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| ![](media/i   | **UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**    |
| mage1.wmf){wi |                                                      |
| dth="1.083333 | **WASHINGTON, D.C. 20460**                           |
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|               | **OFFICE OF THE ADMINISTRATOR**                      |
|               |                                                      |
|               | **SCIENCE ADVISORY BOARD**                           |
+---------------+------------------------------------------------------+

December 18, 2008

EPA-SAB-09-007

The Honorable Stephen L. Johnson

Administrator

U.S. Environmental Protection Agency

1200 Pennsylvania Avenue, N.W.

Washington, D.C. 20460

> Subject: SAB Advisory on Aquatic Life Water Quality Criteria for
> Contaminants of Emerging Concern

Dear Administrator Johnson:

The Science Advisory Board (SAB) Ecological Processes and Effects
Committee, augmented with additional experts, reviewed the EPA White
Paper titled *Aquatic Life Criteria for Contaminants of Emerging
Concern* ("White Paper"). EPA's 1985 *Guidelines for Deriving Numerical
National Water Quality Criteria for the Protection of Aquatic Organisms
and Their Uses* ("Guidelines") specify procedural and data requirements
for deriving ambient water quality criteria for the protection of
aquatic life (aquatic life criteria). The Agency is faced with a number
of technical issues and challenges in deriving aquatic life criteria for
contaminants of emerging concern (CECs). To address these technical
issues, the Office of Water and Office of Research and Development have
proposed recommendations for interpreting and/or adapting principles in
the 1985 Guidelines. EPA's White Paper describes the proposed
recommendations, focusing in particular on CECs that disrupt endocrine
function in animals. The White Paper also explores these recommendations
in the context of a case example CEC, ethynylestradiol, a synthetic
pharmaceutical estrogen.

EPA's Office of Water (OW) requested that the SAB: 1) comment on the
technical merit, practicality, and implementability of recommendations
in the White Paper; 2) comment on whether the White Paper identifies the
appropriate issues to be addressed in deriving aquatic life criteria for
CECs; 3) suggest ways to improve the utility of the ethynylestradiol
case example; and 4) offer other suggestions to assist the Agency in
implementing recommendations in the White Paper. The enclosed advisory
report provides the advice and recommendations of the SAB.

Overall, the SAB finds that, in the White Paper, EPA has identified
appropriate technical issues to be considered in deriving aquatic life
criteria for CECs. However, EPA was constrained by the 1985 Guidelines
which, although excellent when developed, were never envisioned for use
with the current CECs. The 1985 Guidelines established a complex process
to evaluate risk by using information from many areas of aquatic
toxicology. The SAB finds that the derivation of aquatic life criteria
needs to be more broadly risk-based, using a transparent and consistent
framework that provides necessary flexibility not presently possible
within the algorithm approach of the 1985 Guidelines. Hence, the SAB
recommends that, to the extent practicable, the derivation of aquatic
life criteria be risk-based using the principles defined in EPA's 1998
*Guidelines for Ecological Risk Assessment* and the more recent *Advice
to EPA on Advancing the Science and Application of Ecological Risk
Assessment: A Report of the U.S. EPA Science Advisory Board* (U.S. EPA
Science Advisory Board, 2007).

Within the context of risk-based aquatic life criteria, the SAB
recommends that EPA consider issues in addition to those identified in
the White Paper, and that the Agency customize and update the 1985
Guidelines to address these issues. In particular, we urge EPA to
include consideration of probable direct and/or indirect impacts on food
webs, ecological processes and services, and endangered or unique
species of special value or concern. These issues could be incorporated
through development of a conceptual model as exemplified in Figure 1 of
the enclosed report. We also recommend that EPA develop multiple lines
of evidence, consider uncertainty, and bolster consideration of mode of
action in the criteria development process. We suggest that mammalian
pharmacology data available from the drug discovery process,
genomics/proteomics/metabolomics, and quantitative structure activity
relationships (QSARs) be used to screen CECs for modes of action and
assess potential multiple modes of action for individual CECs. To
increase efficiency, parallel processes could then be considered when
developing aquatic life criteria for compounds with similar modes of
action.

The SAB generally supports EPA's proposed approaches for interpreting
and/or adapting principles in the Guidelines to address technical issues
discussed in the White Paper. However, we have noted specific concerns
about these approaches and provide recommendations to improve the White
Paper. We emphasize that many CECs will require special consideration
because they do not fit the effect model discussed in the White Paper
(i.e., disruption of endocrine function), or may be not be well enough
understood to allow appropriate judgment of their mode of action. In
addition, we note that specific issues such as the potential for joint
interactions affecting toxicity exist for many CECs that may occur in
mixtures in the environment and which may also interact with
environmental variables such as temperature. Such possible interactions
should be considered. As more information is developed to account for
the interactive effects of CECs, it is possible that water quality
criteria may be revised up or down for individual CECs based upon data
on joint interactions; use of such data would produce more risk-based
criteria.

The SAB finds that the ethynylestradiol illustrative example in the
White Paper is a well-written and thorough review of the existing
literature. It illustrates the complexities inherent in generating
aquatic life criteria for CECs. However, we do provide recommendations
to clarify the example and make it more useful.

The SAB also provides other suggestions to assist EPA in implementing
the proposed recommendations in the White Paper. These suggestions focus
on: data collection and research activities; developing tissue
residue-based criteria; developing exposure and effect indicators that
could be used in future derivation of criteria; special considerations
for sensitive or commercially/recreationally important species; and
obtaining input from private industry and state governments.

Thank you for the opportunity to provide advice on this important topic.
The SAB looks forward to receiving the Agency's response to this
advisory and to updates on any additional follow-up activities.

> Sincerely,

*/**Signed/ /Signed/***

Dr. Deborah L. Swackhamer, Chair Dr. Judith L. Meyer, Chair

Science Advisory Board Ecological Processes and Effects Committee

**U.S. Environmental Protection Agency**

**Science Advisory Board**

**Ecological Processes and Effects Committee**

**Augmented for the Advisory on the EPA's Aquatic Life Water**

**Quality Criteria**

**CHAIR**

**Dr. Judith L. Meyer**, Distinguished Research Professor Emeritus, Odum
School of Ecology, University of Georgia, Athens, GA

**MEMBERS**

**Dr. Richelle Allen-King**, Professor and Chair, Department of Geology,
University at Buffalo, Buffalo, NY

**Dr. Fred Benfield**, Professor of Ecology, Department of Biological
Sciences, Virginia Tech, Blacksburg, VA

**Dr. Ingrid Burke**, Professor and Director, Haub School and
Ruckelshaus Institute of Environment and Natural Resources, University
of Wyoming, Laramie, WY

**Dr. G. Allen Burton**, Professor and Director, Cooperative Institute
for Limnology and Ecosystems Research, School of Natural Resources and
Environment, University of Michigan, Ann Arbor, MI

**Dr. Peter M. Chapman**, Principal and Senior Environmental Scientist,
Environmental Sciences Group, Golder Associates Ltd, North Vancouver,
British Columbia, Canada

**Dr. Loveday Conquest**, Professor, School of Aquatic and Fishery
Sciences and Director, Quantitative Ecology and Resource Management
Program, University of Washington, Seattle, WA

**Dr. Wayne Landis**, Professor and Director, Institute of Environmental
Toxicology, Western Washington University, Bellingham, WA

**Dr. Charles Rabeni**, Leader of Missouri Cooperative Fish and Wildlife
Research Unit, U.S. Geological Survey, University of Missouri, Columbia,
MO

**Dr. Amanda Rodewald**, Associate Professor of Wildlife Ecology, School
of Environment and Natural Resources, The Ohio State University,
Columbus, OH

**Dr. James Sanders**, Director and Professor, Skidaway Institute of
Oceanography, Savannah, GA

**Mr. Timothy Thompson**, Senior Environmental Scientist, Science,
Engineering, and the Environment, LLC, Seattle, WA

**Dr. Ivor van Heerden**, Associate Professor and Director, Department
of Civil and Environment Engineering, LSU Hurricane Public Health
Research Center, Louisiana State University, Baton Rouge, LA

**CONSULTANTS**

**Dr. Kenneth Dickson**, Regents Professor, Department of Biological
Sciences, University of North Texas, Aubrey, TX

**Dr. Karen Kidd**, Canada Research Chair and Professor, Biology
Department, University of New Brunswick, Saint John, New Brunswick,
Canada

**Dr. Ellen Mihaich**, President, Environmental and Regulatory
Resources, LLC, Durham, NC

**Dr. Daniel Schlenk**, Professor, Department of Environmental Sciences,
University of California, Riverside, Riverside, CA

**Dr. Heiko Schoenfuss**, Professor of Aquatic Toxicology, Department of
Biological Sciences, Aquatic Toxicology Laboratory, St. Cloud State
University, St. Cloud, MN

**Dr. Geoffrey Scott**, Director, Center for Coastal Environmental
Health and Biomolecular Research, National Ocean Services, National
Oceanic and Atmospheric Administration, Charleston, SC

**Dr. Glen Van Der Kraak**, Professor and Associate Dean, Integrative
Biology, College of Biological Science , University of Guelph, Guelph,
Ontario, Canada

**SCIENCE ADVISORY BOARD STAFF**

**Dr. Thomas Armitage**, Designated Federal Officer, U.S. Environmental
Protection Agency, Washington, DC

**U.S. Environmental Protection Agency**

**Science Advisory Board**

**CHAIR**

**Dr. Deborah L. Swackhamer**, Professor of Environmental Health
Sciences and Co-Director Water Resources Center, Water Resources Center,
University of Minnesota, St. Paul, MN

**SAB MEMBERS**

**Dr. David T. Allen**, Professor, Department of Chemical Engineering,
University of Texas, Austin, TX

**Dr. John Balbus**, Chief Health Scientist, Environmental Health
Program, Environmental Defense Fund, Washington, DC

**Dr. Gregory Biddinger**, Coordinator, Natural Land Management
Programs, Toxicology and Environmental Sciences, ExxonMobil Biomedical
Sciences, Inc., Houston, TX

**Dr. Timothy Buckley**, Associate Professor and Chair, Division of
Environmental Health Sciences, School of Public Health, The Ohio State
University, Columbus, OH

**Dr. Thomas Burke**, Professor, Department of Health Policy and
Management, Johns Hopkins Bloomberg School of Public Health, Johns
Hopkins University, Baltimore, MD

**Dr. James Bus**, Director of External Technology, Toxicology and
Environmental Research and Consulting, The Dow Chemical Company,
Midland, MI

**Dr. Deborah Cory-Slechta**, Professor, Department of Environmental
Medicine, School of Medicine and Dentistry, University of Rochester,
Rochester, NY

**Dr. Terry Daniel**, Professor of Psychology and Natural Resources,
Department of Psychology, School of Natural Resources, University of
Arizona, Tucson, AZ

**Dr. Otto C. Doering III**, Professor, Department of Agricultural
Economics, Purdue University, W. Lafayette, IN

**Dr. David A. Dzombak**, Walter J. Blenko Sr. Professor of
Environmental Engineering, Department of Civil and Environmental
Engineering, College of Engineering, Carnegie Mellon University,
Pittsburgh, PA

**Dr. T. Taylor Eighmy**, Interim Vice President for Research, Office of
the Vice President for Research, University of New Hampshire, Durham, NH

**Dr. Baruch Fischhoff**, Howard Heinz University Professor, Department
of Social and Decision Sciences, Department of Engineering and Public
Policy, Carnegie Mellon University, Pittsburgh, PA

**Dr. James Galloway**, Professor, Department of Environmental Sciences,
University of Virginia, Charlottesville, VA

**Dr. John P. Giesy**, Professor, Department of Zoology, Michigan State
University, East Lansing, MI

**Dr. James K. Hammitt**, Professor, Center for Risk Analysis, Harvard
University, Boston, MA

**Dr. Rogene Henderson**, Senior Scientist Emeritus, Lovelace
Respiratory Research Institute, Albuquerque, NM

**Dr. James H. Johnson**, Professor and Dean, College of Engineering,
Architecture & Computer Sciences, Howard University, Washington, DC

**Dr. Bernd Kahn**, Professor Emeritus and Director, Environmental
Radiation Center, Nuclear and Radiological Engineering Program, Georgia
Institute of Technology, Atlanta, GA

**Dr. Agnes Kane**, Professor and Chair, Department of Pathology and
Laboratory Medicine, Brown University, Providence, RI

**Dr. Meryl Karol**, Professor Emerita, Graduate School of Public
Health, University of Pittsburgh, Pittsburgh, PA

**Dr. Catherine Kling**, Professor, Department of Economics, Iowa State
University, Ames, IA

**Dr. George Lambert**, Associate Professor of Pediatrics, Director,
Center for Childhood Neurotoxicology, Robert Wood Johnson Medical
School-UMDNJ, Belle Mead, NJ

**Dr. Jill Lipoti**, Director, Division of Environmental Safety and
Health, New Jersey Department of Environmental Protection, Trenton, NJ

**Dr. Lee D. McMullen**, Water Resources Practice Leader, Snyder &
Associates, Inc., Ankeny, IA

**Dr. Judith L. Meyer**, Distinguished Research Professor Emeritus, Odum
School of Ecology, University of Georgia, Athens, GA

**Dr. Jana Milford**, Professor, Department of Mechanical Engineering,
University of Colorado, Boulder, CO

**Dr. M. Granger Morgan**, Lord Chair Professor in Engineering,
Department of

Engineering and Public Policy, Carnegie Mellon University, Pittsburgh,
PA

**Dr. Christine Moe**, Eugene J. Gangarosa Professor, Hubert Department
of Global Health, Rollins School of Public Health, Emory University,
Atlanta, GA

**Dr. Duncan Patten**, Research Professor , Department of Land Resources
and Environmental Sciences, Montana State University, Bozeman, MT, USA

**Mr. David Rejeski**, Director, Foresight and Governance Project ,
Woodrow Wilson International Center for Scholars, Washington, DC

**Dr. Stephen M. Roberts**, Professor, Department of Physiological
Sciences, Director, Center for Environmental and Human Toxicology,
University of Florida, Gainesville, FL

**Dr. Joan B. Rose**, Professor and Homer Nowlin Chair for Water
Research, Department of Fisheries and Wildlife, Michigan State
University, East Lansing, MI

**Dr. Jonathan M. Samet**, Professor and Chair , Department of
Epidemiology, Bloomberg School of Public Health, Johns Hopkins
University, Baltimore, MD

**Dr. James Sanders**, Director and Professor, Skidaway Institute of
Oceanography, Savannah, GA

**Dr. Jerald Schnoor**, Allen S. Henry Chair Professor, Department of
Civil and Environmental Engineering, Co-Director, Center for Global and
Regional Environmental Research, University of Iowa, Iowa City, IA

**Dr. Kathleen Segerson**, Professor, Department of Economics,
University of Connecticut, Storrs, CT

**Dr. Kristin Shrader-Frechette**, O\'Neil Professor of Philosophy,
Department of Biological Sciences and Philosophy Department, University
of Notre Dame, Notre Dame, IN

**Dr. V. Kerry Smith**, W.P. Carey Professor of Economics , Department
of Economics , W.P Carey School of Business , Arizona State University,
Tempe, AZ

**Dr. Thomas L. Theis**, Director, Institute for Environmental Science
and Policy, University of Illinois at Chicago, Chicago, IL

**Dr. Valerie Thomas**, Anderson Interface Associate Professor, School
of Industrial and Systems Engineering, Georgia Institute of Technology,
Atlanta, GA

**Dr. Barton H. (Buzz) Thompson, Jr.**, Robert E. Paradise Professor of
Natural Resources Law at the Stanford Law School and Perry L. McCarty
Director, Woods Institute for the Environment Director, Stanford
University, Stanford, CA

**Dr. Robert Twiss**, Professor Emeritus, University of
California-Berkeley, Ross, CA

**Dr. Thomas S. Wallsten**, Professor, Department of Psychology,
University of Maryland, College Park, MD

**Dr. Lauren Zeise**, Chief, Reproductive and Cancer Hazard Assessment
Branch, Office of Environmental Health Hazard Assessment, California
Environmental Protection Agency, Oakland, CA

**SCIENCE ADVISORY BOARD STAFF**

**Mr. Thomas Miller**, Designated Federal Officer, U.S. Environmental
Protection Agency, Washington, DC

> **NOTICE**
>
> This report has been written as part of the activities of the EPA
> Science Advisory Board, a public advisory group providing extramural
> scientific information and advice to the Administrator and other
> officials of the Environmental Protection Agency. The Board is
> structured to provide balanced, expert assessment of scientific
> matters related to the problems facing the Agency. This report has not
> been reviewed for approval by the Agency and, hence, the contents of
> this report do not necessarily represent the views and policies of the
> Environmental Protection Agency, nor of other agencies in the
> Executive Branch of the Federal government, nor does mention of trade
> names or commercial products constitute a recommendation for use.
> Reports of the EPA Science Advisory Board are posted on the EPA
> website at http://www.epa.gov/sab.

TABLE OF CONTENTS

[***List of Acronyms*** xii](#__RefHeading___Toc213670703)

[**1.** **EXECUTIVE SUMMARY** xiii](#__RefHeading___Toc213670704)

[**2.** **INTRODUCTION** 1](#__RefHeading___Toc213670705)

[**3.** **CHARGE TO THE COMMITTEE** 3](#__RefHeading___Toc213670706)

[**4.** **RESPONSE TO CHARGE QUESTIONS**
5](#__RefHeading___Toc213670707)

[**4.1** Charge **Question 1. Commments on Recommendations in the White
Paper** ....5](#__RefHeading___Toc213670709)

[4.1.1 Relevance of Acute Toxicity Effect Concentrations
6](#__RefHeading___Toc213670710)

[4.1.2 Defining Minimum Data Requirements Regarding Taxonomic Coverage
8](#__RefHeading___Toc213670711)

[4.1.3 Use of Non-resident Species in Criteria Development
12](#__RefHeading___Toc213670712)

[4.1.4 Defining Appropriate Chronic Toxicity Data
15](#__RefHeading___Toc213670713)

[4.1.5 Selection of Effect Endpoints for Criteria Developmen
17](#selection-of-effect-endpoints-for-criteria-development)

[4.1.6 Involvement of an Expert Panel 21](#__RefHeading___Toc213670715)

[**4.2** Charge **Question 2. Comments on Technical Issues Addressed in
the White Paper** 22](#__RefHeading___Toc213670716)

[**4.3** **Charge Question 3. Comments on Part II of the White Paper**
27](#__RefHeading___Toc213670717)

[**4.4.** **Charge Question 4. Suggestions to Assist EPA in Implementing
the Recommendations** 30](#__RefHeading___Toc213670718)

[**5.** **REFERENCES** 37](#__RefHeading___Toc213670719)

***List of Acronyms***[]{#__RefHeading___Toc213670703 .anchor}

ACR - Acute to Chronic Ratio

AhR - Aryl Hydrocarbon Receptor

ALC - Aquatic Life Criteria

AV - Acute Value

CCC - Criterion Continuous Concentration

CEC - Contaminant of Emerging Concern

CMC - Criterion Maximum Concentration

CV - Chronic Value

CYP3A - Cytochrome P450 3A

EC~10~ - Concentration causing an effect in 10 percent of the test
organisms

EC~20~ - Concentration causing an effect in 20 percent of the test
organisms

EC~x~ - Concentration causing an effect in x percent of the test
organisms

EDC - Endocrine Disrupting Compound

EE2 - Ethynylestradiol

ELS - Early Life Stage Test

EPA - U.S. Environmental Protection Agency

ER - Estrogen Receptor

F~0~ - The initial parent generation in a multigeneration reproduction
study

F~1~ - The first offspring generation in a multigeneration reproduction
study

FDA - U.S. Food and Drug Administration

FFLC - Fish Full Life Cycle

FIFRA - Federal Insecticide Fungicide and Rodenticide Act

LC50 - Test concentration causing in mortality to 50% of the test
population

LOEC - Lowest Observed Effect Concentration

LOEL - Lowest Observed Effect Level

NOAA - National Oceanic and Atmospheric Administration

NOEC - No Observed Effect Concentration

NOEL - No Observed Effect Level

OECD - Organization for Economic Cooperation and Development

ORD - U.S. Environmental Protection Agency Office of Research and
Development

OSWER - U.S Environmental Protection Agency Office of Solid Waste and
Emergency Response

OW - U.S. Environmental Protection Agency Office of Water

PBPK - Physiologically Based Pharmacokinetic Model

PDBE - Polybrominated diphenyl ether

PFOS - Perfluorinated octynyl sulfonate

PLC - Partial Life Cycle

QSAR - Quantitative Structure Activity Relationship

ROPC - Receptor of Potential Concern

SAB - U.S. Environmental Protection Agency Science Advisory Board

SETAC - Society of Environmental Toxicology and Chemistry

SSD - Species Sensitivity Distribution

SSRI - Selective Serotonin Reuptake Inhibitor

TSCA - Toxic Substances Control Act

USDA - U.S. Department of Agriculture

**1. EXECUTIVE SUMMARY**[]{#__RefHeading___Toc213670704 .anchor}

EPA's Office of Water (OW) requested that the Science Advisory Board
(SAB) provide advice on the Agency's proposed recommendations pertaining
to derivation of water quality criteria for the protection of aquatic
life (aquatic life criteria) for contaminants of emerging concern
(CECs). The Agency's proposed recommendations are provided in a white
paper titled *Aquatic Life Criteria for Contaminants of Emerging
Concern* (White Paper). The White Paper, prepared by the EPA Office of
Water/Office of Research and Development Emerging Contaminants
Workgroup, was reviewed by the SAB Ecological Processes and Effects
Committee (Committee). To augment the expertise on the Committee for
this advisory activity, several environmental toxicologists with
specific knowledge of the effects of endocrine disrupting chemicals also
participated in the review.

EPA's Office of Water develops ambient water quality criteria that
provide guidance to states and tribes for adoption of water quality
standards. The EPA document, *Guidelines for Deriving Numerical National
Water Quality Criteria for the Protection of Aquatic Organisms and Their
Uses* (hereafter referred to as the "Guidelines") (Stephan et al.,
1985), sets forth a methodology for deriving ambient water quality
criteria for the protection of aquatic life. The Guidelines specify
various data and procedural recommendations for evaluating risk and
deriving criteria and also define general risk management goals for the
criteria. Most of EPA's aquatic life criteria have been derived using
methods in the Guidelines, and EPA has stated that the Agency intends to
continue using the Guidelines to derive aquatic life criteria. However,
EPA has also indicated that it faces a number of technical challenges in
deriving aquatic life criteria for CECs. In its White Paper, the Agency
described these technical challenges and proposed recommendations to
interpret and/or adapt Guidelines principles to address the challenges.
One of the Committee's key recommendations is that EPA incorporate risk
assessment principles, as defined by the 1998 *Guidelines for Ecological
Risk Assessment* (U.S. EPA, 1998), within the framework of the 1985
aquatic life criteria Guidelines. Criteria derived within the risk
assessment framework will provide additional consistency with other
ongoing work at EPA and will provide necessary flexibility not presently
possible within the algorithm approach of the 1985 Guidelines. In this
regard, it is suggested that EPA also consider recommendations and
findings in the recent SAB report, *Advice to EPA on Advancing the
Science and Application of Ecological Risk Assessment: A Report of the
U.S. EPA Science Advisory Board* (U.S. EPA Science Advisory Board,
2007).

The term "contaminant of emerging concern" or CEC has been used by EPA
to identify a variety of chemical compounds that have no regulatory
standard, have been recently discovered in the natural environment
because of improved analytical chemistry detection levels, and
potentially cause deleterious effects to aquatic life at environmentally
relevant concentrations. The Agency is particularly concerned about
pharmacologically active chemical compounds and personal care products
because: 1) they are commonly discharged at wastewater treatment plants,
and 2) some of these compounds are designed to stimulate a physiological
response in humans, plants, and animals.

The first part of EPA's White Paper (Part I), *General Challenges and
Recommendations*, describes: 1) the technical challenges EPA faces in
deriving aquatic life criteria for CECs; and 2) the proposed
recommendations to address those challenges. The second part of the
White Paper (Part II), *Illustration of Recommendations Using Data for
17α -- Ethynylestradiol (EE2)*, explores EPA's recommendations in the
context of an example CEC, ethynylestradiol (EE2), which is a synthetic
pharmaceutical estrogen. In its charge to the SAB, EPA requested
comments on the technical merit, practicality, and implementability of
recommendations in the White Paper to address: a) relevance of acute
toxicity effect concentrations in setting aquatic life criteria for
CECs; b) defining minimum data requirements regarding taxonomic coverage
in toxicity testing; c) use of non-resident species in criteria
development; d) defining appropriate chronic toxicity data; e) selection
of effect endpoints upon which to base criteria; and f) involvement of
an expert panel in the criteria development process. In addition, EPA
asked the SAB to: comment on whether the Agency has identified the
appropriate issues to be addressed in deriving aquatic life criteria for
CECs; offer suggestions that may improve the utility of Part II of the
White Paper; and offer suggestions that would assist the Agency in
implementing proposed recommendations in the White Paper. In response to
the charge questions, the Committee has provided comments and
recommendations to improve the White Paper and assist EPA in deriving
aquatic life criteria for contaminants of emerging concern.

*Relevance of acute toxicity effect concentrations in deriving aquatic
life criteria for CECs*

Many CECs are physiologically active at concentrations orders of
magnitude lower than those causing acute lethality, and concentrations
sufficient to cause lethality may never occur in the environment.
Therefore, in the White Paper the Agency recommends that, when
sufficient information demonstrates a negligible risk of acute lethality
for a CEC, the "criterion continuous concentration" (i.e., the
concentration intended to protect against the longer term effects of
exposure on survival, growth, and reproduction) be used to derive
aquatic life criteria. In principle, the Committee supports EPA's
suggestion to derive aquatic life criteria solely from criteria
continuous concentrations (CCCs) for CECs when available information
indicates that this is appropriate. However, we have recommended the
following amendments in the White Paper:

-   Not enough is known about some classes of CECs (e.g., nanoparticles)
    to determine whether acute toxicity needs to be taken into account
    in deriving aquatic life criteria. Therefore, all available data on
    any new class of CECs should be used in determining whether acute
    toxicity is likely to occur in environmentally relevant settings.

-   Some CECs appear to have differing modes of action for acute
    toxicity vs. chronic toxicity. Lowest Observed Effect Concentrations
    (LOECs) and LC50s (test concentrations that result in mortality to
    50% of the test population) are within one order of magnitude for
    some CECs, making acute toxicity relevant in deriving aquatic life
    criteria. Therefore, "criteria maximum concentrations" (CMCs) to
    protect against acute effects should be derived for compounds where
    LOECs are found to be within 1-2 orders of magnitude of LC50s.

-   Pulsed discharges of CECs may occur during natural disasters and
    spills and result in atypically high concentrations in the
    environment. Therefore, criteria documents for CECs should always
    identify the CMC as a data gap when it is not used to derive
    criteria. Furthermore, as discussed in Section 4.1.1 of this report,
    aquatic life criteria derivations should consider whether
    concentrations capable of causing acute toxicity may occur during
    these pulsed discharges. Under this scenario, it may be important to
    use CMCs in addition to CCCs in the aquatic life criteria derivation
    process.

-   Mixtures of CECs with comparable modes of action may result in
    higher effective concentrations than would be expected based on the
    concentrations of any single compound. Therefore, research is needed
    to determine how aquatic life criteria for CECs can take into
    account the fact that aquatic organisms are exposed to mixtures of
    chemicals with similar modes of action.

-   To maintain transparency in cases when CMCs are not used in criteria
    development, a summary of all available data that provide
    information on the relevance of acute toxicity should be included in
    any aquatic life criteria document.

*Defining minimum data requirements regarding taxonomic coverage in
toxicity testing*

In the White Paper, EPA has recommended that, for CECs without complete
chronic toxicity data sets to fulfill minimum data requirements, there
be an evaluation of whether sufficient information exists to conclude
that certain taxa would not be sensitive to a particular chemical. Thus,
EPA recommends that the minimum data requirements for taxonomic coverage
(specified in the Guidelines) be viewed as information requirements
instead of toxicity test requirements. The Committee understands and
appreciates the desirability of avoiding the extra work required to
develop chronic data on species that are unlikely to be sensitive to
certain CECs. However, we emphasize that it is equally important to
perform adequate testing to ensure protection of aquatic life. We
generally support the broad taxonomic coverage requirements in the
Guidelines but agree that these could be viewed as information
requirements instead of test requirements. We find that, if sufficient
information exists on the insensitivity of certain taxa to particular
chemicals, expert judgment concerning data development should prevail.
This would result in a more focused approach to data development,
keeping in mind weight of evidence rather than a requirement for testing
all taxa specified in the Guidelines. As indicated below, we have
provided specific recommendations to improve the process of determining
appropriate taxonomic coverage to develop aquatic life criteria for
CECs:

-   EPA needs to define what constitutes a sufficiently robust set of
    chronic data for criteria development. Although the example used in
    the White Paper generally illustrates EPA's proposed process for
    making decisions concerning taxonomic coverage, it would be helpful
    if EPA were more explicit in identifying what constitutes a
    \"sufficiently robust set of chronic data\" and \"a reasonable
    understanding of the mode of action for the chemical that may allow
    inferences."

-   The White Paper should place greater emphasis on information useful
    for development of aquatic life criteria, rather than just toxicity
    test requirements. Incorporating effects on ecological processes
    (e.g., food webs, nutrient cycling, primary production) rather than
    only target species would be valuable in criteria development, and
    would follow more recent scientific thinking.

-   As further discussed in Section 4.1.2 of this advisory report, EPA
    should consider shifting from an approach requiring a minimum level
    of taxonomic coverage to the approach of determining receptors of
    potential concern (ROPCs).

-   Examples showing the unanticipated effects of CECs on non-target
    organisms (e.g., the impact of antibiotics on plants and effect of
    atrazine on the quality of algae available as food for other
    species) should be used in Part I of the White Paper to help
    describe how the aquatic life criteria development process needs to
    be more flexible depending on the compounds under evaluation.

*Use of non-resident species in criteria development*

Historically, EPA has not included data from toxicity testing with
non-resident species in the actual criteria derivation process. In the
White Paper, EPA recommends that "non-resident" species data be used in
the aquatic life criteria derivation process if such data would enable a
better estimation of species sensitivity distributions. The Committee
agrees; we find that the exclusion of non-resident species data from
criteria derivation is biologically and practically inconsistent with
the intent of the Guidelines (i.e., providing an objective, internally
consistent, appropriate, and feasible way of deriving national
criteria). We have provided a number of specific recommendations
concerning the use of non-resident species data:

-   Because of the frequent use of non-resident species in toxicity
    testing, such species could potentially be over-represented in
    aquatic life criteria databases. Therefore, the proportion of the
    data set that should include resident species should be carefully
    evaluated by an expert advisory panel assembled to review each
    criterion.

-   Although non-resident species can be used for criteria development,
    in no case should a criterion be developed on the basis of
    non-resident species data alone. Although the Guidelines have been
    designed to protect aquatic communities (including endangered
    species), EPA should support research that addresses the suitability
    of the use of surrogate species in assessing the responses of
    various resident aquatic species (e.g., endangered or long-lived
    species and species with varying life history strategies) to
    endocrine disrupting and other CECs.

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-   Differences in strains, husbandry, health, and parasite and pathogen
    load (i.e., other stressors) contribute to variations in toxicity
    test response and thus should be considered in the criteria
    development process.

-   Issues to be considered in prioritizing species responses should
    include their vulnerability, endangerment status, and recreational,
    commercial and ecological value.

-   Non-resident and resident species data must meet test guidelines for
    data and method validity.

*Defining appropriate chronic toxicity data*

In the White Paper, EPA recommends that the Guidelines requirements for
chronic toxicity test data be tightened by requiring at least one full
life-cycle test for a fish (life-cycle tests are already required for
invertebrates) unless there is a compelling body of information
indicating that life processes outside the early life stage or partial
life-cycle exposure/observation window are not critical to capturing the
biologically important effects of chronic exposure to the chemical. As
further discussed in Section 4.1.4 of this report, the Committee
strongly supports the use of fish full life-cycle test data in
appropriate cases to develop aquatic life criteria. We find that it
would be useful to develop a tiered testing approach to determine an
appropriate rationale for use of data from fish full life-cycle, partial
life-cycle, and possibly multigenerational testing to derive aquatic
life criteria for CECs with parallel modes of action. We have provided
additional recommendations concerning the requirement for chronic
toxicity data.

-   EPA should critically review data dealing with transgenerational
    responses of aquatic species and evaluate whether this additional
    testing would provide significant new information to inform the
    criteria development process.

-   Test guidelines should include flexibility to include assessment of
    key developmental events, and professional judgment from an expert
    panel should be used to evaluate the relevance of non-traditional
    endpoints such as immune function and organism behavior. Behavioral
    endpoints (e.g., predator-prey interactions) may hold some promise
    for criteria development if the assays can be related to
    population-level responses and variability can be understood.

*Selection of effect endpoints upon which to base criteria*

In the White Paper, EPA has identified a number of endpoints that could
be considered (in addition to the "traditional" endpoints of survival,
growth, and reproduction) in developing aquatic life criteria for CECs.
Moreover, the Agency has recommended more thorough exploration of the
use of such endpoints in criteria development. Generally, the Committee
agrees that EPA should continue to explore the possibility of using
sublethal endpoints in helping to set aquatic life criteria. However, we
caution EPA that such "non-traditional" endpoints must ultimately be
linked to population endpoints (i.e., potential impacts to populations
must be considered, not solely effects on individual organisms). We have
provided a number of recommendations concerning use of these endpoints:

-   EPA should use "non-traditional measures" to develop an
    understanding of and confirm mode of action of CECs.

-   As further discussed in Section 4.1.5 of this advisory report, EPA
    should use human health information and toxicology tools
    (genomics/physiologically-based pharmacokinetic models \[PBPKs\]) to
    reduce the uncertainty of aquatic life criteria for CECs.

-   EPA should consider the following key points concerning use of the
    non-traditional endpoints discussed in the White Paper: 1)
    vitellogenin in males and juveniles is an indicator of exposure to a
    feminizing stressor, but its linkage to population effects is
    limited; 2) strong correlations between vitellogenin and fecundity
    have been observed in females, but this is not necessarily tied to
    altered endocrine mode of action; 3) anomalous intersex can be
    indicative of exposure to a feminizing stressor(s) but may not, at
    present, be directly tied to population effects; and 4) gender ratio
    can be indicative of endocrine alteration, but baseline information
    on appropriate life stages is necessary for this evaluation.

*Involvement of an Expert Panel*

Because the development of aquatic life criteria for CECs may be
dependent on technical interpretations of a wide range of toxicological
information, EPA has proposed that expert panels be used to provide
professional judgment during criteria development. The Committee
strongly supports the use of panels comprised of experts with a balanced
range of perspectives to provide professional judgment during the
process of developing aquatic life criteria. However, we note that the
use of expert panels could lead to less consistency in how aquatic life
criteria are determined if the panels are not selected carefully. To
help alleviate this potential problem, we recommend that EPA develop
specific guidance on the role of expert panels in problem formulation,
data evaluation, and generation of advice to support criteria
development. Specifically, we recommend that:

-   The process for the use and selection of expert panels be described
    in detail and that it be transparent.

-   The panels be given clear charges and understanding of their roles
    in the process.

-   EPA take advantage of similar expert panel processes occurring in
    Europe and Asia to the extent possible.

*Technical issues addressed in the White Paper*

The Committee was asked to comment on whether EPA has identified the
appropriate technical issues in the White Paper, and whether there are
additional important issues that the Agency has not identified. We find
that EPA has identified appropriate technical issues in the White Paper.
However, as further discussed in Section 4.1.6 of this advisory report,
we recommend that the Agency address additional issues to customize and
update the 1985 Guidelines and thereby increase the flexibility and
specificity of the aquatic life criteria derivation process. The
following additional issues are of particular importance:

-   In the White Paper, EPA should articulate principles that can be
    applied when modifying the 1985 Guidelines to develop water quality
    criteria for CECs. In particular, as further discussed in Section
    4.2 of this advisory report, these principles should address: 1)
    obtaining a wide range of inputs from diverse perspectives; 2)
    developing a conceptual model as exemplified in Figure 1 of this
    report; 3) developing criteria for using multiple lines of evidence;
    and 4) identifying/including uncertainties (quantitative and
    qualitative) associated with criteria development.

-   It is particularly important that understanding and presenting
    uncertainty become an intrinsic part of the aquatic life criteria
    development process. For example, the uncertainties inherent in
    understanding modes of action, concentration-response relationships,
    extrapolation of sensitivities, and derivation of ecological effects
    should be quantified and/or described in a narrative sense.

-   EPA should bolster the consideration of mode of action in the
    aquatic life criteria derivation process. It is important that
    aquatic life criteria for CECs take into account the fact that
    aquatic organisms are exposed to mixtures of these chemicals. As
    more information becomes available to account for the interactive
    effects of CECs, it is possible that water quality criteria may be
    revised up or down for individual CECs based upon data on joint
    interactions. Use of such data would produce more risk-based
    criteria. Understanding the mode of action of a compound is very
    important in estimating mixture interactions. In fact,
    pharmacological mode of action is the basis for evaluating multiple
    drug prescriptions in humans by pharmacists. EPA should use
    mammalian pharmacology data available from the drug discovery
    process, genomics/proteomics/metabolomics and quantitative structure
    activity relationships (QSARs) to screen CECs for modes of action,
    identify CECs that may act in an additive manner as mixtures, and
    assess potential multiple modes of action for individual CECs. The
    Committee strongly recommends enhancing the communication and data
    transfer capabilities between agencies such as the U.S. Food and
    Drug Administration (FDA) and EPA to provide mode of action
    information.

-   In deriving aquatic life criteria for CECs, EPA should bolster
    consideration of ecology and indirect ecological effects and also
    give special consideration to the protection of threatened and
    endangered species.

*Part II of the White Paper*

Part II of the White Paper uses ethynylestradiol (EE2) as a model
chemical to illustrate the technical issues presented and provide a
basis for understanding the recommendations in Part I. The Committee was
asked to offer suggestions to improve the utility of Part II. The
Committee finds that Part II is a well-written and thorough review of
the existing literature on EE2. We agree that EE2 is an appropriate
initial focal CEC given the extensive data available relative to other
CECs and the ease with which it illustrates the complexities inherent in
generating CEC-specific water quality criteria. We have provided a
number of specific recommendations to improve Part II:

-   EPA should explicitly recognize that EE2 is unique in being a
    data-rich CEC. The White Paper should highlight the fact that the
    Agency's interest in CECs goes beyond endocrine-active substances,
    and discuss how the process outlined for EE2 might be applied to
    other substances, particularly those for which less data are
    available and which have different modes of action.

-   The Committee suggests that some of the illustrative pieces of Part
    II could also be presented in Part I in the form of succinct text
    boxes illustrating key concepts derived from the various
    recommendations, and that the recommendations could be best
    illustrated if the text boxes were not restricted to EE2 but rather
    included other CECs.

-   Part II should discuss how the individual effects of EE2 on biota
    might be changed by mixtures of compounds, especially those with
    similar modes of action.

-   As stated previously, a criterion should not be developed on the
    basis of non-resident species data alone. Therefore, Part II should
    indicate that resident species data, especially data from life-cycle
    tests using resident species, remain extremely valuable and that
    results from non-resident species tests may not be generalized to
    resident species without comparative sensitivity studies.

-   The possibility of transgenerational effects should be explicitly
    addressed in Part II.

-   A broader array of endpoints should be included in Part II. For
    example, although EE2 is a potent estrogen receptor agonist, it can
    also affect the central nervous system (through steroid
    biotransformation), and an endpoint should be considered to reflect
    this. Part II should also note that relevant and reproducible
    endpoints indicative of adverse population level effects need to be
    used.

-   As further discussed in Section 4.3 of this advisory report, the use
    of weight of evidence is implicit in the evaluation done in Part II,
    and should be explicitly discussed. Furthermore, when appropriate
    data are available, EC~x~ values (i.e., concentration causing an
    effect in x percent of the test organisms) should be used in Part II
    instead of NOECs/LOECs (i.e., no observed effects
    concentrations/lowest observed effects concentrations). The use of
    the EC~x~ values takes advantage of more of the information from a
    toxicity test, and confidence intervals can be generated. The raw
    data from most toxicity tests can be used to calculate an EC~x~
    value. The selection of a specific EC~x~ value for derivation of an
    aquatic life criterion depends upon the level of protection or
    effect that decision makers are willing to accept or detect in the
    field. However, an EC~20~ has been used for most species and an
    EC~10~ has been used for threatened and endangered species. The
    Committee notes that if data are not available to calculate an EC
    value, EPA should recommend in Part II that such values be developed
    and used in future criteria derivation. Published data sets are
    available for much of the fathead minnow and other species toxicity
    tests conducted at EPA's Duluth Laboratory and other laboratories.
    If the data are available then the regression should be calculated.
    The Committee also notes that if the data are not available then the
    value of the NOEL/LOEL (no observed effect level/lowest observed
    effect level) should be carefully evaluated. Without information on
    the variability of the test results, and consequently the
    statistical power, it is not clear what the values represent.

-   As further discussed in Section 4.3 of this report, the clarity and
    transparency of Part II could be improved in a number of areas.

*Suggestions to assist EPA in implementing recommendations discussed in
the White Paper*

In Section 4.4 of this advisory report, the Committee has provided
comments and recommendations to assist EPA in implementing the
approaches discussed in the White Paper. The following key
recommendations are provided:

-   As noted at the beginning of this Executive Summary, the principles
    for conducting Ecological Risk Assessment should be incorporated
    into the process of deriving aquatic life criteria for CECs. The
    Committee recommends that, pending revision of the 1985 Guidelines,
    EPA develop a separate process document that discusses the intended
    application of aquatic life criteria for CECs. This process document
    should establish linkages between the Guidelines, EPA's Ecological
    Risk Assessment Principles (U.S. EPA, 1992, 1998), the recent SAB
    report, *Advice to EPA on Advancing the Science and Application of
    Ecological Risk Assessment: A Report of the U.S. EPA Science
    Advisory Board* (U.S. EPA Science Advisory Board, 2007), and the
    White Paper.

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-   EPA should prioritize the list of CECs for which aquatic life
    criteria will be developed. Data needs for these chemicals should be
    identified, and EPA should fund the research and data collection
    activities necessary to support aquatic life criteria development
    for CECs. In this regard, the Committee recommends that EPA's Office
    of Water and Office of Research and Development look for
    opportunities to leverage EPA research with ongoing research in
    other federal agencies, international agencies, and industry groups.

-   EPA should incorporate use of conceptual models and ecosystem-based
    criteria into the process of deriving aquatic life criteria for
    CECs. The Committee notes that EPA programs are moving toward
    developing more comprehensive ecosystem-relevant criteria that take
    into consideration population-community structure, ecosystem
    functions and processes, and ecosystem services. Accordingly, the
    Committee notes that it is important to develop the link between the
    protected resource, the assessment endpoint, and the measurement
    endpoint, and a conceptual model would clarify those linkages.

-   For bioaccumulative CECs where food chain transfer is a concern, EPA
    should consider developing tissue-based criteria (i.e., expressing
    the criterion as a concentration of the pollutant in fish tissue
    rather than a concentration in the water).

-   EPA should also consider expanding the definition of CECs to include
    chemicals and other substances of increasing environmental concern
    due to anthropogenic activities and inadequate regulatory
    approaches. The White Paper focuses on endocrine disrupting
    chemicals. However, the Committee notes that some CECs do not fit
    the effect model of endocrine disrupting chemicals, or are not well
    enough understood at this time to allow a judgment of their mode of
    action. Nanoparticles are an example of such a class of compounds.
    Additional work is needed to further develop recommendations for
    deriving aquatic life water quality criteria for these other kinds
    of chemicals.

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-   In Section 4.4 of this advisory report the Committee recommends
    additional research to address important issues such as: the effects
    of mixtures of CECs, interactions between CEC and other stressors,
    modes of action of CECs, comparative sensitivities of resident and
    non-resident species, and use of field study results to inform the
    derivation of aquatic life criteria. The Committee also recommends
    that the discussion of taxonomic coverage in the White Paper be
    expanded to include specific recommendations concerning derivation
    of criteria to protect marine organisms. EPA's 1985 Guidelines call
    for assessment of marine organisms in the same manner as freshwater
    organisms. However, due to specific issues unique to marine
    organisms, such as physiological requirements (e.g., maintenance of
    salt balance) and life-history strategies (e.g., reproduction tied
    to tidal cycles), more specific guidance for CECs is likely needed.
    We suggest that such guidance may be best addressed by convening a
    "Pellston" type workshop (Society of Environmental Toxicology and
    Chemistry, 2008) that is comprised of experts from multiple
    disciplines and types of organizations.

**2. INTRODUCTION**[]{#__RefHeading___Toc213670705 .anchor}

EPA's Office of Water (OW) requested that the Science Advisory Board
(SAB) provide advice on the Agency's proposed recommendations pertaining
to derivation of water quality criteria for the protection of aquatic
life (aquatic life criteria) for contaminants of emerging concern (CECs)
such as pharmaceuticals and personal care products that are commonly
discharged in municipal wastewaters. EPA's proposed recommendations are
provided in a white paper titled *Aquatic Life Criteria for Contaminants
of Emerging Concern* (White Paper). The White Paper, prepared by the EPA
Office of Water and Office of Research and Development Emerging
Contaminants Workgroup, was reviewed by the SAB Ecological Processes and
Effects Committee (Committee). To augment the expertise on the Committee
for this advisory activity, several environmental toxicologists with
specific knowledge of the effects of endocrine disrupting chemicals also
participated in the review. The Committee held a public teleconference
on June 23, 2008 to discuss its charge and receive a briefing from EPA,
met on June 30th -- July 1, 2008, and held a follow-up discussion in a
public teleconference on September 16, 2008.

EPA's Office of Water is charged with protecting aquatic life, wildlife,
and human health from the adverse water-mediated effects of
anthropogenic pollutants. In support of this mission, OW develops
ambient water quality criteria that serve as guidance to states and
tribes for adoption of water quality standards. The EPA guidance
document, *Guidelines for Deriving Numerical National Water Quality
Criteria for the Protection of Aquatic Organisms and Their Uses*
(Guidelines) (Stephan et al., 1985), sets forth a methodology for
deriving ambient water quality criteria for the protection of aquatic
life. The Guidelines specify various data and procedural recommendations
for criteria derivation and also define general risk management goals
for the criteria. Most of EPA's aquatic life criteria have been derived
using methods in the Guidelines. EPA has informed the Committee that the
Agency intends to continue using the Guidelines to derive aquatic life
criteria. However, EPA has also stated that it faces a number of
technical challenges in deriving aquatic life criteria for CECs. The
white paper describes these technical challenges and proposes
recommendations to interpret and/or adapt Guidelines principles to
address the challenges.

The term CEC has been used by EPA to identify a variety of chemical
compounds that have no regulatory standard, have been recently
discovered in the natural environment because of improved analytical
chemistry detection levels, and potentially cause deleterious effects to
aquatic life at environmentally relevant concentrations. The Agency has
indicated that it is particularly concerned about pharmacologically
active chemical compounds and personal care products that are commonly
discharged at wastewater treatment plants and may stimulate
physiological responses in humans, plants, and animals. Many of these
compounds are known to disrupt endocrine function in animals, and are
thus referred to as endocrine disrupting chemicals. These chemicals may
demonstrate low acute toxicity but cause significant reproductive
effects at very low levels of exposure. In addition, the effects of
exposure of aquatic organisms to CECs during the early stages of life
may not be observed until adulthood. These chemicals may also have very
specific modes of action that affect only certain types of aquatic
animals (e.g., vertebrates such as fish). Therefore, EPA has suggested
that traditional chronic toxicity test endpoints specified in the
Guidelines may not be sufficiently comprehensive, and Guidelines
requirements for taxonomic coverage in toxicity testing may not be
appropriate to derive aquatic life criteria for these chemicals. The
White Paper focuses on recommendations to derive aquatic life criteria
for endocrine disrupting chemicals.

The first part of EPA's White Paper (Part I), *General Challenges and
Recommendations*, describes: 1) the technical challenges facing EPA in
deriving aquatic life criteria for CECs; and 2) the recommendations to
address those challenges. The second part of the White Paper (Part II),
*Illustration of Recommendations Using Data for 17α -- Ethynylestradiol
(EE2)*, explores EPA's recommendations in the context of an example CEC,
ethynylestradiol (EE2), which is a synthetic pharmaceutical estrogen*.*
In its charge to the SAB, OW requested comments on the technical merit,
practicality, and implementability of recommendations in the White Paper
to address: a) relevance of acute toxicity effect concentrations in
setting aquatic life criteria for CECs; b) defining minimum data
requirements regarding taxonomic coverage in toxicity tests; c) use of
non-resident species in criteria development; d) defining appropriate
chronic toxicity data; e) selection of effect endpoints upon which to
base criteria; and f) involvement of an expert panel in the criteria
development process. In addition, OW asked the SAB for: comments on
whether the Agency has identified the appropriate issues to be addressed
in deriving aquatic life criteria for CECs; suggestions to improve the
utility of Part II of the White Paper; and suggestions to assist the
Agency in implementing proposed recommendations in the White Paper.

The Committee generally supports EPA's proposed approaches for
interpreting and/or adapting Guidelines principles to address the
technical challenges discussed in the White Paper. However in this
advisory report we have recommended improvements to the approaches
proposed in the White Paper. In addition, we have noted a number of
specific technical and practical issues and caveats that should be
considered by EPA when implementing the proposed approaches.

The Committee finds that, in the White Paper, EPA has identified
appropriate technical issues and challenges to developing aquatic life
criteria for CECs. However, we recommend that the Agency address
additional issues to customize and update the Guidelines and thereby
increase the flexibility and specificity of the aquatic life criteria
derivation process. We find that EPA could clarify the process of
developing aquatic life criteria for CECs by articulating a clear set of
principles that could be applied when modifying the Guidelines. We also
emphasize the importance of developing a conceptual model, as
exemplified in Figure 1 of this advisory report, to guide the process of
developing aquatic life criteria for CECs. The Committee finds that Part
II of the White Paper is a well-written and thorough review of the
existing literature on EE2 that illustrates the complexities inherent in
generating aquatic life criteria for CECs. However, we have provided
recommendations to improve the usefulness of this case example. In
particular we suggest that EPA more explicitly describe how the
illustration in Part II was developed from the recommendations in Part I
of the White Paper.

The Committee has also provided other suggestions to assist EPA in
implementing the proposed recommendations in the White Paper. These
suggestions focus on: improved data collection and research activities;
development of tissue residue-based criteria (i.e., expressing the
criterion as a concentration of the pollutant in fish tissue rather than
a concentration in the water) for bioaccumulative CECs where food chain
transfer is a concern; use of indicators for future development of
criteria; special considerations for endangered or
commercially/recreationally important species; obtaining input from
private industry and state governments; and consideration of a mixture
strategy for CECs.

**3. CHARGE TO THE COMMITTEE**[]{#__RefHeading___Toc213670706 .anchor}

EPA's Offices of Water (OW) and Research and Development (ORD) sought
advice from the Science Advisory Board on the scientific and technical
merit of a draft white paper on aquatic life water quality criteria
(ALC) for contaminants of emerging concern (CEC). The white paper
developed by the EPA Emerging Contaminants Workgroup describes how the
Agency intends to address the challenges it faces in developing ALC for
CECs. The specific charge questions below were provided to the
Committee:

1.  The following recommendations have been developed to address
    important technical challenges and issues in deriving water quality
    criteria for CECs. Please comment on the technical merit,
    practicality, and implementability of the recommendations addressing
    the following issues as described in Part I of the white paper and
    the ethynylestradiol (EE2) case study in Part II.

*a. Relevance of Acute Toxicity Effect Concentrations in Setting ALC for
CECs*:

> Criteria consist of a Criterion Maximum Concentration (CMC), intended
> to address acute lethality and a Criterion Continuous Concentration
> (CCC), intended to address effects of chronic exposures on survival,
> growth, and reproduction. Many CECs are physiologically active at
> concentrations orders of magnitude lower than those causing acute
> lethality, and the high concentrations sufficient to cause lethality
> may never occur in the environment. Rather than rotely requiring a
> robust acute toxicity data set for such chemicals, the workgroup
> recommends that aquatic life criteria consist of only a CCC and that
> no CMC be derived, when sufficient information demonstrates risks of
> acute lethality are negligible.

*b. Defining Minimum Data Requirements Regarding Taxonomic Coverage*:

> If an acute criterion is not calculated, then the CCC cannot be
> calculated using the acute to chronic ratio (ACR) approach and must be
> instead calculated directly from chronic toxicity data. Procedures for
> this are included in the Guidelines (pages 40-42), but they require
> that acceptable chronic toxicity tests be conducted for a broad range
> of taxonomic groups. In the case of many CECs, toxicological research
> tends to focus on organisms for which the mode of action is most
> relevant (e.g., vertebrates for estrogen mimics) and may have limited
> data coverage for other taxonomic groups that will likely be less
> sensitive. To avoid generation of resource-intensive chronic toxicity
> data for insensitive species that will have little impact on the final
> criterion, the workgroup recommends interpreting the minimum data
> requirements for taxonomic coverage as [information]{.underline}
> requirements instead of [toxicity test]{.underline} requirements. By
> this we mean that, rather than requiring a specific chronic toxicity
> test, the data requirement for certain taxonomic group expected to be
> insensitive might be met by a body of information demonstrating
> insensitivity of the taxon to the CEC.
>
> *c. Use of Non-Resident Species in Criteria Development*:
>
> Historically, EPA has not used data derived from toxicity testing with
> non-resident species in the actual criteria derivation process.
> Excluding species simply because they are not resident may be
> unnecessarily restrictive for the purposes of deriving national
> criteria, and may actually increase rather than decrease uncertainty.
> The workgroup recommends that non-resident species be considered for
> use in criteria derivation calculations, focusing on those species
> with widely used and standardized test methods and for which there is
> reason to believe that they would represent the sensitivity of
> comparable resident species. Furthermore, the workgroup specifically
> suggest accepting data for zebrafish (*Danio rerio*) and Japanese
> medaka (*Oryzias latipes*), to reflect international efforts toward
> data equivalency.
>
> *d. Defining Appropriate Chronic Toxicity Data*:
>
> For fish, the Guidelines allow the use of early life stage (ELS; egg
> to juvenile) exposures in lieu of full life-cycle (F~0~ egg to F~1~
> offspring) or partial life-cycle (F~0~ adult to F~1~ juvenile)
> exposures for determining chronic toxicity of chemicals, unless there
> is reason to believe this is inappropriate. Current understanding of
> many CECs, particularly endocrine disrupting compounds (EDCs), is that
> important effects of these chemicals may not occur, or at least not be
> expressed, until after the ELS exposure window; in fact, partial
> life-cycle exposures may also miss important effects, such as those on
> sexual development. For such chemicals, it is clear that the
> definition of an acceptable chronic test must include consideration of
> key windows of exposure and effect (e.g., to include sexual
> development and reproduction in assessments of steroid hormone
> agonists/antagonists). However, even more broadly, the workgroup
> recommends that the Office of Water consider amending the chronic data
> acceptability requirements in the Guidelines to require at least one
> full life-cycle test for a fish (for invertebrates, life-cycle tests
> are already required) unless there is a compelling body of information
> indicating that life processes outside the early life stage or partial
> life-cycle exposure/observation window are not critical to capturing
> the biologically important effects of chronic exposure to the
> chemical. This amended requirement would include all chemicals, not
> just EDCs/CECs.
>
> *e. Selection of Effect Endpoints upon Which to Base Criteria*
>
> Aquatic life criteria typically are based on direct measures of
> survival, growth, and reproduction; other measures of response are
> generally not included unless they can be shown to be closely linked
> to expected changes in population dynamics. The workgroup supports
> this existing guidance, but recognizes that many CECs, particularly
> those with very specific modes of action like steroid hormone
> agonists/antagonists, will have data for a wide variety of
> histological, biochemical, physiological, or behavioral endpoints that
> may warrant consideration as measures of biologically important
> effects. The degree to which such measures can be used to infer
> population level effects is likely endpoint-, chemical-, and/or
> organism-specific, and developing a universal list of recommended
> endpoints is therefore beyond the scope of the workgroup's activities.
> Rather, the recommendation here is simply that criteria development
> more thoroughly explores such possibilities.

*f. Involvement of an Expert Panel*:

> While not addressed explicitly in the Guidelines, the complexities
> involved in the assessment of many CECs, and the reliance on
> professional judgment in making some of the determinations required
> under the workgroup's recommendations, make clear the need to bring
> the best scientific knowledge to bear in the development of criteria
> for CECs, as well as other chemicals. The workgroup supports the
> recommendation from a Society of Environmental Toxicology and
> Chemistry (SETAC) Pellston workshop held in 2003 (Mount et al., 2003)
> indicating that criteria development should involve recruitment of an
> expert panel early in the process to insure that all relevant issues
> are considered during initial development of the criterion and to
> provide scientific perspective on decisions that are made as part of
> the process. Such a panel would not undermine the authority of the
> Agency to make policy decisions regarding criteria, but would ensure
> that such policy decisions are made from the best possible technical
> foundation. It is envisioned that expert panels would be formed around
> specific chemicals, or perhaps groups of chemicals with chemical or
> toxicological similarities (e.g., same mode of action).

2.  Please comment on whether EPA has identified the appropriate issues
    to be addressed in deriving ALC for CECs. Are there additional
    important issues that EPA has not identified?

3.  Part II of this white paper was specifically developed as a
    companion to Part I and focuses on the use of ethynylestradiol as a
    model chemical to illustrate the technical issues presented by the
    workgroup, as well as providing a basis for understanding the
    recommendations. Does the Committee have suggestions that may
    improve the utility of Part II of this white paper for the purposes
    stated above?

4.  Does the Committee have suggestions that would assist EPA in
    implementing the proposed recommendations discussed in the white
    paper, particularly with respect to developing the necessary
    scientific data and information and/or providing expert scientific
    input at the appropriate stages of the risk assessment process?

**4. RESPONSE TO CHARGE QUESTIONS**[]{#__RefHeading___Toc213670707
.anchor}

In the responses to each of the charge questions, the Committee has
listed the key findings and comments as bullets. These comments are
followed by numbered lists of the key recommendations.

1.  **Charge Question 1**[]{#__RefHeading___Toc213670709 .anchor}**.
    Please comment on the technical merit, practicality,**

> **and implementability of recommendations addressing the following
> issues as described in Parts I and II of EPA's white paper on Aquatic
> Life Criteria for Contaminants of Emerging Concern: a) relevance of
> acute toxicity effect concentrations in setting aquatic life criteria
> for contaminants of emerging concern; b) defining minimum data
> requirements regarding taxonomic coverage; c) use of non-resident
> species in criteria development; d) defining appropriate chronic
> toxicity data; e) selection of effect endpoints upon which to base
> criteria; and f) involvement of an expert panel.**

**4.1.1 Relevance of Acute Toxicity Effect
Concentrations**[]{#__RefHeading___Toc213670710 .anchor}

As discussed in EPA's White Paper, aquatic life water quality criteria
consist of a Criterion Maximum Concentration (CMC) intended to protect
against severe acute effects of exposure to contaminants, and a
Criterion Continuous Concentration (CCC) intended to protect against the
longer term effects of exposure on survival, growth, and reproduction.
EPA's Guidelines (Stephan et al., 1985) specify various data and
procedural recommendations for criteria derivation. The CMC is
determined based on available acute values (AVs). Acute values are
median lethal concentrations or median effect concentrations from
aquatic animal acute toxicity tests (48 to 96 hours long) meeting
certain data quality requirements. The CCC is generally determined based
on available chronic values (CVs), which are either: a) the geometric
mean of the highest no observed effect concentration (NOEC) and the
lowest observed effect concentration (LOEC) for effects on survival,
growth, or reproduction in aquatic animal chronic tests; or b) in some
recent criteria the EC~20~ (the test concentration that would cause a
reduction in survival, growth, or reproduction in 20% of the test
population) based on concentration-effect regression analyses of the
toxicity test data. If chronic toxicity test data are not available for
at least eight genera of aquatic organisms with a specified taxonomic
diversity, the CCC is derived on the basis of an acute to chronic ratio
(ACR) (i.e., the ratio of the AV to CV from parallel acute and chronic
tests for at least three species with a specified taxonomic diversity).
EPA's White Paper states that many CECs are physiologically active at
concentrations orders of magnitude lower than those causing acute
lethality, and that concentrations high enough to cause acute lethality
may never occur in the environment. Therefore, in the White Paper the
Agency recommends that, when sufficient information demonstrates a
negligible risk of acute lethality for a CEC, the ALC for that
contaminant could consist of only a CCC.

In principle, the Committee supports EPA's recommendation to derive
aquatic life criteria directly from CCCs thus forgoing CMCs and ACRs.
The Committee recognizes that, for many CECs, acute toxicity may only
occur at concentrations several orders of magnitude greater than those
likely to occur in the aquatic environment. The Committee also
recognizes that the suggestion to forgo derivation of CMCs is not
designed to truncate the aquatic life criteria development process, but
rather is designed to allocate resources to areas most likely to affect
the final aquatic life criteria and to avoid delaying implementation of
aquatic life criteria due to a lack of data for species that are not
likely to be sensitive. It is noted, however, that in cases of emergency
releases of CECs (e.g., during floods or equipment failure), the
potential for acute toxicity would need to be considered. Therefore,
criteria documents for CECs should always identify the CMC as a data gap
when it is not used to derive criteria.

*Caveats concerning use of the Criterion Continuous Concentration for
aquatic life water quality criteria*

Although the Committee generally supports EPA's recommendation to derive
aquatic life criteria for CECs directly from CCCs, we note that the
following points should be considered by the Agency when implementing
this recommendation:

-   [Some CECs do not fit the effect model of endocrine disrupting
    chemicals.]{.underline} Foremost on the Committee's list of concerns
    is that some CECs do not fit the effect model of endocrine
    disrupting chemicals (EDCs), or are not well enough understood at
    this time to allow a judgment of their mode of action. Nanoparticles
    are an example of such a class of compounds. Additional work is
    needed to further develop recommendations for deriving aquatic life
    water quality criteria for these other kinds of chemicals. EPA's
    White Paper focuses in particular on CECs that disrupt endocrine
    function in animals. Thus, many of the Committee's comments address
    deriving ALCs for CECs with modes of action similar to those of
    EDCs.

-   [For some CECs, acute toxicity may occur in environmental
    settings.]{.underline} The Committee notes that for some CECs, the
    LOECs and LC50s (test concentrations that result in mortality to 50%
    of the test population) are within one order of magnitude of each
    other, indicating that acute toxicity may occur in environmental
    settings. For these chemicals derivation of a CMC may be
    appropriate. Examples of such chemicals include fluoxetine (a
    selective serotonin reuptake inhibitor or SSRI) and gemfibrozil (a
    blood cholesterol regulator).

-   [Some compounds have differing modes of action for acute and chronic
    toxicity.]{.underline} The Committee is particularly concerned that
    some compounds may have differing modes of action for acute and
    chronic toxicity. In these cases, acute toxicity may be of concern
    in environmental settings and it may be appropriate to derive both a
    CMC and CCC.

-   [Pulsed discharge may result in high ambient concentrations of
    CECs.]{.underline} The Committee is concerned that the pulsed nature
    of some CEC releases (for example: pulsed industrial discharge;
    tidal action in the marine environment; and recurring natural events
    such as fluctuations in environmental concentrations of contaminants
    in ephemeral waterbodies due to evaporation and hurricanes that can
    cause flooding and release of untreated sewage) may result in
    short-term concentrations of CECs that could exceed what would
    generally be considered environmentally relevant concentrations.
    Although CCCs may be applicable in these situations, the Committee
    finds that acute toxicity should be considered to account for the
    effects of compounds where extreme pulses may occur more frequently
    than the three-year benchmark set by the Guidelines.

-   [Consideration of mixture effects is important.]{.underline} An
    additional concern of the Committee is the need for the
    consideration of mixture effects in determining whether acute
    toxicity could occur in natural settings. The White Paper explicitly
    references common modes of action for multiple compounds (as in the
    examples of EE2, estrone, and estradiol). The Committee feels
    strongly that mixture effects of compounds with similar modes of
    action should be taken into account in determining whether acute
    toxicity may occur in environmental situations. Thus a mixtures
    strategy is needed to guide development and interpretation of
    aquatic life criteria for CECs.

*Committee recommendations concerning the relevance of acute toxicity
effect concentrations*

As a consequence of the Committee's discussion and concerns listed
above, we provide the following recommendations to amend the White Paper
text concerning derivation of aquatic life criteria on the basis of the
Criterion Continuous Concentration:

1.  Part 1 of EPA's White Paper contains a bulleted list (on page 28)
    identifying the kinds of information that should be reviewed in
    order to determine whether the differences between the CMCs and CCCs
    would be great enough to conclude that the CMC is not needed to
    develop ALC. The Committee finds that this list is very helpful. It
    addresses some of the concerns raised during the Committee's
    deliberation and it may be particularly useful in providing lines of
    evidence to determine whether acute toxicity data are needed.
    Therefore, we encourage expansion of this list in the final White
    Paper to include additional information addressing the points
    mentioned above.

2.  The Committee suggests that all available data on any new class of
    CECs should be used in determining whether acute toxicity is likely
    to occur in environmentally relevant settings. These data should be
    summarized to document when additional data are needed, or when it
    is justifiable to move aquatic life criteria development forward
    without the derivation of CMCs.

3.  The Committee recommends that CMCs be derived for compounds where
    LOECs are found to be within 1-2 orders of magnitude of LC50s.

4.  The Committee recommends that the likelihood of pulses of exposure
    to contaminants be considered in determining the range of
    environmentally relevant concentrations for criteria development.

5.  The Committee suggests that EPA consider the mixture effects of
    compounds with similar modes of action when determining the range of
    environmentally relevant concentrations for criteria development.

The Committee finds that, together with those in the White Paper, these
considerations should allow a robust determination of whether CMCs are
necessary for derivation of ALC for CECs.

**4.1.2 Defining Minimum Data Requirements Regarding Taxonomic
Coverage**[]{#__RefHeading___Toc213670711 .anchor}

EPA's draft White Paper states that a consequence of dropping acute
toxicity testing requirements for deriving aquatic life criteria for
CECs is the inability to calculate a CCC using the ACR approach. The
Committee notes that CCCs could, however, be developed directly from
sufficiently robust sets of chronic data using procedures in the
Agency's Guidelines (Stephan et al., 1985, pages 40-42). These
procedures require that acceptable chronic toxicity tests be conducted
for a broad range of taxonomic groups. EPA has suggested that, if
insufficient data from actual toxicity tests are available to fulfill
the minimum data requirements for CECs, a reasonable understanding of
the toxicological mode of action for a chemical may allow inferences as
to what taxa (and endpoints) are most likely to be insensitive, and
measured chronic values for those taxa might not be needed. Thus, in the
White Paper, EPA has recommended that, for CECs without complete chronic
toxicity data sets to fulfill minimum data requirements, there be an
evaluation of whether sufficient information exists to conclude that
certain taxa would not be sensitive to the chemical. To accomplish this,
EPA recommends interpreting the minimum data requirements for taxonomic
coverage as "information requirements" instead of "toxicity test
requirements." EPA notes that this would avoid generation of
resource-intensive chronic toxicity data for insensitive species that
would have little impact on the final criterion. The Committee agrees
with EPA's recommendation. However, as further discussed below, the
Agency needs to define: 1) what constitutes a sufficiently robust set of
chronic data for criteria derivation, and 2) what constitutes a
reasonable understanding of the mode of action for the chemical that may
allow inferences concerning the insensitivity of particular taxa. In
addition, the Committee has noted a number of concerns that should be
addressed by EPA as it implements the proposed approach.

The Committee finds that the White Paper contains a comprehensive
discussion of the issue of taxonomic coverage for developing aquatic
life criteria. EPA's 1985 Guidelines require that data be available for
the following organisms: a salmonid in the class Osteichthyes, a second
family in the class Osteichthyes, a third family in the phylum Chordata,
a planktonic crustacean, a benthic crustacean, an insect, a family in a
phylum other than Arthropoda or Chordata, and a family in any order of
insect or other phylum not already represented. This requirement is the
same for freshwater as well as marine organisms. In the White Paper, EPA
notes these taxonomic coverage requirements but recommends movement to a
more "expert judgment" approach that is logical and should address some
of the unique properties of CECs. The Committee understands and
appreciates the desirability of avoiding the extra work required to
develop chronic data for species that are unlikely to be sensitive to
certain CECs. On the other hand, we emphasize that it is equally
important to perform adequate testing to ensure protection of aquatic
life. Therefore it is important to define what constitutes a
sufficiently robust set of chronic data for criteria derivation and also
to provide additional guidance concerning the data needed to infer that
various taxa are insensitive to chemicals with specific modes of action.

As further discussed in Section 4.2 of this report, the derivation of
aquatic life criteria should be risk-based and include consideration of
probable direct and/or indirect impacts on food webs; ecological
processes and services; and unique, endangered, and sensitive species.
Thus, a major factor in determining that toxicity test data are not
needed for particular taxa should be an assessment of the potential
consequences of incorrectly concluding that a contaminant would have no
effect. The ecological data requirements for supporting a conclusion of
no effect (i.e., the level of "power" deemed sufficient for detecting a
specified consequential effect) depend at least in part on an assessment
of the social and biological values at risk and the potential for
consequential losses. Moreover, because goals for aquatic life criteria
should extend to the protection of ecosystems and their services rather
than individual targeted organisms or specific subsystems, there is a
need to assure that biological assessments adequately address a broad
range of taxa and environmental contexts.

*Concerns regarding taxonomic coverage for testing CECs*

The Committee emphasizes that there are instances in which CECs have
been shown to have unanticipated effects on non-target organisms.
Examples include the impact of antibiotics on plants (Brain et al.,
2008) and atrazine effects on the quality of algae (Pennington and
Scott, 2001). These types of examples should be used in Part I of the
White Paper to help describe how the aquatic life criteria development
process might need to be more flexible depending on the compounds under
evaluation. In addition, we note the following important points to be
considered concerning appropriate taxonomic coverage for deriving
aquatic life criteria for CECs:

-   [There is a need to maintain broad taxonomic coverage for
    development of aquatic life criteria.]{.underline} The White Paper
    suggests that knowing certain modes of action could potentially
    focus testing on a particular type of organisms (e.g., vertebrates
    for "estrogenic" compounds). This suggestion is not wholly supported
    by the Committee. As stated in the 1985 Guidelines, the procedure
    for estimating the 5^th^ percentile final chronic value is to use
    the four lowest values in the data set. This approach considers
    primarily vertebrates, and it is appropriate for EE2. However, it is
    not always appropriate (e.g., in the case of the weak estrogenic
    compound bisphenol A) to give primary consideration to vertebrates.
    Staples et al. (2008) compared four species sensitivity distribution
    methods to develop a predicted no-effect concentration for the
    aquatic environment for bisphenol A. Their study indicated that when
    using the Guidelines approach, the four lowest predicted values
    belonged to three invertebrates and one vertebrate. Clearly, this
    finding suggests that there is a need to maintain a broad taxonomic
    coverage in the development of aquatic life criteria.

-   [Little is known of chronic effects of CECs on "wild type"
    species.]{.underline} The Committee is concerned that much of the
    toxicity testing for CECs has been done on animals that are highly
    amenable to laboratory conditions and little is known of chronic
    effects of chemicals on \"wild types.\" There is also some
    probability that criteria protecting \"lab species\" might not
    protect species of special concern like the endangered short-nosed
    sturgeon, several species of Pacific salmon, or the bull trout.
    Research is needed to evaluate the differences and similarities
    between life-histories and sensitivities of endangered/threatened
    and standard laboratory animals used for toxicity testing in order
    to have more confidence that surrogate species will provide
    sufficient information to develop protective criteria.

-   [Modes of action are not known for some CECs.]{.underline} The
    Committee notes that it is not safe to assume that a known mode of
    action is the only mode of action for a CEC. Different organisms may
    be affected in different ways by the same compound both as adults
    and at earlier stages of development. There is also the potential
    for synergism among CECs in mixtures and in interactions with
    environmental variables. It is the exception rather than the rule
    that modes of action are known for CECs.

*Committee recommendations to improve the process of determining
appropriate taxonomic coverage*

Although the example used in Part II of EPA's White Paper to illustrate
derivation of aquatic life criterion for an endocrine disrupting
chemical is data-rich, the Committee notes that the same cannot be said
for all or even most CECs. As EPA correctly states in the White Paper,
in many cases non-traditional endpoints (i.e., endpoints not
traditionally measured in toxicity testing) will almost certainly need
to be considered for CECs. However, the use of non-traditional endpoints
requires an understanding of their relevance to the health of the
organism, and ultimately the population, and also an understanding of
the variability inherent in the measure. The key to determining
appropriate taxonomic coverage and endpoints is ecological relevance.
These considerations call for keeping the taxonomic coverage as broad as
possible, considering the trophic position of the test organisms, and
establishing a clear process or set of guidelines to determine the
\"insensitivity\" of taxa. The Committee provides the following
recommendations to improve the process of determining appropriate
taxonomic coverage for criteria development:

1.  EPA needs to define what constitutes a sufficiently robust set of
    chronic data. Although the example used in the White Paper generally
    illustrates EPA's proposed process for making decisions concerning
    taxonomic coverage, it would be helpful to be more explicit in
    identifying what constitutes a \"sufficiently robust set of chronic
    data\" and \"a reasonable understanding of the mode of action for
    the chemical that may allow inferences.\" The language in the White
    Paper introduces uncertainty in both the general approach and in
    setting up specific test conditions.

2.  EPA should consider emphasizing in the White Paper information
    necessary for development of aquatic life criteria rather than just
    toxicity test requirements. To that end, guidance on information
    needed to determine effects on ecological processes (e.g., food
    webs, nutrient cycling, and primary production) rather than only
    target species would be valuable in criteria development, and would
    follow more recent scientific thinking. In addition, there is a need
    for consideration of appropriate conceptual models that include fate
    pathways and exposure to the CECs. An understanding of exposure
    pathways could help direct testing toward more relevant species.

3.  An approach that might be considered by EPA would be to shift from a
    minimum level of required taxonomic coverage toward determining
    receptors of potential concern (ROPCs). EPA acknowledges in the
    White Paper example illustrating development of an aquatic life
    criterion for EE2 that certain types of organisms might be
    differentially sensitive or impacted by a compound. The Committee
    notes that, if sufficient information exists on sensitivity, then
    expert judgment concerning data development should prevail. This
    would result in a more focused approach to data development keeping
    in mind a weight of evidence rather than a broad requirement for
    testing all eight taxa specified in the Guidelines. This would be a
    more flexible risk-based rather than set approach and would be
    consistent with the risk-assessment terminology used throughout Part
    I of the White Paper.

4.  Examples showing the unanticipated effects of CECs on non-target
    organisms (e.g., the impact of antibiotics on plants and atrazine
    effects on the quality of algae) should be used in Part I of the
    White Paper to help describe how the aquatic life criteria
    development process might need to be more flexible depending on the
    compounds under evaluation.

5.  The Committee recommends that the discussion of taxonomic coverage
    in the White Paper be expanded to include specific recommendations
    concerning the marine environment. EPA's 1985 Guidelines call for
    assessment of marine organisms in the same manner as freshwater
    organisms. However, a discussion of testing marine organisms was
    omitted from EPA's White Paper. We note that including consideration
    of testing marine organisms would be consistent with the approach
    taken by the European Union as it developed its Water Framework
    Directive (European Commission, 2008). Due to specific issues unique
    to marine organisms, such as physiological requirements (e.g.,
    maintenance of salt balance) and life-history strategies (e.g.,
    reproduction tied to tidal cycles), more specific guidance for CECs
    is likely needed. The Committee suggests that this guidance may be
    best addressed by convening a "Pellston" type workshop (Society of
    Environmental Toxicology and Chemistry, 2008) that is comprised of
    experts from multiple disciplines and types of organizations. Since
    testing requirements for marine organisms are already being
    considered by EPA, this should be stated in the White Paper.

**4.1.3 Use of Non-resident Species in Criteria
Development**[]{#__RefHeading___Toc213670712 .anchor}

EPA's Guidelines limit the data used for aquatic life criteria
development to tests with native species while allowing use of
non-resident species data to provide additional narrative evidence for
criteria development. In its White Paper, EPA suggests that excluding
species from testing simply because they are not resident may be
unnecessarily restrictive for the purposes of deriving national
criteria, and may actually increase rather than decrease uncertainty.
The White Paper recommends that these "non-resident" species data be
used in the aquatic life criteria derivation process if the non-resident
species data would enable better estimation of species sensitivity
distributions (SSDs). EPA recommends that criteria derivation
calculations focus on test data from species for which widely used and
standardized test methods are available, and for which there is reason
to believe that data would represent the sensitivity of comparable
resident species. EPA specifically recommends accepting data for
zebrafish (*Danio rerio*) and Japanese medaka (*Oryzias latipes*), to
reflect international efforts in harmonization of test methods. As
further discussed below, the Committee agrees with this recommendation.

*Benefit of using non-resident species data*

The Committee finds that the exclusion of non-resident species data from
criteria derivation is biologically and practically inconsistent with
the intent of the Guidelines (i.e., providing an objective, internally
consistent, appropriate, and feasible way of deriving national
criteria). Furthermore, we find that, as advocated by the White Paper
authors, use of such data would greatly benefit the development of
scientifically sound aquatic life criteria CECs. Although geographic
differences in species tolerance to contaminants have been documented
(Chapman et al., 2006), it is important to note that the U.S. covers a
wide range of geographic areas (from tropical \[Florida, Hawaii\] to
arctic \[Alaska\]). Previous criteria development has focused on
temperate species. Thus, inclusion of non-resident species has the
potential to cover not only data needs but also the geographic (e.g.,
temperature) range of biota in the U.S. and arguably could increase the
protectiveness of the derived criteria.

The White Paper states that only "species with recognized international
equivalency \[will\] be included in criteria derivation with the full
weight given to data from resident species." This approach supports
international test harmonization efforts. Specifically, the White Paper
recommends use of zebrafish and Japanese medaka. These two species have
been largely used for EDC testing and have shown sensitivity similar to
native fathead minnows and other species. Tests conducted with the
zebrafish and Japanese medaka provide insight into the biochemical and
physiological mechanisms involved in the toxicity of CECs. It is
important to match the mode of action with the appropriate test species.
The conservative nature of the endocrine system, a target for most
endocrine disrupting chemicals and likely many CECs, renders the
exclusion of non-resident species from aquatic life criteria development
biologically indefensible. Certainly the use of any test species would
be useful if it could aid in the interpretation of modes of action,
relative taxa tolerance, and endpoint sensitivity comparisons. For
example, studies with surrogate species have been conducted to
demonstrate the toxicity of CECs to resident species, such as the Rio
Grande silvery Minnow and the North American Sturgeon, that are too
endangered for laboratory testing (Beyers, 1995; Dwyer et al., 2000).
Additional studies of the sensitivity of marine and freshwater test
species are cited in the recommendations below. In such cases test data
from closely related non-resident species may provide laboratory
evidence useful in the development of protective aquatic life criteria
for the endangered resident species

*Concerns regarding the use of non-resident species data*

Although the Committee supports the use of non-resident species data for
deriving aquatic life criteria for CECs, we note the following concerns
that should be considered by EPA:

-   [Non-resident species are defined in different ways.]{.underline}
    The Committee notes that EPA's Guidelines define "non-resident"
    species as those not native to the continental United States and
    Canada. However, non-resident species have been defined in other
    ways. At the federal level, they have been defined as species that
    are not native to North America. Many states use the term
    non-resident species to mean species not native to their specific
    region. Hence local criteria are sometimes derived substituting
    species found locally. The definition of "non-resident" (or
    non-native) and invasive species should be clearly stated in EPA's
    White Paper. The White Paper should indicate whether organisms that
    have migrated (or invaded or been stocked) are considered
    "resident." In this regard, the Committee notes that global climate
    change and other factors associated with the migration of organisms
    potentially make the definition of resident or non-resident species
    a moving target.

-   [It is important to consider the concept of "representative" species
    in criteria derivation]{.underline}. An underlying assumption in the
    exclusion of non-resident species data from criteria derivation is
    that non-resident species do not represent the response expected
    from native species in a geographic area. It is more important to
    consider the ecophysiological make-up of a species and its alignment
    with the ecological conditions in which the exposure occurs than the
    geographic home range of the species. It would be easy to postulate
    a case where resident or native warm water species are not as
    representative of risks to resident cold water species as the
    response of a non-resident cold water species which occupies the
    same or similar niche in a different geography.

-   [Non-resident species data may dominate the criteria derivation
    process.]{.underline} The Committee is concerned that non-resident
    species and their large respective databases could dominate the
    criteria derivation process. The recommendation to use non-resident
    species data, as presented in the White Paper, is reasonable when
    looking at criteria derivation from a continental perspective.
    However, including non-resident species data in the criteria
    derivation process could lead to inappropriately biased criteria
    development in certain sensitive geographic areas, such as cold
    water and oligotrophic systems. More detailed information is needed
    in the White Paper to address this concern.

-   [Variation in test organism response is often unknown.]{.underline}
    The Committee notes that variation among the strains of test
    organisms used in laboratory studies is often unknown. Therefore, it
    is difficult to understand whether the variation observed between
    native and non-native species is within the uncertainty of the test
    data for either species. Differences in husbandry, health, parasite
    and pathogen load (i.e., other stressors) may contribute to
    differences in test results between resident and non-resident
    species. Within Pacific herring of Puget Sound there are apparent
    stock differences in the frequency of malformations of new
    hatchlings that are not related to spawning site (Hershberger et
    al., 2005). Differences in sensitivity have also been observed for
    clones of *Daphnia magna* (Baird et al., 1990). While the issue of
    response variation should be considered, many studies have shown
    parallel responses when fairly close relatives are used.

*Committee recommendations regarding the use of non-resident species
data*

Excluding the use of use non-resident species data from the process of
developing aquatic life criteria for CECs may result in failure to meet
the minimum data requirements. Therefore, the Committee finds that use
of available data for non-resident species is warranted. Although the
use of resident species information is preferable to non-resident
species, data from tests using non-resident species, such as zebrafish
and Japanese medaka, can provide extremely useful information on modes
of action. The appropriate use of non-resident species data in criteria
development will allow better estimation of species sensitivity
distributions and also improve international harmonization and
equivalency efforts. The Committee provides the following
recommendations concerning the use of non-resident species data:

1.  As noted above, non-resident species could potentially be
    over-represented in aquatic life criteria databases. The proportion
    of the data set that should include resident species is a matter
    that should be carefully evaluated by the expert advisory panel
    assembled to review each criterion.

2.  In no case should a criterion be developed on the basis of
    non-resident species data alone. Certainly if it is shown that
    non-resident species are ecologically relevant and appropriately
    sensitive then they should be used for criteria derivation as long
    as the studies meet appropriate quality criteria. Test species used
    in toxicity testing tend to be easy to rear and test, and have
    appropriate sensitivity levels. However, other factors should be
    considered when ample data are available for prioritizing species
    responses for criteria development. These factors include
    vulnerability; endangerment status; and recreational, commercial or
    ecological value. In order to protect endangered species, studies
    should be completed to compare toxicity test responses of common
    test species and endangered organisms and thereby determine the
    relevance of surrogates in the criteria development process.
    Previously EPA and the U.S. Fish and Wildlife Service (Besser et
    al., 2005; Dwyer et al., 1999, 2005; and Sappington et al., 2001)
    compared the sensitivity of common freshwater and marine testing
    species with protected/endangered fish species and found that these
    surrogate test species (e.g., rainbow trout) may equally protect
    endangered species. However, these surrogate fish species do not
    necessarily provide protection for other threatened and endangered
    non-fish species such as marine mammals, wildlife, and birds that
    reside and feed in aquatic ecosystems and provide ecosystem goods
    and services. Additional consideration of these other non-fish
    protected species is required in developing risk-based approaches
    for CECs that fully protect all threatened and endangered species.

3.  The statement that criteria would be developed "...with full weight
    given to data from resident species" should include a qualifier
    concerning the validity of the data. An available resident species
    study with no obvious protocol, no measurement of test
    concentrations, or other protocol concerns should be assigned a
    lower priority than a fully valid Organization for Economic
    Cooperation and Development (OECD)/EPA guideline study with a
    non-resident species. However, the Committee qualifies this
    recommendation by emphasizing that all scientifically valid data
    should be used in setting criteria.

4.  Differences in strains, husbandry, health, and parasite and pathogen
    load contribute to response variation and should be considered in
    the aquatic life criteria development process.

5.  Non-resident as well as resident species test data must meet
    Guidelines requirements for data and method validity.

**4.1.4 Defining Appropriate Chronic Toxicity
Data**[]{#__RefHeading___Toc213670713 .anchor}

EPA's Guidelines state that acceptable chronic tests for derivation of
aquatic life criteria are full life-cycle exposures (F~0~ egg to F~1~
offspring) for vertebrates and invertebrates, as well as partial
life-cycle (adult to juvenile) and early life-stage (egg to juvenile)
tests for fish. EPA's White Paper states that some CECs may have potent
effects on life processes that lie outside the exposure period
represented by early life stage tests or effects may not be manifested
until later in development. Thus, early life stage tests might not be
good predictors of chronic toxicity for these chemicals. In the White
Paper, EPA recommends that the Guidelines requirements for chronic
toxicity data be tightened by requiring at least one full life-cycle
test for a fish (for invertebrates, life-cycle tests are already
required) unless there is a compelling body of information indicating
that life processes outside the early life stage or partial life-cycle
exposure/observation window are not critical to capturing the
biologically important effects of chronic exposure to the chemical.

The Committee strongly supports EPA's recommendation to amend the
chronic data acceptability requirements in the Guidelines. However, we
are divided in our assessment of the "guilty until proven innocent"
approach in the White Paper (page 17). Some Committee members view it as
appropriate while others view it as extremely precautionary. The White
Paper states that "...it is probably wiser to require that the chronic
toxicity data for fish include exposure and observation over a full
life-cycle unless there is an affirmative reason to believe that it is
not necessary." The statement is used in the context of requiring a full
life cycle study instead of relying on an early life stage test for
fish. Some Committee members find that the statement does not appear to
fit the process of setting aquatic life criteria, whereas others find it
to provide an important perspective for establishing aquatic life
criteria.

The Committee also supports extending the recommendation to amend the
chronic data acceptability requirement to all chemicals, not just
endocrine disrupting chemicals and CECs. The Committee finds that EPA's
recommendation is justified based on evidence showing that a number of
chemicals may exert effects during the period of gonadal
differentiation, and that these effects may not be manifested until much
later in life. Including at least one full life cycle test in the test
guidelines for fish ensures that these types of effects are captured.

*Issues to be considered in defining appropriate chronic toxicity data*

Although the Committee supports EPA's recommendations concerning use of
chronic toxicity data for development of aquatic life criteria, we note
the following issues that should be addressed in defining appropriate
chronic toxicity test data:

-   [Transgenerational effects of CECs are potentially important and
    should be considered.]{.underline} There is evidence for some
    chemicals that exposure in one generation creates effects in a later
    generation that were not observed in prior generations even in the
    same life stage. Accordingly, the chronic toxicity data requirements
    include a full life-cycle test to be conducted for at least one
    species of fish. There is still some uncertainty as to whether a
    full life-cycle test might underestimate the chronic effects that
    would be seen in exposures extending over more than two generations
    (multigenerational testing). We do not recommend adding a
    requirement for multigenerational testing to the Guidelines, but
    suggest that EPA critically review data dealing with
    transgenerational responses of aquatic species and evaluate whether
    this additional testing provides significant new information that
    informs the evaluation process. This critical review should examine
    the utility of multigenerational tests relative to proposed fish
    full life-cycle (FFLC) tests as well as partial life-cycle (PLC)
    tests and early life-stage studies. The intent of this
    recommendation is to ensure that a full range of development (e.g.,
    early life stage to adult) is evaluated sufficiently to assure
    adequate aquatic life protection. The Committee generally supports
    the concept of fish full life-cycle testing because it spans the
    entire exposure window in the early life-cycle to adults. The
    Committee also supports further development of a tiered testing
    approach to derive an appropriate rationale for the use of FFLC,
    PLC, and possibly multigenerational testing for chemicals with
    parallel modes of action. In this regard, it is noted that the
    decision to use data from partial versus full life-cycle and/or
    multigenerational tests requires a consideration of tradeoffs
    between the costs of additional testing and the social and
    biological values at risk and the potential losses from missing an
    important effect.

-   [Flexibility in test guidelines is needed to include key
    developmental events.]{.underline} Test guidelines must have the
    flexibility to include assessment of key developmental events (e.g.,
    metamorphosis in amphibians, acquisition of saltwater tolerance),
    particularly if these processes are identified in a ROPC.

-   [Test methods should include non-traditional measures that may be
    linked to ecologically relevant endpoints.]{.underline} There is a
    need to ensure that the test methods include provisions to consider
    non-traditional endpoints such as immune function and organism
    behavior. These endpoints may directly impinge on
    ecologically-relevant endpoints such as growth, reproduction and
    survival. In this case, professional judgment from an expert panel
    is needed to determine the relevance of these non-traditional
    endpoints.

The Committee also notes the following practical issues that should be
addressed if the chronic toxicity data recommendation in the White Paper
is to be implemented:

-   [Surrogate test species may be needed.]{.underline} A key issue to
    be addressed is the suitability of surrogate test species.
    Surrogates may be needed in the case of: 1) long-lived species with
    delayed sexual maturity; 2) organisms of large size (which precludes
    their suitability as a test species in the laboratory), 3)
    endangered species, and 4) species for which there is little
    knowledge of the husbandry conditions or background biology. There
    is also uncertainty in how differences in the physiology and life
    history strategies (i.e., long-lived versus short-lived species,
    differences in maternal-fetal transport of contaminants) may affect
    the response of aquatic species to CECs and endocrine disrupters.
    Many of these issues represent significant data gaps that need to be
    addressed. In these cases, expert opinion may be needed to assist
    EPA in determining the suitability of surrogate test species for use
    in criteria development.

*Committee recommendations regarding defining appropriate chronic
toxicity data*

As discussed above, the Committee strongly supports EPA's recommendation
concerning the use of at least one full life cycle test for a fish in
appropriate cases for testing all kinds of chemicals when deriving water
quality criteria for the protection of aquatic life in marine and
freshwater environments. We provide the following recommendations to
implement the requirement for chronic toxicity data:

1.  As discussed above, EPA should critically review data dealing with
    transgenerational responses of aquatic species and evaluate whether
    or not this additional testing provides significant new information
    that informs the evaluation process.

2.  EPA should support research that addresses the suitability of the
    use of surrogate species in assessing the response of aquatic
    species (e.g., endangered or long lived species; species with
    varying life history strategies) to CECs.

3.  Test guidelines should include flexibility to include assessment of
    key developmental events, and professional judgment from an expert
    panel should be used to evaluate the relevance of non-traditional
    endpoints such as immune function and organism behavior.

# **4.1.5 Selection of Effect Endpoints for Criteria Developmen****t**

In the White Paper, EPA has stated that the selection of endpoints
appropriate to the derivation of aquatic life criteria must be tied to
the goal of aquatic life criteria (i.e., to protect aquatic organisms
and their uses). EPA further states that survival, growth, and
reproduction are processes directly related to this goal. The Agency
notes, however, that there are many more biological responses that have
been observed in response to toxicant exposure. In the White Paper, EPA
has identified a number of sublethal endpoints that could be considered
in developing aquatic life criteria for CECs. The Agency has recommended
that the use of such endpoints be more thoroughly explored for
development of aquatic life criteria.

*Points to be considered in selecting effect endpoints*

Generally, the Committee agrees that EPA should continue to explore the
possibility of using sublethal endpoints to help set aquatic life
criteria. However, we caution EPA that non-traditional endpoints must
ultimately be linked to the population, and not solely to
individual-level endpoints. The ultimate goal of any aquatic life
criterion is to protect populations of aquatic organisms from the
"harmful" effects of chemicals (or other stressors). Thus, reproduction,
growth and survival are the predominant effect endpoints currently
utilized in laboratory studies supporting criteria development. The
Committee discussed: 1) the usefulness of information provided by the
non-traditional endpoints identified in the White Paper; and 2) whether
the endpoints might provide information to assess effects on
populations, particularly when considering mixtures and indirect
effects. We provide the following comments to be considered by EPA in
selecting effect endpoints to develop criteria for CECs:

-   [Contaminants effects should be linked to different levels of
    biological organization.]{.underline} Definitions of "biologically
    important effect" and what constitutes a "good population" are
    needed. We also note that not all biological responses represent an
    "adverse" effect. This is consistent with a principle laid out in
    the White Paper (i.e., the White Paper states that chemicals such as
    endocrine disrupters have been shown to produce a wide variety of
    measurable changes at many different levels of biological
    organization, and the challenge is to select from among those
    endpoints that have sufficiently clear connection to expected
    effects on populations or communities of aquatic organisms).

-   [Activational biological effects can provide useful
    information.]{.underline} CECs often induce changes in behaviors,
    secondary sexual characteristics, or levels of hormones or
    hormone-induced products. Many of these responses are transitory or
    may revert to their prior or normal condition with cessation of
    exposure. Accordingly, it is often difficult to interpret these
    activational responses in relation to higher level biological
    effects. Nevertheless, these endpoints do provide useful
    information, particularly regarding mode of action. Consideration of
    such effects would certainly help reduce uncertainty in a risk
    assessment paradigm. While it is clear that these endpoints alone
    could not be utilized to set criteria, the Committee notes that
    sublethal endpoints integrated with toxicodynamic and kinetic
    factors could provide useful data in a problem formulation step
    related to some CEC, and could also be used to help identify data
    gaps that may be filled to reduce uncertainty and aid in criteria
    development.

-   [Use of non-traditional sublethal endpoints holds promise but
    further validation of such endpoints is needed.]{.underline}
    Behavioral endpoints related to population (e.g., predator-prey
    interactions) and reproduction may hold some promise for criteria
    development if the assays can be validated and variability can be
    understood. The implicit model for considering behavioral endpoints
    is that biological changes in individual organisms in response to
    contaminants may produce changes in individual characteristics and
    behavior which may have implications for populations and ecosystems.
    It is also noted, however, that social factors can affect the
    behavior of individuals, which in turn can affect neurological and
    other systems and functions. Immune function and genetic variation
    are also endpoints that should be explored (Filby et al., 2007). In
    addition, models capable of extrapolating laboratory endpoints to
    the population level should be targeted for development (Ankley et
    al., 2008; Chandler et al., 2004). Exploration of endpoints related
    to ecological processes (e.g., primary productivity, decomposition
    rate) is also warranted.

-   [Research is needed to determine how aquatic life criteria for CECs
    can take into account the fact that aquatic organisms are exposed to
    mixtures of these chemicals.]{.underline} As noted previously, in
    developing aquatic life criteria for CECs it will be particularly
    important to consider the effects of mixtures. The Committee
    provides a number of comments in this regard. We note that
    understanding the mode of action of a compound is extremely
    important in estimating mixture interactions. Mixtures of CECs with
    comparable modes of action may result in higher environmental
    concentrations than would be expected for any single compound. In
    fact, pharmacological mode of action is the basis for evaluating
    multiple drug prescriptions in humans by pharmacists. For example,
    if it is known that a vertebrate is exposed to aryl hydrocarbon
    receptor (AhR) agonists and estrogen receptor (ER) agonists, it is
    likely that antagonism of each effect could occur. Information
    regarding mode of action should be made available to EPA from
    manufacturers or other governmental agencies (e.g., available from
    the U.S. Food and Drug Administration \[FDA\] or from testing under
    the requirements of the Federal Insecticide, Fungicide, and
    Rodenticide Act \[FIFRA\]). It is through use of this information
    that non-traditional measures can confirm similar or different modes
    of action in targeted ROPCs. The Committee strongly recommends
    enhancing the communication and data transfer capabilities between
    agencies such as FDA and EPA to provide these data.

-   [Mode of action fingerprints developed by evaluating combined
    sublethal endpoints should be linked to *in vivo* species
    testing.]{.underline} The Committee notes that much of the toxicity
    testing for compounds such as pharmaceuticals and personal care
    products has been conducted using mammals and other vertebrates.
    Additional data are needed for other "keystone" species. We suggest
    that the choice of species, critical life stages, and complicating
    stressors (i.e., salinity and temperature) could be potentially
    identified in a problem formulation/conceptual model stage of a risk
    assessment paradigm. If these data are not available, research and
    development could be undertaken to obtain mode of action
    "fingerprints" for a CEC or any other compound through combined
    sublethal endpoints (i.e., genomic-transcriptomic, proteomic,
    metabolomic) and toxicodynamic/kinetic feature evaluations within
    sentinel species (to cover taxonomic issues). It is likely that
    through this process additional "side-effects," or species-specific
    modes of action, could be obtained. These data could be integrated
    with "fingerprints" of other compounds with different modes of
    action and utilized to help address mixture issues or potential
    indirect effects. The toxicity to a particular species at a
    particular trophic position could then be modeled to assess indirect
    impacts on other populations.

-   [Additional research is needed to link biomarkers to
    effects.]{.underline} The Committee notes that the concept of using
    biological responses occurring prior to impacts on growth,
    reproduction, and survival has been proposed for more than 20 years
    as a way to detect adverse effects in a population before the
    population is altered. While there are examples of such "biomarkers
    of effect," we find that the linkages between biochemical,
    histological, and behavioral endpoints and reproduction, growth, and
    survival are likely life-stage dependent and are difficult to
    validate, particularly in the field. We note that "biomarkers of
    exposure" are available but research is needed to interpret their
    significance.

-   [Vitellogenin production is an excellent biomarker of exposure to
    feminizing chemicals.]{.underline} One of the best examples of
    exposure biomarkers is the biological response of vitellogenin
    production in male or juvenile animals. Vitellogenin is an excellent
    *in vivo* biomarker for exposure to feminizing chemicals. If the
    response is measured in the whole animal, it incorporates estrogenic
    as well as anti-androgenic or other modes of action that can cause a
    feminized response (production of an egg-yolk precursor). It is
    important to point out that this assay is not identical to estrogen
    receptor (ER) - based *in vitro* bioassays. Some compounds such as
    EE2 are very potent ER agonists but also have other modes of action
    that may alter endocrine systems (Tabb and Blumberg, 2006) such as
    the inhibition of several isoforms of cytochrome P450 (e.g., CYP3A),
    which are important in the clearance of endogenous steroids
    (Parkinson, 2001). Nonylphenols also have multiple modes of action
    other than direct binding to the ER that lead to enhanced estradiol
    synthesis (Harris et. al, 2001; Kazeto et al., 2004; Martin-Skilton
    et al., 2006; Meucci et al., 2006; Thibaut and Porte, 2004). So the
    observation of vitellogenin induction within an oviparous male or
    juvenile organism does not indicate total specificity with regard to
    mode of action. Anything that increases endogenous estrogen
    biosynthesis or diminishes clearance would also provide this
    biological response. The Committee notes that the reduction of
    vitellogenin in females may not indicate anti-estrogenic effects or
    even alterations of endocrine activity, as basic hepatotoxicants in
    females can elicit a similar effect. However, we point out that the
    correlations between fecundity and vitellogenin in females have been
    observed to be strong even though this may not indicate mode of
    action (Miller et al, 2007) (see discussion below). Additional
    studies are needed to examine hepatotoxicants or compounds with
    modes of action exclusive of endocrine targets.

-   [The linkage of vitellogenin production to biological effects is
    limited.]{.underline} While the linkage of vitellogenin to exposure
    is reasonably solid, linkages of vitellogenin in males/juveniles to
    higher biological effects such as altered reproduction, survival and
    growth are limited, even though the relationship may make intuitive
    sense. Several studies have shown relationships between vitellogenin
    and reproduction in the laboratory, often at concentrations beyond
    probable effect concentrations (Thorpe et al., 2007), but few
    examples of population alterations have been noted in the field.
    Even in the United Kingdom, where gender shifts to females were
    originally noted and correlated with vitellogenin induction within
    males, intersex individuals, and other histological anomalies,
    overall abundance declines within the species of interest have not
    been reported. In fact, only one study (Kidd et al., 2007) has
    linked population crash with vitellogenin or histopathological
    alterations in fish. A similar occurrence has been noted in
    laboratory studies where vitellogenin expression may or may not be
    linked to intersex (Grim et al., 2007), which in turn may or may not
    lead to gender shifts. Even the relatively clear signal of gender
    shift, while clearly impacting reproduction in laboratory animals
    optimized to a specific gender ratio, may not significantly impact
    field populations in an uncharacterized species (Munday et al.,
    2006). Clearly, a better understanding of the population dynamics of
    a ROPC is needed to determine the phenotypic plasticity of the
    gender ratio. Thus, gender shifts should be viewed with caution,
    particularly in species that have not been well studied.

*Committee recommendations regarding selection of endpoints*

The Committee agrees that EPA should continue to explore the possibility
of using sublethal endpoints in helping to set aquatic life criteria. We
provide the following recommendations in this regard:

1.  EPA should pursue the use of "non-traditional measures," or
    endpoints for criteria development, as discussed in the White Paper.
    The Agency should ensure that such measures can be tied to impacts
    on populations or ecological processes, not just to effects on
    individual organisms.

2.  EPA should use "non-traditional measures" when appropriate to
    develop an understanding of and confirm mode of action.

3.  EPA should use human health information and toxicology tools
    (genomics/ PBPKs) when appropriate and available to reduce the
    uncertainty of aquatic life criteria.

4.  EPA should consider the following key points concerning use of the
    non-traditional endpoints discussed in the White Paper: 1)
    vitellogenin in males and juveniles is an indicator of exposure to a
    feminizing stressor(s), but its linkage to population effects is
    limited; 2) strong correlations between vitellogenin and fecundity
    have been observed in females, but this is not necessarily tied to
    altered endocrine mode of action; 3) Anomalous intersex is
    indicative of a gender stressor(s), but has not been strongly tied
    to population effects; and 4) gender ratio can be indicative of
    endocrine alteration, but baseline information on appropriate life
    history is necessary for this evaluation.

**4.1.6 Involvement of an Expert Panel**[]{#__RefHeading___Toc213670715
.anchor}

Because development of aquatic life criteria for CECs may be dependent
on technical interpretations of a wide range of toxicological
information, EPA has proposed that expert panels be used to provide
professional judgment during criteria development. The Committee concurs
that strong, active participation by a panel of outside experts will be
necessary to ensure that the approaches used (including the designs for
toxicity testing, the selected endpoints, and the necessary species and
tests to be used, i.e., the ROPCs) are the most appropriate for the
compound under scrutiny. As the EPA moves away from firm requirements
for species and tests, it will become increasingly important that expert
panels comprising diverse expertise be utilized to ensure that the best
data are selected for necessary decisions. The National Academy of
Sciences and Society of Environmental Toxicology and Chemistry have
suggested similar approaches. In a recent report dealing with ecological
risk assessment in environmental decision making (U.S. EPA Science
Advisory Board, 2007), the SAB strongly recommended that expert panels
be used to provide assistance to EPA during the problem formulation
phase of ecological risk assessments. The same recommendations are
appropriate for development of aquatic life criteria. Involving a suite
of experts with a balanced range of perspectives during the very early
stages of problem formulation, and continuing their involvement as
external reviewers at strategic junctures throughout the process, will
significantly improve quality, utility, and defensibility of the
criteria. It is noted that implementing a risk-based approach to
deriving aquatic life criteria that protect ecosystems and their valued
services will necessitate including social scientists, economists, and
relevant publics/stakeholders on expert panels.

*Committee recommendations concerning the use of expert panels*

As stated above, the Committee concurs with the use of expert panels to
provide professional judgment during the process of developing aquatic
life criteria. We offer the following recommendations concerning the
formation and use of expert panels:

1.  The process for the use and selection of expert panels should be
    described in detail and should be transparent. The process used to
    select and convene the panels, the general attributes of panel
    composition, and methods used to address issues such as
    identification and elimination of conflicts of interest must be
    described (U.S. EPA, 2006). In this regard, one possible model to be
    considered is the process used to select SAB committees and panels,
    whereby national and international experts are identified from
    multiple sectors representing broad disciplinary expertise and
    professional affiliation (e.g., academic, appropriate governmental
    agencies \[such as FDA\], non governmental organizations, and
    private industry).

2.  The charge to the panel and the expected end result must be clearly
    defined.

3.  There are likely similar expert panel processes occurring elsewhere.
    The Committee recommends that EPA determine whether similar
    processes are underway in Europe and Asia, and if so, consider them
    as models to provide additional insight and/or expertise.

4.  The Committee is concerned that the use of expert panels could lead
    to less consistency in how aquatic life criteria are determined. To
    help alleviate this potential problem, we recommend that EPA develop
    specific guidance on the roles of expert panels in problem
    formulation, data evaluation, and the generation of recommendations
    leading to criteria derivation.

**4.2** **Charge Question 2.**[]{#__RefHeading___Toc213670716 .anchor}
**Please comment on whether EPA has identified the appropriate issues to
be addressed in deriving ALC for CECs. Are there additional important
issues that EPA has not identified?**

As stated previously, EPA's White Paper identifies technical issues that
need to be addressed in deriving aquatic life criteria for CECs. The
Committee was asked to comment on whether the Agency has identified the
appropriate issues in the White Paper and whether there are additional
important issues that EPA has not identified. The Committee finds that
appropriate technical issues have been identified in the White Paper.
However, EPA could clarify the process of developing aquatic life
criteria for CECs by articulating a set of principles that could be
applied when modifying the 1985 Guidelines to develop water quality
criteria for such contaminants. We also emphasize the importance of
developing a conceptual model to guide the process of developing aquatic
life criteria for CECs. The conceptual model should address more than
the fate and direct effects of CECs. It should include consideration of
probable direct and or indirect impacts on food webs, ecological
processes and services, unique, endangered or keystone species or
species of special societal value or concern. The example provided in
Figure 1 illustrates components that could be included in such a
conceptual model. Use of a conceptual model to

![](media/image2.jpeg){width="6.000694444444444in"
height="3.2256944444444446in"}

Figure 1. A Generalized Conceptual Model for Deriving Aquatic Life
Criteria With

Examples for Each Step

support criteria development would improve EPA's ability to address
emerging questions about unique mechanisms, fate processes, and effects
endpoints. Use of the conceptual model is further discussed below.

*Committee recommendations concerning additional issues to be addressed*

Although the Committee finds that EPA has identified appropriate
technical issues in the White Paper, we recommend that the Agency
address the additional issues listed below in order to customize and
update the 1985 Guidelines and thereby increase the flexibility and
specificity of the aquatic life criteria derivation process. It is
important to note that several of the following recommendations (e.g.,
the recommended shift toward an ecological risk assessment model and the
recommendation to seek inputs from diverse perspectives) will require
explicit and systematic assessment of the concerns of relevant
publics/stakeholders. This in turn will require greater involvement of
social and economic sciences in the aquatic life criteria setting
process, especially in the context of identifying and prioritizing
contaminants of emerging concern.

1.  In the White Paper, EPA should articulate principles that can be
    applied when modifying the 1985 Guidelines to develop water quality
    criteria for CECs. The Committee recommends that these principles be
    directly linked to EPA's Guidelines for Ecological Risk Assessment
    (U. S. EPA, 1992, 1998). The committee in fact recommends that the
    1985 Guidelines be updated to incorporate risk assessment principles
    and guidelines that did not exist when the Guidelines were developed
    over 20 years ago. In other words, the derivation of aquatic life
    criteria needs to be fully risk-based, using a transparent and
    consistent framework that provides necessary flexibility not
    presently possible within the algorithm approach of the 1985
    Guidelines. A recent SAB report, *Advice to EPA on Advancing the
    Science and Application of Ecological Risk Assessment in
    Environmental Decision Making: A Report of the U.S. EPA Science
    Advisory Board*, (U.S. EPA Science Advisory Board, 2007) contains
    additional recommendations that may be considered in order to enable
    more effective use of ecological risk assessment in the derivation
    of aquatic life criteria.

2.  In line with using a risk-based approach, principles for developing
    aquatic life criteria for CECs should include the following: seek a
    wide range of inputs from diverse perspectives; determine
    appropriate ROPCs; develop a robust conceptual model; develop
    multiple lines of evidence; and identify uncertainties (quantitative
    and qualitative) associated with criteria development. Each of these
    risk assessment-based principles is further discussed below:

-   [Seek a wide range of inputs*.*]{.underline} EPA should seek input
    from a diversity of experts representing: Agency scientists,
    academic scientists, scientists in business and industry, state and
    tribal scientists, and the environmental community on the problem
    formulation, conceptual model development, modifications to the
    Guidelines dictated by the properties of a CEC, and the resulting
    recommendation for the aquatic life criterion. Adherence to this
    principle will ensure that the process stimulates a robust
    discussion and is informed by and acceptable from a diversity of
    perspectives. This diversity should include input from chemists,
    modelers, toxicologists, ecologists, and risk assessors.

-   [Determine appropriate ROPCs.]{.underline} The process needs to
    clearly identify the need to determine appropriate receptors of
    potential concern and not simply focus on "traditional" test
    organisms.

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-   [Develop a robust conceptual model*.*]{.underline} At the start of
    the criterion development process, the available data on fate and
    effects should be examined and used to develop a conceptual model
    (e.g., Figure 1). Structure activity data and modes of action of
    similar compounds/materials should be consulted to inform model
    development. An expert panel should be convened to assist in the
    problem formulation and conceptual model development step.
    Uncertainty should be identified in the model and used to identify
    strategic efforts to reduce uncertainty. The conceptual model should
    include more than fate and effects data. It should include
    consideration of probable direct and or indirect impacts on food
    webs, ecological processes and services, and unique, endangered or
    keystone species or species of special societal value or concern
    (charismatic species).

-   [Develop multiple lines of evidence.]{.underline} The committee
    finds that a multiple line of evidence approach has the potential to
    inform decision making and the criterion recommendation. It also can
    serve to reduce uncertainty when the lines converge and reinforce
    each other.

-   [Identify uncertainties and conduct uncertainty
    analysis]{.underline}*.* As further discussed below, EPA should
    identify the uncertainties associated with the criteria developed
    for CECs. At all stages of criteria development, uncertainty should
    be quantified and/or qualitatively discussed. Uncertainty should be
    used to focus and prioritize data generation efforts.

3.  EPA should develop a system or process to assist the development of
    criteria for CECs. The system would establish a set of rules to
    enable analysis of information supplied by the user and lead to
    recommendations concerning one or more courses of user action. The
    Committee finds that such a system would be an important tool for
    capturing and maintaining the state of the art in aquatic life
    criteria development. It would serve as a vehicle for connecting
    fate and effects assessment tools and capturing expert knowledge,
    and it could serve as a platform for deriving priorities for future
    research in assessing the risks of contaminants to aquatic life and
    ecosystems.

4.  The Committee strongly recommends that understanding and
    presentation of uncertainty become an intrinsic part of the aquatic
    life criteria development process. The presentation of uncertainty
    needs to be an explicit and transparent part of the analysis. For
    example, the uncertainties inherent in understanding modes of
    action, determination of concentration-response relationships,
    development of species sensitivity distributions, and derivation of
    ecological effects should be quantified or described in a narrative
    sense. An important aspect of this is developing an a priori
    understanding of the amount and types of uncertainties that preclude
    the derivation of an aquatic life criterion. These uncertainties can
    be classified into the categories listed below:

-   Uncertainties that preclude the derivation of an aquatic life
    criterion.

-   Areas in which uncertainties may be important and can be resolved
    with additional modeling, research or a better understanding of the
    relationship of the uncertainty to the standard setting process.

-   Uncertainties that do not preclude the setting of an aquatic life
    criterion but form the basis for future research programs.

> Identification of uncertainties in these categories can be addressed
> in development of the conceptual model in consultation with the expert
> panel.

5.  EPA should bolster the consideration of mode of action and ecology
    in the aquatic life criteria derivation process. A better
    understanding of the molecular interactions and modes of action will
    reduce uncertainty in that aspect of the conceptual model. A better
    understanding of the ecological effects and context will allow more
    specific and flexible predictions of risks to individuals,
    populations and ecological structure and function. This will reduce
    predictive uncertainty. The Committee encourages the developers of
    the aquatic life criteria to further integrate these advances into
    the criteria derivation process.

6.  In the White Paper, EPA should discuss the importance of considering
    environmental context (i.e., site specific considerations) in
    deriving aquatic life criteria for CECs. These modifying factors
    should be mentioned in the CEC criteria themselves. For example,
    characteristics of the receiving environment affect bioavailability
    and toxicity to organisms (e.g., trophic status, dissolved organic
    carbon, pH, and substrate types) as well as longevity of their
    exposure due to impacts on the degradation and partitioning rates of
    these chemicals. Several CECs have the potential, based on their
    physical-chemical properties, to bioaccumulate and bioconcentrate,
    and this may result in diet-borne toxicity to a predator.
    Degradation/biotransformation products of CECs should be considered
    because there are instances where their toxicity is greater than the
    parent compound. In addition, the Committee recommends considering
    analytical chemistry because some aquatic life criteria have the
    potential to be set at concentrations that are at or below current
    (widely available) abilities to easily quantify CECs.

7.  The Committee recommends that EPA keep abreast of the new science
    related to CECs in order to ensure that the latest approaches for
    assessing the effects of these chemicals are considered in criteria
    derivation. These types of effects may include impacts on natural
    selection and genetic diversity, indirect effects through changes in
    prey quality and quantity, and alteration of ecosystem function. We
    also point out that effects of CECs may be non-linear, which would
    pose challenges in derivation of aquatic life criteria. We note that
    consideration needs to be given to the diversity of phylogenies,
    functions, and habitats represented in the data used to establish an
    aquatic life criterion in order to ensure that the overall goals of
    the process (adequate, appropriate level of population-level
    protection) are met.

8.  As mentioned previously, the Committee recommends that EPA use
    mammalian pharmacology data available from the drug discovery
    process, genomics/proteomics/metabolomics and QSARs to screen CECs
    for modes of action and assess potential multiple modes of action
    for individual CECs. This would facilitate exploration of the use of
    parallel processes to develop aquatic life criteria for CECs with
    similar modes of action. To increase efficiency when determining an
    aquatic life criterion for one compound (such as EE2), the process
    could be repeated (or developed in parallel) for compounds (such as
    estradiol or E2) with similar modes of action. In addition, some
    guidance should be provided for site-specific applications where
    mixtures of compounds occur that may have additive effects that
    exceed individual aquatic life criteria.

9.  Natural history of a ROPC can determine the magnitude of effects of
    CECs and should therefore be considered in the derivation of aquatic
    life criteria. The timing of breeding seasons, immaturity periods,
    intrinsic rates of reproduction, survivorship, and life span all
    influence the magnitude and direction of possible changes in
    population size and age structure. Fisheries take should be
    considered for recreationally or commercially important species.

10. In developing aquatic life criteria for CECs, EPA should give
    special consideration to the protection of threatened and endangered
    species. Unlike other species, threatened and endangered species are
    managed so that effects on individuals, not populations, are
    avoided. Specific mortality of threatened and endangered
    individuals, along with the contribution of each to the survival of
    the population, are parameters requiring accuracy with a minimum of
    uncertainty. In certain cases specific populations or evolutionarily
    significant units are the assessment endpoints to be considered.

**4.3 Charge Question 3.**[]{#__RefHeading___Toc213670717 .anchor}
**Part II of this white paper was specifically developed as a companion
to Part I and focuses on the use of ethynylestradiol as a model chemical
to illustrate the technical issues presented by the workgroup, as well
as providing a basis for understanding the recommendations. Does the
*Committee* have suggestions that may improve the utility of Part II of
this white paper for the purposes stated above?**

The Committee finds that Part II of EPA's white paper, which is intended
to illustrate application of EPA's recommendations concerning aquatic
life criteria for CECs (rather than serve as a comprehensive case-study)
is a generally well-written and thorough review of the existing
literature on EE2; however, some improvements are recommended to enhance
clarity. The Committee agrees that EE2 is an appropriate initial focal
CEC given: 1) the extensive data available relative to other CECs; and
2) the ease with which it illustrates the complexities inherent in
generating CEC-specific water quality criteria to protect aquatic life.
Nevertheless, there may be limitations as to how readily the insights
gained from the EE2 illustration can be applied to other CECs.
Therefore, the EE2 illustrative example should be presented more clearly
as an illustration of the aquatic life criteria setting process, rather
than the derivation of a criterion for a specific CEC that is important
in its own right (although the latter is certainly true). In this
regard, more frequent and elaborated discussions of how the EE2 example
illustrates points raised in Part I would be very useful. That is, the
EE2 example could be used more forcefully to illustrate important issues
and principles applicable across the breadth of CECs. The following
recommendations are provided to improve the usefulness of the EE2
example.

*Committee recommendations to improve the usefulness of the illustrative
example*

1.  In the White Paper, EPA should explicitly recognize that EE2 is
    unique in being a data-rich CEC. The White Paper should highlight
    the fact that the Agency's interest in CECs goes beyond
    endocrine-active substances, and discuss how the example of EE2
    might be extrapolated to other substances, particularly to data-poor
    substances. EPA should consider conducting a similar assessment for
    a compound with a minimal data set (in contrast to the maximal set
    of data available for EE2) and evaluate the new approach
    accordingly. Other CECs with differing modes of action such as
    polybrominated diphenyl ethers (PDBEs), bisphenol A, and
    perfluorinated octynyl sulfonate (PFOS) could be considered. These
    are problematic and controversial CECs and concerns about these
    chemicals differ from the stated concern in the White Paper over
    pharmaceutical and personal care products entering the aquatic
    ecosystem from wastewater treatment plants. They are nonetheless
    important and instructive case studies that might shed new light on
    revising the 1985 Guidelines.

2.  The Committee suggests that some of the illustrative pieces of Part
    II could also be included in Part I in the form of succinct text
    boxes illustrating key concepts derived from the various
    recommendations (e.g., why certain steps in the Guidelines were
    included and others were not). Further, we suggest that the
    recommendations could be best illustrated if the text boxes were not
    restricted to EE2 but rather included other CECs (e.g.,
    non-endocrine-active compounds, data-poor CECs). In making these
    revisions, we urge the authors to ensure that the high level of
    readability inherent in the present version of Part I is retained.

3.  Regarding the scope of the material included in the EE2 example, we
    note that the White Paper fails to address how the influence of EE2
    might be affected by mixtures of compounds, especially those with
    similar modes of action (e.g., estradiol, estrone), as well as
    environmental (e.g., temperature) and biological (e.g., disease,
    starvation) modifying factors. Although the Committee recognizes
    that various offices/groups within EPA are investigating mixtures of
    compounds, and the White Paper cannot address all relevant issues in
    the development of guidelines, the document needs to be explicit
    regarding the importance of considering multiple stressors as well
    as synergies among CECs. For example, the White Paper should, at the
    very least, state the rationale for not considering all estrogens
    within a given body of water, and should provide examples of
    mixtures and synergies that could affect the toxicity of EE2.

4.  Regarding choice of taxa for criteria derivation, the Committee
    agrees that, although use of non-resident species to assess EE2
    effects appears to fit this case example, such may not always be the
    case. As such, the document should indicate that: 1) resident
    species data, especially life-cycle tests from resident species,
    remain extremely valuable, and 2) results from non-residents, while
    providing useful information, may not be generalized to resident
    species unless data are available to compare the sensitivities of
    the non-resident and resident species. We are also concerned that
    certain sensitive taxa such as amphibians were not included in Table
    3.2, and that the key issue of development time to sexual maturity
    for long-lived charismatic species, such as sturgeon, is not
    addressed in the document. Research should be conducted to develop
    comparisons between long-lived species and surrogate test species.

5.  The Committee is concerned that transgenerational effects were not
    considered in Part II of the White Paper. On page 14 in Part II of
    the White Paper, EPA states that "it does not seem that the evidence
    for transgenerational effects is sufficient for requiring their
    inclusion in the definition of an acceptable chronic test." Given
    EE2's role as an endocrine disrupting chemical, it is surprising
    that transgenerational effects were not included in the treatment of
    EE2. Further, given the "guilty until proven innocent" rule
    mentioned previously, the Committee recommends that the possibility
    of transgenerational effects be explicitly addressed in this
    illustration. Although transgenerational effects may not be expected
    in the case of EE2, potential transgenerational consequences must be
    addressed in a clear and transparent manner to ensure the
    development of a process that can also be applied to substances for
    which transgenerational effects are expected.

6.  The Committee recommends that a broader array of endpoints be
    included in Part II. For example, although EE2 is a potent estrogen
    receptor agonist, it also can affect the central nervous system
    through indirect effects (steroid biotransformation).
    Non-traditional endpoints such as genomic or physiologically based
    pharmacokinetic modeling (PBPK) studies might be considered. As
    noted previously, use of non-traditional endpoints requires an
    understanding of their relevance to the health of the organism and
    ultimately the population. The illustration in Part II needs to
    answer the question as to whether or not it is possible to calculate
    population-scale impacts with EE2 and, if not, how a criterion can
    be developed that will truly protect populations within a reasonable
    level of uncertainty (consistent with the intent of the Guidelines).

7.  Two key recommendations regarding Part I of the White Paper are
    repeated here for the sake of consistency. First, the use of weight
    of evidence is implicit in the evaluation, but it needs to be
    explicit in the Part II of the document. Interactions between weight
    of evidence and the Precautionary Principle (i.e., appropriate
    levels of uncertainty) should be clarified. Second, when appropriate
    data are available, ECx values (i.e., the concentration causing an
    effect in x percent of the test organisms) should be used rather
    than NOECs/LOECs (i.e., no observed effects concentrations/lowest
    observed effects concentrations). The EC~x~ value reflects the
    information in the entire concentration-response curve and
    confidence intervals can be calculated as part of the curve fitting
    process. In contrast, the use of NOECs or LOECs by hypothesis tests
    are dependent upon the test concentrations that are used, the
    variability of the experimental technique, and the power of the
    statistical test. It is also not possible to generate confidence
    intervals for the NOEC/LOEC determinations. When available, the data
    used in a NOEC/LOEC determination should be used to calculate the
    EC~x~ value. Curve fitting, which uses more of the information
    contained in a data set and enables derivation of confidence
    intervals in the estimation of the EC~x~, is the preferred method
    for representing dose (concentration)-response information. The
    selection of a specific EC~x~ value for derivation of an aquatic
    life criterion depends upon the level of protection or effect that
    decision makers are willing to accept or detect in the field.
    However, an EC~20~ has been used for most species and an EC~10~ has
    been used for threatened and endangered species.

8.  The Committee finds that the clarity and transparency could be
    improved in several areas. In particular, the authors need to more
    explicitly describe how the illustration was developed from the
    recommendations in Part I. Part II also needs to be more explicit
    regarding how specific conclusions and assessments were derived from
    the data. The following specific revisions are suggested:

-   Data used to arrive at the values shown in Table 3.1 need to be
    provided in an appendix.

-   Table 1 arguably includes chronic data (*Lytechinus* and
    *Strongylocentrotus* echinoderm embryo development tests and the
    *Acartia* embryo test) that, not surprisingly, provide the most
    sensitive responses. While the Committee concurs that there is
    "ample evidence that a CMC is not needed and that it is unnecessary
    to conduct further tests to meet the minimum data requirements," the
    differentiation between acute and chronic data needs to be clearer
    and more transparent along with the implications of including
    equivocal data. Confusion between acute and chronic data can result
    in unnecessary levels of uncertainty and variability in criteria
    development. We note that slide 11 of the presentation provided by
    Dr. Russell Erickson of EPA ORD at the Committee meeting on June 30
    provides the requisite level of clarity and transparency and could
    usefully be included in the document.

-   More explicit discussion of what constitutes "sufficient
    information" at various decision points would be helpful.

-   The validity of using non-resident species is justified by text
    referring to complex tables, which do not provide the level of
    clarity and transparency necessary. Given the importance of
    validating the use of non-resident species, a graphic representation
    of the data is required (e.g., SSDs or horizontal lines indicating
    ranges for survival, growth and reproduction showing where the
    non-resident species fit).

-   The Committee suggests that the authors add a concluding section
    that summarizes how the process of developing an aquatic life
    criterion for EE2 was modified by use of the new/revised guidelines.
    Part II should also provide an overview of how the process is
    expected to ultimately influence the criteria derived (in other
    words, how the new recommendations changed the final outcome).

-   The EE2 example in Part II relies on nominal concentrations in
    addition to measured concentrations. The Committee assumes that
    criteria will not be based on nominal concentrations. However, it is
    acknowledged that as long as measured concentrations are within 20%
    of the nominal concentrations employed in a study, the
    concentrations reported could be the nominal concentrations. This
    needs to be made clear in the document.

-   The first two paragraphs on page 13 of Part II would benefit from
    additional information on the timing of exposures to clarify that a
    16% reduction in growth occurred after 28 days (paragraph 1, line
    4). The timing for lower reproduction at 0.2 and 1 ng/L (paragraph
    1, line 9) should also be clarified. We have a similar suggestion
    for effects on fertilization success (paragraph 2, lines 7-8).

-   EPA should include in the appendix the residency status of each
    species or genus. The authors refer to residency in interpretations,
    but this information is missing from the document.

-   A list of acronyms such as that provided for Part I also would be
    useful for Part II.

-   A few questions are raised regarding citations: (1) Wenzel et
    al. (2002) is cited in the text (p. 14, paragraph 3, line 3) but not
    in the References; should the date of the reference be 2001? (2) Is
    the Kolpin et al. (2002) reference correct (both here and in
    Part I) - it does not seem to apply as it is a 2-page response to a
    comment, not a full paper? (3) Lee and Choi (2006) is listed in the
    References as "in press" but surely this is not still the case 2
    years later? (4) The reliance on McKim et al. (1978) is questioned
    regarding the assertion that a "factor of 2 difference is generally
    found for other chemicals" (page 13, incomplete paragraph beginning
    the page, last line). We note that the McKim et al. (1978) paper
    only referred to one chemical, copper, and was published thirty
    years ago in a journal that does not have a high level of peer
    review.

**4.4. Charge Question 4.**[]{#__RefHeading___Toc213670718 .anchor}
**Does the Committee have suggestions that would assist EPA in
implementing the proposed recommendations discussed in the white paper,
particularly with respect to developing the necessary scientific data
and information and/or providing expert scientific input at the
appropriate stages of the risk assessment process?**

The Committee has provided comments and recommendations to assist EPA in
implementing the proposed recommendations discussed in the White Paper.
Many of our comments focus on actions that would assist in
implementation of the recommendations in the White Paper. However, we
have also provided broader suggestions to facilitate future development
of aquatic life criteria for CECs. Some of our comments and
recommendations elaborate upon points discussed in previous sections of
this advisory report.

*Points to be considered in implementing the proposed recommendations in
the White Paper*

-   [Developing new criteria for CECs will require intensive data
    collection/generation activities.]{.underline} In an ideal world, it
    would be the Committee's recommendation that the same level of
    effort required to register a new chemical or pesticide also be
    required to develop aquatic life criteria for CECs. Acknowledging
    that this may not be possible in a world of limited resources, it
    will be important that OW/ORD prioritize the list of CECs for which
    aquatic life criteria will be developed. EPA should also identify
    data needs for these chemicals and leverage research development
    activities to develop the necessary data. Prioritization of CECs and
    data needs is further discussed below. In addition, EPA should
    conduct research to evaluate the sensitivity of test organisms that
    could be used as surrogates for resident and endangered species.
    Research should also compare the sensitivity of traditional and
    non-traditional test endpoints.

-   [Leveraging research efforts of other agencies is
    essential.]{.underline} In a time of decreasing research funds
    within the federal government, it is important that OW/ORD seek
    opportunities to leverage research efforts of other government
    agencies (e.g., FDA, U.S. Department of Agriculture \[USDA\],
    National Oceanic and Atmospheric Administration \[NOAA\]). The
    Committee was informed that EPA and the FDA are coordinating data
    sharing. We recommend that this activity continue and further that
    it be broadened to include other government agencies. We further
    support international collaboration between EPA, the European Union,
    Environment Canada and other appropriate non-U.S. environmental
    agencies. In addition, it is apparent that the regulated community,
    industries, animal husbandry organizations (e.g., National
    Cattlemen's Beef Association) and Publicly Owned Treatment Works,
    are actively engaged in independent evaluation of CECs. Establishing
    a government/industry consortium may be a way of leveraging limited
    funds for broader data development opportunities.

-   [Aquatic life criteria derivation for CECs should be conducted with
    knowledge of data provided by the Toxic Substances Control Act
    (TSCA) new product review process.]{.underline} Chemical
    manufacturers provide data to EPA on new products in accordance with
    the TSCA pre-manufacture notification requirements. The search for
    possible CECs should begin at this stage. At a minimum, aquatic life
    toxicity data provided by manufacturers in this process could be
    used to help derive aquatic life criteria. EPA could also consider
    integrating parts of the aquatic life criteria setting process into
    the TSCA new product review to aid in the assessment of new product
    notifications. Data and other information supplied for the new
    product review under TSCA could also help the Agency prioritize CECs
    for aquatic life criteria derivation.

-   [Linkages between ecological risk assessment and development of
    aquatic life criteria need to be articulated.]{.underline} The
    Committee finds that, in many ways, the 1985 Guidelines contain the
    same principles of evaluating ecological risk that were subsequently
    incorporated into the 1989 *Risk Management Guidance for Superfund,
    Volume 2: Environmental Evaluation Manual*, (U.S. EPA, 1989), and in
    the 1992 *Framework for Ecological Risk Assessment* (U.S. EPA,
    1992). Furthermore, it was apparent from the presentations made by
    EPA to the Committee that the ecological risk assessment principles
    have been considered by OW and ORD in planning further development
    of aquatic life criteria for CECs. However, the link between the
    1989 Risk Management Guidelines and the aquatic life criteria
    derivation process is not apparent. The white paper needs to
    explicitly consider and illustrate risk assessment principles (e.g.,
    identification of ROPCs, development of a conceptual diagram as
    previously recommended by the Committee).

-   [Tissue-based criteria should be considered for bioaccumulative CECs
    where food chain transfer is a concern.]{.underline} As mentioned
    previously, EPA should consider developing tissue-based criteria
    (i.e., expressing the criterion as a concentration of the pollutant
    in fish tissue rather than a concentration in the water). Aquatic
    life may be impaired directly by eating contaminated food, or
    indirectly by loss of prey or other ecosystem alterations that could
    stem from CECs. EPA is developing residue-based criteria for
    selenium (2002 and 2004 draft criteria documents \[U.S. EPA,
    2007\]). Arguably, selenium can be considered a contaminant of
    emerging concern, but it does not fit the definition provided in
    Section 1.1 of Part I of the White Paper. The Committee finds that
    it may be useful to consider using selenium as an example for
    development of tissue-based aquatic life criteria for CECs.

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-   [Quantitative linkages are needed between mode of action indicators
    and population-level endpoints.]{.underline} The proposed
    recommendations in the White Paper are consistent with bettering the
    risk assessment process. However, it will be important to set
    priorities for technical research that addresses significant gaps in
    knowledge needed to develop: 1) new indicators; 2) modeling
    capabilities; and 3) tools that provide integration and linkage of
    data sources. As mentioned previously, one of the most important
    challenges facing EPA will be linking mode of action indicators of
    exposure/effects to known population-level effects measurement
    endpoints such as survival, growth, reproduction and development.
    Developing conceptual models will guide criteria development but
    quantitative linkages will be needed to discern how mode of action
    indicators connect with population-level end points. The White Paper
    (p. 20, lines 21- 21) states that it is important to clearly link
    mode of action indicators such as histopathology to growth,
    reproduction and development. The Committee notes that in some
    instances it may be possible to define scaled risk (e.g., level of
    biological response in cell, tissue, etc.) and relative risk. This
    will make it possible to develop mode of action fingerprints that
    may provide earlier warning and greater sensitivity in predicting
    population-level effects.

-   [Additional factors may need to be considered to protect certain
    species.]{.underline} As noted previously, development of aquatic
    life criteria to provide adequate levels of protection for
    endangered, highly managed, protected and "charismatic" species
    (e.g., marine mammals, eagles, polar bears, sturgeon) may require
    consideration of additional factors. For example, in marine mammals
    a dive reflex can force more contaminant into tissue due to pressure
    gradients. Endangered species may have very different lag times for
    sexual differentiation and uptake characteristics of CECs than the
    commonly used test species. For example, sturgeons are both
    endangered and charismatic fishes, and they are known to readily
    accumulate many CECs for an extended developmental period prior to
    reproduction. Given their long lifespan, a life cycle chronic test
    to determine uptake would be impossible, and an early life cycle
    test would be inappropriate.

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-   [There is a need to compile a list of priority CECs.]{.underline} To
    facilitate development of aquatic life criteria, the Committee finds
    that it would be useful for federal agencies working on CECs (e.g.,
    EPA, the U.S. Geological Survey, the U.S. Food and Drug
    Administration, the National Oceanic and Atmospheric Administration,
    and others) to compile a list of priority CECs that may pose the
    greatest risks to aquatic life -- in other words, use a risk
    assessment approach in a problem formulation exercise to determine
    contaminants of potential concern. It is noted that compilation of a
    list of priority CECs can be further facilitated by greater
    involvement of public/stakeholders and relevant social sciences.
    Related to effective prioritization of CECs for criteria derivation
    is the need for consistent classification of CECs into categories
    relevant to aquatic life criteria. As suggested in other parts of
    this advisory report, mode of action may be a very useful basis for
    such classifications, as well as for addressing the issues of
    mixtures of multiple contaminants and of environmental pulses and
    concentrations. Analytical chemistry methods should be developed for
    CECs that are not already being measured in aquatic environments.
    The Committee suggests that calculation of the ratios of the Maximum
    Environmental Concentrations to meaningful measures of biological
    effects (e.g., CCCs, or LC~x~s from toxicity testing) could
    initially be used to develop a list of high priority CECs. This kind
    of exercise would likely, but not certainly, show that estrogens
    should be a top priority for aquatic life criteria, as indicated in
    the White Paper.

-   [There is a clear need for continued development of analytical
    capabilities to measure levels of CECs in the aquatic
    environment.]{.underline} The ability to detect many of the CECs at
    appropriate concentrations in a controlled laboratory setting may be
    entirely different from detecting those same low concentrations in
    the aquatic environment. Addressing such issues will help current
    long term monitoring programs (e.g., NOAA National Status and Trends
    and Mussel Watch programs, U.S. Geological Survey National Water
    Quality Assessment Program, EPA Environmental Monitoring and
    Assessment Program) implement a coordinated approach to better
    define CEC exposures in the environment. Efforts to develop
    methodological approaches for lowering limits of detection and
    standards for CECs should involve discussion among agencies as well
    as the regulated community. It may be important to include the
    National Institute of Standards and Technology in the development of
    environmental standards for new CECs.

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-   [Input into the aquatic life criteria development process is needed
    from private industry and state government.]{.underline} The
    perspective of these important stakeholders is needed before
    finalizing the White Paper. These groups should be asked to provide
    input on the science associated with the modifications of the
    Guidelines related to CECs because aquatic life criteria will be
    used to develop state water quality standards.

-   [It would make sense to consider using parallel processes to develop
    aquatic life criteria for compounds with similar modes of action
    (e.g., the estrogens, SSRIs).]{.underline} Since estrone, estradiol
    and EE2 all act through the estrogen receptor in the most sensitive
    taxa, fish, and there is growing evidence in the literature that
    their effects are additive (Thorpe et al., 2003), it would make
    sense to develop aquatic life criteria for the natural and synthetic
    estrogens using parallel processes. Similar approaches may be
    possible for other CECs with highly specific modes of action such as
    different classes of antibiotics, statin drugs, and other
    pharmaceuticals that are CECs.

-   [Further questions to consider.]{.underline} As EPA develops a
    research plan to support derivation of aquatic life criteria for
    CECs, it may be useful to consider the following questions mentioned
    previously: How can aquatic life criteria be developed to take into
    account the fact that aquatic organisms are exposed to mixtures of
    CECs and mixtures of CECs, known contaminants, and other stressors?
    What are the likely modes of action of CECs that are known to be
    present in the environment? How can field study results be used to
    inform the derivation of an aquatic life criterion for a CEC?

*Committee recommendations to assist EPA in implementing proposed
approaches to developing aquatic life criteria for contaminants of
emerging concern*

The Committee provides the following specific recommendations to assist
EPA in implementing the Agency's proposed approaches to developing
aquatic life criteria for CECs. Some of these recommendations have been
discussed in the context of responses to the other charge questions in
this report.

1.  EPA should develop a list of high priority CECs that may pose the
    greatest risks to aquatic life. Additional work should then be
    completed to further assess the potential risks posed by these
    chemicals and fund the research and data collection activities
    needed to support future development of aquatic life criteria. In
    this regard, we recommend that EPA's Office of Water and Office of
    Research and Development look for opportunities to leverage existing
    research with those ongoing in other federal programs, similar
    programs in international agencies, and industry groups, to gather
    the data needed to develop the aquatic life criteria. In particular,
    aquatic life criteria derivation for CECs should be conducted with
    knowledge of data provided by the Toxic Substances Control Act new
    product review process. The Agency should also work with other
    federal agencies to develop analytical chemistry detection methods
    and standards for these chemicals.

2.  EPA should explicitly incorporate the principles for conducting
    Ecological Risk Assessment into the process of deriving aquatic life
    criteria for CECs. The Committee recommends that the EPA develop a
    separate process document that discusses the intended application of
    aquatic life criteria for CECs, and cross-links the 1985 Guidelines,
    EPA's 1992 Ecological Risk Assessment Principles, and the 2008
    aquatic life CEC criteria White Paper. This cross-link document
    should also incorporate relevant ecological risk principles from
    other similar documents developed for FDA, the Toxic Substances
    Control Act, or the Federal Insecticide, Fungicide, and Rodenticide
    Act. The document should not only outline the process of aquatic
    life criteria development, but address elements such as contaminant
    exposure through food uptake, Water Effects Ratios, Whole Effluent
    Testing, mixtures of compounds with similar modes of action, and
    application of aquatic life criteria for CECs in sediment management
    programs. The Committee is not recommending the development of a
    large, comprehensive document, rather something short and concise
    similar to the Eco Update Bulletins that have been published by
    EPA's Office of Solid Waste and Emergency Response (OSWER).

3.  As previously discussed, the Committee recommends that EPA
    incorporate the use of conceptual models and ecosystem-based
    criteria into the process of deriving aquatic life criteria for
    CECs. We note that EPA programs are moving toward developing more
    comprehensive ecosystem-relevant criteria that take into
    consideration population-community structure, ecosystem
    functions-processes, and ecosystem services. The data available to
    develop CCCs are often "traditional" toxicity test data. It is
    important to develop the link between the protected resource, the
    assessment endpoint, and the measurement endpoint. An appropriate
    conceptual model for deriving aquatic life criteria for a CEC (see
    Figure 1) may be used to develop the fate and effects data and data
    quality objectives needed to support the aquatic life criterion.

4.  As previously discussed, EPA should consider (where appropriate)
    developing tissue residue-based aquatic life criteria for CECs. The
    Agency should consider developing tissue-based criteria using the
    selenium example and expanding the definition of contaminants of
    emerging concern to include "chemicals and other substances of
    increasing environmental concern due to anthropogenic activities and
    for which current regulatory approaches are inadequate." Tissue
    residue-based criteria should be considered for CECs that have
    potential to bioaccumulate (e.g., carbamazepine) and bioconcentrate
    (e.g., flame retardants). At a minimum, the conceptual model could
    be used to help determine how to evaluate the available
    environmental data and models to assess the main routes of exposure
    for aquatic organisms.

5.  EPA should use a "mode of action" approach to develop more effective
    aquatic life criteria not only for CECs, but also for legacy
    contaminants and mixtures. Additional studies in genomic and
    toxicodynamics processes would provide necessary data for the
    identification of "mode of action" fingerprints and aid in this
    process, particularly in the problem formulation stage of risk
    assessment. This should help guide regulators to carry out the most
    efficient bioassays which will be used in setting thresholds or
    criteria.

6.  The Committee recommends that EPA appropriately use novel
    environmental indicators (molecular, genomics, proteomics) developed
    by other agencies, industry, and academia in future development of
    criteria. For example, NOAA has developed a robust health effects
    assessment for bottle nosed dolphins that addresses many CECs
    including flame retardants and antibiotic resistance (Fair et al.,
    2006; Goldstein et al., 2006; Houde et al., 2006; National Oceanic
    and Atmospheric Administration, 2008; Reif et al., 2006). This
    assessment involved analysis of immune function data and other
    animal health information such as clinical evaluation, blood
    chemistry, contaminant and hormone data. Since dolphins are apex
    predators that breathe the air, swim in the water and constantly eat
    seafood, they provide a most exposed individual model. This type of
    insight may be pivotal in enhancing what EPA can do using the
    approach outlined in Part I of the White Paper.

7.  EPA should take into consideration appropriate additional factors to
    ensure that aquatic life criteria are protective of sensitive and
    commercially/recreationally important species. These species are
    protected by additional laws (e.g., Magnuson Stevens Fishery
    Conservation and Management Act, Marine Mammal Protection Act) and
    this may invoke other special considerations when developing aquatic
    life criteria.

8.  Before finalizing the White Paper, EPA should obtain input from
    private industry and state government on the Agency's proposed
    approaches for developing aquatic life criteria for CECs .

9.  EPA should consider developing a mixture strategy to develop aquatic
    life criteria for classes of compounds with similar modes of action.
    As previously mentioned parallel processes could be used to develop
    aquatic life criteria for broad classes of CECs with similar modes
    of action (e.g., the estrogens, SSRIs).

**5. REFERENCES**[]{#__RefHeading___Toc213670719 .anchor}

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