories (HAs), and Regulatory Determination Documents (RDDs), which
contain drinking water Relative Source Contribution (RSC) calculations
for the contaminants of interest. A default contribution is adopted if
there are inadequate or incomplete data to calculate the drinking water
contribution to the total exposure to the contaminant. PBPK models may
be used to reduce the uncertainty in the RSC under such a circumstance.
In addition, HECD is developing a QSAR capability to support OGW/DW's
Contaminant Candidate List (CCL) process for those contaminants that
have inadequate data for risk and exposure assessments. Therefore, a
PBPK modeling availability will be significantly useful to this effort
to provide less uncertain dose, route-to-route, species, and
intra-species equivalencies and extrapolations.

**Appendix B: Chemical Information Search Resources**

+-----------------------------------------------------------------------+
| **Chemical Information Search Resources**                             |
|                                                                       |
| updated December 2005                                                 |
+=======================================================================+
| IRIS edocket and official records (IRIS Hotline 202-566-1676)         |
+-----------------------------------------------------------------------+
| IRIS central files (6^th^ floor CGB -- some ref. files for chemicals  |
| entered on IRIS from 2001-present)                                    |
+-----------------------------------------------------------------------+
| RfD/RfC and CRAVE meeting notes - pre-1995 IRIS meeting notes on      |
| chemicals reviewed for IRIS (6^th^ floor CGB or IRIS Hotline)         |
+-----------------------------------------------------------------------+
| IRIS internet and intranet.                                           |
|                                                                       |
| [www.epa.gov/iris](http://www.epa.gov/iris)[;                         |
| intranet.epa.gov/iris]{.underline}                                    |
|                                                                       |
| [Intranet includes literature screen chemical summaries.]{.underline} |
+-----------------------------------------------------------------------+
| Science at EPA (research, specific chemical information, etc.)        |
|                                                                       |
| [www.epa.gov/epahome/research.htm]{.underline}                        |
+-----------------------------------------------------------------------+
| Federal Register                                                      |
|                                                                       |
| [http://www.gpoaccess.gov/fr/index.html]{.underline}                  |
+-----------------------------------------------------------------------+
| EPA OLS (Online library network for the EPA including regional and    |
| laboratory libraries)                                                 |
|                                                                       |
| [h                                                                    |
| ttp://cave.epa.gov/cgi/nph‑bwcgis/BASIS/ncat/pub/ncat/sf]{.underline} |
+-----------------------------------------------------------------------+
| EPA SRS (Substance Registry System - information on chemical          |
| nomenclature, regulations, and direct links to EPA data, including    |
| TSCATS 2.0.                                                           |
|                                                                       |
| [http://www.epa.gov/srs/]{.underline}                                 |
+-----------------------------------------------------------------------+
| EPA NSCEP (National Center for Environmental Publications - EPA       |
| publications)                                                         |
|                                                                       |
| [http://www.epa.gov/ncepihom/]{.underline}                            |
+-----------------------------------------------------------------------+
| EPA NEPIS (National Environmental Publications Information System -   |
| EPA publications)                                                     |
|                                                                       |
| [http://www.epa.gov/nepis/]{.underline}                               |
+-----------------------------------------------------------------------+
| EPA Provisional Peer-Reviewed Toxicity Values (PPRTV)                 |
|                                                                       |
| Contact NCEA-Cin                                                      |
+-----------------------------------------------------------------------+
| Acute Exposure Guideline Levels (AEGL)                                |
|                                                                       |
| http://www.epa.gov/oppt/aegl/chemlist.htm                             |
+-----------------------------------------------------------------------+
| General Search Engines                                                |
|                                                                       |
| [www.webcrawler.com]{.underline}                                      |
|                                                                       |
| [www.askjeeves.com]{.underline}                                       |
|                                                                       |
| [www.google.com](http://www.google.com/)                              |
+-----------------------------------------------------------------------+
| Scientific Search Engines                                             |
|                                                                       |
| [www.scirus.com](http://www.scirus.com/)                              |
+-----------------------------------------------------------------------+
| DIALOG: TOXFILE, BIOSIS, EMBASE, SCISearch, Dissertation Abstracts    |
| (Contractor search only; no EPA account)                              |
+-----------------------------------------------------------------------+
| PubMed (Medline)                                                      |
|                                                                       |
| [http://pubmed.gov]{.underline} or http://www.nlm.nih.gov             |
+-----------------------------------------------------------------------+
| TOXNET (cluster of data bases such as HSDB, IRIS, GENE-TOX, CCRIS,    |
| TOXLINE, DART/ETIC, TRI, ChemIDplus; see descriptions below)          |
|                                                                       |
| http://toxnet.nlm.nih.gov/index.html                                  |
+-----------------------------------------------------------------------+
| HSDB (Hazardous Substance Data Base)                                  |
|                                                                       |
| [http://toxnet.nlm.nih.gov]{.underline}                               |
+-----------------------------------------------------------------------+
| CCRIS (Chemical Carcinogen Research Information System (NCI)          |
|                                                                       |
| [http://toxnet.nlm.nih.gov]{.underline}                               |
+-----------------------------------------------------------------------+
| GENE-TOX (data on mutagenicity studies)                               |
|                                                                       |
| [http://toxnet.nlm.nih.gov]{.underline}                               |
+-----------------------------------------------------------------------+
| TOXLINE (Toxicology Literature derived from PubMed)                   |
|                                                                       |
| [http://toxnet.nlm.nih.gov]{.underline}                               |
+-----------------------------------------------------------------------+
| ChemIDplus                                                            |
|                                                                       |
| [http://toxnet.nlm.nih.gov]{.underline}                               |
+-----------------------------------------------------------------------+
| DART/ETIC (developmental and reproductive toxicity/environmental      |
| teratology information center)                                        |
|                                                                       |
| [http://toxnet.nlm.nih.gov]{.underline}                               |
+-----------------------------------------------------------------------+
| EMIC (Environmental Mutagen Information Center)                       |
|                                                                       |
| http://wlu.tug‑libraries.on.ca/indexes/descriptions/emic.html         |
+-----------------------------------------------------------------------+
| Chemfinder (for CAS and chemical synonym searches)                    |
|                                                                       |
| http://chemfinder.cambridgesoft.com/                                  |
+-----------------------------------------------------------------------+
| NTP Results and Status Search (National Toxicology Program)           |
|                                                                       |
| [http://                                                              |
| ntp‑server.niehs.nih.gov/main_pages/NTP_ALL_STDY_PG.html]{.underline} |
+-----------------------------------------------------------------------+
| NTP Management Status Report                                          |
|                                                                       |
| [http://                                                              |
| ntp‑server.niehs.nih.gov/main_pages/NTP_ALL_STDY_PG.html]{.underline} |
+-----------------------------------------------------------------------+
| RoC (Report on Carcinogens from NTP)                                  |
|                                                                       |
| http://ntp‑server.niehs.nih.gov/NewHomeRoc/AboutRoC.html              |
+-----------------------------------------------------------------------+
| SRC TSCATS (Toxic Substance Control Act Test Submission Data Base -   |
| OPPT - maintained by SRC)                                             |
|                                                                       |
| [http://esc.syrres.com/efdb/tscats.htm]{.underline}                   |
+-----------------------------------------------------------------------+
| TSCATS 2.0 (database with information on unpublished toxicity, health |
| and safety studies received form industry and other groups under      |
| various section of TSCA. TSCATS 2.0 is the results of the merger of 3 |
| legacy databases---CECATS, Triage, and the original version of TSCATS |
| from SRC. Where available, PDFs of submission are attached to         |
| records.)                                                             |
|                                                                       |
| http://yosemite.epa.gov/oppts/epatscat8.nsf/ReportSearch?OpenForm     |
+-----------------------------------------------------------------------+
| RTECS (NIOSH Pocket Guide to Chemicals)                               |
|                                                                       |
| [http://www.cdc.gov/niosh/npg/npgdcas.html]{.underline}               |
+-----------------------------------------------------------------------+
| NIOSHTIC 2 (searchable data base for reports and health publications  |
| from NIOSH)                                                           |
|                                                                       |
| [http://www2.cdc.gov/nioshtic‑2/Nioshtic2.htm]{.underline}            |
+-----------------------------------------------------------------------+
| ATSDR (Agency for Toxic Substances Disease Registry) Interaction      |
| Profiles                                                              |
|                                                                       |
| [http://www.atsdr.cdc.gov/iphome.html]{.underline}                    |
+-----------------------------------------------------------------------+
| ATSDR Toxicological Profiles                                          |
|                                                                       |
| [http://www.atsdr.cdc.gov/toxpro2.html]{.underline}                   |
+-----------------------------------------------------------------------+
| CalEPA (Office of Environmental Health Hazard Assessment)             |
|                                                                       |
| http://www.oehha.ca.gov/risk.html                                     |
+-----------------------------------------------------------------------+
| ILSI (International Life Sciences Institute - health assessments and  |
| information)                                                          |
|                                                                       |
| http://www.ilsi.org/                                                  |
+-----------------------------------------------------------------------+
| IARC (International Agency for Research on Cancer - Monograph         |
| Series - WHO)                                                         |
|                                                                       |
| [http://monographs.iarc.fr/htdig/search.html]{.underline}             |
+-----------------------------------------------------------------------+
| IPCS INCHEM (International Programme on Chemical Safety (WHO) -       |
| Chemical Safety Information from Intergovernmental Organizations -    |
| numerous sources of chemical information: CICADS (Concise             |
| International Chemical Assessment Documents; EHC (Environmental       |
| Health Criteria); SIDS (Screening Information Data Sets for High      |
| Production Volume Chemicals)                                          |
|                                                                       |
| [http://www.inchem.org/]{.underline}                                  |
+-----------------------------------------------------------------------+
| WHO assessments (CICADS, EHC)                                         |
|                                                                       |
| http://www.who.int/ipcs/assessment/en/                                |
+-----------------------------------------------------------------------+
| Health Canada First Priority List Assessments                         |
|                                                                       |
| [http://www.hc‑sc.gc.ca/hecs‑sesc/exsd/psl1.htm]{.underline}          |
+-----------------------------------------------------------------------+
| Health Canada Second Priority List Assessments                        |
|                                                                       |
| [http://www.hc‑sc.gc.ca/hecs‑sesc/exsd/psl2.htm]{.underline}          |
+-----------------------------------------------------------------------+
| TERA (Toxicology Excellence for Risk Assessment - develops toxicity   |
| values, conducts peer reviews, etc.)                                  |
|                                                                       |
| http://www.tera.org/                                                  |
+-----------------------------------------------------------------------+
| ITER (International Toxicity Estimates for Risk from numerous         |
| sources - maintained by TERA)                                         |
|                                                                       |
| [http://iter.ctcnet.net/publicurl/pub_search_list.cfm]{.underline}    |
+-----------------------------------------------------------------------+

##  

## **Appendix C: Quality Assurance Instructions for Contractors Citing Secondary Data.**

## 

Section 515 of the Treasury and General Government Appropriations Act
for fiscal year 2001 directed the Office of Management and Budget (OMB)
to issue guidelines to all Federal agencies to ensure and maximize the
quality, objectivity, utility, and integrity of the information they
disseminate. This law and the OMB guidance subsequently issued in 67 FR
8452 (02/22/02) underscore the need for EPA/NCEA to assess the quality
and credibility of the secondary research information cited in its
assessment documents.

Secondary research information is defined as information that was
originally produced for one purpose but is now being recompiled or
reassessed for a different purpose. Secondary research information
usually originates from such primary sources as journal articles, books,
government and industry reports, databases, and models. The set of
processes that follows serves as a guide to evaluate the strength of
secondary data gathered from these primary sources.

The Contractors must list the sources for the references cited in
his/her document chapters or sections. The source list will include but
not be limited to the names of any commercially available or local
databases searched by computer or by hand, the search terms and search
strategy used, and the time period of the search. List any print sources
like books or journal articles which provided references. List any
sources of raw data.

After fully reporting all of the reference sources, identify the most
relevant information or key studies among the references you cite and
critically evaluate them. Key studies are those most crucial or pivotal
to answer the research questions for the project. The key study may have
positive or negative results and may even be all that is currently
available on the research topic, but the key study is integral to any
discussion of the topic. Sometimes, the key study is not recognizable
until all of the literature is gathered and evaluated. Key studies
should exhibit at least most of the general attributes defined below:

FOCUS: the work not only addresses the area of inquiry under
consideration but also contributes to its understanding;

VERIFY: the work is consistent with accepted knowledge in the field or,
if not, the new or varying information is documented within the work;
the work fits within the context of the literature and is intellectually
honest and authentic;

INTEGRITY: Is the work structurally sound? In a piece of research, is
the design or research rationale logical and appropriate?

RIGOR: the work is important, meaningful, and non-trivial relative to
the field and exhibits sufficient depth of intellect rather than
superficial or simplistic reasoning;

UTILITY: the work is useful and professionally relevant; it makes a
contribution to the field in terms of the practitioners' understanding
or decision-making on the topic.

CLARITY: Is it written clearly and appropriately for the nature of the
study?

Use the check list on the following page to evaluate the key studies.

[^1]: An estimate of an exposure for a given duration to the human
    population (including susceptible subgroups) that is likely to be
    without an appreciable risk of adverse health effects over a
    lifetime.

[^2]: Clark LH, Setzer RW, Barton HA. Framework for evaluation of
    physiologically-based pharmacokinetic models for use in safety or
    risk assessment. Risk Anal. 2004 Dec;24(6):1697-717.

[^3]: Chiu WA, Barton HA, DeWoskin RS, Schlosser P, Thompson CM,
    Sonawane B, Lipscomb JC, Krishnan K.

    Evaluation of physiologically based pharmacokinetic models for use
    in risk assessment. J Appl Toxicol. 2007 May-Jun;27(3):218-37.