Proceedings and Summary of the
  Workshop on Finfish as Indicators of
           Toxic Contamination
            Sponsored by the          :
                                      |
  U.S. Environmental Protection Agency
Office of Marine and Estuarine Protection
            July 27-28, 1986
            Airlie, Virginia

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                               CONTENTS
1.  Overview of the National Estuary Program and Objectives of the
    Workshop on Finfish as Indicators of Toxic
    Contamination. .	»	.3
2.  Summary of the Opening Plenary
                                                                      .6
    Session	•	• •	
                                                      i
3.  Summary of Plenary Session on Subgroup  Reports.	.9
                                                      i
4.  Summary Report  from  the  Subgroup  on Anatomic
    Pathology.	•		..,..,.	21
 5.   Report  from the Subgroup on Bioaccumulation and   |
                                                                      •an
     Enzymes	• •«	«	• *	• ° •e	JU
             •
 6.   Report  from the Subgroup on Reproduction/Development,
     Physiology, Behavior, and Population.....'	 ,	 .38
                                                      I
 7.   Summary Report from Subgroup on
     Immunology	«	-	......*	51
     Appendices

     A.   Letter of Invitation
     B.   Workshop Agenda
     C.   List of Participants
     D.   Participant Workgroup Assignments
     E.   Workshop Background Paper

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           1.   OVERVIEW OF THE NATIONAL ESTUARY PROGRAM AND
                     OBJECTIVES OF THE WORKSHOP ON
             'FINFISH AS INDICATORS OF TOXIC CONTAMINATION
     In- 1985, the U.S. Environmental Protection Agency (EPA) initiated
the  National Estuary Program.  The program was designed to protect and
restore  water  quality and living resources in the nation's estuaries.
Under  the  authority   of the Clean Water Act, the program establishes
working  partnerships  with  other  Federal  agencies,  state and local
governments,   academic  and  scientific  communities,  industries  and
businesses,  public  organizations,  and private citizens.  The goal of
these working partnerships is to address collectively the environmental
and/or  management  problems of estuaries.  The national program, which
is  administered  within  EPA  by  the  Office  of Marine and Estuarine
Protection  (OMEP), seeks  to
     o  increase  public  understanding of  the nature of estuaries
        and their environmental and  management problems5

     o  provide   state and  local managers with  the best scientific
        and technical  information  available;

     o   transfer  technical and  management  expertise and  practical
         experience to  state and  local governments;

      o  increase  understanding  of both the need for; area-wide or
         basin-wide planning and its benefits;

      o  develop  plans  to  control  pollution sources and restore
         living resources; and                        !
                                                      i
      o  gain  acceptance  of  the  public  and  private  costs  of
         increased pollution controls and estuarine restoration.

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Current  estuary  programs  include the Buzzards Bay (MA), Narragansett
Bay   (RI),   Long   Island "  Sound   (NY,   CT),   Puget  Sound  (WA),
Albemarle/Pamlico Sounds (NC), and San Francisco Bay (CA)-programs.

     In  each  estuary  program,  the EPA regional office(s) works with
program participants to define the problems of the estuary and to reach
agreements  to  reduce  the  causes  of  point source pollution and the
polluting  effects  of  other  human  activities  contributing to these
problems.    Estuary programs may establish goals to maintain currently
existing  conditions,  to  restore a selected level of water quality or
living resources, or to maintain pristine conditions within an estuary.
Population growth and its associated increasing and conflicting demands
for  water uses can cause participants of estuary programs to reexamine
and refocus their existing programs and to develop new initiatives that
adequately protect the estuary.

     The  principal  goal  of  each  estuary  program  is  to produce  a
comprehensive  Master  Environmental  Plan  that  describes  actions to
control point and non-point sources of pollution? to manage and protect
living  resources;  to  implement  sound  land use practices; to control
freshwater  input  and  removal;  and/or  to establish anti-degradation
policies  for pristine areas.  To be effective,  this plan must identify
the  parties  responsible  for   these  actions,  and the  revenue sources
necessary  to do  the job.  The plan also  must provide for monitoring of
environmental  quality in  the estuary, periodic  program  review, program
redirection in response to new problems or information,  and a mechanism
to resolve conflicts among participants.

     In regional  estuary programs, ambient environmental quality  should
be  monitored  primarily to set  priorities for  pollution control  and  to
verify  the  success  of   management  strategies implemented under  the
Master  Environmental  Plan.  In addition, the  National  Estuary Program
needs   to  determine  whether indicators  of finfish health  can serve  as
warnings  of   toxic  contamination,  and  can   thus  assist   in setting
priorities   among   estuaries   for  inclusion   in  the   program.     To
                                   2

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successfully  conduct  such  a  trend-monitoring program, indicators of
environmental  quality  that  are  both  scientifically appropriate and
cost-effective  must  be  identified and/or developed.  The Workshop on
Finfish  as  Indicators  of  Toxic Contamination will partially fulfill
this  need  by  identifying  a  set  of appropriate indicators of toxic
contamination  for  assessing  potential  human  health  and ecological
concerns.

     OMEP   sought   scientific  input   to assist in an jevaluation of  the
many  possible  finfish   indicators of toxic  contamination  to determine
which    indicators    may  be appropriate,  at  present,  as  estuarine
monitoring   tools.  Therefore,   the   purpose  of   the  workshop  was to
systematically  organize  and  set  a  priority   ranking of  a list of
methods,  for use of  fish as indicators of  the health  of estuaries  both
emphasizing  those  most  useful  to   immediate   management needs   and
identifing  those  that   show  the most promise  for  future  development.

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               2. SUMHARY OF THE OPENING PLENARY SESSION
     Dr.  Tudor Davies, Director of EPA's OMEP opened the workshop.  He
reviewed the current structure of most EPA regulatory programs, many of
which are media-based (i.e., programs intended to address only specific
environmental  media, such as air, land, or water).  Permit limitations ,
for  toxic  pollutants  typically  are  technology-based,  with limited
testing  of  effluent  toxicity  and  modeling of wasteload allocation.
Monitoring,  therefore,  is typically oriented towards assessing either
effluent  pollutant  loads  or ambient concentrations of pollutants for
which  wasteload  modeling can be conducted, only recently has the need
for ambient biological monitoring received increased attention in EPA's
surface  water  programs.  The National Estuary Program, in particular,
is seeking  to develop and apply a set of scientifically appropriate and
cost-effective  indicators of estuarine environmental quality as ambient
monitoring  tools.    This  workshop's  goal is to assess the extent  to
which finfish indicators can serve  this purpose.

     Ms.  Michelle   Hiller,  Chief  of OMEP's Technical Guidance Branch,
then  summarized   the  goals  and   objectives  of EPA's National Estuary
Program and described  how  finfish  indicators of  toxic contamination may
be  used within   the  program.     As   one  potential use, EPA wants  to
determine   whether such  indicators  can  assist  in selecting estuaries  to
be  included   in  the national program by serving as  warnings  of serious
toxic   contamination  that either  threatens or occurs in an estuary.  In
addition,   indicators  are  needed   within  estuaries once the estuaries
have   been  included  in the National Program.  They are needed to help
determine   where   the  most severe biological  effects are occurring;  the
spatial  extent  of  critical   impacts;  where  possible,   the specific
pollutant   or  pollutants   most  responsible   for   critical   biological
impacts;  and  the  success  of  toxic   pollutant   abatement  strategies
implemented for an estuary.

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     The workshop moderator, Dr. Gary Petrazzuolo, Technical Resources,
Inc., then described the subjects of each working group for the initial
discussion  and  ranking  of indicators.  These subgroups, based on the
participants' areas of expertise and interest, were   i
     o  Anatomic Pathology                            i
                                                      l

     o  Immunology

     o  Bioaccumulation and Enzymes

     o  Reproduction and Development,

     o  Physiology, Behavior,  and  Population.         |

     Each  of  the  subgroups   was  to  develop  a list  of  indicators,  to
 consolidate  and organize the list  by  merging  closely related methods,
 and   to    characterize  each   of   the   indicators.     Indicators  were
 characterized  by  considering their usefulness for  identifying effects
 of  toxic  contamination  to  fish,  the ecosystem, and/or human health,
 along with the following set of characteristics:

      o  biological  significance (i.e., there is a widely accepted
         cause-and-effect  relationship between toxic pollution and
                                                      i
         the  indicator,  or there are either few or  no conflicting
         plausible  explanations for the observed effect other than
         toxic pollution);

      o  cost-effectiveness;

      o  availability for widespread use; and
      o  applicability, including  their use as
                                                      I
              early  or late  indicators (i.e.,  sensitivity  —  the
              effect will appear following acute or chronic
              exposures);                              !

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        -   pollutant-specific indicators (i.e.,  those that can
            indicate exposure to a specific pollutant or class  of
           'pollutants);
            species-specific (i.e., those that can be applied only
            to a few or one species of fish);  and
            spatially-restricted indicators (i.e., those that are
            only useful on small spatial scales).

     The  final  objective  of each subgroup was to rank the identified
indicators.    The  ranking  was  to  be  based only on the first three
criteria     (biological    significance,    cost-effectiveness,    and
availability).  Information on the various aspects of applicability was
reported, but did not necessarily indicate greater or lesser usefulness
of  a  given  indicator.  Ranking was to be accomplished by asking each
subgroup to provide lists based on the four following ranking methods:

     (1) identify the best indicator on the list;

     (2) identify  the  best  one-third  of  the  indicators  from
         the list;

     (3) rank   each    of   the    indicators   in   order  of   its
         importance,and

     (4) rank each indicator as either "good" or  "bad."

     Dr.   Petrazzuolo  noted   that   the   technical   background  paper,
prepared   for   the  workshop  by   Dr.  Margaret   McFaden-Carter  of  the
University of Delaware, provided a starting point  for each  subgroup's
discussion.     This  paper   (see   Appendix E)   surveys  the available
indicator  methods.  Dr. Petrazzuolo  then  opened  the  plenary session to
questions  and  asked whether  the participants felt any  major categories
of   indicators  had  been  omitted  from  the  background  paper.   No such
categories  were   identified   in  the   opening  session.     (However,
additional  indicators  were  later identified and evaluated  by  the four
subgroups).
                                   6

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         3. SUMMARY OF THE PLENARY SESSION ON SUBGROUP REPORTS
     Following  the  subgroup sessions, all workshop participants again
met  in  a  plenary  session  to  summarize and discuss each subgroup's
findings.    (See the individual subgroup summaries for a more detailed
description  of  these discussions.)  The most highly ranked indicators
from  each  subgroup  are  presented  in  Table  1.   A glossary of the
indicator methods follows in Table 2.
                                                      i
     Workshop  participants  were  asked  to choose the best indicators
from    those   by   the   subgroups  considered.    Several  participants
questioned whether  the group, as a whole, was capable of making such an
evaluation.    A  lengthy  discussion   followed  in  which participants
presented  possible  scenarios   for  using  various sets or groupings of
toxic  pollution indicators.   To clarify  the technical questions  being
asked,  an EPA  representative  described the  major stages of each estuary
program's data analysis  in detail.   The stages are
                                                      i

      o  problem definition,                           j

      o  characterization,  and                        |

      o  design and implementation of a monitoring program.

      To  screen  estuaries  for incorporation into the National Estuary
 Program,  a  process  analogous  to  the  first  phase of an individual
 program  (problem  definition)  is  used.     Then  individual, regional
 programs  carry  out  all  three  steps  to define problems, to develop
 management and abatement strategies, and to monitor
 recovery.    Different  indicators  or sets of indicators could be used
 during  each of these phases.  Workshop participants agreed to evaluate
 the indicators according to  their usefulness in each of these phases of
 an estuary program.

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 TABLE 1.   SUMMARY OF SUBGROUP RANKINGS OF FINFISH INDICATORS
   SUBGROUP

 Anatomic Pathology



'Bioaccuraulation/Enzymes

          a.  Bioaccuraulation
          b.  Enzymes
 Reproduction and Development,
 Physiology, Behavior, and
 Population

          a.  Reproduction/
              Development
          b.  Physiology
    RANK OF METHODS

1.  Gross changes
2.  Ordinary histological methods
3.  Ultrastructural histology
1.  Residue levels
2.  Models
3.  Metabolite profiles
1.

2.


3.
Induction (e.g., mixed function
oxygenases and metallothionein)
Inhibition
(Acetylcholinesterase
 and gill ATPase)
Blood chemistry (clinical)
1.
2.

3.

1.
2.
Cytogenetics
Larval development and
viability
Embryo viability

Hematology (blood chemistry)
Swimming stamina
          c.  Behavior


          d.  Population



          Immunology
 1.  Avoidance/attraction
 2.  Abnormal behavior

 1.  Spatial distribution profile
 2.  Abundance
 3.  Age  structure  profile

 1.  A  triad of macrophage
    indicators
       (phagocytosis,
    chemiluminescence,
       and killing ability)
 2.  Experimental measures  of
    disease
       resistance
 3.  Jerne plaque assay

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TABLE 2.  GLOSSARY OF FINFISH INDICATOR METHODS
Anatomic Pathology

   1.  Gross changes—this category includes obvious abnormalities such
      as fin erosion, skeletal deformities, tumors, etc.

   2. Ordinary  histological  methods—observations  that  can  be made
      using  standard   light microscopy  techniques are included in this
      category.
                                                           i
   3. Ultrastructural histology—these techniques generally| require  the
      use of scanning or  transmission electron microscopy.
                                                           i
Bioaccumulation

   1. Residue  levels—this   term  refers to the  analysis of tissues  for
      contaminant  levels  of  some or all  of  the 129 priority pollutants,
      or other contaminants  of local concern.

   2. Models—mathematical    models   can  be   used   to  predict   the
      bioaccumulation   potential  of  a  particular compound or  group of
      substances    based   on   physical,  chemical,   and   structural
      information.
                                                           l
   3. Metabolite   profiles—many  organic  compounds  are metabolized by
      finfish.    These metabolites are not  included  in standard residue
      analyses.     Because  some  metabolites  bind   tightly   to tissue
      macromalecules,   information  on  contaminant metabolites  may  be a
      better   indication   of  past exposure history  than  information on
      residue levels of the  parent compounds.

 Enzymes

    1. Induction—certain  enzymes  or  proteins   may  be  produced by an
       animal  as  a result of exposure to a xenobiotic.   Mixed function
       oxygenases   (MFOs)  are  enzymes  that   oxidize  some  non-polar
       organic  compounds  to  more hydrophilic forms.  Metallothioneins
       are proteins that bind to certain metals.   Specific MFOs or metal
       binding  proteins  may  be  produced as a result of exposure to a
       particular contaminant.

    2.  Inhibition—particular  enzymes or physiological processes may be
       inhibited  by  exposure   to  contaminants  and, therefore, such a
       response may indicate a deleterious effect.

    3.  Blood  chemistry—a number of measurements of blood chemistry are
       performed  routinely in clinical diagnosis,  and may be adapted to
       diagnosing  pollutant  stress  in  fish,    They include both the
       levels   of   certain  substances  (e.g.,   glucose,  cholesterol,
       triglycerides,   albumin)  and  enzyme  activities (eLg., alkaline
       phosphatase, lactate dehydrogenase).


                                          •9

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TABLE 2.  GLOSSARY OF F3MFISH INDICATOR METHODS (Continued)


Reproduction/Development    ,    '

   1. Cytogenetics—the  study  of the relationship between chromosomal
      aberrations and pathological conditions.

   2. Larval  development  and  viability—includes  such  endpoints as
    '  growth rates, percent abnormalities and mortality.

   3. Embryo   viability—for  many   fish  species  this  is  the  most
      sensitive  stage  in  their life history.  The endpoints that are
      commonly   employed  include  development rate, type and extent of
      developmental abnormalities, hatching success, and mortality.

Physiology

   1. Hematology—the study of  the blood.  This includes the same  types
      of  clinical blood measurements  described above.

   2. Swimming   stamina—this   is a measure of the general fitness of a
      fish  as determined  by its  ability  to swim against a current.

Behavior

   1. Avoidance/attraction—changes   in  these behavioral attributes are
      measured   by   comparing   the   reactions of  fish before and  after
      exposure  to  the  test material.

   2. Abnormal   behavior—in  addition to avoidance/attraction behavior,
      other  behavioral  changes  (e.g.,  erratic   swimming,  lethargy)
      indicate   specific  modes  of  toxicity  (e.g.,   neurological   or
      metabolic dysfunction).

Population

    1. Spatial-    distribution    profile—analysis   of   the    spatial
      distribution   of   a   species   of  fish  within  the   estuary.
      Distribution  may  be  directly  related   to avoidance/attraction
      behavioral changes.

    2. Abundance—a relative measure of population demographics.

    3.  Age  structure  profile—a  skewed  age  structure profile may be
       indicate an unstable population.
                                         10

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TABLE 2.  GLOSSARY OF FINFISH INDICATOR METHODS (Continued)
                                       *
                                                           i	__^^^_____
_	—	!                      |

Immunology                                                 '

   1. A triad of macrophage indicators (phagocytosis,
      chemiluminescence, and killing ability).
          a.    phagocytosis—a  measure  of  the ability of macrophage
              cells  to  engulf microorganisms, other cells, or foreign
              particles.

          b.  chemiluminescence—the   relative   chemiluminescence  of
              macrophages  may correlate with the degree of exposure to
              xenobiotics.                                 i

          c.  killing  ability—a   measure  of the ability of macrophage
              cells  to kill microbes or  tumor cells.

   2. Experimental measures of disease resistance—by injecting disease
      microorganisms  into  feral  fish,  the relative disease resistance
      of  individuals or  populations can  be  determined.

   3. Jerne   plaque  assay—B-lymphocyte   measurement   of  antibody
      production.
                                         11

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     The   problem   definition  phase  was  divided  into  an  initial
qualitative  step  (called  "problem identification") and a later, more
quantitative  process  (called  "screening").    Problem identification
determines  initially whether an estuary should be considered for toxic
contamination  screening.  Problem  identification  may  be  systematic
(i.e., 'part of an on-going data collection) or anecdotal.  This initial
step  involves  minimal  new  expenditures.   The workshop participants
agreed  that  the  following  finfish indicators would be useful during
this phase:

     o  gross behavioral changes,

     o  anatomical changes,

     o  population changes, and

     o  tainting of  commercial fish.

     During   the    cross-estuary   screening  phase,  scientists  will
determine  whether   fish  are significantly  stressed and whether  toxics
are  a  likely  cause.  The workshop generally agreed  that, during this
phase,   the  following  indicators  of   toxic   stress  would   be  most
appropriate,  on  the  basis  of   their  relatively  low cost and general
applicability:

     o  nonpollutant-specific indicators (immunological,  i.e.,
        blood samples  for hematocrit determinations and  kidneys
        for observation  of macrophage  phagocytes, chemotoxins,  and
        assays  of estuarine waters with  mortality as  the
        indicator);

      o  indicators  of  synthetic  organic  effects  (e.g.,  cytochrome
        P-450 and assays of  liver  for  metabolites);
                                   12

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     o  indicators of toxic metal effects  (e.g.,  metallothionein
        assays and/or metal residue measurements  in liver
        tissues);"and

     o  pesticide analyses (where there is reason to believe
        agricultural activities are a source of pollution).

     However,  a  few  participants thought that the indicators used in
the  screening phase should not be restricted to biochemical types, but
should  also include indicators at the organismal and population levels
(e.g., gross pathology, abundance, and distribution).  They also agreed
that  it would be important during this phase of the program to archive
samples  (i.e.,  brain,  gill,  liver,  kidney,  flesh, and spleen) for
subsequent   tests  or analyses.  If it was determined that there may be
toxic  contamination,  then  further  histological  or residue analyses
would be warranted.

     As part of the  characterization process for an individual estuary,
a  synthesis  of  historical data  should be performed|to further define
problems  and to  identify  data gaps.  This synthesis would include data
on pollutant loads,  ambient water  and sediment conditions, and any data
on   biological  indicators that   may  already   exist.   The indicators
selected  for   the   characterization  phase  also   should be useful for
distinguishing  possible   causes   of  the  toxic stresses observed in the
estuary  whenever  possible.   It  was hoped  that this  information  would
both assist  in   the process   and  perhaps help to defend  the specific
pollutant abatement actions for  an estuary.
         ^
      After    discussing    potential   characterization   indicators,  the
participants    decided     to    divide    characterization   into   two
determinations:     (1)  a  determination   of   the nature, severity, and
extent   of   impacts  on   fish  populations;  and (2) ^ determination  of
cause-and-effect   relationships  between specific pollutants or types  of
pollutants   and  major  observed  impacts.     To  determine the  nature,
severity,   and  extent  of population impacts,  the following indicators
were identified:
                                   13

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     o  cytogenetics,

     o  egg and larval development and viability,

     o  histopathology (within tissue, sublethal effects),

     o  immunological (triad of macrophage tests),  and

     o  enzymes (e.g., mixed function oxygenase (MFO)
        system;(metallothionein).

     To  show  cause-and-effect  relationships,  the workshop agreed it
would  be  necessary  to  conduct:  these  same  tests  under controlled
laboratory conditions.   The  techniques used during the first phase of
characterization  could  be modified for use in a laboratory to include
ambient  water  or  sediment  test phases and pure compounds.  However,
workshop  participants  noted  that  several  highly pollutant-specific
indicators  have been developed under laboratory conditions and now are
ready  for  field   testing.  Other such indicators will be ready in the
next  1  to  2  years. Using such methods, it might soon be possible to
more  effectively   trace  the  causes  of  some impacts observed in the
field.    Participants  also  suggested  that  certain  ultrastructural
analyses,    while    expensive,   could   be   used   for   evaluating
pollutant-specific  causes of stress.

     Monitoring  ecosystem  recovery,  and   the  question  of  suitable
indicators  for  this purpose were then discussed.   Participants agreed
that  the  indicators previously  listed should be used again  to compare
recovery  on   a  site-specific  basis.     For a system-wide,  long-term
monitoring program  (i.e., to be conducted over a period of 5-20 years),
the  workshop  was   then asked  if finfish indicators  should have a role
and,  if so, what should it be?   Participants  agreed  that  the  following
indicators would be beneficial  for such a monitoring program:
                                   14

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     o  population studies,                           '•

     o  residues,
                                                      ! ''

     o  reproductive success (including embryo viability), and

     o  histological markers (sublethal effects).

The  workshop  generally  agreed  that  finfish  should  be  part  of a
long-term  monitoring  program  and  that  finfish  indicators would be
useful for monitoring recovery.
     Finally,  at  the  plenary session, the participants were asked to
identify  finfish indicators relevant to human health.  They identified
tissue  residues  as  the  only  unequivocal finfish indicator of human
health  impacts (toxic, mutagenic, and carcinogenic). ! Metabolites were
considered a subset of residues.
     Each subgroup was asked to identify the most promising methods, of
those they considered, that are presently available and those that need
further  research  and development.  Availability was considered as  (1)
immediate  with  widespread  usage,  (2)  immediate  with  only limited
current usage  (0-1 year),  (3) short-term (1-2 years), and (4) long-term
(3-5 years).   A summary of the subgroup conclusions follows:
     o  Immediately available and  in widespread use

        -  gross  pathology
        -  some histopathological  indicators
           tissue residues
        -  egg and larval viability and development
        -  population  techniques
                                   15

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   o  Immediate availability but not in widespread use (0-1
      year)

      -   metallothionein
      -   cytochrome P-450 (and other mixed  function oxygenase
          system enzymes)
      -   individual macrophage triad  tests

    o  Short-term  availability, with some development  and/or
       field baseline data needed (1-2  years)

       -  macrophage triad (phagocytosis, chemiluminescence, and
          killing ability)
       -  adducts (DNA and synthetic organics)
       -  bioaccuraulation models
       -  cytogenetics
       -  hematology
       -  ultrastruetural pathology
       -  combination of macrophage, T-cell, B-cell, and disease
          resistance methods

     o  Long-term  availability, with methods needing further
       research and development (3-5 years)

       -  blood chemistry (enzymes)
       -  histochemistry
       -  development of inbred fish lines  to support development
            of immunological assays
        -  in vitro tests of several immunological indicators
PLENARY SESSION CONCLUSIONS

     While  trying  to  agree  on a set of finfish indicators, workshop
participants  made  several recommendations and comments concerning the

                                  16

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 use  of  finfish  as  indicators  of toxic contamination.   The workshop
 participants  agreed  that  no single test was adequate.   Instead,  they
 considered  a  suite  of. tests necessary to characterize  toxic effects.
 In  addition,  the  workshop  maintained  that  the suite of indicators
 should  be  field  tested simultaneously in fish collected from several
 study  areas  to  compare  the  sensitivity  of indicators across major
 estuarine  categories.   Participants also stressed the need to study a
 "pristine" reference estuary or set of estuarine areas.  The purpose of
 these  studies would be both to provide baseline data for comparison to
• stressed  systems and to determine the normal ranges of the recommended
 finfish indicators under field conditions.            ;
                                                       i
      Workshop  participants also stated that finfish indicators may not
 be  good  screening   tools for cross-estuary evaluations.  Participants
 indicated   that  more  easily interpreted endpoints can be evaluated to
 assess  whether  or not a system is stressed.  Also, the use of finfish
                                                       i
 as  indicators   in  trend  monitoring  programs within! estuaries may be
 limited  because some key methods have not yet been field verified and
 because  other,  less  mobile organisms (e.g., certain! benthic species)
 may be better suited  as  indicators.  However,  studies using less mobile
 species  also   may  be limited inasmuch as  sampling heterogeneity can be
 more   pronounced on  a local  scale  if pollutant distribution  is patchy.
 Mobile  organisms,   therefore,  may  actually  be  better   suited  at
 integrating  toxic  contamination   burdens  for meso-  or  regional-scale
 assessments.    Furthermore,  EPA   representatives noted  that  there are
 regulatory   and  programmatic needs for resource management agencies  to
 evaluate indicators of  impacts  on  fish.

       The workshop  generally  agreed   that  behavioral,  enzymatic,  and
 immunological  effects   would  appear   earlier (i.e.,  following shorter
                                                       j
 toxicant exposure)  than  histological  or  gross  anatomical changes.
 Therefore,   these effects would be better suited as  early indicators  of
 toxic contamination.                                  |

       The workshop  also  pointed out  that it is currently difficult to
 make  cross-technique  assessments for those methods now used routinely
                                    17

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and  that  it would be valuable to provide longer-term research support
to  develop  methods  for use in the field.  In addition, more detailed
information  should  be . obtained on both what techniques are currently
available and which institutions have the capabilities to perform theme
                                   18

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     4.  SUMMARY REPORT FROM THE SUBGROUP ON ANATOMIC PATHOLOGY
     Although  death  of fish has historically been used, and currently
is  used  often  as  the primary indicator of problems related to toxic
contamination,  this  subgroup  suggested  using  a series of sublethal
effects  occurring  in  a progression that may end in death to describe
and  evaluate  indicators  of  toxics  in  finfish  (Figure  1).   This
                                                      i
progression  includes  early  changes that are usually reversible, late
changes  that  are  usually irreversible, and intermediate changes that
may  or may not be reversible.  It was suggested that the discussion of
indicator  methods  identify the stage(s) in this progression where the
methods  would  be  applicable.   Approaches to the use of pathological
indicators  may  be organ-specific, manifestation-specific, or systemic
(or holistic).
     For   the   organ-specific  approach,  with  organ  defined  as  a
morphologically   discrete   and   functionally   organized  anatomical
component, examples of changes include the following;

     o  Gross
            Externalt   discoloration, skeletal deformities, fin
            rot, skin ulcerations, hyperemia, eye lesions
            (opacities), neoplasia, parasites, edema  !
                                                      I
            Internal;  edema, (including ascites), organ
            displacement, neoplasia, parasite
                                                      i
     o  Histological (tissue)
            Classes of changes; inflammatory, cellular alteration,
            hyperplastic/neoplastic, melanomacrophage aggregation
            increase, parasitic                       ',

     o  Ultrastructural (subcellular)
            Classes of changes; Inclusion bodies, lysosomal,
            parasitic, smooth endoplastic reticulum changes
                                  19

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                      NORMAL
                BIOCHEMICAL CHANGES
              ULTRASTRUCT11RAL CHANGES
                   CELL DEGENERATION
                         1
                   CELL NECROSIS
                          I
                   TISSUE DAMAGE
                    ORGAN FAILURE
                          I
                          :c
                          i
SYSTEMIC FAILURE
                        DEATH
Figure 1.  Progression of Indicators of Toxic Stress
                            20

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     o  Histochemical
            Enzymatic: technologies to be explored include
            differential staining for glutamyl transfesrase, other
            enzymes, ion-specific assays, and microprobej;.
     Using   the   manifestation-specific   approach, !  the   following
manifestations  have  been associated with the following kinds of  toxic
                                                      [
contamination  and  other stresses.  This listing is not all-inclusive.
Additionally, in every case the effects of chemical mixtures in synergy
and opposition must be considered and may be indicated by
     o  Fin erosion—PAHs, PCBs, ammonia, nitrites, water-soluble
        hydrocarbons, trauma

     o  Skin ulceration—PAHs, PCBs, parasites, trauma/injury,
        sunlight (UV radiation)
     o  Eye disease—PAHs, phthalate esters, nutrition, parasites
     o  Gill disease—ammonia, nitrites, metalo-organics (tin),
        organics, PAHs, metals (Cd), parasites
                                                      I
     o  Liver neoplasms—PAHs, PCBs, chloramines, nitrosamines,
        aflatoxins, metals (Cr, Cd), parasites
                                                      I
                                                      I
                                                      I
     o  Skeletal deformities—organochlorines, herbicides:
        (trifluralin), insecticides (organophosphates), metals,
        nutrition
     o  Papillomas—viruses (from contamination?)
     o  Pancreatic diseases—PAHs, nitrosamines, viruses
     o  Kidney diseases—heavy metals (Hg, Pb, Cd), nutrition,
        nitrosamines, parasites                       (
                                  21

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     o  Gastrointestinal tract diseases—PCBs, petroleum
        hydrocarbons,  nitrosamines,  viruses,  bacteria,  parasites.


     The multiple system or holistic approach includes all parts of the
organism  and  all  manifestations.    For  example,   ammonia  has been
associated with effects on gills, skin, gastrointestinal
tract, and aggregate macrophage changes.  Industrial organics have been
associated with effects on brain and liver.

      The  indicators  of pathology discussed  by this subgroup were gross
changes,  historical, •  ultrastructural,  and  histochemical   effects.
Although  all  the  indicators  were   considered useful  for  identifying
 toxic  contamination  in  finfish,  only gross   changes were  useful
 indicators  of toxic contamination at  the  ecosystem level. The value of
 the  other   indicators at the ecosystem level was  uncertain  or unknown.
 Cause-effect  relationships may be implied by associating a  syndrome of
 effects  with  likely  causative  agents.    None of the indicators was
 considered valuable in assessing effects  on human health. The subgroup
 discussed  and  evaluated  the  methods for assessing these indicators.
 Table 3 summarizes the results of  this process.  A brief summary of the
 subgroup's discussion on indicators at all  levels of pathology follows.

 GROSS  CHANGES

      As  indicators  of toxic contamination, gross changes signal a very
 disturbed   ecosystem.     The  methods for   assessing gross changes are
 cost-effective,  widely available,  and easily taught.  It also is of low
 sensitivity.    In  terms  of  the progression shown in Figure 1, gross
  pathology  can  identify  organ failure  and system failure, i.e., where
  the   process   is   usually   irreversible.     This  methods  is  not
  pollutant-specific, but is  specific for space and time.  The methods is
  ready  to be used with  many species (i.e., it is not species-specific).
                                     22

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HISTOLOGICAL EFFECTS
     Histological  effects  may  be  indicators  of minimally disturbed
environments.       Histological   methods   can   detect   subanatomic
manifestations, at early  to intermediate stages in disease progression,
i'.e., in the  transition area between reversible and table 3 here
irreversible  changes  (See  Figure 1).  These methods can be performed
cost-effectively   by   high-production   laboratories,   although  the
availability  of such laboratories may be limited. Histological methods
also  can be  used in highly polluted environments, and are specific for
time  and  space.  Certain pathological lesions can be used to identify
classes   of   pollutants   (heavy   metals,   aromatic   hydrocarbons,
polychlorinated  compounds,  and  mixtures  of  compounds),  but  these
lesions  are  not  specific  for individual pollutants. The methods are
ready to be used with many species.
ULTRASTRUCTURAL EFFECTS
     Ultrastructural effects can be detected by electron microscopy, an
expensive   method   with   limited   availability.   j The  meaning  of
ultra-structural  changes as an indicator of toxic contamination is not
always  understood, although they may offer the potential for detecting
problems  early.    For  example, proliferation of hepatocytes tends to
reflect  drug  or  toxicant exposure within hours of that exposure, and
may   continue   throughout   chronic   exposure.    The  detection  of
ultrastructural  changes  may  also  be  used  as  a confirmatory tool:
detecting   changes  in  mitochondria,  a  characteristic  response  to
cyanide,  was  used  to  confirm cyanide as the cause of a fish kill in
Ohio.
HISTOCHEMICAL EFFECTS
     The  meaning  of histochemical effects as an indicator is unknown,
and  the  methods  for  their  detection  are  expensive and of limited
availability.  Histochemical  methods  may  be  useful  for  validating
                                  23                  i

-------


















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suspected  toxic  contamination,  but they cannot currently be used for
monitoring  because not enough is known about the significance of their
manifestations.  The subgroup suggested that if correct enzymatic tests
are used for putative foci (e.g., the liver), alterations in metabolism
might  be  detected  that  could  be associated with the development of
neoplasms.    These methods may be applied to the multi-stage theory of
carcinogenesis.
DISCUSSION
                                                      I

     It  was  emphasized  that  a  set of tests, rather than any single
test, should be used to identify toxic contamination.  Gross anatomical
examinations  and  histologic  tests should be performed in conjunction
with  chemical  analyses  of water and sediment and residue analyses to
determine body burdens of toxics.
     Laboratory  studies  can establish causal relationships, but their
applicability   to  the  field  must  be  established.    For  example,
trifluralin effects (vertebral injury and hyperostosis), induced by low
concentrations  in  the  laboratory,  have been validated with the same
lesions  in  field-exposed,  wild  populations  of  fishes.  Similarly,
PCB-induced  liver  damage in laboratory-exposed fish has been found in
wild,  PCB-exposed  fish.  However,  native  populations  may develop a
                          .
tolerance  to  the  contamination,  which  probably  would not occur in
laboratory or field testing.

     The   use  of  tumors  as  indicators  requires  evaluating  their
significance  in  fish  populations.    Neoplasms in finfish, including
carcinomas,  have been associated with contamination by PAHs, PCBs, and
heavy  metals.    The  subgroup  suggested that if a fish has a visible
tumor,  it  may  contain a level of carcinogens that can pose potential
health  effects  for  humans ingesting it.  Therefore, fish with severe
fin  erosion  (fin rot), integumental ulcerations, and cataracts should
not  be  eaten.   Further, an incidence of tumors that is significantly
                                  25

-------
above  expected  levels  in  wild  populations  of a particular aquatic
system  indicates that toxicants or carcinogens may be a major cause of
stress in the ecosystem.

RECOMMENDED INDICATORS

     Based on  the evaluation criteria and ranking by  the four  suggested
methods,  the anatomic pathology indicators  recommended were

     o   Gross  changes (for highly disturbed ecosystems)

     o   Histological effects (for minimally disturbed
         environments).

 RESEARCH NEEDS

      The  following  research  needs  were identified for improving the
 usefulness  of  anatomic  pathology indicators of toxic contamination in
 finfish:

      o  Gross changes

         -  Conduct  field  tests to quantify changes across
            disturbed environments to help  assess significance and
            commonality;

          -  Define  impacts of fish sampling techniques on  gross
            lesions;

          -  Develop reference works  on documented pathology and on
             gross and microanatomy of fishes [It was noted that
             development of a textbook on gross and microanatomy of
             fish (identified as a critical need) is underway].
                                     26

-------
o  Histological effects                          >

   -  Improve specificity and interpretation in relation to
      effects;                                   j

   -  Train fish histopathologists;

   -  Standardize vocabulary and interpretation of lesions;

   -  Establish baseline data on selected species.
                                                 '[
o  Ultrastructural  effects                       |

   -  Conduct   basic  laboratory   research   to  demonstrate
      Ultrastructural effects from  classes  of  compounds;

   -  Conduct   research to  relate laboratory studies  to field
      studies.

 o  Histochemical  effects                         i

    -  Direct  basic  research  to  explore use  as a monitoring
       tool.                                      !
                              27

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 5.  SUMMARY REPORT FROM THE SUBGROUP ON BIOACCUMULATION AND ENZYMES
     The  subgroup  discussion  began  by selecting a spokesperson (Dr.
Jerry  Neff,  Battelle)  and a recorder (Ms. Patricia Fair,  NMFS).  The
group  was  then asked to rank the major finfish indicator methods that
measure  bioaccumulation/metabolism  of toxicants and changes in enzyme
function  due  to  toxic  pollution.    The initial indicators for each
category  are  ranked  below and are followed by brief summaries of the
discussion for each indicator:

     o  Bioaccumulation
        -  Residue Levels
        -  Metabolite  Profiles
        -  Chemical/Physical Models
        -  Kinetic Biology-Based Models
        -  Rapid  Mutagenicity Tests  (Ames/Lambda Prophage)  on
            tissues or  tissue extracts.

     o  Enzymes
        -   Enzyme Induction (Particularly Mixed-Function
            Oxygenases
        -   Enzyme Inhibition
        -   Blood Chemistry
        -   Adaptive Stress Responses

 BIOACCUMULATION
      Residue Concentrations/Metabolite Profiles

      The subgroup ranked residue concentrations and metabolite profiles
 as  the  best  indicators,  according  to  workshop  criteria.    These
 indicators provide a major link to human health effects.   Regarding the
 use  of residue  levels, the subgroup noted that demersal species, which
 form  localized  populations (i.e., have limited migratory ranges), have
 historically  been most useful for monitoring.  The subgroup cautioned,
                                   28

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however,  that  finfish  are not always the best sentinel organisms for
many  types  of  pollutants  because  even  demersal species are mobile
relative  to  benthic  invertebrates.    Also  finfish.  metabolize many
classes  of. compounds rapidly.  It was stressed that residue levels in
finfish should be used in conjunction with other measures of biological
effects  to  establish  causal  relationships  of  particular pollutant
sources to observed field .effects.
     The  subgroup  further  noted  that  for some typies of pollutants,
metabolite  profiles  are  a  better  indicator  of  past exposure than
residues.    Developing  metabolite  profiles  involves identifying the
concentrations,   characteristics,   and   distribution   of  pollutant
metabolites,  conjugates,  and  adducts in various tissues, fluids, and
subcellular  sites.    However,  this  subgroup  also observed that not
enough  is  known  about  the  pharmacokinetics of pollutants and their
metabolites  in  fish  to  firmly  establish exposure history.  Not all
                                     this  was  cited  as  a  topic for
methods  are  currently  available!
continued research.

     Chemical/Physical Models
     The  subgroup  ranked  chemical/physical  models  as the next most
promising  method  for  assessing  the  likelihood  of.  stress  due  to
bioaccumulation.  Models discussed were primarily those used to predict
distribution,  environmental behavior, and fate of pollutants in marine
ecosystems.   the subgroup cautioned, however, that these models cannot
be  used  alone.    They  must  be  used in conjunction with biological
                                                      i
models, and must be calibrated and verified under various environmental
conditions.  These models are useful for providing worst-case estimates
of  bioaccumulation   impacts.    However, models must tbe used carefully
because  they  do  not  provide  the  conclusive  evidence that residue
monitoring can provide.
                                  29

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     Kinetic Biology-Based Models

     These  models  were  characterized primarily as a means to predict
and  assess  food  chain  transfer  of  pollutants.   These models have
potential  uses  for both predicting ecosystem-wide effects and linking
environmental contamination to analysis of human health risk.

     Rapid Hutagenicitv Tests (Ames/Lambda Prophage)

     Rapid  mutagenicity  tests  were  ranked  as   the next most useful
indicators  of   the  effects  of bioaccumulation   and metabolism.  The
subgroup  stated that  it  is often difficult  to interpret  these  tests in
an   environmental context, but  they may  provide a link to  human health
considerations.    These   tests  still require substantial development
because they  must be modified for use  with  tissue/sediment  extracts and
because  they  may  yield  an  unacceptably  high   frequency  of   false
positives or  negatives.

      Table  4  summarizes  the  group's evaluations of these indicators
according  to  EPA's  criteria.    "Unknown" indicates that the subgroup
 could not determine or agree whether the indicator met the criterion.
 ENZYMES

      Enzyme Induction  (Particularly Mixed Function Oxygenases)

      The subgroup  ranked  enzyme  induction as  the best indicator in  this
 category.    This   indicator   is  highly pollutant-specific for certain
 classes of organic and metal  pollutants.  It  is particularly useful for
 detecting  responses  that are initially adaptive, but which may  become
 maladaptive    with  toxification/detoxification.    These  methods   are
 currently  being refined and improved  to make  them  more routine.
       Mixed-function  oxygenase  system induction  was singled  out  as a
 subcategory   of indicators specific to polycyclic  aromatic hydrocarbons
 and   PCBs.   Measurement  of  specific forms  of  cytochrome   P450  in
                                    30

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TABLE 4.  BIOACCUMULATION/METABOLISM INDICATORS
                Residue Levels/    '   Chemical/Physical
Criterion    Metabolite Profiles     Biology-Based Models
                                         Rapid Mutagenicity
                                              Tests
Unequivocal
meaning

Cost-
Effectiveness

Availability

Applicability
  -early/late
   sensitivity
Yes


Moderate

Moderate


Early
Moderate


Yes

Moderate


Early
Yes


Yes

Moderate


Unknown
-pollutant-
specific Yes Yes
Yes
-species-
specific No Can be No
-scope-

specific No No No
(spatial)

                                         31

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particular  is  a  very  specific  and  highly  sensitive  indicator of
exposure  to  particular  pollutants.  Measurements  of  other specific
enzyme  activities  (e.g., aryl hydrocarbon hydroxylase, benzo[a]pyrene
hydroxylase,  etc.)  are  subject  to  substantial variability, but are
still valuable indicators.

     Enzyme Inhibition

     The  subgroup  ranked   this category of indicator next most useful
because many  methods are  readily available.    However, some assays may
need to be adapted  specifically for  fish tissues.    The  subgroup also
noted   that    these   indicators  have  varying  degrees  of   pollutant
specificity,   depending  on   the  particular  enzyme   systems  involved.
Also,   there   are uncertainties about  the effects  of natural  indigenous
and exogenous  factors  on   basal   enzyme  activity. Thus,  the subgroup
urged   caution  in   randomly  applying enzyme   inhibition; instead,  it
should be  used as   an  indication of exposure to specific  classes  of
chemicals.    Also,  baseline  data  are needed to  establish normal ranges.
The subgroup  mentioned  the  following examples  of enzyme inhibitions

     o Acetylcholinesterase
     o  Gill ATPase
      o  S-Aminolevulinate dehydratase
      o  DNA-polymerase
      o  Glucose-6-phosphate dehydrogenase.

      Blood Chemistry

      The  subgroup  ranked  blood chemistries as the next most promising
 set  of  indicators.    They  were  mentioned  as  a  valuable clinical
 approach.    However,   the  subgroup  noted that more baseline data are
 needed to further  the  use of  this group of indicators.
                                    32

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     Adaptive Stress Responses

     Adaptive  stress  responses  were  noted  as  an  important set of
indicators  because  their meaning is fairly veil established, and they
hold promise of being cost-effective. However,  the sulbgroup also noted
that  these  responses  are non-specific, i.e., any kiind of stress will
elicit  the  response.    Three examples of potentially useful adaptive
response   indicators   were   specifically  mentioned—stress  protein
responses,  adrenocortical responses, and neurochemical responses.  The
subgroup felt that  these methods warrant more development; infact, some
methods  (particularly  metallothionein  assays   that  are specific for
metals exposure)  are in the field  testing stage at present.
                                                      j
     The   subgroup  also  evaluated   enzyme   indicators  based  on  the
                                                      I
criteria   provided  by  EPA.   Table 5 summarizes its findings.  Again,
"unknown"  indicates that  the  group could not  determine or agree whether
the indicator met the  criterion.

RESEARCH AND DEVELOPMENT  NEEDS                       ,
                                                      I
     The   group  established   the following priorities  for  the  research
and    development     needs     of    the    discussed     indicators.

      o  Further develop and refine immunologic techniques  to
         quantify specific forms of cytochrome P450 (2-3 years
         development time) to provide a highly specific,
         inexpensive and easy-to-apply assay;

      o  Further evaluate the use of stress proteins, particularly
         metallothioneins, and very low molecular weight proteins,
         as general- and pollutant-specific indices of pollutant
         stress (1-3 years);                          j

      o  Evaluate pollutant specificity of different serum enzyme
         assays,  and develop  databases for species of interest;
                                   33

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TABLE 5.  ENZYME INDICATORS
Criterion
  Enzyme
Induction
  Enzyme         Blood
Inhibition     Chemistry
                                                                 Adaptive
                                                               Stress Response
Unequivocal
meaning
Cost-
Effectiveness

Availability

Applicability
  -early/late
   sensitivity

  -pollutant-
   specific
  -species-
   specific

  -scope-
   specific
   (spatial)
  Yes
   Yes
                               Moderate
  Moderate

  Moderate


  Early



  Yes



  No


  No
   Yes

   Yes


   Unknown



   Yes



   No


   No
Moderate

Variable


Early



 Yes



 No


 No
                No,  any
                stress will
                elicit
                response
Yes

Yes


Unknown
No, except
metallothionein
No
No
                                        34

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     o  Develop immunological or spectrofluorometric techniques to
                                                      I
        quantify pollutant-protein and pollutant-DNA adduct
        relationships in blood and tissues°,
     o  Develop better residue-effects links using long-term,
        mechanistic cause/effects studies;         '   i
     o  Modify rapid mutagenicity tests to improve their
        applicability to tissue extract assays.
     The  subgroup developed a number of general points relevant to all
of the indicators discussed.  They are as follows:

     o  In using measurement of residue concentrations as an
        indicator, it is vital to the proper interpretation of the
        results that it be linked to effects analysis (i.e., used
        in conjunction with other indicators);
     o  No single test is sufficient; a number of different
        indicators should be used in any given field study;
     o  Analysis must address the combined effects of major
        pollutants as this is what is found in the field;

     o  The mechanism of the effect must also be addressed.
        Without an understanding of mechanistic links, the
        indicators have little or no predictive value.
                                  35

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                    6.   REPORT FROM THE SUBGROUP ON
                 REPRODUCTION/DEVELOPMENT,  PHYSIOLOGY,
                        BEHAVIOR, AND POPULATION
     After  selecting  a recorder (Dr. Judith Weis,  Rutgers University)
and  a  spokesperson  (Dr.  Joel  O'Connor, NOAA),  this subgroup listed
possible  finfish  indicators  of  toxic  pollution  for  each  of  the
subcategories:  reproduction and development; physiology; behavior; and
population.  Initially, the subgroup was asked to identify all possible
indicators  without  discussing  the worthiness of a particular choice.
This  resulted  in a long list of indicators that was then consolidated
by  merging  related  and redundant indicators, and then deleting  those
considered least useful or outside the scope of the subgroup.

     During   this  discussion,   fishery  closures   (i.e.,  closure of  a
fishery  by   a  regulatory   agency  due  to contamination of  the  fish by
toxic   chemicals)  were   considered.     The subgroup questioned  whether
closures   should  be  considered  as an  indicator at all,  and then  agreed,
with reservation,  to consider them as a  separate category.

     The subgroup also decided to  consider resistance  or acclimation to
pollutants when evaluating indicators.   The subgroup  agreed to consider
and'  evaluate  pollutant  resistance  as  a  separate category.  Table 6
presents  the  final  list  of indicators considered for evaluation and
 ranking for each category.

      The  subgroup  then tried to determine the relevance of each final
 indicator  to  each endpoint (fishes, ecosystem, and human health). The
 subgroup  found that all of  the indicators listed applied to the  health
 of  individual  fish  and   fish  populations  and  that none applied  to
 ecosystem or human health effects.

      After   agreeing  on  a final list  of finfish  indicators,  the group
 evaluated  each  indicator based on EPA  criteria.   Tables  7-10 summarize
 thesse findings.  The presence of "unknown"  indicates  that  the  subgroup
                                   36

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TABLE 6.  LIST OF INDICATORS CONSIDERED FOR RANKING BY THE SUBGROUP
ON REPRODUCTION AND DEVELOPMENT/PBYSIOLOGY/BEHAVIOR/POPULATION
     o  Reproduction and Development

        -  number of eggs
        -  embryo viability
        -  cytogenetics
        -  larval development and viability
        -  growth
        -  fin  regeneration

     o  Physiology

        -  respiration
        -  hematology
        -  endocrinology
        -  swimming stamina

     o  Behavior

        -  schooling
        -  avoidance/attraction
        -  reproduction
        -  predatory behavior
        -  food habits
        -  miscellaneous  (predator avoidance/orientation/
           coordination/refuge-seeking behavior)
                                                        I
      o  Population

        -  abundance
        -  age structure profile
         -   spatial distribution profile

      o   Fishery Closures

      o   Pollutant Resistance (acclimation)
                                    37

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TABLE 7.  REPRODUCTION AND DEVELOPMENT
                                              Indicator
Criterion
               Number     Embryo     Cytogenetics  Larval
               of Eggs   Viability                Development
                                            Growth      Fin
                                                    Regeneration
Unequivocal
Meaning

Cost-
Effectiveness

Availability

Applicability

   -early/late
    sensitivity
No


Yes

Yes
No


Yes

Yes
Early    Early
                      Yes
Yes
Yes
             Early
                         No
Yes
Yes
            Early
No


Yes

Yes



Early
No


Yes

Yes



Early
-pollutant-
specific
'-species-
specific
-scope-
specific
spatial
temporal
No
No


Unknown
2-6 mo
No
No


Yes
days or
weeks
No
No


Yes
few days
to 6 mo
No
No


Yes
1 week to
2 mo
No
No


Yes3
1 week to
2 mo
No
No


Yes
1 mo to
1 yr
 *  Needs expertise
 ^  But not widely
 7 .For resident species                                          .
 4  Could be a function of  the  female taking up toxicants and passing them on to the
    embryo, in which case the time scale could be 2-6 months.
    An extreme case would be up to a year
                                           38

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TABLE 8.  PHYSIOLOGY
                                        Indicator
Criterion
                 Respiration    Hematology    Endocrinology    Swimming
                                                               Stamina
Unequivocal
Meaning
Cost-
Effectiveness
Availability
No
Yes
Yes
No3
Yes
Yes
No !
Unknown
l
Unknown
No
Yes
Yes
Applicability
                      e
  -early/late    Early^
   sensitivity

  -Pollutant-
   specific      No

  -Species-
   specific      No

   -Scope-
    specific
                    2
      spatial    Yes
                    2
      temporal   Yes
Early
No
No
Yes'

No
Early
No
No
Yes'

Yes
Late



No


No
Yes

No
   There may be other potential  indicators (e.g., scope for growth:   the
   amount of energy available  to an organism for growth and reproduction
   in excess of the energy  required for maintenance)

   Can be

   Potential is there
                                      3,9

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TABLE 9. BEHAVIOR

Criterion
Unequivocal
Meaning
Cost-
Effectiveness
Availability
Indicator
Schooling Avoidance/ Predatory Food Jisc.
S Attraction Reproduction Behavior Habits Behaviors
No No No No No No
No Yes No No Yes2 Yes4
Yes Yes Yes Yes Yes Yes
Applicability

   -early/late
    sensitivity
Early
Early
Early
 ^  Must be schooling species
 2  Can be
 •7  Depends -on species
 ^  Fairly cost-effective
                                    Early
                                    Late    Early
-pollutant-
specific No No No
-species-
specific No Yes No
-scope-
specific
spatial Yes Yes Yes
temporal Yes Yes Yes
No No No
No No No


Yes Yes3 Yes
Yes Yes Yes
                                           40

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TABLE 10.  POPULATION
Criterion
Unequivocal
Meaning

Cost-
Effectiveness

Availability

Applicability

   -early/late
    sensitivity
                                      Indicator
Abundance      Age Structure   Spatial Distribution
   No


   Yes1

   Yes



   Late
No


Yes1

Yes



Late
NCI



Yes


Yes
  l



Early
-pollutant-
specific No
-species-
specific No
-scope-
specific
2
spatial Yes
temporal No

No No

No - No
'

Yes2 Yes
No Yes
I
    For local stocks
    For anadromous and resident species
                                        41

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was  unable  to  determine  or  agree upon the relationship between the
indicator  and  the  criterion.   The two potential finfish indicators,
pollutant resistance and fishery closures, are not directly related but
are presented together in Table 11, for convenience.

     Following   evaluation,  each  indicator  was  ranked  within  its
category  on  the  first three criteria only (unequivocal meaning, cost
effectiveness,  and  availability).   The ranking.within categories was
performed using the four methods specified:

     o  Select the best single indicator,
     o  Select the best few indicators,
     o  Give a numerical rank to each indicator,  and
     o  Classify  each  indicator as  "good" or "bad."

     Tables  12-15 summarize the results  of  the  rankings.   Although  the
indicators   "pollutant resistance" and  "fishery  closures"   were  not
ranked,  the group agreed  to present the evaluations of these indicators
to  the  workshop.   Although the  group did  not  agree how  to rank these
two    indicators,   this   does  not  imply  that   they  are  not  useful
indicators.    In  fact, these two  indicators  met  the workshop's criteria
well.
                                   42

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 TABLE 11.  POLLUTANT RESISTANCE AND FISHERY CLOSURE
                                      Indicator
Criterion
Unequivocal
Meaning

Cost -
Effectiveness

Availability

Applicability

   -early/late
     sensitivity

   -pollutant-
     specific

   -species-
     specific

   -scope-
     specific

       spatial

       temporal
Pollutant
Resistance
Fishery
Closures
   Yes



   No

   Yes



   Late



   Yes


   No
    Yes

    No
   Yes
       I



   Yes ;

   Yes



   Late



   Yes


   No
    Yes

    Yes
                          1
    For resident species
                                    43

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TABLE 12.  REPRODUCTION AND DEVELOPMENT
Indicator
#1
Best
Relative
Rank
Good/Bad
Number of eggs

Embryo viability

Cytogenetics

Larval development
and viability

Growth

Fin regeneration
          X

          X

          X
            4

            3

            1

            2


            6

            5
                Good

                Good

                Good

                Good


                Good

                Good
                                   44

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TABLE 13.  PHYSIOLOGY
Indicator
#1      Best
Relative
Rank
                                                      Good/Bad
Respiration

flematology

Endocrinology

Swimming Stamina
X
3 or 4

   1

3 or 4

   2
Good

Good

Good

Good
                                  45

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TABLE 14.  BEHAVIOR
Indicator
#1
Best
Relative
Rank
                                                     Good/Bad
Schooling

Avoidance/
 Attraction

Reproduction

Predatory Behavior

Food Habits

Miscellaneous
 Behaviors
X
         X
            1

            5

            6

            4

            2
              Good


              Good

              Bad

              Bad

              Good

              Good
                                 46

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TABLE 15.  POPULATION
Indicator
#1      Best
Relative
Rank
                                                      Good/Bad
Abundance

Age Structure
  Profile

Spatial Distribution
  Profile
         X
         X
  2


  3


  1
Good


Good


Good
                                  47

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                SUMMARY REPORT FROM SUBGROUP ON IMMUNOLOGY
     The  field  of  immunology  is contributing to new,  sensitive,  and
rapid methods for the detection and identification of microorganisms in
animals,   humans,  and  the  environment.    These  methods,  such  as
enzyme-linked  immunoassays,  macrophage  activity  assays, and passive
heraolytic  assays,  may  be used to detect changes in animals caused by
toxic  contaminants.   The Immunological Indicators subgroup considered
which  methods  might be applied to detect changes in the immune system
of finfish caused by contaminants.

     The immune system in higher animals, including finfishes, is based
on  antigen  exposure,  resultant:  antibody  or  cellular response, and
eventual  protection  (if  a  disease agent is involved).  The subgroup
approached   this  problem  in   the  chronological  order  of  the immune
response:    first  considering  the afferent immune response—pickup and
processing of  antigen, and' then the efferent immune response—producing
the  physiological  result,  e.g.,  antibody, cellular activation,  etc.
Table  16 presents the inital list  of  immune indicators.

     This  subgroup assigned   points to determine  the relative  rank  of
the  monitoring  methods   relying  on  the  immune  response,  with  1 the
lowest  rating,  and 5  the highest rating.  (See Table 17).   Evaluations
are  summarized below.

HACROPHAGE TESTS

      One  method,  which included examining a combination of macrophage
 phagocytosis,   macrophage  killing  of  microorganisms,   and macrophage
 chemoluminescence,  was  judged  a  very  good  method.    Two committee
 members  considered  this the best and the other two members considered
 it among the top three methods.

      The  members  also  considered  the use of macrophage phagocytosis
 alone  a  good  method,  but  not  nearly  as  powerful as the combined
                                   48

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TABLE 16.  INITIAL LISTING OF IMMUNE INDICATORS
     Macrophage indicators
          phagocytosis
          chemotaxis
          pinocytosis (soluble particles)
          killing                                       !
            microbes                                    |
            tumor cells                                 i
          chemoluminescence  (a technique)
          aggregates of macrophages  (in kidney, for example)
          melanin accumulation by macrophages
          MAP  (macrophage activation factor)            j
          MIF  (macrophage inhibition factor)
     Lymphocyte indicators
          T-lymphocytes                                 ;
               blastogenesis
               cytotoxicity                             i   •     •
               lymphokine production
               delayed  type  hypersensitivity
               graft rejection (fish scale  rejection)
          B-lymphocytes                                 ;
               blastogenesis
               antibody production  (Jerne assays)       |

     Humoral antibody                                   j
          Direct detection of antibody in serum to  specific microbes
          via  techniques  of  agglutination,  precipitation,  or ELISA

     Disease resistance                                 j
          Directly  measured  by experimental animal  exposure to a
          specific  pathogen
          Assessed  epidemiologically; unknown field challenge
                                                        I
     Nonspecific defense  mechanisms          ,         |
          CRP  (C-reactive protein in blood)
          natural killer  cells
          nonspecific  antibody-like molecules
           interferon
                                       49

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TABLE 17. RANKING OF METHODS SUITABLE

Method
Macrophage tests
phagocytosis alone
phagocytosis,
chemoluminescence
and killing
chemo taxis
melanin &
aggregation
pinocytosis
T-lymphocyte
grafting
B-lymphocyte
Jerne assay
Humoral
Antibody produced
in injection
Antibody, non-
specific in field
Disease Resistance
Experimental
exposure
Epidemiologically
measured exposure
Natural killer cells
f" Rating scheme: 1 =
^ Tt<*«fS*4s>ts4 /M^TMT /\ne
Usefulness,
Unequivocal
Meaning

4
,

4.5
3

2
4

3

4


4

2

h
3/1°
b
3/1
2
FOR FIELD-TESTING

Cost-
Effectiveness

4


5
5

3
4

3

3


2

4


3

3
3
AT PRESENT

Availability

4


3
4

4



4'



4

5

,



2
lowest, 5 = highest
50

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approach described above. Adding the other tvo macrophage indicators to
a  monitoring  scheme  was considered cost-effective.  Other macrophage
tests  were  considered  as indicators, but ranked low in comparison to
the above.                                             I

DISEASE RESISTANCE

     The   second  highest  ranked   category  of   toxic   indicators  from
immunological   methods   was    the  disease  resistance   area.    The
experimental  measurement of disease  resistance  in feral fish  (i.e., by
injection   of   disease  microorganisms)   ranked   high.   However, a few
members  opposed   this  method  on  the   grounds  that   its meaning is
equivocal.  The method also  had a  higher  cost  compared  to  others.
                                                       I
      The    group    considered    epidemiologic    assessment  of  disease
resistance  to have one especially positive feature:  jit is universally
available.    Again,  however, the opinion was divided! as  three members
 felt it was useful, and one member strongly opposed  it.
                                                       I

' JERNE ASSAY                                          .!    ..     .
                                                       I
      A  final  method  judged  to  be  one of the strongest immunologic
                                                       i
 approaches  was ,that of Jerne assay as applied to detect B-lymphocytes
 as  antibody-producing cells.  This method received strong support from
 most members and moderate support  from all.  Members also considered it
 widely available and  cost-effective.
 OTHER METHODS
                                                       I
                                                       !
      Other   methods  considered  at  least moderately usipful by a majority
 of  the members  were  the following:
                                                       I
      o   Blood  levels of antibody (humoral)  in  feral  fish injected
          with microorganisms (not well tested,  somewhat  expensive,
  •
          widely available);
                                    51

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     o  Graft rejection (T-lymphocyte involvement),  not well
        tried, not widely available, but promising.

     The  ranking  of  methods  showed  that  all methods are generally
applicable   to   assessing   toxic  contaminant  impacts  on  finfish.
Macrophage assessments were given high utility.  These methods also can
be  pertinent to assessing impacts on the ecosystem as well as on human
health, but are less direct measures of such impacts.

Recommended Immune Indicators for Field Testing as Monitoring Tools

     Based on the evaluation criteria and ranking by the four suggested
methods, the recommended ranking of immune indicators was as follows:

     (1)  A combined macrophage assay consisting of
          chemoluminescence, phagocytosis, and killing ability5

     (2)  Experimental measurement  of disease  resistance in  feral
          fish by injection of known antigens  or microorganisms!

     (3)  Jerne  plaque assays,  (B-lymphocyte measurement of
          antibody  production);

      (4)  Blood  levels of  humoral  antibody  after defined          '  '
          injection.               ;

Research Needs

     The  subgroup identified  the following  research needs  for improving
 the usefulness  of immune indicators of  toxic  contamination in finfishs

      (1)  Immune parameters for indicating toxic assessment should
          be derived from each section of the  immunological system,
          including
          o  Macrophage assays,
          o  T-lymphocyte assays,
                                   52

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    o  B-lymphocyte assays,  and
    o  Determination of disease resistance.       I

(2) Tests in vivo should be validated with assays in vitro,
    e.g., culture of immune cells or organs and demonstration
    of effects of additives.
                                                 [
                                                 I
(3) To obtain better statistical information on the immune
    assays, inbred lines of fish are needed.

(4) Because the endocrine system of finfish greatly affects
    their immune parameters, the effects of stress on the
    immune response  in  fish requires more investigation.
                               53

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     Workshop
     on Finfish
  as Indicators
       of Toxic
 Contamination

  Sponsored by the
 U.S. Environmental
 Protection Agency,
Office of Marine and
Estuarine Protection
                      On behalf of the U.S. Environmental Protection Agency,  Office
                      of Marine and Estuarine Protection, I would  like  to  invite you
                      to participate in a workshop on Finfish as Indicators of Toxic
                      Contamination in Estuaries.  The workshop will be divided into
                      various working groups of government and academic scientists
                      and resource managers.  The primary objective of  the workshop.
                      is to determine preferred methodologies available for analyzing
                      the significance of toxic impacts on estuarine finfish.

                      The workshop will be held at the Airlie House in  Airlie,
                      Virginia, on July 28-30, 1986.  Technical Resources, Inc. (TRI)
                      will provide technical and logistical support.  Enclosed is a
                      registration form.  Please return this form  to TRI by July 11,
                      1986.        .                                !
                                                                   |

                      Also enclosed for your information is a background document,
                      Finfish as Indicators of Toxics in Estuaries, developed by
                      Margaret McFadien-Carter of the University of Delaware.
                              •
                      I hope to see you in July and look forward to your contributions
                      to this project.

                      Sincerely,   '                                ]
                      Tudor T. Davies
                      Director
                      Office of Marine and Estuarine  Protection

                      enclosures
                                                   A-l

-------

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                     WORKSHOP ON FINFISH AS INDICATORS OF TOXIC
                             CONTAMINATION IN ESTUARIES  I
                Sponsored by the U.S.  Environmental  Protection  Agency
                      Office of Marine and Estuarine Protection
                                  July 28-30, 1986
                                    Airlie House
                                  Airlie, Virginia       i
Monday July 28
10:00"a.m. - 11:15 a.m.
11:15 a.m. - 12:15 p.m.
12:30 p.m. - 2:00 p.m.
 2:00 p.m. - 3:20 p.m.
 3:20 p.m. - 3:40 p.m.
 3:40 p.m. - 6:00 p.m.
 6:00 p.m. - 7:00 p.m.
 7:00 p.m. - 8:00 p.m.

Tuesday, July 29
 7:30 a.m. - 8:30 a.m.
 8:30 a.m. - 10:20 a.m.
10:20 a.m. - 10:40 a.m.
10:40 a.m. - 12:00 p.m.
12:00 p.m. - 1:30 p.m.
 1:30 p.m. - 3:20 p.m.
 3:20 p.m. - 3:40 p.m.
 3:40 p.m. - 7:00 p.m.
 7:00 p.m.
Introduction:
  Tudor Davies
  Michelle Hi Her
  Gary Petrazzuolo
 Store Room
Background Paper Discussion  Store Room
Lunch
Individual Subgroups
Break
Individual Subgroups
Reception - Cash Bar
Dinner
Breakfast
Subgroup Summarizing
Break
Subgroup Plenary Session
Lunch
Plenary Session
Break
Plenary Session
Cash Bar and Barbeque
      B-I.
 Main Dining Room
 Livery,  Silo House
 Hitching Post,  Silo House
 Granary, Silo House
|West Room,  Main House
 South Room, Main House
 Livery,  Silo House
 Hitching Post,  Silo House
 Granary, Silo House
 West Room,  Main House
 South Room, Main House
 Garden Room, Main House
 Main Dining Room
 Main Dining Room
 Store Room
 Main Dining Room
 Store Room

 Store Room
 The Lodge

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neunesady, uuiy JU          '  -
 7:30 a.m. - 8:30 a.m.       Breakfast                   Main  House
 8:30 a.m. - 10:20 a.m.      Suogroup Summaries           Store Room
10:20 a.m. - 10:40 a.m.      Break
10:40 a.m. - 12:00 n         Closing Summary             Store Room
                                     B-2

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           FINFISH AS INDICATORS OF TOXIC CONTAMINATION IN ESTUARIES
                               July 28-30, 1986
                                 Airlie House
                               Airlie, Virginia
                               Participant List
Dr. Douglas Anderson
National Fish Health Research Lab
U.S. Fish and Wildlife Service
P.O. Box 700
Kearneysville, WV 25430
304-725-8461

Mr. Seth Ausubel
Office of Marine and Estuarine Protection
U.S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
202-475-7111

Dr. Michael E. Bender
Professor of Marine Science
Virginia Institute of Marine Science
College of William and Mary
201 Waller Mill Road
Williamsburg, VA 23185
804-642-7237

Dr. Richard 0. Bennett
University of Maryland
School of Medicine
Department of Pathology
10 S. Pine Street
Baltimore, MD 21201
301-528-7276

Mr. .Roland Borey
Project Biologist
Texaco Research
P.O. Box 1608
Port Arthur, TX 77641
409-989-6361

Dr. Anthony Calabrese
Laboratory Director
N.E. Fisheries Center
Milford Laboratory
National Marine Fisheries Service
212 Rogers Avenue
Milford, CT 06460
203-783-4200
                                      C-l

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 Dr.  Jeffrey N.  Cross
 Southern California Coastal Water
 Research Project
 646  West Pacific Coast Highway
 Long Beach, CA 90806
 213-435-7071

 Dr.  Tudor T. Davies
. Office of Marine and Estuarine Protection
 U.S. Environmental Protection Agency
 401  M Street, SW
 Washington, DC 20460
 202-382-7166

 Dr.  Kim Devonald
 Office of Marine and Estuarine Protection
 U.S. Environmental Protection Agency
 401  M Street, SW
 Washington, DC 20460
 202-475-7114

 Dr.  David W. Engel
 Acting Chief
 Division of Ecology
 National Marine Fisheries Service
 National Oceanic and Atmospheric Administration
 Southeast Fisheries Center
 Beaufort Laboratory
 Beaufort, NC 28516-9722
 919-728-8741'

 Ms. Patricia Fair
 National Marine Fisheries Service
 National Oceanic and Atmospheric Administration
 217 Ft. Johnson Road
 Charleston, SC 29412
 803-762-1200

 Ms. Mary Jo Garreis
 Chief of Division  of  Standards  and  Certification
 Department of Health  and Mental Hygiene.
 State of Maryland
 201 W.  Preston Street
 P.O Box 13387
 Baltimore,  MD  21202
 •301-225-6293

 Mr. Larry Goodman
 Research Biologist
 U.S.  Environmental Protection Agency
 Sabine Island
 Gulf  Breeze,  FL 32561
  904-932-5311
                                     C-2

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Dr. William J. Hargis, Jr.
Virginia Institute of Marine Science
College of William and Mary
Gloucester Point, VA 23062
804-642-7362

Ms. Michelle Hiller  -
Office of Marine and Estuarine Protection
U.S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
202-475-7102

Dr. Joseph B. Hunn
U.S. Fish and Wildlife Service
Columbia National Fisheries Research Laboratory
Route 1
Columbia, MO 65201
314-875-5399

Dr. Kenneth D. Jenkins
Molecular Ecology Institute
California State University, Long Beach
Long Beach, CA 90840
213-498-4906

Dr. Braulio D. Jimenez
Research Associate
Oak Ridge National Laboratory
Environmental Science Division
P.O. Box X
Oak Ridge, TN 37831
615-574-7321

Mr. Caret Lahvis
Aquatic Biologist
Great Lakes National Program Office
U.S. Environmental Protection Agency
230 South Dearborn
Chicago, IL 60604
312-353-2694

Dr. Eric B. May
Department of Pathology
University of Maryland
School of Medicine
10 S. Pine Street
Baltimore, MD 21201
301-528-7276 or 5184

Dr. Margaret McFadien-Carter
Marine Scientist
Robinson Hall
College of Marine Studies
University of Delaware
Newark, DE 19732
302-451-1194

                                     C-3

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Mr. Victor McFarland
Aquatic Biologist
Waterways Experiment Station
U.S. Army Corps of Engineers
P.O. Box 631
Vicksburg, MS 39180
601-634-3721

Mr. Dale Miller
Northeast Utilities Environmental Laboratory
Millstone Nuclear Power Station
P.O. Box 128
Rope Ferry Road
Waterford, CT 06385
203-447-1791 x4533

Dr. Jerry Neff
Battelle New England Marine Laboratory
397 Washington Street
Duxbury, MA 02332
617-934-5682

Dr. Joel S. O'Connor
Ocean Assessments Division
National Oceanic and Atmospheric Administration
11500 Rockville Pike
Rockville,°MD 20852
301-443-8698

Dr. William A. Richkus
Director, Ecological Sciences and Analysis
Martin Marietta Environmental Systems
9200 Rurasey Road
Columbia, MD 21045
301-964-9200

Mr. Norman Rubenstein
Research Aquatic Biologist
U.S. EPA Laboratory
South Ferry Road
Narragansetft, RI 02882
401-789-1071

Mr. Jay Sauber
State of North Carolina
Division of Environmental Management
P.O Box 27687
Raleigh, NC 27611
919-733-6510

Dr. Jan Spitsbergen
Research Associate
University of Wisconsin/Madison
37 Pine Hill Road
Port Jefferson, NY 11777
516-928-7869
                                      C-4

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Dr.  John  Stegeman
Associate Scientist
Bepar-tsneiYt  of Biology
Woods Hole  Oceanographic Institute
Woods Hole, MA  02543
617-548-1400 x2320

Dr.  James P. Thomas
Estuarine Program Office F/EPO
National  Oceanic and  Atmospheric  Administration
Universal Building, Room 625
1825 Connecticut Avenue,  NW
Washington, DC  20235
202-673-5243

Dr. Beverly Anne Weeks
Associate Professor
Virginia  Institute of Marine Sciences
College of William and Mary
Gloucester Point,. VA  23062
804-642-7346

Dr. Judith Weis
Professor
Department of Biological  Science
Rutgers University
Newark, NJ 07102
201-648-5387
                                       C-5

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a:a
              ur IUAIU UUN i
                                       Participant.'; by Work Group
ANATOMIC PATHOLOGY:

    Eric May, Chair
    Mary Jo Garreis, Recorder

    William Hargis
    Joseph Hunn

BIOACCUMULATION AND ENZYMES:

    Jerry Neff, Chair
    Patricia Fair, Recorder

    Michael Bender
    David Engel
    Kenneth Jenkins
    Braulio Jimenez
                                      Garet Lahvis
                                      Victor McFarland
                                      Norman Rubenstein
                                      John Stegemari
                                      Dale Miller
                                      William Richkus
                                      James Thomas
REPRODUCTION AND DEYELOPMENT/PHYSIOLOGY/BEHAYIOR/POPULATION:

    Joel 0'Conner, Chair
    Judith Weis, Recorder

    Roland Borey
    Anthony Calabrese
    Jeffery Cross
    Larry Goodman

IMMUNOLOGY:

    Richard Bennett, Chair
    Douglas Anderson, Recorder

    Margaret McFadien-Carter
    Jan Spitsbergen
    Beverly Anne Weeks

WORKSHOP LEADERS, FACILITATORS, AND SUPPORT STAFF

    Tudor T. Davies, Director, OMEP
    Michelle Hiller, Chief, Technical Guidance Branch OMEP
    Seth Ausubel, OMEP
    Kim Devonald, OMEP (facilitator, Immunology)

    Gary Petrazzuolo, TRI (Workshop Moderator)
    Joanna Fringer, TRI (facilitator, Anatomic Pathology)
    Darcey Rosenblatt, TRI (facilitator, Bioaccumulation and Enzymes)
    Drew Zacherle, TRI (facilitator, Reproduction etc.)    !
    Willie Sanderson, TRI                                  ;
    Lorraine Sickels, TRI
                           D-l

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1

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              Background Paper
Finfish as Indicators of Toxics in Estu«iries
 For  EPA  Cooperative Agreement CX812956-01-1
                Submitted  tos            |

    U.  S.  Environmental Protection Agency
  Office  of Marine  and Estuarine  Protection
            Washington, DC  20460       I

                Prepared by:

          College of Marine  Studies
           University of Delaware
           Newark,  Delaware  19716

                 June,  1986

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1

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                        TABLE OF CONTENTS
1.  INTRODUCTION	    3
      1.1  Workshop Objectives .........  e  o  	    3
      1.2  Biotic Indicators for Toxic Pollution	  .    3
2.  OVERVIEW OF FINFISH AS INDICATORS OF TOXIC POLLUTION ...    4
      2.1  Working Definitions of Toxic  Pollution and Stress  .    4
      2.2  Historical Sources of Toxic Substances  	    8
      2.3  Use of Finfish as Indicators of Toxic Pollution .  .   12
      2.1  The Problem of background Noise
3.  FINFISH INDICATORS OF TOXIC POLLUTION  .  .  .	15
      3.1  Bioaccumulation/Tissue Concentrations  	   16
      3.2  Histopathology  ...	   17
            3.2.1  Non-Oncogenic	• .	17
            3*2.2  Oncogenic .	  .  .	   19
      3.3  Immunology  .	   21
      3.4  Reproduction and Development  ...;.;	23
      3.5  Enzymology	j.......   26
            3*5.1  Enzyme Induction	.   26
            3.5.2' Molecular Pathology	!	29
      3.6  Physiology	31
      3.7  Population	•...;.	33

SUMMARY	, . . . o	35

LITERATURE CITED ... 	 ...........   36
                              TABLES               i

TABLE 1  Survey of Effects of Toxic Chemicals in Finfish ...    6

TABLE 2  Abbreviated Listing of Industrial Uses of Some
           Potentially Toxic Metals  	 .. .,	 .    9
                           E- 1

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                         1.'INTRODUCTION




1.1   Workshop Objectives








      The primary  objective  of this workshop is to determine  the



relative  usefulness  of  finfish  indicators for  toxic impacts  in



estuaries.   Technical  specialists  and  resource  managers  will  help



determine the most accurate, replicable,  and cost effective  metho-



dologies immediately  available  for  analyzing  toxic impacts  in



estuarine  finfish.   Potential  indicator  methodologies will  be



evaluated  based  on workshop  participants'- answers  to  a  set  of



questions  and criteria provided  by  the  workshop  coordinators.



These  evaluations  will offer estuary program managers a technical



appraisal  of  the strengths  and  weaknesses  of  approaches using



finfish indicators to  assess toxic  impacts.








1.2   Biotic Indicators for Toxic  Pollution







       Physical factors (e.g., hydrodynamics, sediment type, sediment




transport)  and cnemical  factors  (eg., salinity, redox  reactions,



sorption/desorption processes, and chemical reactions)  affect  the



 fates and effects of  toxic substances.  Input rates.of  nonconser-



 vative pollutants to the environment can also  influence  their  fate



 and the  expression of toxic responses (Cairns,  1986a).  Organisms



 can  accumulate,  and transport,  metabolize  (resulting  in  both



 detoxification and  intoxification), and physically process  (e.g.,



 fecal pellet formation)  toxic compounds, thus affecting the physical




                           E-2

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and chemical factors  that  influence  the  fates of toxic substances


in the environment.  Consequently,  the impact of toxics in estuaries


depends on  both abiotic and biotic  characteristics  and processes


that  interact  through complex relationships.  Pollutant  loads and


ambient concentrations  may not,  in themselves,  offer good predic-


tions of toxic  impacts.  Because'of the variability of environmental


conditions, measurements of effects of toxicity often provide a more
                                                   I

meaningingful indication of environmental quality (Cairns, 1936b).
                                                   I

 Field analyses of toxic responses are desirable  to evaluate actual

                                                   i
impact on any given estuary.  It is also particularly desirable to
                                                   I

identify members  of  the  biota  that will  offer  accurate  early


warning systems of pollutant damage.
    2.  OVERVIEW OF FINFISH AS INDICATORS OF TUXIC POLLUTION
2.1   Working Definitions of Toxic Pollution and Stress
      The  words  "toxicants"  and  "toxics" will  be used  in this
    .
                                                   i
paper to mean chemicals that  produce acute or chrome deleterious
                                                   l

effects  on finfish and/or other estuarine biota,  j Effects caused


by toxics  may be systemic, teratogenic and carcinogenic as well as


any other  effects  that reduce reproductive fitness! or shorten the


individual's  natural life.
                                              pressure
      The  term  "stress"  may refer  to any


principal that alters the natural processes (physiological



                         E-3
•!  or  forcing


 al, develop-

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mental, or behavioral) of an organism.  Stress induced by exposure



to  a  toxic  chemical  could ultimately have  negative or  neutral




effects.







      Examples  of negative  stress would  be toxic  effects  that



ultimately  shorten the  organism's life,'  impair  its reproductive



success,  or  result in adverse,  toxic  effects in organisms higher



on the food chain,  through accumulation or metabolic transformations




of toxic  substances.







       An  example of stress  with neutral  effects  might  be the




metabolism  of a small  amount of  a toxic  chemical  to .a non-toxic



excretable daughter chemical, with no production of  toxic, reactive



intermediates.   This type of  stress  utilizes energy reserves  of



the  organism.  However,  the organism  is not  permanently impaired,



and  significant  effects  on reproductive  success   are  unlikely.







       Beneficial results of stress are feasible.  An example here



would be the stimulation of  metal binding proteins  by exposure  to



 a toxic metal that increases  an  organism's resistance to subsequent



 exposures  to  toxic  metals.    However,  these  benefits generally



 apply  only  to  further  toxic stresses, and  often  do  not  include




 larger ecosystem  effects.







     .  For  the  remainder of  this  paper both neutral and negative



 effects  will be considered.  The  emphasis, however,  will be on  the
                         E-4

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concept  of negative stress.  In summary the  following  classifica-

tions  of "stress  caused by toxic  chemicals"  will  bei  considered:
      Neutral  stress:    pressure from toxic  chemicals on  finfish
                                                   I
                         causing altered  physiology  or inorphology

                         without permanent impairment of the  orga-

                         nism's lifespan  or reproductive success.

      Negative stress;   toxic  pressures  causing  acute or  chronic
                                                   l

                         and subiethal  effects  that  decrease an


                         organism's lifespan and/or its  reproductive

                         success„   These pressures might result in
                                                   i
                         Deduced  survival  of  offspring,   altered

                         fecundity, lowered growth rate,, suppression

                         of  immune responses,  pathological tissue
                                                   i
                         changes,  genetic  changes, or anatomical or

                         physiological  changes deleterious  to the

                         individual organism.


      Types  of  effects due  to  toxic  stress considered  in  this
                                                   I

paper are shown in Table 1.  It  is useful to distinguish among (a)
                                                   l
pathological, (b)  physiological without pathological!  (c) pathologi-
                    '
cally-induced  behavioral,  and  (d) strictly  behavioral effects of

toxic stress.  The selection of stress indicators for;.  this paper was

based,  in part,  on identification  by  investigators  of  probable

causative factors  for  the  effects being  studied.  'These  are  also
                                                   l
                                                   i
shown in Table 1 .  While negative effects due to negative stresses
                                                   I
are emphasized, neutral stresses and their effects are also consi-

dered.

                         E-5

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                                    Table 1
                Survey of Effects of Toxic Chemicals in Finfish
I.  Negative effects/negative stress: chronic, sublethal effects deleterious to
    individual organism.
Effect

A.  Bioaccumulaton/
    Tissue Concentrations
                                          Type of Effect
                  Documented
                  Causative Agents
Physiological/    PAH, PCB, Chlorinated
pathological      hydrocarbons
B.  Histopathological                     Pathological
      1. Fin erosion, ulcers,  cataracts
      2. Neoplasms
                  PAH, PCB, Chlorinated
                  hydrocarbons
C.  Immune effects
    (repression/stimulation)


D.  Reproductive  and developmental
    effects
 E.   Deleterious results reflected by
     enzyme alteration

 F.   Deleterious metabolism of
     chemicals (toxification)
Physiological:    PAH, PCB, Metals
 can lead to
pathological

Physiological:    Metals,  PAH,  PCB,
 can- lead to      Chlorinated
pathological      hydrocarbons
 Physiological
 Physiological
    reflects
 pathological
 G.  General physiological alterations     Physiological/
     (gill respiration, osmoregulation)    pathological
PCB, PAH,  Metal


PAH, PCB
                   PAH, PCB, Chlorinated
                   hydrocarbons
 H.  Behavioral and population alterations Pathologically    PAH, Metals,
     ^.,« *„ off^t-.* on individuals         or                Chlorinated
                                           %*•
                                           Physiologically   hydrocarbons
                                           induced behavior
 II. Neutral effects/neutral  stress: chronic effects with latered physiology but
     with no permanent  impairment  of organism.

                                           Type of Effect     Documented Stress
 &f rGCt*                                    •  •" •—  """

 A   Non-injurious  enzymatic  alterations   Physiological/     PAH, PCB, Metals
                                           non-pathological
  B.   Metabolism of  toxic parent to
      non-toxic daughter chemical
      (detoxification)
 Physiological/     PAH,  PCB
 non-pathological
                               E-6

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2.2  Historical Sources of Toxic Substances





                                                  i

      The sources,  fates ana possible effects of toxics in estuaries



currently are subjects of  considerable concern among scientists and



environmental managers.   Toxics  include  polyaromatic  hydrocarbons



(PAHs)  and  other  petroleum-related compounds,  polychlorinated



biphenyls  (PCBs),  pesticides, other  synthetic organics,  and  toxic



metals.




                                                  I


      Petroleum-related  sources  include marinei transportation,



accidental  spills,  municipal  wastewater discharges,  refinery



wastes, industrial wastes and urban runoff. Nonpoint  sources such
                                                  i
                                        .

as urban runoff may constitute a major portion of petroleum poilu-
   •


tion.  There is also concern that atmospheric transport may contri-



bute more to petroleum pollution of surface waters than previously



believed or documented (National Research Council, 1985).
      Primary sources  of  PCBs to the environment  include  leakage



from closed electrical  systems, such as transformers and capacitors,



and  losses during  the manufacture and  use  of hydraulic  fluids,



lubricants  and heat  transfer  fluids.  Other  sources  include  adhe-



sives, plasticizers, pesticide extenders,  and dyes.   PCBs  disposed



in landfills also may represent a significant pollution hazard.
      Pesticides  typically  reach surface  waters  from  nonpoint



sources, runoff and atmospheric  settling which result from agricul-






                        E-7                       !

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tural, parkland, suburban, or urban pest control  efforts.  Another



source  of  increasing concern  is municipal wastewater  effluents,



which contain surprisingly  high pesticide  concentrations  as a



result of household use (Carter, 1985).







      Other  synthetic organic  toxicants  of particular concern



include: dioxins, phthalate esters, haloethers, chlorinated hydro-



carbons  (other  than  pesticides),  organoraetallic  compounds, nitro-



benzenes,  nitrosamines,  benzidines,  phenols,  acrolein, acrylo-



nitrile, dichloro-5-fluoromethane, benzo(a)pyrene.  These chemicals



are released from a number of industrial,  domestic, and agricultural



sources.







      Toxic  metals  includes   aluminum,  antimony,  arsenic, barium,



beryllium,  bismuth,  boron,  cadmium,  chromium,  cobalt, copper,



gold, iron,  lead, lithium, manganese, mercury, molybdenum, nickel.



palladium, platinum, selenium, silicon, silver, tellurium, thallium,



tin,  titanium,  vanadium,  zinc and zirconium.   Sources  of most  of



these metals are primarily industrial.  A partial list of industrial



metals considered toxic to humans is demonstrated in Table 2.
                         E-8

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Metal
                      Table  2
   Abbreviated Listing of Industrial Uses of Some
              Potentially Toxic Metals

             *  -  Considered highly toxic
Table developed from data available in Berman (1980)

           Modern Use                        I
 Antimony:



*Arsenic:


*Barium:


 Beryllium:


 Bismuth:


•Cadmium:
 Chromium:


 Cobalt:

•Copper:


 Gold:



 Iron:



"Lead:
           alloyed with  lead,  tin  and copper, a  flame retar-
           dant  in paints,  enamels  and lacquers: also  used
           in  printed  type.

           smelting, rodenticides,  insecticides,  herbicides,
           glass  and enamel  manufacture.     i

           electroplating,  glass manufacturing,  sugar refi-
           ning;  also  in television  tubes  and explosives.

           alloyed with  copper in  electrical equipment;  used
           in  producing  optical glass,  nuclear reactors.
                                    *
           used  in  electrical fuses, facial  powders and
           producing artificial pearls.

           used in electroplating,  engraving, 'dental  amalgam,
           glass  manufacture,  ceramic glazes; Jaune brilliant
           (Cadmium  sulfide)  used  to  color  glass, soaps,
           fireworks and textiles.
           used in manufacture of  stainless  steel,  in  photo-
           graphy and  as  corrosion inhibitor.

           used in alloys and nuclear  technology.

           insecticides,  fungicides, germicides; as pigment
           in textiles and ceramics.
           other  than currency,  used medicinally,  in  printed
           circuits,  semi-conductors and in the space industry
           in glass  to metal  seals.

           other  than manufacture of  steel; ferric chroraate
           in pigments, ferric hydroxide  in water  purifica-
           tion,  the oxide as a  polishing  agent and pigment.
                                            l
                                            I
           although  reduced in paints, still high  levels  in
           putty  and plaster,  glazed earthenware,  in  pewter,
           chafing dish candles,  hair dyes,  color in maga-
           zines.
                                 E-9

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Metal
                   Table 2
Abbreviated Listing of Industrial Uses of Some
           Potentially Toxic Metals

       Modern Use
*Lithium:


*Molybdenum:




 Nickel:



 Palladium:



 Platinum:

*Selenium:


*Silver:



"Thallium:


 Tin:



 Titanium:




  Vanadium:



  2inc:


  Zirconium:
       aerospace  alloys,  lubricating greases,  metal
       cleaners photography.

       as  alloy  for  special  steel  in rifle  barrels,
       propeller  shafts, boiler plate,  x-ray  tubes;  as
       lubricant additive (toxicity has  been demonstrated
       to  be  species specific).

       storage batteries, spark plugs, cooking utensils,
       detergents; Raney  nickel  (equal parts  aluminum
       and nickel)  used  for hydrogenation of oils.

       metal  plating;  catalyst  in electrical  industry;
       as  alloy with Ag, Au or Cu for  jewelry and dentis-
       try.

       dentistry,  jewelry, and  in  electrical industry.

       manufacture of plastics,  rubber,  ceramics, ink,
       glass, paint pigments, photoelectric cells.

       besides  tableware,  jewelry,  and  dentistry,  as
       alloy with  many  metals.   Also as steel coating;
       in manufacture  of solder.

       amalgam with Hg;  alloy in switches;  in manufacture
       of pigments and dyes,  as rat poison.

        diverse uses:  food containers, electrical,  radio,
        automobile parts; color for china, fabric  dying;
        organic complexes as  biocides.

        for strengthening  steel;  useful alloy with many
        metals; titanium dioxide used  in creams, powders,
        sun protection,  in paint,  plastics  and  leather
        work, trichloride in laundering.

        allows with Pb, Mn, Cr::  rust resistance, strength-
        ening steel, photographic developer, dying cottons,
        silks, leathers and furs.

        manufacture of  bronze  and  brass.   coating  on
        iron, steel.

        shielding in nuclear submarines and power reactors,
        used  in  production  of  paints, flashbulbs  and
        detonators; chloride and acetate as textile water
        repellents.

                       E-XO

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2.3  Use of Finfish as Indicators of Toxic Pollution
      Criteria  for  evaluating toxic  effects  in Ecosystems  have

been suggested  by the  National  Academy of Sciences  (NRC,  1981).

They  surveyed  laboratory  and field  methods,  including  chemical

characterizations, single-species  tests, multi-species  tests,  and

ecosystem tests.  Ultimately they suggested that:  |

      "research should be conducted to develop test procedures
      that can  provide  multiple  sets  of data.  Tests snould
      be designed  to  provide short-term results  about long-
      term effects."
      This NRC study recommended  that  four  classes
should be collected:

      •  Characterization of test substance

      •  Physiological responses of species

      •  Multi-species responses

      •  Ecosystem responses.
of information
      Collecting all four classes of data will serve  the following

purposes for testing toxic effects:

      •     determine partition coefficients  for  movement  of

            chemicals in the system,

      •     identify the toxic potential  for  major transformation

            or degradation products,

      •     account for  variability in natural syistems  affecting

            dose to biota  or exposure time within a  compartment,

            and help distinguish  natural variations ;from chemically

            induced variations in ecosystems  (NEC  1981).


                             E-ll

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      By evaluating  physiological responses of  sensitive  species



in the laboratory,  discrete morphological genetic, biochemical, and



pathological  effects of  particular  chemicals can  be  identified.



Subsequent  ecosystem response studies can  evaluate the  extent to



which these processes are expressed  in the  field,  and the ways in



which occurrence of  morphological, genetic,  biochemical and patho-



logical  changes in  single species  in situ affect  the  abundance



and distribution of  the species of concern and those that interact



with  them.   Identification of some  single  species  impacts in the



field may then  offer pollution abatement monitoring programs rapid



identification  methods for  long-term problems.








     ' Finfish,  as  a  group,  offer  monitoring programs several bene-



fits.   Analyses  of  physiological and pathological  effects of



parent  and daughter chemicals  have  demonstrated that finfish are



susceptible to  a number of  readily identifiable  and some less well



understood  effects  of toxic  stress  (Couch  and Harshbarger,  1985;



O'Connor et al., 1986; Malins et  al.,  1980, 1983, 1985; Murchelano.



and  Wolke,  1985;  NRC  1985; Hargis  et  al.,  1984).   They are also



capable of transforming  parent chemicals into more toxic  daughter



chemicals  (TetraTech,  1985).  They are  at sufficiently high trophic



levels  that  they  are  likely to serve as early-warning  indicators



because of bioconcentration  effects.   Altered  finfish  physiology



and  pathology  in  field  specimens therefore  seem  likely to  offer



environmental  managers  particularly  useful  warning  systems for



chemical pollution of estuaries.






                           E-12

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      One potential  problem with the use of  finfish as indicator

                                                  i

organisms is  their mobility.   The benefits  and  disadvantages  of

                                                  i

using relatively mobile  organisms  as  toxic  stress indicators will



be discussed later in this background paper.
     The Problem of Background Noise
      To  identify  pollution  due  to  toxics,  it  is  necessary  to


distinguish  between toxic effects  and  background noise  in  any


given population or ecosystem.  Background noise may be defined as
                                                  i


natural  variations  in  Measurable  biotic  processes that  are  not
                                                  i

causally related to the toxic pollutant or other  disturbance that


is of concern. Differentiation between toxic effects and background

                                                              •

noise can be  difficult  to  accomplish.   Clear causal relationships


should be  established in the laboratory  whenever  possible.  It is


necessary to  measure background noise  in all  monitoring programs
                                                  i

to obtain valid  stress  analyses in the  field.   Robert Livingston
                                                  i

has  provided  an excellent review of  the problem of evaluating


background noise;  this  review is  included as  Appendix A  of tnis


document.
                         E-13

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            3o   FINFlbH INDICATORS  OF TUXIC  POLLUTION
      The remainder of this background document  describes specific



effects of toxics on finfish as listed  in Table 1.  An introductory



chapter  summarizing  and characterizing the  effects reviewed  is



followed by a  series  of  papers by  specialists describing methodo-



logies for analyzing  particular  effects.   In some cases, where  a



previously published  review .article or technical  report presents



the necessary information on a. given method or  methods, that  article



or report has been included with  the author's  permission in lieu of



preparing original text  for  this report.







       Effects ' are discussed under the following  major  headings?



Bioaccumulation/Tissue concentration; Histopathology: Non-oncogenie;



Histopathology:  Oncogenic;  Immune  Effects; Effects on Reproduction



and Development;  Enzyme Alterations; Metabolism  of Toxicants;



General  Physiological  Alterations;  and  Population Alterations.



Many effects fall into  more than  one of these categories, and  it



 is not intended that  great significance  be placed on the details



of the categorization  presented here for purposes  of discussion.



 The  objective  of  the workshop  discussions will  be  to  address



 strengths  and  weaknesses  of  individual  measurable  effects  as



 indicators,  and the merits of methodologies used for these measure-



 ments.   Each indicator will  be  evaluated  on  its own merits,  so



 that  assignment  to  one  or another  general category should  not




 affect the evaluation.





                             E-14

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3.1  Bioaccumulation/Tissue Concentrations
      The biological uptake of toxics through food, water, sediment
                                                  i
contacts or a combination of exposures and retention in tissues is

called  bioaccumulation.  A number of factors affect this process.

The  bioaccumulation  potential of a  substance  is  dependent  on its

chemical properties, the affected organism's mechanisms for uptake

and  elimination,  and  the  environmental  factors influencing its

bioavailability.   Examples  of the  variability  of  intrinsic and
                -              -                    I
extrinsic chemical processes in bioaccumulation of various toxicants

are given by trace metals.  While bioaccumulation of Cd and Cu are
                                                  I
                                                  I
primarily  dependent  on  free  ion  activity,  bioaccuraulation and

toxicity of silver appears dependent on formation of chlorocomplexes

(Engel et al., 1981).                             j



    .
      Physical  and  chemical partitioning of  toxics  as  they enter

an  estuary  influences  exposure routes  to  the  biota.   Benthic
                                                  I
fauna and demersal fish are most likely to be affected by toxicants'
                                                  I

associated with particulates.  it has been demonstrated that  direct

sediment contact  contributes  significantly  to PCB bioaccumulation

in  demersal  fish.  Although  dietary contributions  of PCBs  were

high, fish without direct sediment contact accumulated significantly

lower PCB residues (Rubenstein et al., 1984).
                           E-15

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      Bioaccumulation is  ultimately  determined by the  organism's
ability to metabolize, transform, and excrete a  toxicant„  Clearance
ability can be related to amounts  of  adipose tissue  as  well as to
length or  pattern of exposure  to' the  chemical.  Lipid binding aue
to hydrophobia  interactions, has been demonstrated by the greater
bioaccumulation of aromatic hydrocarbons over alkenes in petroleum
polluted  waters  (Neff,  1976).   Ultimate clearance rates appear to
vary considerably among taxonomic  groups of  fishes and may even be
species-specific (Neff, 1976;  TetraTech, 1985).

       Other biological influences  on ultimate tissue  burden  include
membrane  permeability and the potential for translocation of  the
chemical   from  the  absorption  site  to  other  tissues  (TetraTech,
1985). For  a more  detailed  discussion of  this topic the reader is
referred  to O'Connor's review  in Appendix B.   Finally,  it  should
be noted that low tissue  burdens   do  not  necessarily  indicate
 insignificant  effects  of bioaccumulation since some  metabolized
 daughter compounds   are toxic in extremely  small amounts (TetraTech,
 1985).

 3.2   Histopathoiogy
 3.2.1  Non-Oncogenic

        Sublethal  chronic  exposure  to  certain toxics  can  cause
 cellular  damage in  the skin, liver,  eye lens and  intestines of
                              E-16

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pelagic  and  benthic  fish  (Hargis  et  al., - 1984:  Haiwkes,  1979).



Chronic exposure to petroleum causes  not only direct tissue lesions



but also  apparently via  the lesions  increases  susceptibility to



parasitism, bacterial  infection and viral disease  indirectly via



these toxicant-induced lesions (Hodgkins et al.,  1977; Sinderraann,



1979).






      Synergistic  actions of  toxicants can  increase  severity of



tissue lesions.    Hawkes  (1979)  demonstrated  that while  chronic



exposure to RGBs alone caused sloughing of intestinal mucosa, the



severity of  the problem  increased when the  fish were exposed to



combined PCBs and petroleum fractions.  Fin rot and cataracts have



been correlated with sublethal chronic exposure of finfish to sewage



effluents, and  synergistic  actions  of pollutants .including toxics

   .

have  been  identified  as  a  possible cause of these  pathological



disturbances (Hillman et al., 1986),,
                                                  i





      Controlled studies have specifically correlated integumental



lesions with .certain-toxics.  Finfish exposed to  sediment contami-



nated with PAHs  demonstrated severe  lesions  and  uiceration within



8 days while  control fish demonstrated no  lesions  (Hargis et al.,

               .

1984).   Weis and coworkers  have  suggested that  fin deterioration



is a  natural  occurrence due to abrasion in demersal  fish and that



lesions  result from   inhibition of  regeneration  due  to  toxics
                                                  i


(pers. corani.  J. Weis, May,  1986).   Methylmercurie  chloride and



cadmium  chloride have  been shown to  retard fin regeneration in




                             E-17


-------
fishes (Weis and Weis,  1978).   Fin regeneration was also retarded



by DDT, malathion, carboryl, zinc, parathion and PCBs.  It was not



strongly  affected by  quantitative diet  changes or  fish density




pressures  (pers. cbmm.  J. Weis, May, 1986)«







      The  possibility, of adaptation to  pollution is suggested by



increased  raethylmercurie tolerance in female killifish  correlated



with  increased fin  ray count (Weis et  al.,  1981;  Weis and  Weis,



198H).   A  paper  in preparation  by J.  Weis,  P. weis and  Zimmerer



discusses fin regeneration  and its usefulness as a  monitoring tool



for toxics. The correlation of exposure to toxics,  especially PAHs



and PCBs, with integuraental lesions including finrot, gill deteri-



oration, and  cataracts has been well  documented and  is reviewed



more  thoroughly,  with  descriptions  of current  methodologies for




 measuring the effects  in Appendix C.
 3.2.2  Oncogenic







        Occurrences well  above background levels of liver neoplasms



 in  finfish in  polluted estuaries have  been clearly demonstrated




 over  the  last  decade (Malins  et  al.,  1980,1983; McCain  et al.,




 1977,  1982).   Such neoplasms have also been reported in fish from



 polluted fresh waters.   While most estuarine and freshwater fish




 studies  have  concentrated on the  effects of  PAHs  and PCBs  there  is



  evidence that heavy metals  can also be correlated with carcinomas




  (Couch & Harshbarger, 1985).




                              E-18

-------
      Malins et al. (1985) have recently demonstrated field corre-



lations  of  increased hepatic  lesions among  English sole  with



sediment contamination  by aromatic  hydrocarbons.   In this  case



the dietary  uptake of the  chemicals  was documented.  Baumann  et



al. (1982)  have similarly documented hepatomas in wild populations



of English sole and tomcod.
      Contradictory  evidence  has  been presented  with regard  to



cutaneous papillomas in demersal fish.   While Dawe and Harshbarger



(1975)  demonstrated  increased occurrence of  these disorders  in



industrialized  areas,  Iwaoka  et al.  (1979) presented  inconclu-



sive data on the relationship of  toxic effects and siuc'h superficial




tumors.
      Pituitary alterations can also  be indicators tbf toxic stress.



Pseudocysts developed in sheepsheaa minnows'  pituitary glands when



the fish were subjected  to  the  herbicide  trifluralin.   These fish



were consequently functionally damaged, demonstrating bone disorders



including vertebral dysplasia (Couch, 1984).       ;
      In  overview,  there  is  a  considerable  body of  literature



indicating  correlation  of PAHs,  PCBs,  and heavy metals with  in-



creased  occurrence  of  cutaneous  carcinomas,  liver neoplasms  and



histopathological  changes  in freshwater  and estuarine  finfish



(O'Connor et al., 1986;  and Malins,  1983).
                            E-19

-------
      The body of information showing correlations of toxic  chemi-



cals with lesions ana subsequent infection and with carcinomas  has



lea to considerable effort towards classifying tumors and monitoring



f inf ish histopathology in polluted estuaries (Couch and Harshbarger,



1985; O'Connor et. al., 1986; Whipple, 1984; Whipple et al.,  1984).



A  detailed review  of  carcinomas is  provided in Appendix D.   An



important  objective of  the present  workshop will be  to discuss



strengths and  weaknesses   of  available field  monitoring method-



ologies  for these effects, as well as what is known of the signifi-



cance of  the  effects  on  individual organisms,,  populations  and



biological communities..
3.3   Immunology







       As noted above, chronic sublethal exposure to toxic chemicals



is  believed to predispose finfish to parasitic,  bacterial,  fungal



and viral infections (Hawkes, 1979; Weeks et  al.,  1986a;  Whipple,




1984; Whipple et al.,  1984)).







       Investigations  comparing estuarine  species from  polluted



waters  with  controls from unpolluted areas  have  demonstrated that



 macrophage activity  in finfish is markedly affected  by water (or



 sediment) quality.   Macrophages serve  as the  first line of defense



 against  infection by  uptake  or  endocytosis of  disease agents.



 Chemotaxis  (response  to chemical  stimulus),  phagocytosis (uptake



 of  particulates)  and  pinocytosis (uptake  of fluids)  are processes





                          .E-20

-------
 involved in normal  endocytosis.   Research  has demonstrated that

 each  of  these  processes  can be altered by  the presence of environ-


 mental  pollutants,  increasing finfish susceptibility to infection
                                                  i
 .
 and  disease.   However,  variations  are  species-specific.   Also,

 subsequent  return of fish  to  clean water has been found to reverse


 macrophage  activities to normal (Weeks et al.,  1984,  iy86a, 1986b).


'

      Freshwater studies of the cellular  immune response in finfish


 have  further suggested that primary and secondary responses are diet

 related  (Blazer et  al.,  1984K   This  would  suggest  the  impor-

 tance of toxicant uptake through ingestion.




      Other studies have  found  that fish exposed]  to  enderin had
                                                  j
 increased  serum  cortisol  concentrations,  contributing  to  the

                                                         "
 repression  of tne immune response   (Bennett  et al.,   1985  a,b).


 It  has  also been suggested that  analyses of pigmented macrophages

 from  finfish  reticulo-endothelial systems (RES) may  serve as  a

 means of monitoring immune alterations  and  fish health (Wolke et

 al.,  1980).
       A  detailed review of  immune  effects of 'toxic  chemicals


 including  a  description  of state-of-the-art  methodologies  has

 been  prepared for  this report by Weeks, et al. (Appendix E)
                            E-21

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3.U  Reproduction and Development








      A  number  of  studies  have  described reduced  reproductive




capacity, fecundity and gamete viability in fish exposed to chronic



sublethal  toxic stress  (e.g. Engle,  1979; Whipple,   1984;  Spies



1985).   Surviving  juveniles  are often subject  to abnormal hemato-



poesis  (Longwell et  al.,  1983; Perry et  al.,  1984)  as  well  as



neurological and skeletal abnormalities (Weis & Weis,  1979).   Some



examples  of  effects of toxicants are  discussed  below.   Detail  on



these and discussion of other effects of toxic chemicals on repro-



duction and development may  be  furthered during the workshop.








      Monocyclic aromatic  hydrocarbons (MAH),  zinc, DDT, PCBs and



total residual  chlorine  have  frequently been  correlated with



reproductive  and  larval  abnormalities.   Increased petrochemical



concentrations  have been found   correlated with egg resorption and



abnormal  reproduction.  Benzene has  been found to  cause a  particu-



larly large number  of effects including induction of egg resorption



and association with gill parasites in adults.  Blood cell  destruc-



tion  and decreased serum proteins  in juveniles are also associated



with  benzene.   When combined;  with  zinc,  benzene affects striped



bass  by  severely accelerating parasitism,  blood  cell deterioration



and a decrease in  serum proteins.







       Aonormal egg development  has  been  directly associated with



 levels of DDT in striped bass ovaries (Whipple et  al., 1984).  DDT
                                 E-22

-------
is also associated with neurological defects  in sheepshead  minnow

development (weis & Weis, 1979).  PCBs caused delayed egg maturation

in  striped  bass (Whipple et  al.,  1984).   Arclor  125^  (a  PCB)

likewise reduced survival of embryos and fry of sheepshead minnows

(Hansen et  al.,  "1973).   Tests of  toxicity  of the cupric  ion  on

eggs of spot and Atlantic silverside found considerable differences

in  sensitivity  at  time  of  hatching, with  the  jsilverside  more
                                                  I
severely affected (Engel  et al., 1979).  Cadmium,!  copper,  nickel
                                                  i
and zinc  have all been associated  with reduced egg  viability  in

the striped  bass (whipple  et al.,  1984).   Exposure to a number  of

heavy metals caused skeletal  defects  in  developing  killifish

juveniles.  Mercury salts most severely affected skeletal develop-

ment  while  lead  impairs  uncurling in  certain estuarine fish after

hatching (Weis & weis (1979).   Kepone was found to pause scoliosis,

neurological  impairment and impaired growth in juvenile sheepshead

minnows (Hansen  et al., 1977).




      Killifish   develop  cyclopia  and other  optic abnormalities

in  response  to  a  number  of  toxic chemicals.   (When  exposed  to

carbaryl and parathion,  killifish showed developmental arrest and

cardiovascular abnormalities.




      Longwell  has  shown  that  the  chorion of certain fishes can

become  contaminated  by oil-derived hydrocarbons  and has suggested
                                                  l
that  species differences  in  these contaminations:  may be related

either  to  species spawning habits  with regard to  depth  of water
                          E-23

-------
column, or to the particular developmental stage at which eggs are



exposed to the  oil  (Longwell, 1978). She has also shown significant



correlations between surface-layer toxics and cytologic, cytogenetic



and  embryological health of  mackerel  eggs  (Longwell  &  Hughs,



1980).  By  analyzing  the  yolk sac  membrane in  fish  eggs,  Longwell



and  Hughs  (1981 a,b)  have demonstrated significant  correlations



between mitotic-chroraosome irregularities  and contamination  with



hydrocarbons and  heavy metals,   this and subsequent  studies  have



focused on decreased  egg  health,  defined  by Longwell and  Hughes



as "embryo moribundity, chromosome-mitotic abnormalities , develop-



ment rate, cell differentiation problems, gross embryo malformation



and  total egg  number sampled."  Their studies  show that poor egg



health  is  related  to toxics,  salinity and  temperature  (Longwell



and  Hughes,  1980,  1982a,b;   Longwell  et  al..  1984;   Cnang and



Longwell,  1984,  1985).   Longwell  discusses  methodologies and



results  of  much  of this  work  conducted on  fish of  the  New York



Bight  in  Appendix  F.







       In  summary, effects  of  toxic  stress on  reproduction and



 development of estuarine f inf ish are numerous but variable according



 to type of toxicant and type of fish.   A manual prepared by  Whipple



 et al.,  1984b  provides methodology for the analyses of each aspect



 of reproductive health of striped bass.  An account  of congenital



 effects  of toxics on  a  range  of estuarine fish can be found  in



 Weis  and  fceis  (Appendix G)  while Spies  discusses reproductive



 impairment/success related to  toxic stress in  Appendix H.





                           E-24

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3.5 Enzymology
3.5.1   Enzyme Induction
      There  is  a  considerable body of  evidence [documenting the

effects of  chronic sublethal exposure to several  types of toxics
                                                  I
on  the mixed-function oxygenase system (MFC) in finfish*

                                                  i

      The MFO system consists of an electron transport system that

oxidatively transforms nonpolar  lipophilic  organic compounds into

more water soluble metabolites. In fish it has been located prima-
                                                  I
rily in the  liver, with lesser activity occurring  in the kidney,

gills, gonads  and heart.  It  consists of  NADPH/cytochrome P-450,

reductase, cytochrome P-450  and  phospholipids,  which combine with
                                    .
NADPH, oxygen and a substrate.  The substrate  may'  be transformed

into highly reactive toxic intermediates, and to more or less toxic
                                                  I

daughter compounds prior to excretion.  This  has lead some investi-

gators to refer  to the MFO system as  a  toxification /detoxifica-

tion system (Neff,  1984).  The activity  of  the  hepatic MFO system
                           '
is  induced  (increased)   in finfish  exposed to  petroleum  and PAHs

(Lech et al., 1982; Neff, 1976; Neff 19b4;  Stegeman, 1981).  PCBs,
                                                  i
dioxins and  heavy metals  may  also induce  MFU  activity  (Lech  et

al., 1982; NRC,  1985).  Natural environmental factors and intrinsic
                                                  i
biological  chemicals  (e.g.  testosterone)   may  also  increase  or
                                                  i
decrease MFO activity, suggesting that it be used jwith caution as

an  indicator  of  environmental  pollution (Neff,  1984;  NRC, 1985).

                           E-25                   !

-------
However, induced MFO activity can indicate rather specific exposure



to  several  organic pollutants  (Neff,  1984).   This  fact combined



with  its potential  to increase  the  toxic load  in  the organism



through production of carcinogenic metabolites encourages continued



research on  the system.  Stegeman has  provided a review of toxic



effects on enzyme systems, particularly the  MFO systems in Appendix




I.
      The  components  and  function of  the MFO  system,  sometimes



referred to as  the  toxification/detoxification system, were intro-



duced above.  MFO enzymes  metabolize environmental xenobiotics and



endogenous steroids (Spies et  al.,-1982).  The resulting molecules



(e.g. sulfates) are small and polar, thus easily excreted.  While



this  prevents  accumulation of  PAHs and  certain  other  toxics  in



tissues,  their  oxidation can  produce  carcinogenic .and mutagenic



daughter  compounds  (Kurelec et al.,  1977; Spies,  1982; Varans -et



al.,  1980).    The  system responds  in a  similar  fashion to  PCBs



 (Gruger et  al., 1977,  Spies et al.,  1982).







       Ingested PCBs and PAHs increase  aryl hydrocarbon hydroxylase



 (AHH)  and  microsomal  proteins  in some  flatfish  (Spies,  1982).



 As a result  of these  studies,  it  has  been  the  suggested  that



 activity of  the MFO  system be used as  an indicator of  at  least



 petroleum pollution (Payne and Penrose, 1975; Stegeman, 1978,1980)=



 Toward this  end research has  demonstrated  that,  unlike  mammalian



 systems where there are specific inducers, the finfish show similar






                               E-26

-------
qualitative  responses  to  petroleum,  PCBs  and  a range  of other



xenobiotics  (Spies et  al.,  1982).   However, DDT and  DDE do not
                                                   I


induce MFO  activity in  flatfish  (Addison  et  al(i,  1977; Spies,



1982), but do induce  MFO activity  in white croaker«  (Brown et al.,



1982).  Thus  MFO induction by chlorinated hydrocarbons may not be


universal in  finfish.



       While PCBs from sewage effluents seem poorly  metabolized by



flatfish,  chronic  sublethal  exposure to  PCBs jjeems  to hinder
                                                   I

reproductive  success  in starry flounder. This suggests a  possible



indirect  toxic effect of PCB  metabolic  intermediates via the MFO


system (see Spies's Appendix H).




                                                 .


      Metallothioneins are components of an intracellular mechanism



for sequestering and detoxifying  trace  metals.   Metallothioneins


are metal  binding, low  molecular  weight, cysteine  rich  proteins



that lack aromatic amino acids.  Metallothionein systems have been


studied in fish and other animals, including  mammals.   While the



metallothionein  system  is  believed to  sequester  metal-s that might



bind  to  sensitive cellular  sites, it  has  also  been found to  be



part of the normal metabolism of copper and zinc in mammals  (England



Houseyidi  pers. • comra.;  Jenkins  et al.,  1982).    |Metallothionein
                                                   |

synthesis is induced by low levels  of a number of metals resulting
                                                                .

in  highly  stable  metal-thiol  bonds which  allow tihe organism  to



tolerate increasing amounts of the  trace metals.   Metallothioneins



thus  serve as an  excellent  specific  indicator  for metals,  but



their  activity has caused  difficulties  in  analyses  of  potential




                           E-27

-------
toxicity  of  these metals.   Cytosolic metal  distribution  studies



offer a  possible  approach  to resolving such difficulties,,  as  well



as a method for clarifying avenues of metal uptake and synergistic



activities of metals with other pollutants.







      A  survey of the research on metallothionein systems in parti-



cular and current methods for assessing toxicant metabolic activi-



ties in  general can be found in Jenkins1 review  in Appendix J.








3.5.2  Molecular  Pathology







      Blood  enzymes  have long been used for clinical diagnosis in



mammals. Changes in concentrations of tissue-specific enzymes are



routinely used in  the  diagnosis of  liver and  heart  disease or



damage,  for instance.   Activity  in  fish  tissue-specific enzymes



may  also be  useful for diagnosing pollution caused cellular damage



and  pathological  conditions.  For example,  delta amino levulinic



acid dehydratase  (ALA-D)  is  an enzyme involved in the synthesis of



hemoglobin  and  other  porphyrin-proteins.   Lead  inhibits ALA-D



activity in finfish  erythrocytes (Beritid  et al., 1977).
       Two other blood enzymes of use in analyzing pollutant  damage



 to fish  are glutamate oxaloacetate transaminase  (GOT) and  gluta-



 mate-pyruvate  transaminase  (GPT).   Activity  changes  in  these



 enzymes  primarily  reflect  liver  damage although  GOT  can  also



 reflect  damage to  heart  tissue.   GOT  activity decreases  with





                             E-28

-------
exposure of certain finfish to lead but increases with exposure to
                                                  I
phenol, PCBs and municipal sewage effluent with synthetic organics

(Neff 1984). GPT increases with exposure to all of these pollutants
                                                  i
(lead,  phenol,  PCBs,  municipal  sewage  effluent). •  Otner  blood


enzymes found to vary  in activity  when  fish  are exposed to pollu-


tants are LDH (lactate dehydrogenase), alkaline phosphatase, glucu-


ronidase, amino  levulinic acid dehydratase and isocyfcric dehydro-
                                                  I
genase.   However,  several of  these  enzymes, as well as creatine

phosphokinase, show  less change in the plasma  with CC1,. exposure

than do GOT and GPT (Neff, 1984).   At present then, ALA-D, GPT,  and

GUT appear the most promising blood enzyme indicators  of pollutant


mediated damage.   Further investigations of pollutant  effects  on
                                                  I

enzyme  systems, and  of  non  pollutant  effects  on blood  enzyme

activity may expand this list.
      Tissue enzyme analyses  have  included  in  vitro  cissays  and  in

vivo studies.  The results  of the  two forms of ansilysis are often

quite different.   Also,  it is not always clear whether  pollutant

mediated enzyme  changes  will  result in  significant  changes  in

metabolic processes in the fish (Neff, 1980).
      Relationships have been  demonstrated  between  toxicant  expo-
                                                  i
sures  and  altered activity  of some  tissue enzymes.   The  gill


epithelia  contain several  adenosine triphospatases  (ATPases).


These  are  important  in osmotic  and ionic  regulation.   Direct
                                                  i

correlations between chronic  sublethal exposure to;  pollutants  and



                            E-29

-------
changes in activity of  these  enzymes  have  been  documented (Miller



and Kinter,  1977;  Neff, 1984).   Likewise  altered  acetylcholines-



terase  (AChE)  activity  in the  brain,  gill and  muscles of  fish



clearly  correlates  with  exposure to  chlorinated  hydrocarbons,



carbamate and organophosphates (Neff, 1981).







      As  with blood enzymes, further research  would  be needed to



determine what relationships exist between tissue enzyme activities



in  finfish  and  most toxicant  stresses, and between  any altered



enzyme  activities  and ultimate biological effects.
 3.6  Physiology







       Alterations of physiological functions such as osmoregulation




 and respiration can also indicate toxic stress in fish.   However,



 distinguishing physiological effects from other effects is sometimes



 difficult.   Coho salmon sraolt  demonstrate  osmoregulatory  failure



 under toxic  burdens,  for example,  but it has  been suggested that



 this failure  is secondary and symptomatic of other negative stres-



 ses. The investigators found no evidence of toluene or naphthalene



 altering osmoregulatory  ability in  the smolt  as a  function  of




 salinity (Stickle  et  al.t 1982).







       While  respiratory rates have  been examined as indicators of



 sublethal  stress  by  toxics  (esp.  petroleum), results  are again






                         .   E-30

-------
inconsistent ' because of  the numerous  other  factors  that affect

respiration.   It  has also been shown that responses vary conside-

rably among animal classes.  Oxygen-consumption  rates are depressed

in  silver  stressed  cunners  and mud- snails,  but- elevated  in all

bivalves studied  (Goulde  et  al.,  1977).  Severely ulcerated gills

of  finfish  caused by PAH  exposure do clearly demonstrate impaired

respiration  (R.   Huggett  pers.  comm.,  April  1986).   A potential

answer  to  the  problems  of separating  individual physiological
                                                  i
effects from other possible primary causes is the use of an energy

budget  to  evaluate toxic stress effects  on  respiration and other

physiological  parameters  (Bayne  et  al.,  1976,, J1979).    Such  a

method  is valuable because  it  avoids a need  to  separate intrinsic

and extrinsic effects on respiration and offers  comparisons within

and  among  species on integrative  stress  indices   such  as growth

rate (NRC,  1985).        " -
      Bioenergetics  methods have  been  effectively used  as  toxic

stress  indicators  by several  investigators  (Gilfillan  et  al.,

1985; NRC, 1985).  Estimations of the catabolic energy of proteins
                                                  i

and amino acids, for example, can be determined by determining the
                                                  i
ratio of oxygen used to nitrogen excreted (0:N ratio)«,

       r

      Another way of assessing physiological effects of pollutants

is  through  correlation of  altered enzyme activity,  as  discussed

above, with altered physiological function.   ATPases may  be either
            .

stimulated or inhibited by pollutants including chlorinated hydro-


                            E-31                   !

-------
carbons, metals and  crude oil (Poston et al., 1979; Lorz et al.s



1978; Miller  et  al., 1977).   These  ATPases are found in finfish




gills and control ionic and osmotic regulation.








      Other  biochemical  changes "induced by  toxicants have  also



been shown  to  correlate with specific physiological dysfunctions



and  toxic  stress.   Changes  in the adenylate energy charge  (AEC)



for  instance,  reflect  the  metabolic  energy available from  the



adenine nucleotide  pool.  Stresses altering  this  pool then  alter



available metabolic energy (Neff, 1984).  Declines in liver glycogen



have been  shown to  coincide  with hyperglycemia  (Neff,  1984),,



Decreased  growth rates  and  fecundity  as  well  as  altered  energy



metabolisms  have  been correlated with toxicant  induced depression



in liver glycogen and hypoglycemia (Conan,  1982; Neff, 1984).







      Thus  physiological  dysfunctions  may serve  as relatively



easily  observed symptoms of  some biochemical and enzyme impairments




due  to  toxic stress.








 3.7   Population







       Population effects  can  include those  caused by changed



 reproductive rates,  or  changed distribution and migration patterns.



 Effects of suppressed reproductive rates on population density have



 been clearly demonstrated  in the diminishing  population  of  the



 striped bass in San Francisco Bay.   The  suppressed  reproductive






                           .   E-32

-------
 rates  have  been  shown by  these authors to  correlate with  toxic

 concentrations in the Bay (Whipple  et  al.,  1984).

                                                  i

      Several  laboratory  studies  have  demonstrated  that  certain

 fish can avoid toxics including DOT,  enderin, and Duroban.   There

 is,  however,   no proof  that  fish avoid  toxicants  in  the  field

 (Hansen  et al.t  1972,  1974;  Hansen,  1969).   However,  if they

 do, the  potential for beneficial effect on natural populations is

 considerable.   If the behavior  is genetically controlled, it  would
                                                  I
 tend  to increase through  selection  in  environments with   "hot

 spots"  of pollution.   The  hotspots  would be increasingly avoided

 by such  species and  the  population would suffer  less exposure to

 toxic effects.



      Observations of the entire life  cycle  of individuals under

 toxic stress can  serve as a first  level of  research in effects of

 toxics on whole populations.  Such laboratory studies have suggested

 severe  effects on reproductive efficiency  in  sh^epshead minnows
                                                  i
 (Hansen  and Parrish,   1977; Hansen et al., 1977).
      One of  the  greatest  problems  in  analyzing  effects  of toxics
                                                  I
on populations  is  separating direct toxic  effects^from natural  or

non-pollution related  variations  including overfishing.   Appendix

K provides a discussion of this problem.
                           E-33

-------
SUMMARY







      The effects of toxic stress on finfish may be deleterious as



in the case of neoplasms or neutral as in the cases of raetallothi-



onein binding of metals or  metabolism and excretion of the pollu-



tants.  The effects may be histopathological, biochemical, physio-



logical,  behavioral or  combinations  of  these.    It  is necessary



for  pollution  assessment and abatement programs to identify which



toxic  effects  on  biota can be  of immediate value  as indicators



of  toxic  contamination in  estuaries.    There is  an especially



pressing need  for indicators that will give early warning of long



term problems.    The  choice  of effects  to  use  at  present must



center around those that already have well developed methodologies.



The  effects should be  easily  observed and measured at affordable



cost in  order  to serve as a screening system for  pollution  in  the



field.   There  are often a number  of methodologies available  for



measuring  the same or  similar  effects.   Each  of these should be



 considered and  the  most suitable  for  immediate use  in  pollution



monitoring and  abatement  programs be  given  highest  priority  for



 refinement and field implementation at  this time.   The most  promi-



 sing methods for future use should be recommended to  research  and



 development arms of management agencies for continued  support.
                             E-34

-------
 LITERATURE CITED                                 !

 Addison,  R.  F.  M.  E.  Zinck and D. E. Willis.  1977.  Mixed function
       oxidase  enzymes  in  trout  (Salvelinus  fontinalis)  liver:
       absence of  induction  following feeding of  P.P-DDT  or P,P,
       DDE. Comp. Biochem. Physiol.  57C:  39-13.

 Baumann,  P.  C., W. D. Smith and M. Ribick.  1982.  Hepatic tumor
       rates  and polynuclear aromatic  hydrocarbon levels  in two
       populations of  Brown  bullhead   (Ictalurus  nebulosus)  In
       Polynuclear Aromatic Hydrocarbons:  Sixth  International
       Symposium on  Physical  and Biological  Chemistry.    M.  W.
       Cooke,  A.  J. Dennis and G. L.  Fisher (Eds.).  Battelle Press,
       Columbus,  OH.   pp. 93-102.
                                                  i
 Bayne,  B. L..,  D.  R.   Livingston,  M.  N.  Moore and  J.  Widdows.
       197b.   A cytocheraical and  biochemical index of  stress  in
       My til us edulis.    L. Marine Pollution Bulletin..  7:221-224.

 Bayne,  B. L.,  M.  N.  Moore,  J.  Widdows,  D.  R.  Livingston  and  P.
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