FINAL
            Un-red Sta.es                                ECAO-CIN-414
            Environmental Protection                           April, 1988
            Agency


&EPA     Research  and

            Development


            DRINKING WATER CRITERIA DOCUMENT FOR
            POLYCHLORINATED BIPHENYLS  (PCBS)
            Prepared for


            OFFICE OF DRINKING WATER
             Prepared by

             Environmental Criteria and Assessment Office
             Office of Health and Environmental Assessment
             U.S. Environmental Protection Agency
             Cincinnati,  OH 45268

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                                  DISCLAIMER

    This  document  has  been  reviewed  1n  accordance  with  the  U.S.  Environ-
mental  Protection  Agency's   peer  and administrative   review  policies  and
approved  for  publication.   Mention  of  trade  names  or commercial  products
does not constitute endorsement or recommendation for use.

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                                   FOREWORD


    Section  1412  (b)(3)(A)  of  the  Safe  Drinking Water  Act,  as  amended  In
1986,  requires- the Administrator  of  the  Environmental Protection  Agency  to
publish  maximum  contaminant level  goals  (MCLGs)  and  promulgate  National
Primary  Drinking   Water   Regulations  for  each  contaminant,   which,   In  the
judgment of  the Administrator,  may  have  an  adverse effect on public  health
and  which  1s  known  or anticipated  to  occur  In  public  water  systems.   The
MCLG  Is  nonenforceable and  1s  set  at  a  level  at  which  no known  or  antici-
pated  adverse  health  effects   In  humans  occur  and  which   allows  for  an
adequate margin of safety.  Factors considered  In setting the  MCLG  Include
health effects data and sources  of exposure other than  drinking water.

    This  document provides  the  health  effects basis  to  be  considered  In
establishing the  MCLG.  To  achieve  this objective, data  on pharmacoklnetlcs,
human  exposure, acute and chronic  toxlclty  to animals and humans,  epidemi-
ology and mechanisms  of toxldty  are evaluated.   Specific  emphasis Is  placed
on  literature   data  providing  dose-response  Information.  Thus,  while  the
literature search  and evaluation performed  In support of  this  document  has
been comprehensive, only  the reports considered most  pertinent  In the deri-
vation of the  MCLG are cited In  the document.  The comprehensive literature
data base  1n support of  this document  Includes Information  published up  to
1986;  however, more   recent data  may  have  been  added  during  the  review
process.

    When adequate health  effects  data exist.  Health  Advisory  values for less
than   lifetime  exposures  (1-day.  10-day  and   longer-term.   ~10X   of   an
Individual's lifetime) are  Included In  this document.  These  values  are  not
used  1n  setting the  MCLG,  but  serve as  Informal  guidance to municipalities
and  other  organizations  when  emergency  spills  or  contamination  situations
occur.
                                                 Michael B. Cook
                                                 Director
                                                 Office of Drinking Water
                                      111

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                             DOCUMENT DEVELOPMENT


Debdas Mukerjee, Ph.D.. Document Manager
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency, Cincinnati,  OH

Krlshan Khanna, Ph.D., Chemical  Manager
Office of Drinking Water
U.S. Environmental Protection Agency, Washington,  DC


Authors

Deborah A. Barsottl, Ph.D.               Edo  D.  PelllzzaM,  Ph.D.
The Philadelphia College of Pharmacy     The  Research  Triangle  Institute
  and Science                            Research  Triangle Park, NC
  Philadelphia, PA
                                         Shane S.  Que  Hee, Ph.D.
James R. Olson, Ph.D.                    Department of Environmental Health
School of Medicine                       University of Cincinnati
State University of New York             Cincinnati, OH
  at Buffalo
Buffalo, NY                              Steven H. Safe,  Ph.D.
                                         Texas ASM University
                                         College Station, TX


    The  following  members  of  the  Carcinogen Assessment  Group,  Office of
Health  and  Environmental Assessment,  U.S.  EPA,  Washington,  DC  were  respon-
sible for the preparation of the sections on  cardnogenlclty:

David L. Bayllss, M.S.                   Charallngayya B. Hlremath,  Ph.D.
Vincent James Cogllano, Ph.D.
    An earlier draft of the document was reviewed by the following  persons:

Herbert Cornish, Ph.D.                   Ellen SUbergeld,  Ph.D.
University of Michigan                   Environmental  Defense Fund
Ann Arbor. Michigan                      Washington, DC

Marlon EhHch, Ph.D.
ICAIR
Life System, Inc.
Cleveland, OH
                                      1v

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    The final draft of the document was reviewed by the following:

Vlasta Molak, Ph.D.                      Raymond E. Shapiro,  Ph.D.
Environmental Criteria and Assessment    Consultant to Industry and Government
  Office                                 New York, New York
U.S. Environmental Protection Agency
Cincinnati, OH                           Susan Velazquez
                                         Department of Environmental Health
Virginia Forrest                         University of Cincinnati
Department of Environmental Health       Cincinnati, OH
University of Cincinnati
Cincinnati. OH

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                             TABLE OF CONTENTS

                                                                      Page
  I.   SUMMARY	      1-1

 II.   PHYSICAL AND CHEMICAL PROPERTIES	     II-l

      STRUCTURE AND IDENTIFICATION	     II-l
      PHYSICAL AND CHEMICAL PROPERTIES	     II-7
      PCB ANALYSIS	     11-17
      CHEMICAL REACTIONS	     11-20

           Pyrolysls	     11-20

      STABILITY IN WATER	     11-23

           Photodecomposltlon 	     11-24

      OXIDATION AND HYDROLYSIS	     11-25
      VOLATILIZATION	     11-25
      ADSORPTION	     11-27
      EXCHANGE BETWEEN MEDIA	     11-28
      BIODEGRADABILITY	     11-28
      SUMMARY	     11-29

III.   TOXICOKINETICS	    III-l
                                                 •
      INTRODUCTION	    III-l
      ABSORPTION	    III-5

           Gastrointestinal 	    III-5
           Dermal	    III-6
           Inhalation	    III-7

      TISSUE DISTRIBUTION AND EXCRETION 	    III-7
      PHARMACOKINETIC STUDIES IN HUMANS	    III-26
      FETAL AND NEONATAL STUDIES	    111-28
      METABOLISM	    111-36

 IV.   HUMAN EXPOSURE	     IV-1

      WATER	     IV-1

           United States	     IV-1
           Other Countries	     IV-16

      FOOD	     IV-16

           PCB Residues In Aquatic Life of the United States
           and Canada	    IV-17
           Countries Outside of the United States and Canada.  .  . .    IV-27
                                      v1

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                         TABLE  OF  CONTENTS  (cont.)
                                                                     Page
     AIR .  /	     IV-27
     OTHER EXPOSURES	         IV.31
     ESTIMATED UNITED STATES EXPOSURE	     IV-33
     SUMMARY	     IV_35
 V.  HEALTH EFFECTS IN ANIMALS 	      V-l
     ACUTE  TOXICITY	      V-l
     SU8CHRONIC TOXICITY 	      V-5
          Hepatic System 	      V-20
     CHRONIC TOXICITY	      V-29
     DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY 	      V-45
          Rats	      V-46
          Mice	      V-51
          Rabbits	      V-54
          Other Species	      V-55
     MUTAGENICITY	      V-59
     CARCINOGENESIS	      V-65
          Cardnogenldty	      V-65
     SUMMARY AND CONCLUSIONS 	      V-82
     OTHER  RELATED STUDIES	      V-87
          Promotional and Ant1promot1onal Studies	      V-87
          Considerations 1n Evaluating the Carcinogenic or Anti-
          carcinogenic Potency of the PCB Preparations Tested.  . .      V-95
VI.  HEALTH EFFECTS IN HUMANS	     VI-1
     GENERAL BACKGROUND	     VI-1
     ACUTE  AND SHORT-TERM EXPOSURE	     VI-2
     CHRONIC EXPOSURE	     VI-2
          Occupational Exposure	     vi-3
          Clinical Observations	     vi-11
     DIRECT INTRODUCTION OF PCBs INTO FOODSTUFFS 	     VI-14
          Yusho Incident	     VI-14
          Yu-Cheng Incident	     VI-14

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                           TABLE  OF  CONTENTS  (cont.)

                                                                       Page
       NONCARClNOGENIC TOXIC EFFECTS OBSERVED	    VI-17

            Skin	    VI-17
            Immune System	    VI-18
            Reproductive System	    VI-18
            Clinical Observations	    VI-22

       HUMAN CANCER STUDIES (INHALATION AND DERMAL CONTACT)	    VI-26
       HUMAN CANCER STUDIES (PCB POISONING EPISODES —
       INGESTION ONLY) 	    VI-33

            Yu-Cheng Incident	    VI-38

       HUMAN CANCER STUDIES - SUMMARY	    VI-39
       HEALTH EFFECTS (OTHER THAN CANCER) - SUMMARY	    VI-42

            Reproductive System	    VI-42
            Clinical Observations	    VI-43

 VII.  MECHANISMS OF TOXICITY	   VII-1

       INTRODUCTION	   VII-1
       ROLE OF THE 2,3.7,8-TCDD Receptor Protein 	   VII-2

            Structure-Activity Relationships . . -.	   VII-2
            Pharmacoklnetlc Studies and Response Specificity ....   VII-10
            Summary	   VII-11

       ROLE OF METABOLISM IN PCB TOXICITY	   VII-11
       OTHER MECHANISMS	   VII-13
       SUMMARY 	   VII-15

VIII.  QUANTIFICATION OF TOXICOLOGICAL EFFECTS 	  VIII-1

       INTRODUCTION	VIII-1
       NONCARCINOGENIC EFFECTS 	  VIII-9
       QUANTIFICATION OF NONCARCINOGENIC EFFECTS 	  VIII-17
       CARCINOGENIC EFFECTS	VIII-22
       QUANTIFICATION OF CARCINOGENIC EFFECTS	VIII-23

            Data Selection 	  VIII-24
            Dose-Response Modeling  	  VIII-26
            Potency Estimation 	  VIII-26
            Drinking Hater Criteria	VIII-27
            Sensitivity Analysis — Neoplasm Nodules	VIII-27
            Sensitivity Analysis — Statistical Upper Bounds ....  VIII-29
            Sensitivity Analysis — K1mbrough et al.  (1975) Study.  .  VIII-29
            Cancer Potency Estimates for Aroclor«  1254
            and other PCB mixtures  	  VIII-32

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                         TABLE  OF  CONTENTS  (cont.)

                                                                     Page
     EXISTING GUIDELINES, RECOHMENOATIONS AND STANDARDS	VIII-35
     SUHHARY 	   VIII-36

IX.   REFERENCES	     IX-1
                                    1x

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                               LIST OF TABLES
No.                                  Title                            Page
 II-l   Numbering of PCB Isomers	    II-2
 II-2   CAS and RTECS Numbers for Some Aroclors	    II-8
 II-3   PCDF Content 1n Some PCBs and In Kaneml 011	    II-9
 II-4   Suspected Maximum Levels of Toxic PCOFs 1n Various
        PCBs and 1n R1ce 011s	    11-11
 II-5   Specific PCOFs 1n Commercial PCBs	    11-13
 II-6   Some Physical Properties of Aroclors	    II-H
 II-7   Percent Composition of Aroclors and Kanechlors	    11-15
III-l   Quantitative and Qualitative Analysis of PCBs 1n
        Aroclor 1260 and a Human Breast M1lk Extract	   III-2
III-2   Pharmacoklnetlc Compartment Size Distribution for
        Individual  PCB Congeners 1n the Rat	   111-11
III-3   Pharraacok1net1c Parameters for Individual PCB Congeners
        1n the Rat	   111-12
III-4   Biological  Half-Lives of Individual Chloroblphenyls
        1n Rats	   III-14
III-5   Time Course of 2,2',4,4',5,5'-Hexa-CB Tissue Distribu-
        tion, Elimination, and Recovery (percentage of dose) 1n
        Rats with Constant Adipose Tissue Mass	   111-19
III-6   Tissue Kinetics of 2,2',4,4',5,5'-Hexa-CB 1n Rats
        with Constant Adipose Tissue Nass 	   111-20
III-7   Excretion Kinetics of 2,2',4,4',5,5'-Hexa-CB In Rats
        with Constant Adipose Tissue Mass 	   111-21
II1-8   Hexa-CB Levels 1n Rabbit, Rat and Guinea P1g Adipose
        Tissue, Trout and Japanese Quail Carcasses 29 Days after
        Administration of the Isomer Mix	   111-23
III-9   Metabolism Parameters of Three PCBs In Humans, Monkeys,
        Dogs and Rats 	   111-25
111-10  Distribution of PCBs to Fetuses and Nursing Young 	   111-30
III-ll  Transfer of [14C]Hexa-6-CB from Mothers to Nursing
        Offspring 	   111-32

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                           LIST OF  TABLES (cont.)


No.                                  Title                            Page

111-12  Levels of PCBs In the Tissues and Fluids  from a  Mother
        and Child OccupaUonally Exposed to Kanechlor 300  and 500  .    111-35

 IV-1    Mean Hater Concentration (ng/i)  of Chlorinated
        Blphenyl  Congeners 1n Hudson River Water  at  Roger's
        Island (RI),  Thompson's Island (TI) and Stlllwater  (ST)

IV-2
IV-3

IV-4

IV-5

IV-6
IV-7

V-l
V-2

V-3

V-4

V-5

V-6
V-7
V-8
V-9
V-10

In 1983 	
PCBs In Rain and Snow Around the World 	
Estimated Dietary Intake of PCBs for Adults, Infants
and Toddlers 	
Chlorinated Blphenyl Congener Concentration (vg/g net
weight) In Caddlsfly Larvae taken from the Hudson River . .
Bloaccumulatlon Factors of Hacrolnvertebrate Species
1n the Hudson River 	
PCB Residues In Freshwater Fish in the United States. . . .
Estimated Intake of PCBs from the U.S. Environment by
Adult Males 	
•
Acute Toxldty of PCBs 	
Acute and Subchronlc Toxldty of Orally-Administered
PCBs to Rats 	
Acute and Subchronlc Toxldty of Orally-Administered
PCBs to Mice 	
Acute and Subchronlc Toxldty of PCBs Administered
by Routes Other Than Oral 	
Acute and Subchronlc Toxldty of Orally-Administrated
PCBs to Other Species 	
Effects of Chronic Oral Exposure of Rats to PCBs 	
Effects of Chronic Oral Exposure of Mice to PCBs 	
Effects of Chronic Exposure of Monkeys to PCBs 	
Effects of Chronic Oral Exposure of Other Species to PCBs .
Summary: Teratogenetlc. Fetotoxlc and Reproductive
Effects of Orally Administered PCBs 	
IV-6
IV-11

IV-18

IV-21

IV-22
IV-26

IV-35
V-2

V-6

V-10

V-13

V-17
V-30
V-32
V-33
V-36

V-47
                                     x1

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                           LIST OF  TABLES  (cont.)


No.                                  Title                            Page

  V-ll  Summary of Mutagenldty Assays  of  PCBs  In  Salmonella
        typhlmuMum ........................      Y_
  V-12  Change In Rat Body Height Following Chronic  Exposure
        to Kanechlor 400 ......................      V-67

  V-13  Change 1n Rat Body Weight Following Chronic  Exposure
        to Several Kanechlor Formulations  .............      V-69

  V-14  Prollferatlve Lesions of the Liver  1n Fischer  Rats
        Fed Aroclor 1254 ......................      V-73

  V-15  Progression of Preneoplastlc and NeoplasUc  Hepato-
        cellular Lesions 1n Male and Female Sprague-Oawley Rats
        Exposed to Aroclor 1260 ..................      V-77

  V-16  Incidence of Hepatocellular  Neoplasms in Hale  and Female
        Sprague-Oawley Rats Exposed  to Aroclor 1260  ........      V-79

  V-17  Effects on Liver Tumorlgenes1s and  Carclnogenesls:
        Feeding Studies Using Various Conner c la 1 PCB Preparations  .      V-83

  V-18  Action of Kanechlor 500 and  «-, B-  or ^-Benzene
        Hexachlorlde .............. -. .........      V-88

  V-19  Percent Height Change 1n Kanechlor  500 Exposed Rats  ....      V-91

  V-20  The Liver and Body Height Ratio and the Number of Liver
        Tumors Produced In Offspring Rats  Exposed to PCB through
        Their Dams and Treated with  DEN after Meaning  .......      V-93

  V-21  Number of Isomers at Each Chlorinated Level  for Three
        Different Aroclor 1260 Preparations ............      V-96

  V-22  Analyses of Three Different  Aroclor 1260 and Three
        Different Aroclor 1254 Preparations for the  Presence of
        PCB Isomers Known to Utilize, to Some Degree,  A Metabolic
        Pathway that Forms Arene Oxide Intermediates ........      V-98

 VI-1    Summary of the Symptoms In Sixteen  Cases of  Acneform
        Eruption ..........................     VI-5

 VI-2   Duration of PCB Exposure of  326 Capacitor Manufacturing
        Horkers ..........................     VI-8

 VI-3   Age Distribution of 326 Capacitor  Manufacturing Workers
        by Sex ...........................     VI-9

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                            LIST OF  TABLES  (cont.)


 No.                                   Title                            Page

  VI-4   Prevalence of Reported Dermatologlc  Symptoms  Among 326
         Capacitor Manufacturing Workers	     VI-10

  VI-5   Clinical  Features of Six Electrical  Workers with  Chloracne.     VI-12

  VI-6   Concentration of PCBs and PCDFs  In the Toxic  Rice-Bran
         011s That Caused "PCS Poisoning"  1n  Talchung,  Taiwan.  .  .  .     VI-17

  VI-7   Percent Distribution of Signs and  Symptoms  of  Yusho
         Among 189 Persons	     VI-20

  VI-8   Initial Symptoms of Yusho Among  136  Persons	     VI-23

  VI-9   Relationship Between the Amount  of Kanechlor-Contamlnated
         R1ce Oil  Consumed and Clinical Severity of  Yusho	     VI-24

  VI-10  Relationship Between Clinical Severity of Yusho and Age
         of Affected Persons 	     VI-25

  VI-11  Minimum and Maximum Values of PCBs Recovered  from Workplace
         Surfaces  and Workers Hands Before and After PCBs  Banning
         (1980) and Cleaning Operations	     VI-31
                                                  •
  VI-12  MotalUy from Selected Causes of Male and Female Workers
         Exposed to PCBs (Bertazzl et al.,  1987)	     VI-32

  VI-13  Risk of Death From Cancer of the Liver In 011 Poisoned
         Patients  by Sex and Period of Observation,  Japan and  in
         Fukuoka Prefecture	     VI-35

 VII-1   PCBs: Summary of Structure-Function Relationships  	    VII-8

VIII-1   Data Used as the Basis for the q-j* for Aroclor 1260 ....   VIII-25

VIII-2   Data Used as the Basis for an Alternate Potency
         Calculation for Aroclor  1260	VIII-28
                                      x1M

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                            LIST OF TABLES (cont.)

 No.                                  Title                            Page
VIII-3   Data Used as the Basis for the Previous Potency
         Calculation for Aroclor 1260	VIII-30
VIII-4   Data Used for the Preliminary Cancer Potency
         Estimate or Aroclor* 1254 	     VIII-33
VIII-5   FOA Regulations for PCBsa 	     VIII-37
VIII-6   Summary of Calculated Health Advisories for PCBs	   VIII-39
                                      x1v

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                               LIST  OF  FIGURES
No.                                  Title                            Page
 II-1   Possible Reaction Schemes to Produce PCOFs from the
        Pyrolysls of 2,2' ,4,4' ,5,5' -Hexachloroblphenyl	    11-22
III-l   PCB Pharmacoklnetlc Flow Diagram	   III-9
III-2   Summary of PCB Metabolism 	   111-38
VII-1   Coplanar and Mono-ortho Coplanar PCB Analogs	   VII-5
                                       xv

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                             LIST OF  ABBREVIATIONS

AAH                Aryl hydrocarbon hydroxylase
BCF                Bloconcentratlon factor
BHC                Benzene hexachloMde
BOO                Biologic oxygen demand
bw                 Body weight
CAS                Chemical Abstracts Service
CB                 Chlorinated blphenyl
d                  Deuterium
DCB                Dlchlorlnated blphenyl
DEN                Dlethylnltrosamlne
DMBA               Dlmethylbenzanthracene
OMN                D1methy1n1trosam1ne
DMA                Deoxyr1bonuc1e1c add
OP                 Dlphenyl
DWEL               Drinking water equivalent level
EROO               Ethoxyresorufln o-deethylase
eV                 Electron volts
EXAMS              Exposure Assessment Modeling System
2-FAA              N-2-fluoroenylacetam1de
GC                 Gas chromatography
GI                 Gastrointestinal
gmw                Gram molecular weight
H                  Proton
HA                 Health Advisory
HCB                HexachloMnated blphenyl
HPLC               High performance liquid chromatography
1.0.               Internal diameter
1.p.               Intraperltoneal
K                  Octanol water coefficient
KC                 Kanechlor
L05Q               Lethal dose for SOX of recipients
LOAEL              Lowest-observed-adverse-effect level
                                      xv1

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                         LIST OF  ABBREVIATIONS  (cont.)

LOEL               Lowest-observed-effect level
(M * H)*           Molecular weight 1on plus 1
(M * H2 - Cl)      Molecular weight Ion plus 2  minus chlorine
3-MC               3-methylcholanthrene
MCB                Monochlorlnated blphenyl
3'-MeDAB           3'-methyl-4-d1methylamlnoazobenzene
MFO                Mixed function oxldase
MNNG               N-methyl-N1-n1tro-N'-n1trosoguan1d1ne
MS                 Mass spectrometry
NMR                Nuclear magnetic resonance
NOAEL              No-observed-adverse-effect level
NOEL               No-observed-effect level
PCB                Polychlorlnated blphenyl
PCOF               Polychlorlnated dlbenzofuran
PCE                Polychromatic erythrocytes
PCQ                Polychloroquaterphenyl
PeCB               PentachloMnated blphenyl
pH                 -log (H*)
ppb                ng/mi (liquids); nt/t (gases/vapors); ng/g (solIds)
ppm                jjg/mt (liquids); yt/l (gases/vapors); yg/g (solids)
RfO                Reference dose
RNA                Rlbonuclelc acid
s.c.               Subcutaneous
SNI                Substitution nucleophlUc first order reaction
SU2                Substitution nucleophlUc second order reaction
 N
SNARL              Suggested no adverse response level
STEL               Short-term exposure limit
TCB                Tetrachlorlnated blphenyl
TEN                TMethylenemelamlne
TPA                12-0-tetradecanoylphorbol-13-acetate
trICB              Trlchlorlnated blphenyl
TWA                Time weighted average
UV                 Ultraviolet
                                     xv11

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                                  DEFINITIONS


Isomers            PCBs having the same molecular  weight and chlorine number
                   but with the chlorines substituted differently

Congeners          PCBs having different numbers of chlorines
                                     xvin

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                                 I.  SUMMARY

    Evaluation of the  health  effects  of polychlorlnated blphenyls  (PCBs)  in
the environment  represents  a  highly complex problem.  The  empirical  formula
for  PCBs   Is   C,,H,n  Cl    (n-1-10),  which   1n   theory  allows  for   the
                 \c  iu-n  n
formation of 209 different  Individual  PCBs.  Commercial  formulations  of  PCBs
enter the environment  as mixtures  consisting of a variety  of  Individual  PCS
congeners and  Impurities,   Including  polychloMnated dlbenzofurans  (PCOfs).
The toxlclty  of  some  Individual PCB  congeners  and  specific  Impurities  such
as the PCOFs has been examined using laboratory animals.

    Various commercial mixtures of  PCBs  have been  marketed  under a number of
trade  names  Including Aroclor  (Britain  and  USA),  Phenochlor or  Pyralene
(France),  Clophen  (FRG),  Kanechlor or  Santotheam  (Japan),  Fenclor  (Italy)
and  Sovol  (USSR).    Since  conwerdal  formulations contain  a  complex  mixture
of  PCBs,  the  physical properties of a  given formulation will vary depending
on  the  components  and  composition  of the mixture.   The physical  properties
of  the  blphenyl  family vary considerably, having a molecular weight range of
154  for  blphenyl   to  499  for  decachloroblphenyl  (the PCB  with the  most
chlorines), a  log  octanol/water partition coefficient range of  3.76-8.26 for
PCBs, and an aqueous  solubility range  of  9.77x10-*°  to  4.68xlO'« mol/l.

     Commercial  PCB mixtures are estimated to  volatilize from ambient water,
with  half-lives  ranging from 2 months to  >150 years  for low  and high molecu-
lar  weight  mixtures,  respectively.   The  most  important  Input parameter
affecting  volatilization  rates 1s  the  octanol/water partition  coefficient,
 since   this  reflects  the  amount  of PCBs  partitioning  Into  the  water  from
 sediments  and biota,  and  the amount  available  for volatilization.  Sediments
 02320
I_l                              04/04/88

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and other  organic  matter  adsorb  PCBs effectively,  the more  highly  chlori-
nated congeners  being  adsorbed better than  the  lower  chlorinated blphenyls.
Thus,  the  adsorption  of  PCBs  onto  sediments and  matter  with  high  organic
content   Is  perhaps the  dominant  process for  removal  of  highly chlorinated
blphenyls from water.

    As with  volatilization and water  solublllzatlon,  blodegradatlon  1s  sig-
nificant for  only  the less  chlorinated,  low molecular  weight  PCBs.   PCBs
containing three or  fewer chlorines  will  tend to be  degraded  more  than the
highly chlorinated PCBs.

    The  analysis for  PCBs In  the  environment or biological  tissues  must  be
performed on  a  specific or  surrogate congener basis  using  capillary GC/MS.
because  the  patterns  characteristic  of  Aroclor are  not  retained   In  most
situations except for highly contaminated conditions.

    PCBs  form  PCOFs   when heated,  but   both are  destroyed  at a  2-second
residence  time  at  1200*C  with  3X excess  oxygen  or  a  1.5-second  residence
time  at  1600'C  with 2% excess oxygen.   PCOFs  can  be produced  from  PCBs  by
sunlight  photodecomposltlon   though   the  environmental  Importance  of  the
process  Is unknown.

    PCBs  have  betn  detected  In  almost  all components  of  the  global  eco-
system.  Including water.

    The  major exposure routes to humans  are through food and  by Inhalation.
Dermal exposure  1s  also Important  1n occupational exposures, for swimmers  In
polluted waters, and  1n  cleaning  up PCB  spills  or  from leaking hazardous

02320                                 1-2                              04/04/88

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wast»  sites   containing  PCBs.   In  all  cases,  total  PCB   levels  are  best
characterized by  specific  congener analysis or total PCB by perchlorlnatlon
rather than  1n  terms  of  Aroclors,  because  the  congener  patterns  In environ-
mental media  and biological  tissues  usually do  not  match   those  In  Aroclor
fluids unless massive contamination has occurred  (typical of spills and  some
occupational   situations).    Thus,   predictive  models   based  on   specific
congener data must also be utilized.

    The  less  chlorinated  congeners  predominate  in  air  samples  from  known
contaminated areas, and  In water and wet  deposition samples  with  the temper-
ature and amount  of  sediment In river and  water  samples being Important co-
variables.   In  contrast, the more highly chlorinated Uomers with  substHu-
ents at  the  2,4,5- or 2',4',5'-positions  tend  to bloaccumulate In  some  crop
vegetables, game animals,  fish  and In  human tissue  samples.   PCBs  1n contam-
inated  soils can  be absorbed  by  plants   and  vegetables  with  shallow-root
systems,  although  volatilization 1n this situation  Is  also  favored;  erosion
of  such  particles  will   also cause  contamination  of  sediments.  The  more
chlorinated congeners will  dominate 1n soils and sediments  and  the resident
biota (cash  crops,  vegetables,  fish, aquatic  life).  The absolute  levels in
any  situation  depend on  which   of  the  competing  processes  dominates  as
estimated  1n Table IV-7.  Congeners  of  Aroclor  1016 have  been  detected in
finished  drinking  water  obtained  from  the Hudson  River  and  samples from well
water  taken   during  the  National  Organic  Monitoring Survey.  The finished
drinking  water  from  Oorlty  Reservoir  treatment and  distribution  in upstate
New  York  was reported to  contain  Aroclor  1016.  Water  from  the public water
supply  system of  the village of  Fort  Edward, located  near the  townsMo of
Moreau  of Saratoga County, New York Is obtained from Oorlty Reservoir treat-
ment  and distribution system.   The level  of  Aroclor  1016   In this  finished

02320                                1-3                              04/04/88

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drinking water  corresponded well  to  the  median level  In  the Oorlty  River
water.

    Because of  their Upophlllc and  relatively stable nature, PCBs  rapidly
bloaccumulate  In biota  and the  tissues  of  humans.   PCBs  are  effectively
absorbed  following   oral,  dermal  and  inhalation exposure.   In most  animal
species  that  have been  Investigated there Is an  Initial  uptake of  PCBs Into
the  liver  and muscle because  of  high perfuslon  In  the liver  and  the rela-
tively  large  muscle volume.  Subsequent redistribution of  PCBs Into adipose
tissue  and  skin reflects  the  high  afflnHy of  the  PCBs  for  Upophlllc tis-
sues.   At  equilibrium   the  elimination  of  PCBs  from all  tissues will  be
dependent  on  the  structure-dependent  metabolism  rates  of   Individual  PCB
congeners.   For example,  biological  half-lives  In  the rat range  from 0.15
days  for 2,2'-d1-CB  to -460 days for 2,2',4,4',5,5'-hexa-CB.

     Metabolism  1s  apparently the primary rate-limiting event  regulating the
elimination  of  PCBs from mammalian  systems.  The \n vitro metabolism  of PCBs
has  been Investigated 1n  liver mlcrosomes from  the human,  monkey, dog, and
rat.   The data  suggest  that  the  human metabolism of PCBs would most  closely
resemble that  of  the rat.   Therefore,  tht rat  should be a  good model for
predicting  the  disposition of  PCBs  1n  huaans.

     The position and degree of chloMnatlon substantially  Influence  the rate
 and  extent  of  PCB  metabolism.   As tht degree of chlorlnatlon  Increasts  on
 both phenyl  rings  tht  rate of metabolism dtcrtasts,  though  there  is  also a
 selectivity with respect to  type  of substitution  for Isomers.    The avail-
 ability of  two vicinal  unsubstltuted carbon atoms  facilitates metabolism  of
 trie  PCB  substrate  but   Is  not  a  necessary   requirement  for  metabolism.
 02320
                                      1.4                             04/04/88

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Although phenolic  products  are the major  PCB  metabolites,  sulfur-containing
metabolites,  trans-dlhydrodlols,   polyhydroxylated  PCBs  and  their   methyl
ether  derivatives  have been  Identified.   The presence  of  trans-dlhydrodlol
metabolites  strongly  suggests metabolism  through  an arene  oxide  Intermedi-
ate.   Arene  oxides have  been Implicated  In cellular necrosis,  mutagenUUy
and cardnogenldty;  however,  the  role of metabolism In  the  genotoxldty  of
PCBs has not been delineated.

    Studies  using  laboratory  animals  clearly  demonstrate that PCBs  can cross
the placental  barrier and accumulate  in  the  fetus.  Another  major  route  of
exposure occurs by  lactation  In which the highly I1poph1l1c  PCBs are readily
transferred  from maternal milk to the neonate.  The  latter  route  represents
the most Important route of PCB exposure for the young.

    Preferential  structure-dependent  bloaccumulallon  of  PCB congeners  has
been   observed   In   human    liver,   adipose   tissue,    serum   and   milk.
2,2',4.4',5,5'-hexa-CB,   2,2' ,3,4,4',5'-hexa-CB,   2,2',3,3',4,4',5-hepta-CB
and 2,2',3,4,4',5,5'-hepta-CB are major components of both  a high molecular
weight  commercial  PCB mixture  (Aroclor  1260)  and human  milk.   On  the other
hand,  2,4,4'-tM-CB,  2.4,4',5-tetra-CB,   2,2'.4,4',5-penta-CB,  2.3',4,4',5-
penta-CB  and  2,3,3',4,4',5-hexa-CB   are  Identified as  major components  of
human  milk  extract,   while  representing  only  minor  components of  Aroclor
1260.   Human studies  also  clearly  indicate  the Importance  of  lactation  as
the  major  route  of  Infant   PCB  exposure, and  represent a major  route  of
depuration  for mothers with  high body burden of  PCBs.

    In  evaluating  the health  effects  of  PCBs  in animals, U  Is important to
:onslder  the isomer  specific  composition of  the  PCBs  and potential  Impurl-

32320                                 1-5                              04/06/88

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ties,  the   length  of  exposure,  and  the  species  under  Investigation.    In
general, PC8  mixtures  have  low to  moderate  acute  toxldty  In  mammalian
species.  Single  dose oral  LD,Qs  of  commercial PC8  mixtures  In rats range
from  1.0-11.3 g/kg  bw.   Limited  data  also suggest  that  the  acute toxic
potency of  PCB  mixtures 1s  similar  In  other species following oral,  dermal
or 1.p. exposure.

    Data on purified  PCB  Isomers have established  that the  toxic,  metabolic
and  toxlcoklnetlc  behavior of the different component  molecules varies  not
only  with  the degree  of   chloMnatlon  (greater toxic  potency with  greater
degree  of  chloMnatlon) but  also  with  the  position  of the chlorine  atoms.
The  relative  toxldty  and  persistence of  four  pure  hexa-CB  Isomers   was
examined In mice;  3,4,5-sym-hexa-CB  was found  to  be the most acutely toxic
(L050  «  19  mg/kg bw/day)  and  persistent  (levels  1n  liver  and  adipose
tissue)  Isomer,   followed  by  2,4,6-sym-hexa-CB  >   2,4,5-sym-hexa-C8,   >
2,3,6-sym-hexa-CB.    Although   structure-activity   relationships   are   most
interesting for  this  class of compounds.  It 1s also Important to  note  that
highly  toxic, coplanar  PCB  Isomers,  such  as  3,4,5-sym-hexa-CB,   have  only
been detected as very minor constituents of commercial PCB formulations.

    Animals are sensitive  to  subchronlc  and  chronic  exposures  to  PCBs.   This
Is due  In  part  to the  rapid  bloaccumulatlon of PCBs  to toxic  levels follow-
ing  long-term, low-level exposure.

     A major target organ  for  PCBs  Is  the liver; an Increase 1n the I1ver-to-
body  weight ratio 1s one  of the most  sensitive Indicators  of PCB exposure.
Hepatomegaly  has  been observed  In rats  Ingesting  diets containing as Uttle
as 20  pom Aroclor  1254  {PCB mixture  with an average chlorine content of  54X)

02320                                 1-6                             04/06/88

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for  4  days  (1  mg/kg bw/day).  Hepatomegaly  results  from liver  cell  hyper-
trophy,  which  1s  caused  by  fatty  Infiltration  and  proliferation  of  the
smooth  endoplasmlc  reUculum.  The  latter response  1s associated with  the
Induction  of  certain   hepatic  enzymes,  particularly  the  mlcrosomal  mixed
function  oxldases.   Hepatic fluorescence, which  1s  suggestive of  porphyMa
has  also been  reported after exposure  of rats  for  16 weeks  to 10  ppm  of
Aroclor   1254   (0.5  mg/kg   bw/day).    Focal   necrosis   and   Iron-containing
deposits  In Kuppfer cells have been observed  at higher levels  of exposure.

    PCBs  have  also  been  shown   to  produce  Immunosuppresslon,  which  maybe
associated  with  thymlc atrophy,  lymphocytopenla  and  splenomegaly.    Other
PCB-related  toxldty  Include a reduction  In  food and  water  Intake,  reduced
rate of body  weight  gain  (wasting  syndrome), and  decreased body tempera-
ture.   Another  sensitive Indicator of  PCB exposure 1s an enlarged thyroid.
Ultrastructural evidence  suggestive  of Increased thyroid gland activity  has
been reported   1n  rats  maintained on  diets   containing as  little  as  5  ppm
Aroclor 1254 (0.25 mg/kg bw/day)  for 4 weeks.

    In  a  chronic study  that defined  a  NOAEl, 8ALB/CJ mice  were maintained
for 9  months on diets  containing 0,  3.75, 37.5  or 375 ppm  of the Aroclors
1221,  1242  or  1254 (0.45, 4.57 or 45.7 mg/kg bw/day).   The Aroclor with  the
lowest  chlorine content (1221) produced no liver lesions, whl'e  exposure  to
Aroclor  1242  resulted  In Increased liver  weight  1n  the high-Jos* jroup.   In
mice exposed  to Aroclor 1254, Increased mortality  was  observed in the high-
dose group,  mild hepatopathology observed in the median-dose  group,  and  no
liver  lesions  detected In  the   low-dost  group.   The  NOEL  observed   In  the
study  using mice of 0.45  mg/kg  bw/day Is nearly Identical  to the LOELs  of


02320                                1-7                             04/06/88

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0.5  mg/kg  bw/day  associated  with porphyMa  In rats  and  0.25 mg/kg  bw/day
associated with enlarged thyroid.

    Monkeys have  been  found to  be  highly sensitive to the  toxic  effects  of
PCBs.   Signs  of   tox1c1ty  with  chronic  exposure  to  Aroclor  1248  Include
severe  facial and subcutaneous edema, comedones and  cysts of  the  melbomlan
glands, gastric  lesions,  body  weight loss and reduced hemoglobin  and  leuko-
cytes.  The lesions  are  unique to the monkey and  resemble chloracne  In  man.
In the  monkey,  chronic exposure  as  low  as  0.1  mg/kg bw/day  of Aroclor  1248
produce frank  toxic effects;  no studies  have been conducted from which  a
NOAEL  can  be  derived  or  to Indicate  how close 0.1 mg/kg bw/day  1s  to the
NOAEt for  monkeys.

    There  are  two  reports  of  a  slight  Increase  In  the   Incidence of  cleft
palate  In  the  progeny of  mice exposed  to  PCBs  during gestation.   Several
studies have  reported  fetal toxldty, which consisted of  resorptlons,  abor-
tions,  reduced  birth  weight,  and decreased  postnatal survival,   1n  several
species that was  attributed to PCBs.  The mink and monkey are the most  sen-
sitive  species  tested  to  the reproductive toxldty of  PCBs.  Complete repro-
ductive failure  was observed  1n  mink  maintained on a diet  containing  5 ppm
Aroclor 1242  (0.75 mg/kg bw/day) for  18 months.   Rhesus  monkeys  maintained
on diets containing 2.5  or 5  ppm Aroclor 124B  (0.1 or 0.2 mg/kg  bw/day) for
18 months  had Increased  abortions at the low dose  and maternal toxldty with
no live births at  the  high dose.

    Aroclor 1016  1s less toxic  than Aroclor  1242,  which  caused 100% mortal-
ity  In female mink  at the same  exposure level.   Chronic  exposure  to  2 ppm
Aroclor 1016  In  the diet  (0.3  mg/kg bw/day)  appears  to  be  a NOAEL  >n the

02320                                1-8                             04/06/88

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mink.  Adult  monkeys  exposed to  Aroclor  1016 1n  the  diet  did not  have  any
clinical  growth or  reproductive  abnormalities.   However,  Infants  born  to  the
1  ppm Aroclor  1016 group  (0.042  mg/kg bw/day,  assuming a monkey  consumes
4.2%  of   Us   body  weight/day)  were  significantly  smaller   than  controls.
Thus, 0.25  ppm (0.0105  mg/kg bw/day) appears to  be  a  NOAEL  for  chronic  oral
exposure to Aroclor 1016 In rhesus monkeys.

    Reports of mutagenlcHy  In the  Ames  assay are conflicting.  Host reports
Indicate  a  lack  of  mutagenlcHy.   No  report   of cytogenetlc  changes  or
dominant  lethal  effects   attributable  to  PCBs   have  been  located  In  the
available literature.

    Human exposure  to PCBs may  come from contact  with Industrial  products,
accidental  contamination  of  foodstuffs  or  from association with contaminated
                                                  •
environmental  components.   Similar signs  of toxlclty are associated  with
oral,  Inhalation   or  dermal  exposure.   Chloracne   Is  the  most  commonly
encountered dermatologlc  symptom.   These lesions comprise folllcular kerato-
sls  with  comedone formation  and  acneform eruptions.  Other reported dermato-
loglc  symptoms Include  rash, burning  sensation,  pigmentation  (darkening),
thickening, and discoloration of  the  fingernails.  It  Is  not clear whether
PCB  mixtures  are solely  responsible for  chloracne or whether contamination
of  PCBs with  polychlortnated dlbenzofurans (PCOFs) resulted 1n chloracne and
other  adverse  health  effects.    In Yusho  and Yu-cheng poisoning incidents,
 the  presence  of PCOFs in  the PCB contaminated rice oil and in the  liver and
other  tissues of  the victims Indicates that  PCOFs were the  responsible toxic
compounds.    Hepatic  effects associated  with PCB  exposure  Include hepato-
megaly,  hepatic  enzyme  induction with accelerated  rate of drug metabolism.
 and  hepatic  dysfunction   indicated  by  an  Increase In  serum  hepatic enzyme

 32320                                1-9                              04/06/88

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activities.   A  decrease  In  pulmonary   function   (forced  vital  capacity).
cough, wheezing, tightness  In  chest,,  and  upper  respiratory  or eye Irritation
were also reported 1n capacitor manufacturing workers.

    Two separate groups  of  high-risk  subpopulatlons  for  exposure to  PCBs may
be  Identified.   The first  group  Includes  those  persons with  the  potential
for  frequent  or  high  exposure,  namely,  occupationally-exposed workers  and
breast-fed  Infants,  as  PCBs are  excreted  In  the  breast milk  of  lactating
humans.  The  second  group Includes those individuals with  a  limited ability
to  metabolize and  excrete   PCBs,  such as  fetuses  and  neonates  (2-3 months
old).

    Infants born  to women  exposed  to PCB  during  pregnancy (Yusho Incident)
were  generally  small  for gestatlonal  age and exhibited  dark  brown pigmenta-
tion  on  the skin and mucous membranes,  glnglval 'hyperplasla. early eruption
of  teeth,   and  facial  edema.   The  PCOF Impurities  may also  determine the
severity of these effects.

    The available  data are  Insufficient  to develop a 1-day HA for PCBs.  It
1s  recommended  that the  10-day HA  for the  10 kg child be used for the  1-day
HA  for a   10  kg child.   A 10-day  HA  of  100 vg/l for a  10  kg  child has
been  recommended.   The  toxlclty  of the  PCBs found  In  water  may differ  from
the commercial PCBs  because  the congener  and Impurity composition  may be
very  different fro« the original Aroclor.  Longer-term HAs  on Aroclor  1016
for  a  70  kg  adult  and  10  kg  child are   0.0035  mg/t  and  0.001   mg/i.
respectively.
 02320
1-10                            04/11/88

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    PCBs  (Aroclor   1260,   Kanechlor  500,  Aroclor  1254,  Clophen  A-30  and
Clophen A-60) have been evaluated for cardnogenlclty  in  several  animal  bio-
assays.  Aroclor 1260  Induced a  statistically  significant  Increase  of  hepto-
cellular carcinomas  In two  rat  (Sherman,  Sprague-Oawley) feeding  studies.
Kanechlor 500  produced a  statistically  significant  liver tumor  response  in
dd mice  when  given  1n the diet  for  32  weeks.   Aroclor 1254 fed  In  the  diet
to mice (Balb/cj)  and rats  (Fischer  344)  Induced  Increased  Incidences  of
liver  tumors,  and  while the  Incidences  are  dose-related  they were  not  sta-
tistically  significant.   Clophen A-30  and A-60  Induced  hepatocellular  car-
cinomas  1n  rats after 832 days  of  feeding 100 ppm 1n the diet.  This  level
of carcinogenic  evidence  In rats and mice for  some  commercial  PCBs (Aroclor
1260,  Kanechlor 500 and  Aroclor 1254,  Clophen  A-30 and  Clophen A-60)  con-
stitute  sufficient  evidence for cardnogenldty  of  these  commercial  PCBs  In
animals  using weight of evidence criteria In the U.S.  EPA's  guidelines for
carcinogen  risk assessment. (U.S. EPA,  1986a).   Only  one recent epIdemlologU
study  reports  the  presence of a  carcinogenic  risk of liver  cancer  to humans
by Ingestlon.   A significant  risk of liver cancer was observed among victims
of the Yusho  accident  in  Japan, which Involved exposure to contaminated rice
oil.   There  1s  some  uncertainty   regarding  concurrent  exposure   to  other
possibly carcinogenic  substances.   The authors of the study have not derived
conclusions regarding tht  relationship  of exposure  to PCB-contamlnated Mce
on  and Increased  canctr  risk.   At  present, the  human ep1de»1olog1c evidence
 is suggestive,  but  fro» a wtlght of evidence classification of the data must
be  currently regardtd  as  inadequate because of  the tentative nature of  the
data.   The  authors  of these studies have  urged caution  In tht  interpretation
of their results.
 02320                                I-"                            04/11/88

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    The  positive  evidence  In  rats  and  mice,   together   with   inadequate
evidence 1n humans, places Aroclor  1254 and  1260,  Kanechlor  500,  and  Clophen
A-30  and  A-60  In  the welght-of-evidence  category 82.  as  a probable  human
carcinogen.   PCS  mixtures  containing  significant  amounts  of   components
present  In  Aroclor 1254 and  1260,  Kanechlor 500,  and Clophen A-30 and A-60
are  likely to  present  a  carcinogenic  hazard to  the human population  upon
exposure to PC8s.   Recognizing the variety and variability  of PCS  mixtures,
H  is recommended  that all  commercial  PCB mixtures be  considered  to  have  a
carcinogenic  potential  (category  82) similar  to  that of the  five  compounds
herein  evaluated.   This  1s  thought to be a prudent  public  health judgment
for   which  changes  could  be  made  1f   additional   scientific  evidence  Is
forthcoming.

     A cancer-based criterion has been calculated  for excess lifetime upper-
limit  cancer  risks  of   10"*,   NT»  and   10~».    The  respective  water
concentrations  are 0.5,  0.05  and  0.005  wg/l.   These  calculations  use the
linearized multistage dose-response model with data from a  study In which
hepatocellular  carcinomas were caused by  chronic dietary administration of
the PCB mixture Aroclor 1260 to female Sprague-Dawley rats.  Given a  lack of
Information  about which  constituents   of  Aroclor  1260 or  any  other PCB
mixture are  carcinogenic, Aroclor  1260  Is assmwti  to  be representative of
other PCB mixtures.  Currently,  there  1s no published  report In  the  litera-
 ture that shows the presence of Aroclor  1260 in  finished drinking water.
 02320

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                     II.   PHYSICAL  AND CHEMICAL  PROPERTIES
Structure and Identification
    Polychlorlnated  blphenyls   (PCBs)  are  a  family  of compounds  based  on
blphenyl as  the  parent  compound.   There  are  209  possible  PCS' Isomers  and
c-ongeners of which  some  187 have been chromatographlcally separated and  all
Have been synthesized (Hullln et al., 1984).  A listing  of all  PCS  congeners
1s  given 1n Table  II-l   along  with their  Chemical  Abstract Services  (CAS)
Registry  numbers   and   an   Identifying   numbering   system  developed   by
Ballschmlter and Zell (1980).

    The  structure  and  numbering of a typical PC8  (4,4'-d1chlorob1phenyl)  1s
as follows:
                            3'	2'
Here,  an  unprlmed  locant  1s  preferred  to  Us  primed  locant,  with as  few
primed  locants  used as  possible but  keeping  the sum  of  the  locant  number
(primed plus  unprlmed)  a  minimum.   For  rings with  equal substitution  the
ring with the lower numbered  locants  receives  the unprlmed numbers.   If both
rings are equal, the locant cited first 1s unprlmed.

    PCBs  used  commercially  are  complex mixtures  consisting  of  various  PCS
congeners and  Isomers.   Monsanto (the former  BrUlsh  and  U.S.  manufacturer)
designated a 4-d1g1t cod*  to refer to Us  PCBs marketed under  the tradename
Aroclor.   In  West  Germany  the  name  1s  Clophen; In  France,  Phenochlor  or
Pyralene;  1n  Japan. Kanecnlor or  Santothern; and  In  Italy.  Fenclor.   For
Aroclors  the  first two digits  (12)  indicate   that  the  prepafatlon  is  a

02330                                 II-1                            03/02/87

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 IM
 bi
                                       TABLE  II-l

                               Numbering of PCB I sowers*
LJ
    No.
Structure
CAS No.
No.
Structure
CAS No.
Nofiochlorofet pfctny U
1
2
3

2
3
4

2051-60-7
2051-61-8
2051-62-9

DUhlorobtphMiyU

4
5
6
7
8
9
10
11
12
13
14
15

2.2'
2.3
2.3'
2.4
2.4'
2.5
2.6
3.3*
3.4
3.4'
3,5
4.4'

13029-08-8
16605-91-7
25569-80-6
33284-50-3
34883-43-7
34882-39-1
33146-45-1
2050-67-1
2974-92-7
2974-90-5
34883-41-5
2050-68-2
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Trtchlorobtphenyls
U
11
18
19
20
21
2.2'.3
2.2'.4
2.2'. 5
2.2'.6
2.3.3'
2.3.4
38444-78-9
37680-66-3
37680-65-2
38444-73-4
38444-84-7
55702-46-0
40
41
42
43
44
45
TrUhlorobtphenyls (cent.)
2.3.4'
2.3.5
2.3.6
2.3'.4
2.3'.5
2.3',6
2.4.4'
2.4.5
2.4.6
2.4'.5
2.4',6
2'.3.4
2'.3.5
3.3'. 4
3.3'. 5
3.4.4'
3.4.5
3. 4'. 5
Tetrachloroblphenyls
2.2I.3.3I
2, 2'. 3.4
2. 2'. 3.4'
2. 2'. 3.5
2. 2'. 3.5'
2. 2'. 3.6
38444 -85 -»
55720-44-0
55702-45-9
55712-37-3
38444-81-4
38444-76-7
7012-37-5
15862-07-4
35693-92-6
16606-02-3
38444-77-8
38444-86-9
76708-77-5
55712-37-3
38444-87-0
38444-90-5
53555-66-1
38444-88-1

38444-93-6
52663-59-9
36559-22-5
70362-46-8
41464-39-5
70362-45-7

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                                              TABLE  11-1  (cont.)
No.*
  Structure
                         CAS No.
                     No.*
          Structure
                             CAS No.
letrichlorobtphetiyls  (cent.)
                                                               Tetrachloroblphenyls  (cont.)
 46
 47
 48
 49
 50
 51
 52
 53
 54
 55
 56
 57
 58
 59
 60
 61
 62
 63
 64
 65
 66
 67
 68
 69
 70
 71
 72
 73
2.2'
2.2'
2.2'
2.2'
2.21
2.2'
2.2'
2.2'
2.2'
3.6'
 .4*
 .5
 .5'
 .6
 .6'
5.5'
5.6'
6.6'
2.3.3'.4
2.3.3'.4»
2.3.3'.5
2.3.3'.5'
2.3.3'.6
2.3.
2.3.
2.3.
2.3.
2.3.
2.3.5.6
.4'
.5
.6
o 3«
*.«* •
o V
*••» •
  2V
 »«* •
  2V
 »•» •
2.3'.
2. 3'. 5. 5'
2.3'.5'.6
  4'
  5
  5'
  6
  .5
  .6
41464-47-5
2437-79-8
70362-47-9
41464-40-8
62796-65-0
68194-04-7
35693-99-3
41464-41-9
15968-05-5
74338-24-2
41464-43-1
70424-67-8
41464-49-7
74472-33-6
33025-41-1
33264-53-6
54230-22-7
74472-34-7
52663-58-8
33264-54-7
32598-10-0
73575-53-8
73575-52-7
60233-24-1
32598-11-1
41464-46-4
41464-42-0
74338-23-1
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
96
2.4.4'.5
2.4.4'.6
2'.3.4.5
3.3'.4.4'
3.3',4.5
3.3'.4.5'
3.3',5.5'
3.4.4'.5
                                                              Pentachloroblphenyls
2.2'.3.3'.4
2.2',3.3',5
2.2'.3.3'.6
2.2'.3.4,4'
2 ?' 3
*»' • «»•
  2jt 1
 »* •«».
2.2'.3.
2.2'.3.
2.2'.3.
2.2',3.
.5
.5'
.6
.6'
'.5
',6
2,2'.3.5.5'
2.2'.3.5.6
2.2',3.5.6'
2.2'.3.5',6
2.2'.3.6.6'
2.2'.3'.4.5
2.2'.3'.4.6
                     32690-93-0
                     32598-12-2
                     70362-48-0
                     32598-13-3
                     70362-49-1
                     41464-48-6
                     33284-52-5
                     70362 50 4
52663
60145
52663
65510
55312
38380
55215
73575
68194
68194
52663
73575
73575
38379
73575
41464
60233
-62-4
-20-2
-60-2
-45-4
-69-1
-02-8
-17 3
-57-2
-07-0
-05-8
-61-3
-56-1
-55-0
-99-6
 54-9
-51-1
-25-2

-------
 fO
 01
 0
                                                  TABLE II-l (cont.)
    No.
Structure
CAS No.
                                                                No.
Structure
                                                                                      CAS No.
    PenUchlorobtpfeefiyls  (cent.)
                                                                 Hexachlorobtphenyls
00
o»
99
100
101
102
103
104
105
106
10?
108
109
110
111
112
113
114
IIS
116
117
118
119
120
121
122
123
124
125
126
127
"> >•
* »f •
2.2'.
2.2'.
2.2'.
2.2'.
2.2'.
2.3.3
2.3.3
2.3.3
2.3.3
2.3.3
2.3.3
2.3.3
2.3.3
2.3.3
2.3.4
2.3.4
2.3.4
2.3.4
2.3'J
? 3'
«, j .
? 3'
• • J .
2 3'
c . a ,
?• 3
* •«•»
?• 3
* • •»»
?• 3
* • J»
2'. 3.
3.3'.
3.3'.
, '.5
. '.6
. .5'
. .*'
. '.•
. .*'
'. .4*
'. .5
'. '.s
'. .*•
'. .6
• * k
. ••
'.5.5*
'.5.6
(.5'.b
,4'. 5
,4'.6
,5,6
'.*.*
1.4'. 5
.«•.*
.5.5'
.S'.&
'.4.5
.*'.5
.5.5'
.5.6'
.4'. 5
.5.5'
                                           38380-01-7
                                           39485-83-1
                                           37680-73-2
                                           68194-06-9
                                           60145-21-3
                                           56558-16-8
                                           32598-14-4
                                           70424-69-0
                                           70424-68-9
                                           70362-41-3
                                           74472-35-8
                                           38300-03-9
                                           39635-32-0
                                           74472-36-9
                                           68194-10-5
                                           74472-37-0
                                           74472-38-1
                                           18259-05-7
                                           68194-11-6
                                           31508-00-6
                                           56558-17-9
                                           68194-12-7
                                           56558-18-0
                                           76842-07-4
                                           65510-44-3
                                           70424-70-3
                                           74472-39-2
                                           57465-28-8
                                           39635-33-1
128
129
130
131
132
111
i jj
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
2,2'
2,2'
2,2'
2,2'
2.2'
2.2'
2.2'
2,2'
2,2'
2,2'
2.2'
2.2'
2.2'
2.2'
2,2'
2,2'
2,2'
2.2'
2.2'
2,2-
2,2'
2.2'
2.2'
2.2'
2.2'
2.2'
2,2'
2.3.
1 3' 1 1'
,J,J ,*,*
33' 4 *\
. «J »~.J
,3.3'.4.5'
.3.3'. 4.6
.3.3'. 4.6'
.3.3'.5,6
. 3.3'. 5, 6'
,3,3'.6.6'
.3,4.4'. 5
. 3.4.4'. 5'
,3.4.4'.6
.3.4.4',6'
.3.4.5.5'
.3.4.5.6
.3.4.5.6'
.3.4. 5', 6
.3.4.6.6'
.3.4'. 5.5'
.3.4'. 5.6
.3.4'. 5.6'
,3.4'.5'.6
,3.4'.6.6'
,3.5.5',6
.3.5.6.6'
,4,4'.5.5'
.4, 4'. 5.6'
,4.4'.6.6'
3'. 4. 4'. 5
                                                                                      38380-07-3
                                                                                      55215-18-4
                                                                                      52663-66-8
                                                                                      61798-70-7
                                                                                      38380-05-1
                                                                                      35694-04-3
                                                                                      52704-70-8
                                                                                      52744-13-5
                                                                                      38411-22-2
                                                                                      35694 06 5
                                                                                      35065-28-2
                                                                                      56030-56-9
                                                                                      59291-64-4
                                                                                      52712-04-6
                                                                                      41411-61 4
                                                                                      68194-15-0
                                                                                      68194-14-9
                                                                                      74472-40-5.
                                                                                      61906 Ib 8
                                                                                      68194-13-8
                                                                                      74472-41-6
                                                                                      38380-04 0
                                                                                      68194-08-1
                                                                                      S2663-63-5
                                                                                      68194 09 2
                                                                                      35065-27-1
                                                                                      60145-22 4
                                                                                      33979 03-2
                                                                                      38380 OB 4

-------
                                                        TABLE 11-1  (cont.)
 IVJ
 u>
 u>
 o
No.*
Hexach
15?
ISO
159
160
161
162
163
164
165
166
167
168
Heptact
170
171
172
173
174
175
176
177
178
179
IHO
181
182
Structure
lorobtphenyls (cont.)
2.3.3'. .4', 5'
2.3.3'. ,4'.6
2,3.3'. .5.5'
2,3.3'. .5.6
2.3.3'. ,5'6
2.3.3'. '.5.5'
2.3.3'. '.5.6
2.3.3'. '.5'.6
2.3.3'. ,5'6
2.3.4.4 .5.6
2.3'. 4, '.5.5'
2. 3'. 4, '.5'. 6
3. 3'. 4, ',5.5'
ilorobtphenyls
2. 2'. 3, 3'. .4'. 5
2. 2'. 3, 3'. ,4',6
2 2' 3.3* . .5.5'
2. 2'. 3, 3'. .5.6
2. 2'. 3. 3'. .5.6'
2, 2'. 3.3'. .5'.6
2.?'. 3. V. .6.6'
2. 2'. 3. 3', '.5.6
2.?'. 3, 3'. 5. 5', 6
2.?'.3.3'.5.b.6'
2. 2'. 3. 4.4'. 5. 5'
2. 2'. 3.4. 4'. 5. 6
2. 2'. 3. 4. 4'. 5. 6'
CAS No.
69782-90-7
74472-42-7
39635-35-3
41441-62-5
74472-43-8
39635-34-2
74472-44-9
74472 45-0
74472-46-1
41411-63-6
52663-72-6
59291-65-5
32774-16-6
35065-30-6
52663-71-5
52663-74-8
68194-16-1
38411-25-5
40186-70-7
52663-65-7
52663-70-4
52663-67-9
52663-64-6
35065-29-3
74472 47-2
60145-23-5
No.*
183
184
185
186
18?
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
Structure
Heptachlorobtphenyls (cont
2. 2'. 3. ,4'.5',6
2. 2'. 3. .4', 6. 6'
2, 2'. 3. .5. 5'. 6
2, 2'. 3. ,5.6.6'
2, 2'. 3. '.5, 5', 6
2, 2'. 3. '.5.6.61
2,3.3'. .4'. 5. 5'
2.3,3'. .4'. 5. 6
2.3,3'. .4'. 5'. 6
2,3.3'. .5. 5'. 6
2,3.3'. '.5, 5'. 6
Octachloroblphenyls
2. 2'. 3. 3'. .4'. 5. 5'
2. 2'. 3. 3'. .4'. 5. 6
? ?' 3 3' 4' 5 6'
c,c ,J,J , »^ »•*••*
2,2'. 3. 3', .4'. 6. 6'
2. 2', 3. 3', ,5,5f,6
2. 2', 3. 3'. .5.6.6'
2. 2', 3. 3'. 4, 5', 6. 6'
2, 2', 3. 3', 4, 5, 5,6'
2. 2'. 3. 3', 5.5'. 6. 6'
2. 2'. 3. 4. 4'. 5. 5'. 6
2. 2'3. 4. 4'. 5.6. 6'
2,3,3',4.4',5.5't6
CAS No.
52663-69 1
74472-48-3
52712-05-7
74472 49 4
52663 68-0
74487-85 7
39635-31-9
41411-64 7
74472-50-7
69782-91 8
69782-91-8
35694 08 7
52663 78 2
42740 50-1
33091-17 7
68194-17 2
52663 73 7
40186 71 8
52663 75 9
2136-99 4
52663 76 0
74472-52 9
74472-53 0
oo
cr

-------
                                                   TABLE II 1 (cont.)
o
fO
b>
CJ
      No.
  Structure
 CAS No.
No.*
                                                                            Structure
                             CAS No.
      Nonachlorobtphenyls
       206
       207
       208
2.2'.3.3',4.4'.5.5'.6
2.2'.3.3'.4.4'.5.6.6'
2.2'.3.3',4.5.5*.6.6'
40166-72-9
52663-79-3
5121 88-0
209
        Decachlorobtphenyl

2.2.3.3'.4.4'5,5',6,6'
2051 -24-3
      *BallsclwUer NiMber (BallsclwUer and Zell, 1980)
CD

-------
b1phenyl-C,2 mixture  and  the second  two  digits Indicate  the  chlorine con-
tent percentage by  mass.   Thus, Aroclor  1242  Is a blphenyl mixture with an
average chlorine content of 42%.  Honsanto also developed  a mixture  that was
primarily mono-,  d1- and  trl-chloro  Isomers,  Aroclor  1016.   The  chromato-
graphlc  pattern  and  the  actual percent  chlorine  (41%)  Is  very similar to
Aroclor 1242.

    The CAS  numbers  and  the  Registry  of  Toxic  Effects  of Chemical  Substances
(RTECS)  numbers  for representative Aroclors are given  1n Table II-2.   Toxic
polychloMnated  dlbenzofurans   (PCDFs)  have  been  found  In all  PCB formula-
tions  (Tables  II-3,  II-4 and II-5).

Physical  and Chenlcal  Properties
     Some  physical  properties of some  Aroclors  are summarized  In Table II-6.
                                                 *
Molecular formulas  of  PCB congeners   In  various Aroclors and  Kanechlors are
 listed In  Table  II-7.   The properties  of  the Aroclors  listed are  average
 values,  however,  since the  Aroclors  are mixtures.  For  example, the  molecu-
 lar mass of the PCB congeners  ranges from 154 for blphenyl to  499  for deca-
 chloroblphenyl.   Thus,  the  vapor  pressure  and  water  solubilities  of   an
 Aroclor reflect the lower chlorinated components of  greatest  abundance.

     Individual  PCB  congeners   Increase   1n  vapor pressure  with  decreasing
 chlorlnatlon  (Hutzlnger   et al.,  1974;  Westcott  et  al., 1981; Foreman  and
 bMdlenan,  1985; Burkhard tt al.. 1985a).  The  vapor  pressure of blphenyl  Is
 1.01  pascal  at  25'C,  whereas  that  for  decachloroblphenyl   Is  5.30x10"*
 pascal  (Burkhard  et  al.,  1985a).   The  Henry's Law constants  at 25»C do  not
  02330                                II-7                            03/02/87

-------
                                 TABLE  11-2
                  CAS  and RTECS Numbers for Some Arodors*
Aroclor No.
1016
1221
1232
1242
1248
1254
1260
1262
1268
CAS No.
12674-11-2
11104-28-2
11141-16-5
53469-21-9
12672-29-6
11097-69-1
11096-82-5
37324-23-5
11100-14-4
RTECS No.
NA
TQ 1352000
TQ 1354000
TQ 1356000
TQ 1358000
TQ 1360000
TQ 1362000
NA
NA
Reference
NIOSH, 1983
NIOSH, 1983
NIOSH. 1983
NIOSH, 1983
NIOSH, 1983
NIOSH. 1983
NIOSH, 1983
Al ford-Stevens et al.,
Al ford-Stevens et al.,








1986a
1986a
NA . Not available
02330
II-8
11/13/86

-------
 ro
                  TABLE  11-3


PCDF Content  In  Some  PCBs and In Kaneml 01 la
CJ

00
o»
PCOF Content (PPM)
Substrate
Yu Cheng oil5 (3)
Kaneml o11b (4) (Yusho)
Unused Kanechlor 400b
Used Kanechlor 400b (3)
Kaneml oil (Yusho)
Kaneml oil (Yusho)
Used Japanese
PC8 (Nltsubtshl-
Monsanto T-124B)
Kaneml oil
Kanechlor 300
Kanechlor 300
Kanechlor 400
Kanechlor 400
Kanechlor 400
Kanechlor SOO
Kanechlor 500
Kanechlor 600
Kanechlor 600
PhenoLlor UP -4
Phenoi lor »P-5
Irl- Tetra-

0.15 1.4
--
4.2 4.5
0.02 0.52
6.7
--
0.3 12.2
...
1
0.2 1.7
.
0.2

1.7
4.6
Penta- Hexa-

2.5 1.6
__
5.5 1.4
1.3 0.81
1.6-
1.3
10.4 0.9

.-
1.1 3.1
--
0.5 0.4
--
1.6 0.5
2.7 2.6
Total
0.14-0.18
2-7
33
20-510
5.7
5.0
16
2.7
8.3
1.3
24
18
—
6.1
3.3
1.1
4.0
3.8
9.9
Reference
Nlyata et al.. 1985
Mlyata et al.. 1985
Ntyata et al.. 1985
Ntyata et al.. 1985
Buser et al.. 1978
Nagayama et al. . 1976
Buser et al.. 1978
Horlta et al.. 1977a
MorHa et al.. 1977a
Nagayana et al.. 1976
Horlta et al.. 1977a
Nagayama et al.. 1976
Roach and Pomerantz.
1974
MorHa et al.. 1977d
Nagayama et al., 1976
MorHa et al.. 1977a
Nagayama et al.. 1976
MorHa et al.. 1977a
MorHa et al.. 1977a

-------
                                                    TABLE 11-3 (cont.)
00
o»
PCOF Content (DM)

Substrate
Phenoclor DP -6
Phenoclor OP -6
Aroclor
Aroclor
Aroclor
Aroclor
Ai oc lor
Aroc lor
Aroclor
Aroclor
Aroclor
Aroclor
Aroclor
Clophen
Clophen
tlophen
Clophen
1-1200
T-1241
T-1242
T-1248
1-1248C
1-1254
T-1254
T-1254
1 1260
T 1260
1-1264
A-30
A -40
A SO
A -60
Trl- Tetra-
0.2 2
0
0
2
2
0
0.3 5
0
0
0
0
0
4
.1
.7
.1
.4
.3
.5
.8
.1
.2
.1
.2
.8
.8
1.6 2.3
1.5 5.4
0.7 8
.3
1.4
Penta-
2
10
0
2
2
2
5
0
0
3
0
0
9
1
6
4
.6

.4
.7
.3
.3
.6
.2
.4
.6
.3
.9'
.4
.0
.9
.1
5.0
Hexa-
5.6
2.9
0.5
O.B
—
__
0.7
1.4
0.9
1.9
0.3
0.5
2.0
• -
•-
1.8
2.2
Total
11
14
1
5
4
2
12
1
1
5
0
2
16
4
14
15
8
Reference
Nortta et al.

.0
.9
.5
.8

.7
.5
.6
.8
.2

.9


.4
Bowes
Bowes
Nortta
Nortta
Nortta
Nortta
Bowes
Bowes
Nortta
Bowes
Nortta
Nortta
Nortta
Nortta
Nortta
et al..
et al..
et al.
et al.
et al.
et al.
et al..
et al..
et al.
et al..
et al.
et al.,
et al.,
et al.,
et al.,
Bowes et al.,
. 1977a
1975
1975
. 1977a
, 1977a
. 1977a
, 1977a
1975
1975
. 1977a
1975
, 1977a
, 1977a
, 1977a
, 1977a
, 1977a
1975
C    aNo data touml tor hepla
t>Yu Cheny  oil  also contained  22-113 pp« PCBs  and  9-38 pp*  PCQs.   Kanent  oil also  contained  151-968 ppm
 PCBs  and 490 U66  PINK  PlQs.   Kanechlor  400  also  contained  999.800 ppm  PCBs  and  209  ppm  PCQs.   Used
 Kanechlor 400 also contained 961.900-999.000 ppm PCBs and 690-31.000 ppm PCQs.

CUsed PCB

-------
                                  TABLE II-*

   Suspected Haxlraum Levels of Toxic PCDFs 1n Various PCBs and \n R1ce 011s
          (Kaneml  oil also contained 900 ppn PCBs and 800 ppm PCQs;3
     Yu-Cheng  rice  oil  also contained  60-100 ppm PCBs  and  90-180  ppn PCQs)
                     PCOF Levels (ppn)
Formulation
2.3.7.8-b.c    2,3.4,7,8-M
   TCOF           PeCOF
Total
Percentages of
  Total PCOFs
 for These T«o
  Derivatives
Yu-Cheng Mce
oil (2)*
Kane«1 oil*
Kaneal o11b
Phenoclor*
DP -4
DP-S
DP -6
Kanechlor0
KC-300
KC-400
KC-500
KC-600
Aroclor1*
T-1241
T-1242
T-1248
T-1248*
T-1254
T.I 260
T-1264
0.001-0.005

0.2
0.28

0.7
2.2
0.9

2.2
1.6
0.7
0.1

1.1
0.2
0.2
1.1
_,
..
2.4
0.02-0.70

0.7
0.42

0.4
0.8
0.6

0.6
0.9
0.7
0.1

0.4
0.1
0.8
1.4
1.6
0.1
2.3
0.08-0.10

2.02
2.68

3.8
9.9
10.5

8.3
23.8
6.1
1.1

5.9
4.5
2.8
12
5.6
2.2
16
20-25

45
26

29
30
14

34
11
23
18

25
7
36
20
29
5
29
 02330
                      11-11
                   10/31/86

-------
                              TABLE  II-4 (cont.)
                     PCDF Levels (ppm)
Formulation
2,3.7.8-b-c    2.3.4.7.8-b'd
   TCOF           PeCOF
Total
Percentages of
  Total PCOFs
 for These Two
  Derivatives
C1ophen»
A-30
A -40
A-50

1.0
2.1
3.6

0.1
0.7
0.6

4.9
14
15

22
20
28
'Masuda et al., 1982
Calculated from Norlta et al., 1977a
cBased  on 6C  retention  tine,  but  subsequently  confirmed by  Buser et  al.
 (1978).  This was subsequently found to Include also the 2,3,4,8-TCDF.
dThe  order  of  elutlon  obtained  by  Buser  et  al.  (1978)  Is  assumed  to
 pertain to the GC column utilized.
eUsed PCB
— Below detection limit
02330
                      11-12
                                                                      11/13/86

-------
              TAUf II  S
Specific PCOfs  In CMMrcUl Kts 1*9/1)'
Kl-typ
ryrtl*.
A12S4
A12M
A30
A40
AM
AM
IM
ClMhMC
OlMk
OlMk
•S*wrct: 0*4
NO - N»t «•«
Irl- Iflrf-
UU1 2310 1*U1
100 S3 030
63 19 1.400
10 11 110
MO 35 S13
1300 100 2.MO
1400 33M 20.000
mAAft 4 tM
OJ^W Wf ^^^
41 23 3M
110 54 1.200
MO NO NO
NO NO NO
*••! •!.. 1004
LKt«4
PcftU- MtMi- Hepl*-
12340
12310
10
MO
40
14
M
IM
1100
91
34
NO
NO


23410
f
490
54
20
0
1100
990
122
30
Ml
HI


,.,.,
35
4000
2M
IM
1100
0000
0100
040
210
NO
MO


123419
123410
NO
2500
MO
M
10
100
1MO
520
M
NO
NO


12M10
NO
2100
120
M
M
3M
330
390
1
NO
MO


123109
NO
190
190
Ml
Ml
10
no
M
Ml
Ml
Ml


234611
Nl
130
21
NO
T
M
330
41
Nl
Nl
Nl


Total Toljl
NO NO
10.000 960
1,500 1300
220 1
310 NO
3.100 15
6,000 2000
2.600 220
T NO
NO NO
Nl ND


«ec 2318
UDB X
19
10
M
19
19
95
95
12
19
90
a;



-------
                                                                             I Ail I  11-6

                                                              Son* Physical Properties of Aroclors'-b'c
  u
  g
Ci
o
•o


Appearance

Chlerlne (percent)
Oenstty (*/•*) (M*C)
Olst 1 Hat ten ranfe (*C)
Ivaperatlen toss
« at 100T./4 ne«rs
Animus sel«blllty (•*/*)

llptd selMfclllty
(nrfanlc snlvents)
Vaper pressure
(•• Nf al 25-C)
1*0 ectanel/Mater parti -
lien ceefMclent
Mserptlen capacity ef
activated carben (••/•)
Cenvertlen radars
1 nttt
1 •*/•• •

1014 1221
clear ell clear ell

41 20.5-21.5
1.33 1.15
325-354 275-320
1-1.5
0.42< ..SI-

very soluble very soluble
(4ilO'«J |b.7ilO~*)
4.30^ ,?tj
>5.50«.J 4.0*J.k
HA 242 '


10.05 •**• 0.21 •,/••
00*40 pp* 0.122 ppn

1232
clear ell

31.4-31.5
1.24
2*0-325
1-1.5
MA

very soluble
|4.0f»IO~>)
(3.2)
430)


9.50 «•!/•>•
0.105 ppm
	 VALUf
1242
clear ell

42
1.35
325-344
0-0.4
0.24.0.344
0.13*
very soluble
4.04ilO~«
>5.SO».J
MA


10.9 mt/m*
0.0917 pp.

1240
clear ell

40
1.41
340-375
0-0.3
0.054

very soluble
4.94.10.
|5.751««
>4.1P.J



12.2 «9/e)»
0.0014 pon
	
1254
ll«ht yellow
viscous liquid
54
1.50
345-390
0-0.2
0.012. 0.024*
0.054*
very soluble
7.71ilO »
lk..3,H



13.4 mt/m'
0.0745 ppm

1240
llobt yell^
sticky resin
40
1.50
305-420
0 0.1
0.027

very soluble
4.05x10 *
17.141"
>4.l|i.)

MA

15.4 •!/••
0.06S1 ppa
         frea CallahM et a I.. 197*
•All values net superscripted are frea HMS*M«. 1*74.
C0rackete4 data are estlmtetf.
•^arls el al.. 1*70
'MelllfleM. 1979
'OeHter aM r^avlev. 1*70
OMaejn et al.. 1*74
StoKsck el al.. 1974;  Ckleti et a I.. 1*77
'emeu et al.. 1*77
jPartltte* ceefflcteet ef lewest  chlerliMted blpbeayl present  In slgnlfleant etuniutes
Mulp a«4 Mult Infer.  l*70a
'OaeMnatlMn, 1*04
HA - Hoi available

-------
                                                 TABLE 11-7
o
ro
01
o
Percent Composition of
Aroclors and Kanech1orsa
Mass Percentage In Aroclor
tMplrlca)
ForMila
(•12^10
C]2H9C1
C,2M8C12
C)2H7C13
- C12H6C14
i C12M5C15
C12M4C16
C12H3C17
C12H2C18
C12H,C19
Percent chlorine
'Source: Callahan
1016
<0.l
1
20
57
21
1
<0.1
NO
NO
ND
41
et *!..
1221
11
51
32
4
2
<0.5
ND
ND
ND
NO
20.5-21.5
1232
<0.1
31
24
28
12
4
<0.1
ND
NO
ND
31.4-32.5
1979; 1ABC. 1974; Masuda et
5 ^jL.dilor 600 (Japanese ). Phenoclor OP6
g (Manila et a).. 1974; Hkhbeln. 1974).
\
CD


(trench) and

1242
<0.1
1
16
49
25
8
1
<0.1
ND
ND
42
1248 1254
ND
ND
2
18
40
36
4
NO
ND
ND
48
<0.1
<0.1
0.5
1
21
48
23
6
NO
ND
54
1260b
ND
NO
ND
NO
1
12
38
41
B
ND
60
Kanechlor NiMber
300
NR
NR
16.6
59.8
23.0
0.6
NR
NR
NR
NR
NA
400
NR
NR
3.0
32.8
43.8
15.8
4.6
NR
NR
NR
49
500
NR
NR
NR
5.0
?6.5
55.0
12.8
NR
NR
NR
54
al., 1974
Clophen

A60

(German);

all contain

-60%

Cl



NO - None detected; NR - Not reported

-------
depend on  molecular  weight but  do  for ortho-substHuted  PCBs  (Burkhard et
al..  1985b;  Arbuckle.  1986).   Vapor-particle  partitioning of  PCBs depends
markedly  on  temperature   (Bldleman  et al.  1986);  at   20'C,  only  2.IX of
Aroclor  125*  was retained  on  a filter,  whereas  at 0°C  the  percentage was
25%.   Differential   volatilization  of  the  less  chlorinated  components of
Aroclor  1254  has  been observed  during  air  sampling  with  Tenax-GC,  XAO-2
resin,  and deactivated florlsll  (Brownlow and  Que Hee,  1985;  Lin and Que
Hee,  1987).   Enrichment In the  higher  chlorinated  congeners Is  observed  also
In  the residue  after  volatilization of  the less chlorinated compounds  (L1n
and Que  Hee,  1987).

    Individual  PCB  congeners Increase  1n water solubility,  with decreasing
chlorlnatlon  and Increasing temperature  (Yalkowsky et  al.,  1983;  Mackay  et
al.,  1980; Olckhut  et al., 1986).   Beyond the Cl4-PCBs.  most  of  the  PCBs
tend   to  be  relatively   Insoluble  (Olckhut  et   al.,   1986);  for  example,
3,3',4,4'-Cl4-PCB  has  a   solubility  of  (1.95xlO'») H  at  25«C;  decachloro-
blphenyl  similarly   has   a solubility   of  (1.30xlO~")  M.   Octanol/water
coefficients  Increase with Increasing chlorlnatlon  (Rapaport and Elsenrelch,
1984).  Miller  et  al.  (1985)  showed that  log K    values  at  25'C  varied
                                                    ow
between 3.76 (blphenyl)  and 8.26  for  decachloroblphenyl.   The  Cl^-PCBs had
a  log  K   of  -5.7;  the  Cle-PCBs  of  -6.0, and  tht  Cl,-PCBs  of  -7.0.   In
         OW                  3                            0
 all  of  these  system the chlorine  substitution   In an  Homeric class also
 Influences physical  property.

      PCBs  are aromatic and hence can  be detected with  great sensitivity using
 ultraviolet  (UV)  detectors  (\    are  at  197-222, 214-265  and  267-302  nm
                                (MX
 for  PCBs), and jive  strong molecular  Ions  In mass spectra,  but  because  of


 02330                                11-16                           03/02/87

-------
the  number   of  possible  congeners.   Infrared  spectroscopy  (1200-300  cm"1)
and nuclear  magnetic  resonance  spectroscopy  (7.0-7.6  ppm relative to tetra-
methylsllane) are poor at sensitively distinguishing congeners (Hutzlnger et
al., 1974).  Mullln et al. (1984) have measured the 'H-NHR spectra for Indi-
vidual  C14,  C15,  C16   and   Cl?-PCBs.    As  for  the  Clg  and  Clg-PCBs,
the 2,2',6 and  6'  protons exhibited  the lowest chemical shifts with respect
to  tetramethylsllane.   Protons  at   the  para  positions  gave   the  highest
chemical  shift  values.   The  spectra for  the mono-,   d1-  and  tM-PCBs  were
extremely complex.

PCB Analysis
    Capillary  gas  chromatography  with  nonpolar  columns  1s  Invariably  the
last  step  used  to attain  optimum separation  (Hullln et al.,  1984);  currently
only  187  congeners  of the 209  are  resolvable.  The capillary column used was
50 m  x  0.2 nm 1.0. fused silica coated  with SE-54 and a temperature program
of  l.O*C/m1n from  100-200'C  (Injector,  and "Nl-electron  capture  detector
temperatures  ware 270 and  330'C,  respectively).  The synthesis of all  209
congeners  Is also provided.   The relative retention  times are  highly  depen-
dent  on  congener  structure.    UUhln  each  series  of  Isomers,  there  was
generally an Increase tn retention  tint with a  decrease 1n the  number  of
o-chloro   substUutnts.    The  electron-capture  relative  response  factors
 increase  with  Increasing chloHnatlon,  but  there are wide variations  within
 Homeric  classes.  Cooptr et al.  (1985)  selected 31  surrogate congeners for
 each isomeMc  class  based on electron-capture  response.   PelUzarl et al.,
 (1981,  1985) have  also discussed  these problems.  The molecular Ion (N) and
 M-2C1 have been  most utilized  for  specific   1on monitoring mass  spectroscopy
 after capillary  column  separation.   Electron Impact  (70eV) fragmentation  1s


 Q2330                                11-17                           03/31/88

-------
the most commonly used technique  (Alford-Stevens et al.,  1986a,b;  Gebhart  et
al.,  1985;  Sllven et  al..  1985).  However,  It Is 2-3  orders of  magnitude
less  sensitive  than  the electron  capture  detector.   Electron  Impact  (70eV)
fragmentation Is  recommended  as  the  basis of  U.S.  EPA method 680  (Alford-
Stevens et  al.,  1986b).   It was  shown  that the mass  spectrometrlc  response
factors within an Isomerlc class  varied between  1.3 and  4.6  (Gebhart et  al.,
1985).  Nevertheless,  nine  surrogate congeners  can  represent all  PCBs  In
mass  spectroscoplc response; therefore, the  recommendation  Is  that detection
limits  be  found  In  terms of  these nine surrogates..  The nine  surrogates  In
terms of chlorine substitution are  as follows:   2-, 2,3-,  2.4,5-,  2,2',4,6-,
2,2',3,4,5'-,  2,2',4,4',5.5'-.  2.2',3,4',5,6,6'-,  2,2'.3.3',4,5',6.6'- and
decachloroblphenyl  (for  Cl.  and  Cl-,.).    The  only  Isotoplcally  labeled
PCB   available   1s   3,3',4,4'-Cl4  PCB-d6  (Gebhart  et  al..  1985).    The
recovery of Aroclors   from waters shows a  negative bias between   15  and 27%
                                                 •
when  analysed as  Aroclors,  thus  necessitating  specific congener  analysis
(Alford-Stevens et al.,  1986b).

    Positive  methane  chemical  1on1zat1on-GC/HS of PCBs  has  been  reported  by
Voyksner  et  al.  (1986).   The   (M*H)f   and  (N+H2-C1)*  Ions  were  moni-
tored.  The relative  response  for all congeners varies between 0.14 and 1.79
(compare electron  Impact range  of 0.22-4.08),  and  was generally 2-6  times
more  sensitive than electron  Impact detection (but still not as sensitive as
electron capture detection).

    Environmental  samples  often  require  many  clean-up steps  before Inter-
fering  peaks  can  be  removed.   For example, sediments  require Soxhlet extrac-
tion  or ultrasonic  homogenlzatlon  In hexane/acetone or  Isopropanol/dlchloro-


02330                                 11-18                            03/02/87

-------
methane  followed  by  Florlsll  column chrotnatography,  and  removal of  sulfur
before  GC/HS  analysis  (Alford-Stevens  et al.,  1985).   Using a  Webb-McCall
Analysis  (Webb  and HcCall,  1973),  direct comparison with Aroclor  standards
or specific congener  analysis  can then be performed  (Alford-Stevens  et  al..
1985).   The  Soxhlet  extraction  Is  recommended  for  sediments.   In  general.
direct  comparison  with Aroclor  standards  gives higher  results  than  the
Webb-MeCall method  alone.   The more  heavy  the contamination, the better  Is
the accuracy  of the Aroclor standards comparison.   The  noncorrespondence  of
blood  PCS profiles  with  original  Aroclor  1s  well-known from  occupational
studies  (Wolff  et  al., 1986) and  from  the Yusho  incidents (Chen  et  al.,
1985; Hlyata et al.,  1985;  Hashimoto et  al., 1985; Hara, 1985).   In general,
the sample  (tissue or  blood)  1s  saponified, extracted  with  hexane,  concen-
trated  and  then subjected to  Florlsll chromatography  before  GC/MS analysis.
Pattern  recognition of  the  GC and  GC/HS data from  environmental  (Capel  et
al.. 1985) and tissue  (Wolff et al..  1986) samples has been discussed.

    Solvent extraction with dichloromethane  Is recommended for PCB Isolation
from  environmental waters  In  U.S.  EPA  method  680  (Alford-Stevens  et  al..
1986b).   An  XAD-4  sorbent  method  yielded  competitive  results  with  the
dichloromethane  solvent  extraction  method   for  Aroclor  1232  1n  distilled
water but not  1n  natural water at a  concentration of 10 ppb  (Woodrow et al.,
1986).   Clean-up on HP1C Is  required  for  levels below tht ppt  level.

    UV  detectors  In HP1C can be  effectively utilized for sensitive detection
of PCBs  because of their strong  ultraviolet absorption.  Normal  phase silica
columns  are  usually  used  with hexane as mobile  phast  together with methyl
t-butyl  ether  In  a linear  gradient program  (Woodrow et al.,  1986).   A fluor-


02330                                 ii.19                            11/13/86

-------
escence detector with excitation  at  340 run has also been used after  a  37-50
wBondapak/CorasIl  column  or   a   uBondapak   C1g  column   (Miller  et   al.,
1985).

    Two dimensional TLC using a hexane/ethyl acetate mobile phase  and silica
gel  plates  has  been  reported  (Lay et  al.,  1976);  the fluorescence  char-
acteristics  of  PCBs   1n  a-cyclodextrln  using  room  temperature  phosphor-
escence can discriminate some Individual PCS  congeners  (Femla et  al.,  1985).

    Other analytical  methods of  some  use are  perchloMnatlon  (Lin  and  Que
Hee,  1985)  and  dechloHnatlon  (Seymour  et  al.. 1986).   Perchlorlnatlon  has
been  used  extensively,  especially  for  Yusho samples  (Hlyata et  al.,  1985;
Hashimoto et al., 1985).

Chemical Reactions
    Pvrolvsls.   A  route  with  environmental   Implications  1s  the  thermal
production  of PCOFs  from PCBs.   Buser et  al.  (1978)  and Buser  and  Rappe
(1979)  showed  that  when  specific  PCBs were  pyrolyzed  In quartz  ampules
between  500 and 700*C, PCOF  yields  1n the  1-10% range could  be obtained,
though  they were  accompanied  by  many  other products  Including chlorinated
benzenes, naphthalenes  and  hydroxy PCBs.  Buser et  al.  (1978)  described the
products of pyrolysls  at  600*C Identified by GC/HS.  There appear  to be  four
major paths for  production  of PCDFs from PCBs:  loss of  two  ortho  chlorines,
loss  of ortho  hydrogen as  well  as chlorine,  loss  of  an  ortho hydrogen as
well  as  chlorine  but  Involving  a  shift  of  chlorine  from the  2- to the
3-pos1t1on  and  loss of two  ortho hydrogens.   These paths are  summarized  In
 02330                                H-20                           05/07/87

-------
Figure  II-l  for 2,2',4.4',5,5'-hexachloroblphenyl.   Such paths are  environ-
mentally  Important  In  the  origin  of  toxic  PCOFs  from various PCS  formula-
tions.  Mazer  and  HUeman (1982),  Mazer et  al.  (1983a,b) and  Hlleman  et  al.
(1985)  have  utilized  the  technique after HPLC  separation  and  confirmation by
GC/MS and Kovats Indices  to  produce  110 pure TCDFs  to  act as  chromatographlc
standards.

    The levels  of  PCOFs In PCBs Increase with  the  length of  time  In service
at high temperatures  as heat exchange media  (Morlta et al.,  1977b;  Buser et
al., 1978),  as  originally suggested  by Kuratsune et al.  (1976).   A  contrary
finding has  been reported by  Cull  and  Oobbs  (1984).   Aroclor  1254  on pyroly-
s1s also  contained the major toxic  PCOFs,  but  the relative amounts  of  the
products differed  somewhat  from those  obtained  from  the  MUsublshl-Monsanto
T-1248  (Buser   and  Rappe, 1979).   The major  PCOFs Identified  In  the  used
                                                 *
M1tsub1sh1-Monsanto T-1248 were the  2,3,7,8-TCOF (1.25 ppm),  the  2,3,4,7,8-
PeCDF    (the   pyrolysls   product   of   2,4,5,2',4'.5'-hexachloroblphenyl},
1,2,3.7,8-PeCOF,  2,3,4,6,8-PeCOF.   1,2.3.4,8-PeCDF,   1,3,4,7,8-PeCOF   (also
from  pyrolysls of  2,4,5,2',4'.5'-hexachloroblphenyl) and  the  2,3,4,6,7,8-
HxCOF.  The  2,3,4,8- and  2,3,7,8-TCOFs were later  shown to  co-elute  (Mazer
et  al.,  1983a,b;   Rappe   et   al.,   1984).   The  exact  composition  of  the
2.3,7,8-TCOF peak  Is  still  unreported.   Whereas the used  Mitsubishi-Monsanto
T-1248 was  exposed for years  to  elevated  temperatures In  the  liquid  phase,
the laboratory  pyrolyses  of  Aroclor  1254 and  1260  were performed  in the  gas
phase  for  a few  seconds   up  to a  maximum  temperature  of  700*C  (Buser  and
ftappe.  1979).   WHh   Aroclor   1254  (trl- to  nepta-PCBs),  mostly MCOFs  to
PeCOFs were  formed at  a  level of "2%.  MUh Aroclor 1260  (penta-  to octa-
*CBs), mostly  TrCOFs  to HpCOFs were produced  at a  similar  level.   The toxic


02330                                II-21                            03/02/87

-------
                                    a
                                  lefortho
                                Hand a
                                 FIGUI£ II-l

       Posslblt Rtictton SchMts  to  Product  PCOFs fro» the PyrolysU of
                     2,2'. 4.4'. 5.5'-Htxach1oroblph«ny1

                  Source:  Adapted fro* Baser and Rappt. 1979
02330
11.22
10/31/86

-------
2,3,7,8-TCDF  was  the  most  abundant  TCDF  and  was  most likely  derived  from
2,4,5,2',4',5'-hexachlorob1pheny1  or  2,3',4,4',5'-pentachlorob1phenyl.   The
acutely  toxic 1,2,3,7,8- and  2,3,4,7,8-PeCDFs  were  the  major  PeCOFs.   The
former  probably  Is  produced  from pyrolysls  of 2,3,4,2',4',5'-hexachlorobl-
phenyl,  and the latter  from  2,4,5,2',4',5'-hexa-  or  2,3,4,5,2',4',5'-hepta-
chloroblphenyl.   Pyrolyzed  Aroclor  1254  also contained significant  amounts
of  1,3,4,7,9-PeCDF.   These  results  were  confirmed  by   Paaslvlrta  et  al.
(1985)  who also  found small  amounts  of  chlorinated  phenols,  naphthalenes.
and HCOFs and DCDFs produced between 500 and 700*C.

    PCBs  are  destroyed at  a  2 sec residence  time  at 1200*C with  3% excess
oxygen  and  at  1.5 sec  residence  time   at  1600*C  with   2% excess  oxygen
(Johnston,  1985).   Johnston  (1985)  has also  reviewed the  disposal  methods
for PCB  waste Including thermal  Incineration.   Rubey et  al.,  (1985) showed
that  In  addition to PCOFs. lower PCBs, chlorinated  benzenes,  naphthalenes,
phenyl   ethynes    and    blphenylenes   were   produced   from  pyrolysls   of
2,3' ,4.4'5-penta-CB.   HC1   loss  was  the dominant  mechanism between  750  and
850"C.   PCOF  and  PCB  levels  declined  exponentially >900-C at a  2 sec  resi-
dence time.

Stability in Hater
    Commercial Aroclors are complex  mixtures  of PCBs  rather than single com-
ponents.   Therefore,   the composition  of  an  Aroclor  will change  with  time
because  of  selective adsorption,  evaporation,  solubility  and blodegradatlon
of  specific congeners.  Hater solubility and  vapor  pressure  increase  with
decreasing  chlorlnatlon  (Hutzlnger et  al.,  1974).   In summary, lower chlori-
nated  PCBs are  mostly  removed  from the  water  bodies   by  blodegradatlon,


02330                                n-23                            04/04/88

-------
volatilization  and   solublUzatlon   (Hutzlnger   et  al.,   1974),   although
sedimentation  removal  also  occurs.    Higher  molecular   weight   PCBs   will
principally  adsorb  to  sediments  and  biota, although  some  volatilization
(Hutzlnger et al., 1974) may occur.

    Photodecopposition.    PCBs  1n  water  at  sunlight  wavelengths   can  be
photochemlcally degraded  (Crosby  and  Mollanen, 1973), resulting  1n  reductive
or hydroxylatlve  dechlorlnatlon  as well as  dlbenzofurans.   The  hydroxylated
products  can  also form dlbenzofurans on boiling  or  at high  pH.   Reductive
dechlorlnatlon occurs In  organic solvents at  300  nm; the chlorines  next  to
the blphenyl bridge are  cleaved preferentially (Hutzlnger  et  al.,  1974).

    PCBs  In water can be  photolyzed (Crosby  and  Mollanen,  1973;  Hutzlnger  et
al.,  1974;  Pontrantz et  al.,  1978;  Callahan  et al.,  1979).   Hydroxylatlve
                                                 *
dechlorlnatlon can  also  occur  as well  as  reductive dechlorlnatlon  (Crosby
and Mollanen,  1973;  Hutzlnger  et al.,  1974).   The  rate  and  extent of  PCB
photodegradatlon  by  sunlight  are extremely difficult   to  assess  1n  the
environment.   Complicating  factors  Include   the diversity  of  environmental
conditions  and the  propensity  of  PCBs  (particularly  the  more  photolablle
highly-chlorinated blphenyls)  to adsorb  to  sediments and organic  materials
(Hutzlnger  et  al.,  1974).  Hutzlnger   (1972)  observed 0.2X 2-PCOF  production
after  7 days  of  ultraviolet  Irradiation  (310  m)  of  aqueous solutions  of
2,5,2'5'-tttrachloro- and  2,5-d1chlorob1pheny1s  (S   ng/t).   These  products
were  confirmed by  Crosby  and  Mollanen  (1973).  Hovever,  Hutzlnger  (1972)
found  no  PCOfs after SOM  aqueous PCB  samples  (167 mg/l)  had  been exposed
to sunlight  for  >2 months.   This  discrepancy may  have  arisen  because of the
different  Irradiation tines  and different  wavelengths  used.   The  yield  of


02330                                 11-24                           03/31/88

-------
the products  was  wavelength-dependent.   Irradiation at 254 nm  (mercury  arc)
decomposed  PCOF  photoproducts but  only slowly  at 310  nm or  at  the wave-
lengths  encountered  at  sea  level  for  sunlight, or  for  a solar  simulator.
Triplet  sensltlzers  (for example,  4.4'-dlchlorobenzophenone)  Induced  faster
photodecomposltlon of  2,8-DCDF  In methanollc solution  (Crosby  and Hollanen,
1973).  Thus, the presence of other compounds may be Important.

Oxidation and Hydrolysis
    Oxidation  Is  not  likely  to  be  an  Important environmental  conversion
process  for PCBs  since  severe  conditions  are  necessary  (Hutzlnger  et  al.,
1974).   PCOFs  are  formed   In  very  low  yields  during  oxidation  of  PCBs
(Pomerantz  et al..   1978).   Thus, although  PCDFs  are present  In  commercial
PCS mixtures, the evidence for their environmental  formation Is tenuous.

    PCBs are  also unlikely  to be  affected  by hydrolysis as an environmental
process  because  SM1  and SM2 reactions  do  not  take  place  readily  at  spa
                  N         rl
hybridized  carbons  (Morrison and Boyd, 1973) and  they are not water soluble
enough  to  allow water  to Interact.  However, hydroxylatlve dechloMnatlon In
water has  been  noted at  254 and 310 m»  wavelengths  (Hutzlnger et al., 1974).

Volatilization
    The  collection  of PCBs  In  the atmosphere  and during several  laboratory
studies  have  confirmed the  Importance of volatilization as a removal process
for  PCBs  fro*  water  (Ooskey and  Andren,  1981;  Callahan «t al., 1979; Atlas
et  al.. 1983:  Elsenrelch et al.,  1981; Nackay  and  Lelnonen,  '975).   Vola-
tilization half-life  data   for  environmental  waters  are  .iot  available.
 02330
11.25                           03/02/87

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Modeling  )s complicated by  the  numerous  contradictory  solubilities,  octanol/
water  partition  coefficients,  and Henry's  Law constants  for  each  Aroclor
(Callahan  et   a1..   1979;   Ooslcey  and  Andren,  1981;  Mabey  et  al..  1981;
Burkhard et al.,  1985c; Mackay  et al.,  1986).   This arises  because  Aroclors
are  mixtures.   Thus,  some  Henry's  Law constants  varied over  4 orders  of
magnitude  for  the same Aroclor  (Ooskey  and Andren, 1981).   The  volatiliza-
tion half-lives  for  various Aroclors  calculated, based on a  number  of  Input
values  for these  parameters  (Burns   et al.,  1981),  appear  to  be In  the
following  ranges:   Aroclor  1221  and  Aroclor  1232,  2  months  to   1  year;
Aroclor  1016.  <2-7  years;  Aroclor 1242, 2-7  years;  Aroclor  1248, 3-8 years;
Aroclor  1254,  >4-ll  years;  Aroclor 1260, >60  to >150  years.  However,  exact
data can only be obtained by consideration of  specific congeners.

    One  of  the major controlling  factors found  to  determine the volatiliza-
tion half-life  (Burns  et  al.,  1981) was the octanol/water partition coeffi-
cient,  since  this  1s  Inversely  related to the amount  of PCBs partitioning
into  the water  from sediments and biota  and the  level  available for  vola-
tilization.   This  applies  for  laboratory   as well as  environmental condi-
tions.   Again,  as  expected of mixtures,  several   laboratory values  for  the
octanol/water  partition  coefficient varying  over  2 orders of magnitude were
found  for  the  Aroclors  tCallahan  tt  al.,   1979; Garten  anil Trabalka,  1983;
miler  et  al.,  1985).   The  advantage  of  using  the  Burns et  al. (1981)
approach  Is  that adsorption  is  also  taken  Into  account  when  calculating
volatilization  half-lives,  while  models  for  volatilization  alone do  not
consider adsorption or  do  so  indirectly  (Hackay  and  Lelnonen,  1975).  The
reduction  of  volatilization half-lives In  tht presence of adsorption has
been studied  In the  laboratory.  Oloffs   et al.  (1972,  1973)  showed  that
 02330
II-26                           03/02/87

-------
 Aroclor  1260  (100  ug/l)  volatilized  67%  from river  water  after  12  weeks
 but  only 34%  when  sediment was  added.   Tucker et al.  (1975)  reported  that
 Aroclors  1221  and  1016  volatilized 4.2  and  3.6% from  aerated  samples  con-
 taining  activated sludge.

 Adsorption
    Adsorption  onto sediments  and  other  organic matter,  Including treatment
 plant  sludge,  coagulant  and possibly plastic water pipe  and  coal  tar coated
 water  pipe,  may be an Important  removal  process  for  high molecular weight
 PCBs  1n waters.   Using  the octanol/water  partition  coefficients  available
 (Callahan  et al.,  1979;  Mabey  et al.,  1981;  Mackay.  1982;  Burns  et  al.,
 1981;  Miller  et  al., 1985).  the  following  amounts  of PCB  that  would  be
 adsorbed onto  sediments  have been  predicted:   Aroclor  1221,  45-95%; Aroclor
 1232, 70-98%;  Aroclor  1016  and  1242, 96->99*;  Aroclor 1248,  97->99%; Aroclor
 1254.  98->99%  and  Aroclor  1260,  >99X.   These values  are dependent on  the
 choice of  partition coefficient and on the amount  of organic matter present
 In the  sediment.   These results  appear  to be  consistent with  other experi-
mental  data  {Oloffs et al.,  1973; Haque et al.,  1974; Hoeln et  al.,  1976;
 Hetllng  et  al.,  1978; Paris et al., 1978).  The  adsorption  characteristics
 of each  PCB congener  of  the  Aroclors will,  of  course, vary  considerably.
 The  lower  chlorinated components  will  adsorb  less  strongly  to the organic
matter  than  the  wore  highly   chlorinated  ones.    In  addition,   the  more
 strongly  adsorbed  components  are  also  less   biodegradable  and  hence  more
 persistent.  The  same considerations have been noted in laboratory  investi-
gations using glass equlpatnt (Hutzlnger et al., 1974).
32330                                I1'27                           03/02/87

-------
Exchange Between Media
    Air/water  exchange  of  PCBs  has been  modeled by  Mackay  et al.  (1986).
The example  has  been provided of  a  C15-PCB  In the Great Lakes  Basin.   This
PCB air  concentration 1s 5.7% sorbed  and  94.3% In gaseous  form at  15'C;  in
the water,  19.7% Is  sorbed and 80.3%  Is  dissolved.   While  there  Is a  net
volatilization effect,  this Is  countered  (25%) by wet  and dry deposition.
On  the  average,  rainfall  contains  68.2  ng  PCB/l,  mostly  all associated
with washed  out  particles.  Lower  temperatures will  enhance adsorption  and
sorptlon.   Higher   temperatures  will  enhance  volatilization  and   solublll-
zatlon.   Thus,  a  complex  cycling  of   a  PCB  In  an  ecosystem  is   expected.
Burkhard et al. (1985c)  have noted  that the  relative  proportions of the  PCBs
In environmental mixtures and Aroclors  are different.  They also modeled  how
specific  Cl., Cl-   and  Cl.  PCB  congeners  would  be depleted  or   enriched
in a  3-phase system  (water/alr/suspended  partlculate matter).  The  binding
                                                 *
of  2,2' ,5,5'-tetrachlorob1phenyl  to  dissolved  humlc add  was  studied  by
Hassett  and  NUllcIc  (1985),  using an  aspiration  method.   The equilibrium
binding  constant  1s  7.1x10*.   The rate  constant for release  of  bound  PCB
congener  by  humk  acid  1s  3.5xlO"» mln"1;  the rate constant for  binding
of  dissolved  PCB   congener  by  humlc  acid   Is  1.7x10~4  I  (mg   dissolved
organic carbon)"1 «1n~l.

B1odearadab111tv
    A  number  of  Investigators  have  reported  on  blodegradablltty and  Us
mechanism  for  PCBs  (Hutzlnger  et al..  1972,  1974;  Kaiser  and Wong,  1974;
Branson  et  al..  1975; Berlin et al.,  1975;  Hong and  Kaiser,  1976;  Furukawa
et al.,  1978,  1983;  Tabak  et  al., 1981a,b).   Blodegradablllty  Is  generally
related  to  the number of hydrogens available.  These  positions  appear  to be


02330                                11-28                           03/02/87

-------
hydroxylated  by  ralcrosomal  oxidation.   If an adjacent position  Is  unchlod-
nated. degradation  Is  then  facilitated  by  allowing  the  formation  of  an  arene
oxide.   B1odegradat1on rates vary  considerably  and are dependent upon  many
factors  Including  the amount of chloMnatlon, concentration,  type of mlcro-
blal  population,  available  nutrients  and temperature.  An  example of  this
variation  In  blodegradatlon rate  was  reported  by  Tucker  et al. (1975)  for
Aroclors  using  the Soap  and Detergent Association  semicontinuous  activated
sludge  procedure and  modified  feed  with 48-hour  exposure:  Aroclor  1221,
8U6%; Aroclor  1016,  33±H%; Aroclor  1242, 26*16%  and Aroclor  1254,  19*38%.
Tabak  et al.  (1981a,b)  found  virtually  complete  degradation for  Aroclors
1221  and  1232   at  5  and  10  mg/i  concentrations   using  a  static-culture,
flask-screening  procedure   employing   BOO dilution water   and  a   settled
domestic  wastewater  Inoculum over 28 days.   By contrast,  Aroclors  1016  and
1242  showed moderate  degradation (-40%).  while  Aroclors 1248,  1254  and  1260
showed almost no degradation.

    This  type of  degradation  pattern  has been  reported  by  Oloffs et  al.
(1972),  Moeln et al.  (1976) and Wong  and Kaiser  (1976).    The  results  show
that  mono-,  d1- and  tr1-CBs  (Aroclors  1221  and  1232)  blodegrade relatively
rapidly,  tetra-CBs  {Aroclors  1016 and 1242)  blodegrade  slowly and higher
chlorinated blphenyls  (Aroclors 1248.  1254 and 1260) are recalcitrant.
    Aroclors once  marketed  1n the United States principally  by  Monsanto are
a  family  of compounds consisting  of a mixture of  various  PCB congeners and
Isomers.  The  physical  properties  of the congeners  vary  considerably  with a
molecular mass range of  154-499,  a log  octanol/water  partition coefficient
02330
                                     11-29                           03/02/87

-------
 range  of  3.76-8.26,  and  a  solubility  range  of   9.77xlO"10  to  4.68x10"*
 moles/l   (moles/i   x   molecular   weight    x   10*/l  »   wg/i)   (Yalkowsky
 et al. 1983).

    PCBs will  volatilize  from ambient  waters with half-lives ranging between
 2  months and  >150  years  (Burns et  al..   1981; Doskey  and Andren,  1981;
 Callahan et  al.,  1979;  Habey et  al.,  1981).  The  most  Important  parameter
 affecting volatilization  rates was  found  to  be  the octanol/water  partition
 coefficient, showing that  the  partitioning of  the  PCBs  from  the  sediments
 and biota Into the water was the  limiting factor affecting volatilization.

    Adsorption  appears  to be  the  dominant  removal  mechanism  for  highly
 chlorinated  PCBs.   Using the Input parameters  from  the previously  mentioned
 sources, sorptlon  to sediment effectively  binds  between  45  and  >99X of the
 PCBs present In  water  depending on the PCB  and the organic matter present In
 the sediment.   The higher  the organic  matter 1n the sediment  or the higher
 the chlorlnatlon,  the  more strongly sorbed  will  be  the PCB.  PCBs  have been
 demonstrated to undergo complete  cycling In  ecosystems.

    As for volatilization  and  sorptlon,  blodegradatton  is also a  significant
 removal mechanism  for  the  less chlorinated species   (Callahan et al.,  1979;
 Hutzlnger  et  al.,  1972.  1974;  Kaiser  and  Wong.  1974;  Tabak  et  al.,
 1981a,b).  Based on  published reports, PCBs  containing <3  chlorines  tend to
 be degraded  In  the  environment,  although  estimation of  half-lives  is very
 difficult given  the  great  variability  In the reported literature.  PCBs with
 four  chlorines  appear  to be  sontwhat  less  degradable.   PCBs with  five or
more chlorines  appear to be recalcitrant.
02330
                                     11-30                           03/02/87

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                              III.  TOXICOKINETICS
  Introduction
     As  explained  1n  Chapter  II.  polychloMnated blphenyls  are highly complex
  mixtures of  Isomers  and  congeners  that  have been widely Identified 1n almost
  all components  of the global  ecosystem (Hutzlnger et a!.,  1974;  Risebrough
  et  al., 1968;  Flshbeln.  1972;  Buckley,  1982;  Ballschmlter  et  al.,  1981;
  Wasserman  et  al.,  1979;  H1guch1. 1976;  Cordle et  al..  1978; Holdrlnet  et
  al.,  1977;  Safe,  1982).   Since  PCBs  are  highly  llpophlllc and  relatively
  stable, these pollutants rapidly  bloaccumulate  and are  routinely  detected  In
  fish,  wildlife and human milk, adipose  tissue and  blood  serum (Rlsebrough  et
 al.,  1968;  Flshbeln,  1972;  Buckley.   1982;   Ballschmlter   et   al.,   1981;
 Wasserman  et  al., 1979;  Hlguchl, 1976;  Cordle et  al.,  1978; Holdrlnet  et
 al., 1977;  Safe,  1982).  Since commercial  PCBs  are highly complex mixtures,
 the gas chromatographlc (GC) Identification and quantHatlon  of PCB  residues
 has primarily relied upon specific peak or  pattern  matching  techniques  using
 commercial   PCB   mixtures  as  standards   (Chapter  II  of   this  document).
 However, It Is apparent from analytical studies of  environmental samples and
 residues 1n laboratory animals  treated  with these  compounds  that there can
 be  major differences  between their  composition  and  that  of the commercial
 PCB  products  (Hansen  et al.,  1975; Hansen,  1979; Stalling et  al, 1979;  Burse
 et  al.,  1976).    The development  of high resolution  glass  capillary,  GC
 analytical  procedures and  the  recent synthesis and characterization of the
 209  PCB standards  (Hullln  et  al.,  1984)  has   remarkably  demonstrated  this
 latter  observation  as discussed   In  Chapter  II.   Table  III-l  provides  a
comparative analysis  of PCBs  1n Aroclor  1260 and  an extract  of human breast

-------
                                  TABLE  III-l

         Quantitative  and  Qualitative  Analysis  of  PCBs  In  Aroclor  1260
                       and a Human Breast Milk Extract3
Congener
Maw*
PCB-018
PCB-017
PCB-024
PCB-016
PCB-029
PC8-026
PCB-028
PCB-021
PCB-033
PCB-053
PCB-022
PC8-045
PCB-046
PCB-052
PCB-043
PCB-049
PC8-048
PCB-044
PCB-037
PCB-042
PCB-041
PCB-040
PCB-100
PCB-074
PC8-070*076
PCB-095
PC8-091
Percentage
1n Aroclor
1260
0.12
0.05
0.01
0.04
0.02
0.02
0.04
0.01
0.09
0.04
0.01
0.07
0.02
0.25
0.02
0.06
0.29
0.11
0.04
0.04
0.25
0.03
0.02
0.03
0.15
2.7
0.07
Percentage Congener Percentage
In Hunan NaMb In Aroclor
mile* 1260
NO
NO
NO
NO
NO
NO
8.8
NO
2.2
NO
0.65
NO
0.25
1.9
NO
0.66
0.37
0.78
2.9
NO
1.3
NO
NO
11
0.61
NO
NO
PCB-118
PCB-134
PCB-114
PC8-131
PCB-122
PCB-146
PCB-153
PCB-141
PCB-176
PCB-137
PCB-130
PCB-138
PCB-158
PCB-129
PCB-178
PCB-175
PCB-187
PCB-183
PCB-128
PCB-167
PCB-185
PCB-174
PCB-177
PC8-17U202
PC8-156
PCB-173
PCB-200
0.49
0.35
NO
0.07
0.12
1.3
9.6
2.5
0.33
0.22
NO
6.5
0.70
0.20
1.2
0.49
4.5
2.3
0.47
0.16
4.1
5.5
1.9
1.2
0.45
0.06
0.78
Percentage
1n Human
mifcc
6.5
NO
0.33
NO
0.53
1.9
12
0.29
NO
0.87
0.59
10
0.55
NO
NO
NO
1.5
1.4
0.33
0.85
0.11
0.39
0.61
0.37
4.87
NO
NO
02340
                                     III-2
10/29/86

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                               TABLE  III-l  (cont.)
Congener
Nameb
PCB-056*060
PC8-084
PCB-101
PCB-099
PCB-119
PCB-083
PCB-097
PCB-087
PCB-085
PCB-136
PCB-110
PCB-154
PCB-082
PCB-151
PCB-144+135
PCB-107
PCB-149
Percentage
In Aroclor
1260
0.14
0.65
2.5
0.13
ND
0.04
0.4S
0.45
0.13
1.4
1.7
0.02
0.11
2.5
1.5
0.03
7.4
Percentage
1n Human
MllkC
0.71
NO
0.97
4.8
0.08
NO
ND
0.82
NO
NO
1.0
NO
NO
0.59
0.51
0.31
NO
Congener
Name0
PCB-157
PCB-172
PCB-180
PCB-193
PCB-191
PCB-199
PCB-170
PCB-201
PCB-203
PCB-196
PCB-189
PCB-195
PCB-207 "
PCB-194
PCB-205
PCB-206
PCB-209
Percentage
In Aroclor
1260
ND
0.78
9.1
0.47
0.10
0.33
6.8
2.9
3.1
2.5
0.15
3.1
0.08
1.7
0.11
0.85
0.06
Percentage
In Human
M11XC
0.47
0.31
5.3
0.19
0.90
NO
5.3
0.85
0.79
0.18
2.4
0.31
NO
0.48
0.06
0.24
0.09
^Source:  Safe et al.. 1985b

°Congener names  adapted  from BallschmUer  and  Zell (1980).  See  Table  II-l
  In this document.

cHuman  milk sample  collected  and  extracted  by  the  Michigan Department  of
  Public  Health   under  Cooperative  Agreement  CR807192 with  the  Large Lakes
  Research Station, U.S. EPA.

NO » Not detected
02340                               111-3                            03/02/87

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contrast,  the gas  chromatogram of  a  composite  human  milk sample  does  not
resemble  the pattern  of any  commercial  PCB,  and  pattern  matching  methods
would  not  yield  meaningful quantitative  results.   However,  the high-resolu-
tion  Isomer-spedflc  GC  approach  permitted  quantHatlon  of  all  the  Indi-
vidual  PCB  components  present   \n  this  mixture.    Several PCB  congeners,
Including  2,2' ,4,4' ,5,5'-hexa-CB,  2,2',3,4,4',5'- hexa-CB,  2,2',3.3',4,4',5-
hepta-CB and 2,2',3,4,4',5,5'-hepta-CB  are major components of both  Aroclor
1260 and the  human milk extract.

    Another   major   PCB  present   1n   the  human  milk   extract.   (4.87%),
(2,3,3',4,4',5-hexa-CB)  Is  a  minor component  of Aroclor  1260 and other  com-
mercial PCBs  (Ballschmlter  and Zell, 1980;  Jensen  and Sundstrom,  1974)  and
has previously been  Identified as a major PCB  contaminant  of  Japanese  human
milk extracts (Safe,  1982).   The four  remaining  major PCB congeners  1denr
tlfled   1n   the  human   milk  extract   (2,4,4'-tr1-CB,   2,4,4',5-tetra-CB,
2.2',4,4',5-penta-CB   and   2,3',4,4',5-penta-CB)  are  minor  components   of
Aroclor 1260  (<0.49% for  all  four  Isomers).  It  1s  likely  that these penta-
and tr1-PCB  congeners are  derived from  the  lower  chlorinated  PCB formula-
tions;  however,  H  1s noteworthy  that  with the  exception  of  2.4,4'-tM-CB,
all of  these compounds  also  contain 2»4,5-tr1chloro-substltutlon  on one  of
the phenyl rings and  a p-chloro  group on  the  second phenyl ring.  This  high-
resolution analytical  study has also  identified 2.4.4l-tri-C8 as a  major  PCB
component  and confirms a previous report that  identified  this  compound  in a
Japanese human milk  extract (Yakush1J1 et  al., 1979).   The reasons  for  the
persistence  of this  congener  are  not  apparent.  It was  also of interest  to
note  that   several  other  compounds  Including   2,2',3,5',6-penta-CB  (2.7X),
2.2',3,4',5',6-hexa-C8    (7.4X),    2,2',3.3',4,5.5'-hepta-CB    (5.5X)    and


02340                               II'-4                            03/02/87

-------
2,2l,3,3',4t4l,5.6-octa-CB  (3.IX)  constitute 22.8X  of  the  PCBs  present  In
Aroclor  1260  but are  only  minor  components  (0.81X)  of  the  human milk  PCS
extract.

    These  results  clearly  demonstrate  that there  1s  a  preferential  struc-
ture-dependent  bloaccumulatlon  of specific  PCS  congeners   1n  human  milk.
Several  studies  have also shown that  the biologic and  toxic  effects  of  PCBs
are  also  structure-dependent  because of  their stereoselectlve  Interaction
with a  cytosollc receptor protein  (Safe  et al., 1982; Poland et  a!.,  1979,
1983;  Safe,  1984).   Mot  surprisingly,  the  absorption, tissue  distribution,
metabolism and  excretion  of Individual  PCBs and their  mixtures  Is  dependent
on  their  physlcochemlcal  and  biologic properties,  and  an assessment  of  the
toxlcoklnetlcs  of  this  class  of  chemicals must  recognize  these  Important
structure-dependent effects  (Matthews and OedMck,  1984;  Schnellmann  et al.,
                                                 •
1985; Safe-, 1980).

Absorption
    6astro1ntest1nal.   The  GI  absorption   of  commercial  PCB  mixtures  and
Individual congeners has  been  extensively  Investigated In laboratory animal
studies  (Albro  and  Flshbtln,  1972;  Berlin   et  al.,   1974;  Matthews  and
Anderson.  1975;  Gagt and Holm,  1976; Allen et  al.,  1974a.b;  Tanabe  et al..
1981).   Oral  administration of a complex mixture of Kanechlors 300, 400, 500
and  600 (1.1.1:1  by  weight) In corn oil  to  Immature male Wlstar rats  (Tanabe
et  al., 1981) resulted in  >84X of the  total dose being absorbed from the GI
tract  with <16X of  the dose  excreted  In the  feces.   GC-KS  analysis of the
PCB  1n  the fecal material demonstrated that the absorption efficiency of the
Individual PCBs varied  from 66-96%.   The  major structural determinant  that
 02340
                                     111-5                             03/02/87

-------
 governed  absorption  efficiencies  was  the degree of chloMnatlon,  since there
 was  an Increase In absorption of  PCBs  with  Increasing ring chlorlnatlon and
 molecular  size.  It  Is  also conceivable  that  other  structural  factors  may
 also  play  an Important role  In PCB absorption.   For example,  ortho-chlorine
 substitution  decreases PCB  ring  coplanarHy and  there  Is  evidence  In  both
 fish   and  rats  that  there  may  be  decreased  absorption  of  Isomers  with
 Increasing  ortho-chloro  substltuents  (Tulp  and  Hutzlnger,  1978a,b;  Sparling
 and  Safe,  1980b;  Shaw and  Cornell.  1980).   Several rodent  and  monkey studies
 using  either commercial PCB mixtures,  reconstituted  mixtures  or  Individual
 compounds  confirm that PCBs  are  readily absorbed from the GI  tract  and are
 distributed  rapidly  by the blood to diverse  tissues.  Liver  and  sometimes
 muscle  act  as major  depots for  PCB accumulation  after  Initial  exposure and
 absorption;  these highly  llpophlllc  compounds  are  then redistributed  Into
 adipose  tissue  and  skin  (Matthews and OedHck.  1984).   The  effect  of  the
 vehicle on the GI absorption of PCBs has not been systematically evaluated.

    Dermal.   Several  dermal  studies  wUh PCB  congeners  or mixtures  demon-
 strate  that  these compounds  are  readily  absorbed and elicit   toxic  or  bio-
 logic  effects at  dermal  and  distal  sites  (Nlshlzuml.  1976;   Miller.  1944;
 Puhvel et al.,  1982;  Wester et al., 1983).  A  recent  study by  Wester et al.
 (1983)  reported  the  dermal  absorption  In  guinea  pigs  and  monkeys  of
 synthetic  l*C-labeled  PCBs  containing 42  and  54%  chlorine  (by  weight).
 Dermal absorption was estimated using the  following relationship:
                                  total 14C urinary excretion
                             following topical administration  x 100
           % Dos* Absorbed	total "C urinary excretion
                              following parenteral administration
02340                               HI-6                            11/14/86

-------
    The  estimated absorption  of  the  42  and  54%  i«c  mixtures  was 33  and
56X,  respectively.  In  the guinea pigs and  the  absorption  of  the  42% mixture
varied  between  15  and  34X  depending  on  the  dose  (4.1  wg/cma  or   19.3
vg/cn»2).    Immediate   washing  of  the  applied  l4C-labeled   PCS   (42%  Cl
content) with  water  and  acetone  removed  59% of the  dose  whereas washing  24
hours  after  dermal application  of  the 42  and 54%  14C-labeled  preparations
removed only 1 and 20% of the applied label, respectively.

    Inhalation.   Benthe  et  al.  (1972) exposed  male Wlstar rats  to  Pldranll
A200  as  an aerosol  (0.5-3y  particles.   30 g/«»).   Hepatic   levels  at  15
minutes  were >50%  of  the  maximum  obtained after   2 hours.    The  pharmaco-
klnetlcs of  the  Inhaled  PCBs  were comparable to those observed by absorption
by other  routes; Initial high  PCB  concentrations  In liver and brain peaked
and decreased  within  48  hours  after  exposure and adipose  tissue became the
major reservoir for these compounds.

Tissue Distribution and Excretion
    Transport of  PCBs from  the  site of application  to distal  sites  occurs  by
a  number  of  processes.   The  facile  GI  absorption of  PCBs   (Matthews  and
OedMck, 1984;  Albro  and Flshbeln,  1972;  Berlin et  al.,  1974; Matthews and
Anderson, 1975;  Gage  and Holm,  1976;  Allen et al.,  1974a,b;  Tanabe et  al..
1981)  1s  consistent  with passive absorption  Into  the  I1poph1l1c cell  mem-
branes followed  by transport  to all tissues by blood.  In vitro studies  have
shown  that  2.2'.4.4'.5.5'-htxi-CB  Is  taken up  Into very low  density  I1po-
protelns (VLOL),  low density  llpoprotelns  (LDL), high  density Upoprotelns
(HOL) and other  plasma proteins  (Vomachka et al.,   1983;  Becker  and Gamble.
1982).   2,2',4,4'.5,5l-hexa-CB  Injected   Intravenously  resulted In initial


02340                               HI-7                            03/02/87

-------
 association  primarily  with  LOL;  however,   between  6  and  24  hours  after
 administration  the  nexa-CB  was  redistributed  from  LOL   to  HDL  and  other
 protein-rich  plasma  fractions   (Splndler-Vomachka  et  al..   1984).   Recent
 studies  using  domestic  animals have also  demonstrated  the Importance of the
 lymphatic  system  as a transport  route  for  PCBs  (Zlprln et al., 1980. 1986).
 and  this may contribute to  the  Immunetoxic effects of PCBs.

     The  Initial distribution  of PCB mixtures  and Individual PCB congeners In
 diverse  animal  species  Is  dependent on the structure(s) of the compounds and
 most  Importantly  the  biophysical  factors  that  affect  distribution  of  com-
 pounds  In  a multlcompartment  system  (Matthews  and Dedrlck,  1984).   Figure
 III-l  summarizes  a  flow diagram  for the  pharmacoklnetlcs  of  PCBs In animals
 In which  the Initial distribution  of  serum  containing  PCBs  Is dependent on
 blood  flow  rates,   blood   volumes,  PCB-blood  serum  absorption  affinities.
 tissue/blood partition  ratios, per fusion  rates  and  tissue volumes (Matthews
 and  Oedrlck.  1984).   In  most animal  species  that  have  been Investigated
 there  1s an  Initial  uptake of PCBs  Into the  liver and muscle which Is due to
 high per fusion  In the liver and  the relatively  large  muscle volume.  Subse-
 quent  redistribution  of  PCBs  Into adipose  tissue  and  skin reflects the high
affinity of  the llpophllle PCBs  for llpophlllc  tissues.  At  equilibrium the
elimination  of  PCBs  from  all  tissues will  be  dependent  on  the structure-
dependent  rates   of  metabolism  of   Individual   PCB  congeners  (see  the
Metabolism Section).

    Several  studies  on  the  pharmacoklnetlcs  In  rats  and  mice  have  been
 reported (Matthews  and  Oedrlck. 1984;  Schnellminn et  al.. 1985;  Safe.  1980;
Albro and  Flshbeln,  1972;  Berlin et al.,  1974;  Matthews and Anderson,  1975;


02340                               III-8                            11/14/86

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                               81000
                                   T
                                     URINE
                    LIVER
                                                RBA8SORPTION
                            J 6IUAAY
                             EXCRETION
GUT LUMEN
                                                      FECES
                               MUSCLf
                                SKIN
                                 FAT
                             FIGURE ilM

                    PCS PfurMcoklnttlc Flow DUgr«i

                       Sourct:  Utz ft 4).. 1977
02340
                      10/29/86

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Gage  and Holm,  1976;  Allen et  al.,  1974a,b;  Tanabe et al.,  1981;  Sparling
and Safe.  1980a,b;  Matthews  and Tuey,  1980;  Lutz et al., 1977; Muhlebach and
Blckel,  1981;  Tuey  and  Matthews. 1977a,b,  1980;  Morales et  al.. 1979; MoMta
and Olshl,  1977; Lucter  et  al., 1978;  Clarice et al.,  1984;  Suglura  et  al.,
1975,  1976;  Mlzutanl et  al..  1977;  Felt et  al.,  1977, 1979).  Most  of the
reports  using Individual  PCB  congeners gave  comparable results.   Matthews
and   Anderson   (1975)   administered   0.6  mg/kg   1.v.  of   the   following
14C-labeled  PCB  congeners  to  Sprague-Oawley  rats:   4-CB  (1-CB)  4,4'-d1-CB
(2-CB)  2,2',4,5.5'-penta-CB  (5-CB)  and  2,2'.4,4',5,5'-hexa-CB (6-CB).  Early
time  points  Illustrate  the relatively high levels  of all compounds  1n liver
and muscle;  the  subsequent  decrease of  PCBs  In these tissues was followed by
preferential  bloaccunulatlon  of the  PCB  congeners  In  adipose  tissue  and
skin.    Lutz  et  al.  (1977)  proposed one model based on  the pharmacoklnetlc
data  obtained for  these  Isomers,  the  flow   diagram  illustrated  In  Figure
III-l  and  the known compartment  sizes  and perfuslon rates  from the experi-
mental  animal (Sprague-Oawley rat).    This  pharmacoklnetlc  model has  also
been  reviewed  by Matthews and  Dedrlck  (1984).   The tissue/blood distribution
ratio and  kinetic  parameters are summarized  In  Tables  I1I-2 and III-3.   The
results Illustrate a number of important points, namely:

    1.  The  highly  llpophtllc  parent  compounds tend to preferentially
        bloconcentratt  In llpophlllc  tissues  (adipose  tissue and  skin)
        whereas  the more  polar metabolites are found in the hydrophlllc
        cell tlssues/compartmtnts;
    2.  The  magnitude  of  *he  metabolic clearance  parameters  (Km)  are
        dependent on structure;  the Km  for  the more rapidly metabolized
        CB-1  congener  Is  10.0  whereas  these  values  decrease  with
        Increasing  ring  chlorlnatlon;  the Km  value for 2.2',4,4'.5.5'-
        hexa-CB was <0.» of the Km for  4-CB;
    3   The mathematical  model  developed for  PCB pharmacoklnetlcs using
        the multlcompartment system (see Mgure III-1)  can  simulate and
        predict  the behaviour  of  both   oarent  compound and metabolite.
        For  example,  the mass  balance   equation for  a   tissue  In  which
        metabolism occurs (for example,  liver, L) takes the  form.
02340
                                    ;:i-:o                           11/14/86

-------
                                  TABLE  III-2

               Pharmacoklnetlc  Compartment  Size  Distribution  for
                     Individual PCB Congeners  1n the Rat*
                      (tissue/blood distribution ratios)
Parent
Compartment
Blood
Gut/lumen
Muscle
Liver
Skin
Adipose
1-CB
1
1
1
1
10
30
2-CB
1
1
2
3
10
70
5-CB
1
1
1
6
7
70
6-CB
1
1
4
12
30
400
1-CB
1
1
0.14
2
0.25
0.40
Metabolite
2-CB
1
1
0.40
5
0.30
0.60
5-CB
1
1
0.10
2
0.10
0.40
6-CB
1
1
0.30
4
2
2
•Source:  Adapted fron Lutz et al., 1977

1-CB:{4-CB)
2-CB:(4,4'-d1-CB)
5-CB:(2,2'.4,5,5'-penta-CB)
6-CB:(2,2',4.4',5,5'-litica-CB)
02340
                                     III-ll
03/02/87

-------
                                  TABLE III-3

      Pharnacok1net1c Parameters for Individual  PCB  Congeners  In  the  Rat*
Rate constant
Metabolic clearance.
Km, at/Bln
Kidney clearance.
Kk. at/mm
Biliary clearance.
KB. «ty»1n
Gut reabsorptlon.
KG. Bin"*
Fecal transport.
KF, mln'*
1-CB
10.0

0.20

0.20

0.00016

0.0008

2-CB
2.0

0.133

0.35

0.00016

0.0008

5-CB
0.39

0.033

0.30

O.OOOU

0.0008

6-CB
0.045

0.030

0.30

0.00016

0.0008

•Source:  Adapted fron Lutz et al.. 1977

1-CB:(4-CB)
2-CB:(4,4'-d1-CB)
5-CB:(2,2',4.5.5'-p€iita-CB)
6-CB:(2.2' .4.4' .5.5'-h«a-CB)
02340
111-12
                                                                      10/29/86

-------
where:
    t
    V
    C
    0
    Km
                         d  (VI.CL)  -  
-------
                                                                         IMNC III 4
                                                          M«U-lives of Individual CMoroblpfcenyls  In
10
oa
       fe«k
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22«
23
24
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31
32
33
34
35
34
37
30
39
310
41
42
43
44
U
44
47
40
49
410
411
412
413
0.34
0.10

0.11
0.10
0.21
0.21
0.23
0.32
0.29
1.4
0.20
0.34
0.12
0.12
0.09

3.0

1.4

0.03
3.1

0.29
2.4
.12-0.5
.13-1

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54 A 1.4 0.13-3
55 A 2.1 0.13-7
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0.04
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1.00
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0.92
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1.00
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0.72

0.73

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.3*. 4 2. 3'. 4. 4 2. 3-. 5'. 4
,4-,4 2'. 2. 3.5' 2. 3'. 4. 4 2.2'.«.«'
'.3.4'
-.3.3- 2. 2*. 3, 4

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-.4'. 5' 2. 3.3'. 4
.4.4'
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'.4.4-
14 7-15 1.00 2.2I.3.S'.4
2,2' .3,5" .4
2, 2', 3.5.5'
35 7-M 0.95 2. 2'. 4. 5. 5'

-------
                                                                    TAItf  HI-4 (COAI.)
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2.2'. 4 4-.S
2>!3!4.S' 2.2'. 3.4'. S'
2,2'.3.3\4 2.3.3'. 4'.4
2.3.3'. 4'. 5
2.3'.4.4'.5
2.3.1' .4. 4'
2.2M.3-.4.4-
2.2'.3.3-.S.4«
2.2'. 3.4'. S.4' 2,2'. 3. 5. 5'. 4
2.2'. 3.3-. S.4
2.2'.3,3'.4.4-
2.2-.3.4'.5.S-
2.2'.4.4'.5.5' 2.2'.3.4.5.S'
2.2'.3.3'.4.S<
2.2'. 3.4.4'. 5'

2.2'. 3. 3'. 4.4'
2.3'.4.4'.5.5-
2.3.3- .4.4'.S
2. 2'. 3. 3'. 5. 4.4'
2. 2*. 3. 3'. 4. 4. 4'
2.2'.3.3'.5.5'.4
2,2-.3.4'.5.5'.4
2.2'.3.3'.4.S.4' 2.2'. 3.4.4'. 5'.4
2.2'.3.3'.4.S'.4-
2.2-.3.3'.4.4'.4
2. 2*. 3, 3-. 4. 5. 5'
2. 2'. 3. 4. 4'. 5. 5*
2.2-. 3.3'. 4. 4'. S

2. 1.3', 4. 4'. 5.5'
2. 2'. 3. 3'. 5.5'. 4. '
2. 2-. 3.3- .4.5' .4. •
2. 2'. 3. 3*4. 5.4. 4' 2. 2*. 3. 3*. 4. 4' .4.4'
2. 2'. 3. 3-. 4. 4.5'. •
2. 2'. 3. 3'. 4. 4'. S. -
2. 2-. 3. 4. 4'. S. 5'.
2.2'.3.31.4.4'.S.

O

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-------
                                                                         1AMIE  1114  (cont.)
o
ro
Peak lype
No.
IVM A and live 1 II)
t| l90
                                                                                 0.13-M
2.2
»'.4.4'.S.5'
                                     2.2'.3.31.4.5.5'.b.b1
                                     2.2'.3.3'.4.4'.5.b.b>
                                     2.2'.3.3'.4.4'.5.5'.b
                            tt «1.
                  atetMlstraito* of a atitur*  of Kanecklors 300. 400. SOO and bOO (1:1:1:1)
            (Mrto4 far tbo ciUvUtto* of  »to1o«tc«1  Mlf-lt»es.
            •Mot tf«toct*4 becMtt of tkt dtsappear«iic* of PCI peaks  llaloflcal half  ll¥*s of lype C KIs  aM of subsequent regression of lype • PCIs.
            r • Correlation coefficients obtained from linear regressions.
 CO

-------
(1:1:1:1) orally  administered  to  Immature male Wlstar rats  (Tanabe  et  al..
1981).   Most  congeners exhibited  blphaslc  half-lives (whole body)  In  whkh
the  Initial  ^  value  was  relatively  low  (-0.13-7  days)  for all  congeners
and  the  t?  value  was  much  greater  and  clearly  structure-dependent.   A
closer  examination  of  Individual  t^  and  t.  values  demonstrates  a  remark-
able  similarity  between   the  results  reported  for   the  mixture  pharmaco-
klnetlcs and the  data  obtained for  the studies  that  utilized Individual  PCB
congeners.

    Owing to  the accumulation  of  PCB In  adipose tissue,  studies  have  been
performed on  rats  to  determine the effects  of  adipose tissue  mass on  the
pharmacoklnetlcs  of 2,2l,4,4',5,5'-hexachlorob1phenyl.  This  specific  Isomer
Is metabolized  only to a  very  United extent and Is  found  In human tissues
and milk extracts.  In  a  series of studies  (Muhlebach and  Blckel,  1981; Uyss
et al.,  1982;  Jondorf  et  al..  1983), 2,2' ,4.4' .S.S'-hexa-CB  was  administered
to  rats at  different   stages  of   body fat  depletion Induced  by  a  dietary
restriction paradigm.   Up  to  75X  of  the  dose was  deposited In the fat  of
rats  fed  a  standard diet whereas  adipose-depleted  (dietary  restricted)  rats
retained  <0.1%  of  the   dose  In   adipose  tissue.   As   disposition   of
2. 2'. 4. 4', S.S'-hexa-CB  to  fat  decreased  In  fat-depleted  animals,   the  dis-
position to skin  Increased. Excretion patterns  also  change  whereby a larger
proportion of  the dose Is  excreted  In fat depleted  animals. The  magnitude
of the  Increased excretion can be well  In excess  of a factor  of  2-3  times
greater  than that observed In rats  fed a  normal  diet. Thus. U Is apparent
that  alterations  1n  body  fat content  can  affect   the disposition of  the
2,2' ,4,4' ,5,5'-hexa-CB  body burden  and  the disposition of  subsequent  doses
of this Isomer.
Q234Q                               111-17                           11/14/86

-------
    Long-term kinetics  of  2,2',4,4',5,5'-hexa-CB have  been  studied  In  rats
maintained at  a  constant  adipose  tissue  mass  (Wyss et  al.,  1986).   Table
III-5 Indicates that under these  conditions,  the majority  of  the  body burden
of this  1 sower  Is relegated  to the fat  compartment with  the  skin  accumulat-
ing  the  next highest  load.   There Is  a striking  persistence  of  this  con-
gener, with  49%  of  the dose  still associated with tissue compartments  280
days  after  dosing.   The half-times  for specific compartments  are given  In
Table  III-6.   Levels  In  tissues generally  decline In  a  trlphaslc  fashion
with half-times of the  terminal component on  the order  of  450  days.   As  seen
In Table  III-7,  only minimal amounts of 2,2',4,4',5,5'-hexa-CB are  excreted
In urine.  Extrapolation  to  Infinite time  points  predicts that -83% of  the
total dose will  eventually be  excreted  1n  the feces with  a half-time of  478
days.  Owing  to  Us  persistence  and extremely  long  half-time for  elimina-
tion, this particular  congener has  a high  potential for  accumulation within
the body.

    The  pharmacoklnetlcs  of  PCB  mixtures  and  congeners  In  several  other
species  Including the  dog,  fish.  mink, avlan  species  and  swine have  been
reported  (Sparling  and Safe. 1980b;   Lutz   et  al.,   1984;  Slpes  et  al.,
1982a.b;  Hansen et al.. 1983;  Brunn, 1984; Hornshaw et  al..  1983; Gruger et
al., 1975; Gulney et al., 1979;  Gulney  and  Peterson,  1980).   The results are
somewhat  comparable  for  all  species  with  long-term  accumulation  of  Indi-
vidual PCBs  occurring  primarily  In adipose   tissue.    It  was apparent  that
rates of PCB metabolism were Important  with respect to  tissue oerslstence of
Individual compounds.   Sparling  and Safe  (1980b)   suggested that  the degree
of  ortho-chloro  substitution  (Cl-2;  Cl-6) may contribute  to  the  ultimate
02340                               IH-18                           11/14/86

-------
                                                      TABLE  IH-5
CJ
                        Tine  Course  of  2.2',4,4',5,5'-Hexa-CB  Tissue Distribution. Elimination,
                    and Recovery (percentage of dose) tn Rats  with Constant  Adipose  Tissue  Hassa«b
\
Days:
No. of Rats/
Tine Point:
Blood
Liver
Lung
Muscle
Brain
Skin
Adipose
lisas'
Urine
Feces
Excretion
Recovery6
4
6
0.27
1.5
0.27
5.4
0.13
10. 1
58 9
/b.b
0.15
3.01
3.2
79.8
7
6
0.24
1.1
0.30
4.B
0.12
10.8
63./
80.9
0.21
4.0
4.2
85.1
14
3
0.14
1.05
0.17
4.4
0.11
15.3
64.4
85.5
0.27
5.9
6.2
91.7
28
3
0.12
0.9
0.20
4.0
0.12
12.5
67.8
86.0
0.37
9.3
9.7
95.7
42
6
0.09
0.75
0.10
3.6
0.07
11.0
58.8
74.5
0.48
12.4
12.9
88.4
140
4
0.07
0.56
0.09
3.3
0.05
8.4
44.4
57.0
1.03
28.5
29.5
86.5
175
2
0.06
0.44
0.08
3.15
0.05
7.9
42.7
54.5
1.18
32.7
33.9
88.4
280
4
0.06
0.45
0.07
3.0
0.04
6.9
38.4
49.0
1.49
43.0
44.5
93.5
 ±   b
Source:   Adapted fro* Uyss et a!..  1986
 'Single l.v. dose ul 0.6 «g/kg bu.
Percentage of dose distributed to  all  tissues.
^Percentage of dose excreted In urine and feces.
ePercentage of dose recovered In tissues and excreta.

-------
                                  TABLE  II1-6

            Tissue Kinetics of 2.2',4,4',5,5'-Hexa-CB 1n Rats with
                        Constant  Adipose Tissue Mass*>b
Tissue
Blood
Liver
Lung
Muscle
Brain
Skin
Adipose
Half -life for Reaoval
a-Phase B-Phase
0.114 8.4
0.161 9.9
0.182 12.3
12.1
17.3
13.9
10.9

t-Phase
462
442
433
478
449
431
456
'Source:  Adapted fro> Uyss et al.. 1986

''Half-lives are given In days.
02340
111-20
10/29/86

-------
                                  TABLE  II1-7

           Excretion Kinetics  of  2,2',4,4',5,5'-Hexa-CB  In Rats with
                        Constant  Adipose Tissue Mass*>b
Excretion
Fecal

Urinary

Component
I
II
III

I
II

Decay Rate
Constant
days'1
0.616
0.012
0.001

0.112
0.0095

Half-life
days
1.1
57.3
478

0.95
150

No. of
TIM
Points
7
36
16

5
30

Cunulatlve
Excretion for
Infinite Time
% dose
2.07
13.55
83.45
99.07
0.15
1.8S
2.00
aSource:  Adapted fro> Uyss et al.. 1986

bVa1ues are wans of 4-8 an1«i1s/t1«e point.
02340
111-21
10/29/86

-------
 persistence  of  PCBs  In  various  species.   A  mixture  of  2,2',4,4',6,6'-,
 2.2',4,4',5',6.'-,    2,2',4,4',5,5'-,    2',3,4,4',5.5'- and   3,3'.4.4',5.5'-
 hexa-CBs  (1:1:1:1)  was  administered  by gastric gavage to  rats,  guinea  pigs,
 rabbits,  Japanese  quail  and  trout,  and  the concentrations  In  the fat  or
 whole  carcass  were  determined  after  29 days (Table  III-8).  These  Isomers
 are  all  relatively  resistant  to metabolism  but  contain 0-4  ortho  chlorine
 substUuents  (Cl-2;  Cl-6).   The  total  hexa-CB  levels  In  rat,  rabbU  and
 guinea pig fatty  tissue  were 8.27,  6.84 and 4.74 ppm,  respectively:   whereas
 3.02 and  2.15 ppm  of the hexa-CBs were detected  In  the  trout and  Japanese
 quail  carcasses,  respectively.   The  extent of  ortho-chloro  substitution
 markedly  affected  the levels of  the  Individual  hexa-CB Isomers retained  In
 the  test  animals.   In the  rat, the dl-ortho  substituted  analog was  prefer-
 entially  retained  over  the  other  Isomers  whereas  the  coplanar  most  toxic
 Isomer,  3,3',4,4',5,5'-hexa-CB,  was  present  In  the  lowest  concentration.
 The rabbU and guinea pig  preferentially retained  the  hexa-CBs with  0.  1  and
 2   ortho-chloro   substltuents,   the   Japanese  quail  retained   only   the
 3,3',4,4',5,5'-hexa-C8  Isomer,  whereas  no  striking preferences  In  hexa-CB
 Isomer retention  was observed  In  the  trout.  The narked  differences  1n  the
 retention  of  hexa-CB Isomers with 0,  1,2,3  and 4  ortho-chloro  substitution
 by  different  animal  species  should  be  considered  1n  chronic   toxldty
 studies,  since  the most toxic  polychlor mated blphenyls have minimal  (1  or
 0) ortho-chloro substitutes.

    The  critical  or rate   limiting  event  1n the  elimination  of  PCBs  Is
metabolism.  The  major   site of metabolism  Is the  hepatic  cytochrome  P-450
 dependent  monooxygenase  system.   Species   variation    In   the   Intrinsic
02340                               111-22                           03/02/87

-------
bJ
                                                      TABLE III-8

                             Hexa-CB Levels  In  Rabbit,  Rat  and Guinea Pig Adipose Tissue.
             Trout and  Japanese Quail Carcasses 29  Days after  Administration of  the 1 sower Nix (1:1:1:1)*
Tissue Levels (PPM)
Hexa-CB I sobers
2. 2'. 4. 4'. 6.6'-
2.2'.4.4I.5I,6-
22* 44* 55'-
c ,c ,*•* »•••••
2'. 3. 4. 4'. 5.5'-
331441 5 5«_
«•••* •'•' »jtj
Rabbit Fat
(5/group)
0.302±0.056
0.3S7»0.077
2.043^0.655
2.103-0.508
2. 030 f 0.49 5
Rat Fat
(4/group)
1. 263 f 0.460
2.003*0.847
3.053^0.855
1.433±0.68)
0.529*0.222
Guinea Pig Fat
(2/group)
0.120»0.020
0.074^0.004
0.9 33*0. 004
2.108i0.230
1.500±0.018
Japanese Quail
Carcass
(5/group)
NO
ND
ND
ND
0.215*0.018
Trout
Carcass
(3/group)
0.612»_0
0.838*0
0.559*0
0.462*0
0.553*0
.148
.174
.131
.001
.009
      *Source:   Sparling and Safe, 1980b

      ND   NonJeleilable
 oo

-------
 metabolism of  PCBs  demonstrates  that  different species have different  basal
 capacity  to  njetabollze  these  compounds.    This   difference   In  metabolic
 capacity Is reflected ultimately  1n  the elimination  half-lives  of  the  PCBs.

     Table  III-9  summarizes  data  on the In vitro hepat c  metabolism and Ui
 vivo  metabolic   clearance   of   2,2',3,3',6,6'-hexa-CB,   4,4'-dl-CB,   and
 2,2',4,41,5,5'-hexa-CB  In  humans,  monkeys,  dogs and  rats  (Schnellmann et
 al.,   1985).    Significant  species  variation   was   found  In  the  mlcrosomal
 metabolism of  PCBs.   For each  PCB, the  V^ values  for  metabolism  1n the
 monkey,  dog and  rat  are consistent with  the  respective metabolic clearance
 values  generated  from J_n vivo  studies.   For example, the monkey metabolized
 2,2',3,3',6,6'-hexa-CB at a faster  rate  than  4,4'-d1-CB and did not metabo-
 lize  2,2',4,4',5,5'-hexa-CB.  The .In.  vivo  metabolic  clearance values  Indi-
 cate  that  2.2l.3f3l,6,6'-hexa-CB  was  eliminated  faster   than  4,4'-d1-C8,
 which  1n turn was eliminated  faster than 2,2' ,4,4'  ,5.5'-hexa-Cfl.   The meta-
 bolic  clearance  of  2,2',4,4',5,5'-hexa-CB  In  the  monkey  Is <1  mi/m1n and
 only  18% of a  dose  of  this  Isomer  Is  excreted over 90 days (Slpes  et al.,
 1982a; Lutz et al.,  1984).   In general, the findings with  the rat were  simi-
 lar  to those  observed  In the  monkey.   Unlike  the  rat and  monkey,  the dog
metabolized 2.2'.4.4l,5,5'-hexa-CB  In  vitro.  This result  Is consistent with
 the  fact  that  the dog eliminated  50%  of a dose of  2,2',4,4',5,5'-hexa-C8 In
8  days,  while  the monkey and rat were Incapable of eliminating  50% of the
administered dose during their remaining Hfespan  {Lutz et  al.,  1977; Kato
et al..  1980;  Slpes  et  al., 1982a).   In  summary, the  kinetic  constants for
PCB  metabolism obtained fro«  the  dog,  monkey and rat hepatic  mlcrosomal
preparations were good  predictors  of  in  vivo metabolism  and  clearance for
the three PCBs.


02340                                :::-z4                           n/u/ae

-------
                                  TABLE III-9
    Metabolism Parameters of Three PCBs 1n Humans, Monkeys, Dogs and Rats*
Constant
In Vitro Apparent Km (yra)
2,2',3.31,6,61-hexa-CB
4,4'-d1-CB
2,2'.4.4l,5.5'-hexa-CB
In Vitro Vmax (pmoles/nmoles P-450/m1n)
2.2l.3,3',6.6'-hexa-CB
4,4'-d1-CB
2,2',4,4',5,5'-hexa-CB
In V_1vo Metabolic Clearance (irt/m1n)
2,2',3,3',6,61-hexa-CB
4,4'-d1-CB
Z^'^^'.S.S'-hexa-CB
In Vivo Metabolic Clearance (m/m1n/kg)
2.2',3.31,6,6'-hexa-CB
4,4'-d1-CB
2,2',4.4',5,51-nexa-CB
Human

8.8
0.43
NO

19
4.4
NO

NA
NA
NA

NA
NA
NA
Monkey

5.2
0.92
NO

14
4.3
NO

15
7
0.67

3
1.4
0.13
Dog

0.12
1.3
9.5

29
160
5.8

180
470
16

15
39
1.3
Rat

2.9
0.36
NO

16
6.4
NO

5
2
0.045

20
8
0.18
•Source: Adapted fro* Schnellnann et al., 1985
NO » Not detected
NA . Not analyzed
32340
111-25
03/02/87

-------
Pharmacoklnetlc Studies in Humans
    In  Investigations  directed at  determining  which  species most accurately
predicts  the metabolism  and  disposition  of  PCBs  in  humans,  the  in vitro
metabolism of  2,2',3,3',6,6'-hexa-C8,  4,4'-d1-CB,  and 2,2',4,4',5,5'-hexa-CB
was also  Investigated 1n human  liver  mlcrosomes (Schnellmann  et  al., 1983,
1984).  Data  In  Table III-9 suggest that  the  human metabolism of PCBs would
most closely resemble  that  of  the rat  and  monkey,  but not the dog.  There 1s
good  agreement  between  the V     values  generated from  the  human  and  rat
preparations, whether  expressed per  nmole  P-4SO or  per mg mlcrosomal protein
(Schnellmann  et  al.,  1985).   Since hepatic cytochrome  P-450  concentration
are relatively  similar In  the  human and  the rat,  Schnellmann  et al. (1985)
concluded  that  the  rat would  be  a good model for  human  PCS  disposition
studies.

    In, vivo data  on  the relative persistence of specific PCBs  in humans  are
also consistent  with the above in  vitro  results on  the  metabolism of PCBs.
Jensen and Sundstron (1974)  reported that  2,2'.4.4',5,5'-hexa-CB  was the  PCB
congener found  In the highest  concentration In human  adipose  tissue, while
2.2',3,3',6,6'-hexa-CB was  not  detected.  Since both  compounds are found In
commercial    PCB   mixtures   and   1n  the   environment,   the  presence   of
2,2',4,4',5,5'-hexa-CB  1n  adipose  tissue  is  apparently  related  to  the
resistance of  this  congener  to  blotransformatlon  and elimination (Slssons
and Ueltl, 1971;  Albro et al..  1981).   Other Investigators have measured  the
comparative  rates of   elimination   of  Individual  PCBs  from  the  blood  of
PCB-poUoned patients  In Taiwan  (Chen  et al..  1982).  They found  that  the
olood  concentration   of  2,2',4,4',5,5'-hexa-CB  only  decreased  10%  over
300-500 days.   This  suggests  that   this PCB Is not  readily eliminated and,


02340                                111-26                           03/02/87

-------
thus,  Is  not  metabolized  or   Is   only  minimally  metabolized  by  humans.
Finally,  PCS  concentrations were  measured  1n  the  blood and  adipose  tissue
from workers  In a  capacitor  manufacturing facility  (Wolff et  al.,  1982a).
The  PCBs wHh  unsubstltuted 3,4-pos1t1ons  on  at  least one  of the  phenyl
rings were  In lower concentration  than  PCBs  with  substitutions  1n  the  2,4-
or 3,4-pos1t1ons on both rings.

    Human populations  have accumulated PCBs by  three major  pathways,  namely
environmental  (oral  exposure),   accidental  (oral exposure)  and  occupational
(dermal  and  Inhalation);  several papers have reported  the  Identification  of
PCBs in  human tissues  by  low or  high resolution GC analysis  (Hasserman  et
al., 1979; Hlguchl, 1976;  Cordle et al.,  1978;  Holdrlnet et al., 1977; Safe,
1982; PelllzzaM  et  al..   1985;  Hansen et al..  1975; Hansen,  1979;  Stalling
et al.,  1979; Safe et  al.,  1975b; Jensen and  Sundstrom.  1974;  Yakush1J1  et
                                                 •
al., 1979).   A major  problem associated with  PCBs  In  humans has  been  the
unequivocal  Identification of  the  Individual congeners.  Table  III-l  summa-
rizes the composition  of  the major  Individual  PCBs  Identified In human  milk
determined by high resolution  capillary GC  using all  209 PCB  Isomers  and
congeners as  standards  (Safe et al..  1985a).   U1th  few exceptions  all other
studies  have  been conducted with a  limited  number of  authentic standards.
Although  there  are numerous qualitative  differences 1n  the PCB composition
of   human  tissues.   It   Is   evident  that  several   compounds.  Including
2,2',4.4',5- and  2.3',4,4',5-penta-CB, 2,2',4,4',5,5'-,  2.2',3',4,4',5- and
2,3,3'.4.4',5-hexa-C8.  2.2'.3.4,4'.5.5'- and  2,2'.3.3',4.4',5-hepta-CB  are
routinely Identified  1n all human  tissues  (liver,  adipose  tissue,  serum and
milk).    The  PCB  composition of   serum  or  adipose tissue from occupationally-
exposed  individuals is  highly  dependent on the  point  source pollutant (that


02340                                111-27                           03/02/87

-------
Is, commercial  PCB product).   For  example the  PCB  composition  of serum  or
adipose  tissue  of  workers   exposed  to  the  lower chlorinated  PCB product,
Aroclor 1016, Is significantly  different than observed  In  Yusho  patients and
there  Is bloconcentratlon of  the more  persistent  lower  chlorinated congeners
such    as    2,4,4'-tr1-CB.    2,4.4' ,5-tetra-CB,    2' ,3,4,4'-tetra-CB   and
2.3',4,4',5-penta-CB (Wolff et  al.f 1982b), which are present In  the  commer-
cial product.   The  more  familiar  higher chlorinated  PCB congeners  that bio-
concentrate from environmental  sources  are also  evident  (at  relatively  lower
concentrations)  In  the  gas  chromatograms of  occupationally-exposed worker's
tissue extracts.

    Chen et al. (1982)  Investigated the elimination of  Individual  PCBs  from
the  blood  of  PCB-polsoned  humans In  Taiwan.    The results  Indicate  that
tetra- and pentachloroblphenyls with  adjacent unsubstltuted carbon atoms  at
meta-para positions are rapidly eliminated from  the  blood  of patients,  while
                              s
PCBs with  the  same degree  of  chloMnatlon  but  with adjacent unsubstltuted
carbon atoms at ortho-meta  positions  are eliminated more  slowly.   They  cal-
culated terminal half-lives  of  2,4,5,3',4'-penta-CB  and 2,3,4,3',4'-penta-CB
In  the blood of exposed  humans to  be 9.8±5.0  and  6.7±2.5 months (means  *
SO), respectively.

Fetal and Neonatal Studies
    Several  studies  (Torok  and  Weber, 1981;  Nasuda  et  al..  1978.  1979;
Orberg,  1977;  Curlty »t  al.,  1973;  Baker  «t  al..   1977;  Mlzunoya  et  al.,
1974;  McCormack et al..  1979;  Allen and Barsottl, 1976; latropoulos  et al.,
1978;  Bailey  et al.,  1980;  Takagl et  al.,  1976; Ando,  1978; Vodkinik  and
Lech,  1980;   Vod1dn1k,  1986)  clearly demonstrate  that  PCB  mixtures  and


02340                               HI-:*                           03/02/87

-------
Individual  congeners  can  cross  the  placental  barrier   and  accumulate  In
fetuses.   At  high-dose  levels  of  PCBs  this can  result   In  fetal  toxlclty.
Another major  exposure occurs  by lactation  In  which  the  highly  Upophlllc
PCBs are  readily  transferred from  the  parent to  the  neonate.   Most  studies
Indicate  that  this  latter  route Is the most  Important  route  of  exposure for
the young.

    Table  111-10  summarizes  several studies  using  laboratory  animals,  which
describe  the transfer of PCBs from  mothers  to fetuses  and suckling neonates.
The  results  reported  In most  of  these  papers  are  comparable  and  only  a
selected  few studies will be discussed 1n detail.

    Yodldnlk  and  Lech  (1960)  Investigated the  transfer  of  2,2',4,4',5,5'-
hexa-CB In pregnant mice to  fetuses and  nursing offspring.  The compound was
                                                 •
administered to  the mice 2  weeks before mating  and a group of virgin  mice
served  as controls.   At the  day  of  birth,  PCB  levels  1n  liver,  adipose
tissue and kidney  were higher In the sacrificed  pregnant mice compared with
the  controls.   The  PCB levels   In the  fetuses  were minimal  (that  is,  1000  vg/g  adipose tissue).    Five  days  postpartum  there   were
dramatic  Increases  lit  the PCB levels  In  offspring liver muscle and skin, and
after 20  days  postparturn almost  the entire  body burden of the nursing mother
was transferred to the offspring  (Table III-ll).

    flasuda et  al.  (1979) administered  a  reconstituted mixture  of  seven PCB
congeners     (2.4,4'-tM-C8.     2,3',4,5-tetra-CB,     2,2' ,4,5.5'-penta-CB,
2,2',4,4',5,5'-h«xa-CB.  2,2',3,4,4',5-hexa-CB,   2,2',3,4,5,5',6-hepta-CB and


02340                               III-29                           03/02/87

-------
                                                                              1AHM  111-10

                                                           Distribution of PCis  to fetuses and Nursing Young
                                        Sourer of  PCIs
                                                                Vehicle
                                                                                Dosage/
                                                                        Rout* of Ministration
                                           Distribution to QMS HI Ik or Offspring
                                                                                                                                                      Deference
    HIce/NMRI
    NIce/ddN
                f/NR
                F/10-1S/
                group
    Ntce/ddN
                f/7-12/
                group
trt-CI
i of PCIs
sesaae oil trice aaounts/gavage on
days 13. IS. 1? of
pregnancy
In dMs: fat>aaoMry g1and>ltver>kldney>
ovary-blood.
Fetal: day IB tevels>14. aostly In GI
tract and liver at day IB.
lorok and
Meter. 1981
•-trl-CB;
4.S-te!ra-CI;
4'.S.S' penta I
                                       3.4.S.S'.6  hepta-CB
                                       2',3,3'.4,«>,5,5t-
                             or  2
                             octa-CB

                             Kanechlor-MM
NIce/NMRI       F/21         2.4'.S trt Cl or

                F/2S
Rat/Sheraan     F/6.13X      Aroclor 12S4
                group
Rat/Ml star      F/S/group    Aroclor 12S4
Ral/WIstar-SIC  F/12/group   Kanechlor 400
diet         0.32 ag/kg diet
             0.42 ag/kg diet
             0.44 ag/kg diet
             0.44 ag/kg/dtet
             0.16 ag/kg diet
             0.23 ag/kg diet
diet         0.01 (control). 0.14. B.4
             or M ag/kg diet fro* days
             0 II of pregnancy or day 0
             of pregnancy to S weeks
             postpartua
                                                               peanut  oil    0 or  0.05  ag/days  for
                                                                            days  S  H  of  gestation
                                                                            0 or  O.OS  ag/day for
                                                                            days  1-12  of  lactation
                                                               peanut  oil    0.  10 or SO ag/kg bu/day.
                                                                            days I-1S of gestation
                                                               drinking     ».4 itg/kg bw dally for
                                                               water         9 weeks

                                                               diet          0. 10. SO or 2SO ag/kg
                                                                            diet during gestation
                                                                                                    fetal levels:  greater when PCI fed
                                                                                                    during rather  than before pregnancy.
                                                                                                    In all cases tested,  exposure of  daas
                                                                                                    pregestatlonal elevated fetal tissue
                                                                                                    levels.
                                            Nasuda  el  a).
                                            19/9
fetuses: whole body levels dose-related;   Masuda el a I.
at S6 ag/kg diet level fetal adipose       19/8
tissue PCB >aaternal liver PCI concen-
trations.  PCI levels of offspring
during lactation >100» previous fetal
levels.

Oaas: liver hexa-CB»trl-CB                Or berg. 19/7
fetuses: adipose hexa-CI»trt-CB
Daas: liver hexa-CI»trl CB
Offspring: liver hexa-CB»IM-CI; stoeuch
           contents hexa CB»trl Cl

fetuses: <0.12.  0.63.  1.31 »g/g tissue     Cur ley  et al  ,
Nllk: <0.7S.  20.63. 66.2 ,.g/g atlk          1973
21-day-old weanling Bales:  0.19. 3.35.
  11.24 yg/g  liver

fetal levels:  low:  -1  pg/g whole body
                                                                                                    PCI  concentrations In fetal tissue
                                                                                                    tIssue levels of
                                                                                                    daas.  Tissue  levels of 2B-day-old pups
                                                                                                    whose daas received 50 ag/kg:  llver>
                                                                                                    kldney>1ung>splcen>hearI>braIn.
                                                                                    Baker et al ,
                                                                                    19>7

                                                                                    Nliunoya
                                                                                    et al., I9M
CD

-------
                                                                             1AIK  111-10 (cool
 o
 ro
        Species/Strain   Sea/Number
                        f/MR
                                   Source of Kit
       Bawley
       Monkey/rhesus   f/le
       Monkey/rhesus    f/3
Rat/JU-CI       f
        flats/Wtstar
        Ntce/Sprague-    I
          taw ley
       Ntce/)CR
                             ATM: lor 1244
                             ATM lor 1241
                             Clophen A-M
                                     Radlolabeled
                                     Kanechlor  400
 Vehicle              Oosage/
              Route of Administration
                              Distribution to Dams  Nllk  or  Offspring
                                             Reference
diet
diet
IX methyl
cellulose
In water
                                                          Olive oil
                             Radtolabeled
                             2.2'.4.4'.S.S'-beMa-C«

                             Radtetabeled
                             2.2'.4.4'.S.5> hew Ci
                             Radio labeled
                             2.2'.4.4'-tetra-CI
0. ?S or SO aoykg dtet
star'ttim day • of gesta-
tion - day 14 postpar I ua
0. 2.S or S.O ««/k« diet
contlMMHisly l.S years.
Uart • MMtlis prebreedtug
0 or U ag/kg bw/day by
gavage 22-24 days
             oral administration
             once a week froa
             day I-It of
Olive oil    I.p. administration
Corn oil     compound Injected t.p.
             2 week* prior to mating
Corn oil     t.p. Injection of ISO
             mg/kg on day IS of
             gevtatlon
Dam: fat>manmary>kldney>llver>lung
Nllk: postparturn day 0/293 mg/mt/SO
      mg/kg; postparlum day 14/32
      yg/mt/U) my/kg

Stillborn male S.O mg/kg:  lung>pancreaj>
adrenal>tbymus>splcen>muscle>kldney>
liver.  Hale died at 44 days-2.S mg/kg:
bone marrow~lung>tkymus>adrenal>pancre4t>
ktdney>spleen.

Hood of offspring higher  In KIs than
blood of dams.  PCI levels In milk 10 20
times that of serum of dam.  Higher PCS
levels In tissues of Infant than dam.

10-&M of dose excreted by dams (skin
and placenta-major fetal deposition).
Average dam-fetal transfer 2W of dose.
Average amount of PCIs transferred by
lactation (45 days) - 2X of dose.
Nursing rat  levels of PCIs lower than
dosed pregnant or nonpregnant rats.

transfer by placenta and lactatum was
2.7 and 33.?*, respectively.

Transplacenta) transfer of PCI was
minimal; after 20 days postpartum.
lactation transferred most of the
mothers dose to suckling pups.

Iransplacenlal transfer -1% of maternal
body burden. 90X of maternal body burden
eliminated over a 4-day nursing period.
NcCor mack
et at..  11/S
Allen and
•arsottl. 19/6
latropouloi
et al.. 19IH.
•alley ei al.
1980

lakagt
el al.. 1916
                                                                        Ando.  19 IB
                                                                        Vodlclnlk  

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                                                    TABLE 111-11
                           Transfer of ("C]Hexa-CB from Mother Nice to Nurstng Offspring4
CJ
CJ
o
r«o
GO
Day of Sacrifice
Day 19 pregnancy
Birth
Day 5 postpartiM
Day 10 postpartiM
Day IS postpartiM
Day 20 postpartiM

MJ Hexa-CB/
Total Carcass
0.662
-
0.372
0.167
0.038
0.016
b
Mothers
tig Hexa-CB/g
Utter
5.12
-
8.S9
3.48
0.87
0.37

Percentage
lotal Dose
Eliminated*
0
2.7
56.8
80.6
95.6
98.1
•

•g Hexa-CB/
Litter


0.545
0.810
0.743
0.900
c
Offspring
tig Hexa-CB/
Litter


15.31
13.97
11.18
12.50

Percentage of
Mother's
Dose Accumulated
-
-
3.00e
94.0
86.2
104.4
    aSource: Vodlctntk and Lech (1980)
    bVlrgln  feMle  Mice  pretreated  with 50  «g/kg  (>«C]2.2',4t4>.5.5'-hexa-CB  (-1.25  my/animal)  2 weeks
     before Mtlng.  Each value represents the Mean of two carcasses.
    cEach  value represents the Mean from the carcasses of two pooled Utters.
    ^Represents percentage eliminated  from dose remaining In Mothers at  day  19  of pregnancy.

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2,2'.3.3',4.4'.5.5'-octa-CB)  In  the  diet  to  adult  female  mice  for  18  days
either  before  .or  after mating.   The  results  demonstrated  that   there  was
transfer  of  all  the  PCB  congeners  to   fetuses  and  offspring and 1t  was
apparent  that  lactation was  the  predominant  route  of exposure  for  the  off-
spring.   Mot  surprisingly,  the  more  readily  metabolized  2,4,4'-tr1-C8,
2,3'.4'.5-tetra-CB and  2.2',3.4.5,5',6-hepta-CB were  rapidly eliminated  from
the dams and  their   offspring.   Higher  levels of  the  2,2',4,5,5'-penta-CB
were  detected  1n  the offspring  (aged 5  weeks)  and  this  was  not  expected
since this compound would  also  be rapidly metabolized.   In contrast the more
highly   chlorinated   2,2'.4.4l.5.5'-hexa-CB,   2,2'.3',4,4',5-hexa-CB   and
2,21,3.31.4.4>.5.5'-octa-CB persist  1n the tissue of  both  the dams and their
offspring.   The  two  hexa-CB  1 sowers  also  preferentially  bloconcentrate  1n
human tissues.

   Infant monkeys nursed by  PCB-exposed  dams  rapidly  developed  signs  of
PCB-Induced  Intoxication.   Female  monkeys were  fed diets  containing  2.5 or
5.0 mg  Aroclor   1248/kg  starting   6 months   before  breeding  and  exposure
continued  for  18  months  (Allen  and  Barsottl, 1976).   One male  Infant was
stillborn  and  Us PCB  tissue  levels ranged  from 99.5  wg/g  In lung > pan-
creas > adrenal  > thymus  >  spleen  > muscle  > kidney to  2.5  jig/g In liver.
All of   the  surviving  Infants  developed  typical  facial  skin  lesions  by   2
months  of age.  Tissue  levels of  PCBs In a male  Infant that  had  died at u
days  of age  ranged  fro» 50.8 ng/g  In bone marrow  -lung  > thymus > adrenai
>  pancreas >  kidney to  0.62 ^g/g  1n liver.   Three nursing  rhesus monkeys
were  treated with 16 mg  Clophen  A-30/kg/bw/day  by  gavage starting on  Jays
46-127  post par turn and  continuing  for 22-2S  days  (latropoulos et  al..  19/8;
02340                               111-33                            11/14/86

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Bailey  et al.,  1980).   The  youngest  Infant and  her  dam became  moribund  on
exposure  day . 21.   Necropsy  of  the  Infant  revealed  mild  hepatocellular
pathology and dilation  of renal tubules containing  casts.   Levels of  PCBs  In
nllk  appeared  to  range from  10-20  times  the  levels  In serum.   In  general,
serum levels of  PCBs  In Infants were about  2  times  the levels In their dams.
Body  fat contained  the  highest  levels  (1687  yg/g)  > bone  marrow >  lymph
nodes >  adrenals  >  thymus  >  kidney  > spinal  cord >  liver  (80  vq/q).   In
all  tissues  except the  thymus, Infant  tissue levels were  1.94-5.47 times the
corresponding  levels   1n  the  moribund  dam  sacrificed  after   22  days  of
exposure.   These  studies  confirm the  Importance of  lactation as  the major
source  of PCB exposure  In neonates.

   The Importance  of   lactation as   a  major   route  for  PCB excretion  was
demonstrated  In  a study  of a  woman occupationally exposed  to Kanechlor 300
and  SOO In  a capacitor  factory (Yakushljl  et al..  1978).   The PCB levels  1n
the   tissues and fluids  from the mother  and child are summarized  1n Table
111-12.   Since  PCB levels In umbilical  tissues,  umbilical  blood and amnlotlc
fluid were  considerably  less than  measured In mothers blood It was evident
that  there  were some barriers  to  transplacental exposure to  these toxins.
Other recent studies confirm this  observation  (Jacobson et  al., 1984; Bush
et al.. 1984).  Since  the mother's milk  and  serum contained unusually high
levels  of PCBs,  the  baby was  not  nursed  on  her breast milk.   Lactation  of
this  Individual  resulted  In  the excretion of  200 mg of  PCBs   In 818 l  of
breast  »1tt and resulted 1n  an  overall 76% decrease  1n  (milk)  PCB levels.
02340                                III-34                            03/02/87

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                                TABLE II1-12

      Levels  of  PCBs In the Tissues and Fluids from a Mother and Child
              Occupatlonally Exposed to Kanechlor 300 and 500*
Sanple
Placenta
IMrillcus tissues
(Milieus blood
Mother's blood
tanlon fluid
taentiM adipose tissue
Subcutaneous adipose tissue
(taken from the mother)
Baby's blood
Baby's blood
Date Tissue
(PP»)
July 1975
July 1975
July 1975
July 1975
July 1975
July 1975 16.1
Noventoer 1976 4.1
November 1975
November 1976
Fluid
(PP»)
0.056
0.011
0.016
0.057
0.010
12.2
4.0
0.003
0.004
•Source:  Yakushljl et al..  1978
02340
111-35
                                                                     11/14/86

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These data  clearly  Illustrate the Importance of  lactation  as  the major  route
of Infant PCB  exposure and  as  a major  route of  depuration  for  the  highly
exposed Mothers.

Metabolism
   As  discussed previously  In  this chapter,  the  major factor  that  affects
the long-tern persistence  of Individual  PCBs  In animal tissues  Is  the rate
of metabolism  of  these compounds.   It  was  Initially shown  by Block  and
Cornish  (1959)   that  the lowest  chlorinated blphenyl,  4-CB.  was metabolized
to give  4'-chloro-4-b1phenylol  and  Its  glucuronlde  as urinary metabolites.
Hutzlnger et  al.  (1972)   reported   that  not  only 4-CB  but  several  higher
chlorinated  blphenyls were  metabolized to  give  hydroxylated  and dlhydroxyl-
ated  PCB products as  determined by NS analysis.   These Initial results also
suggested  the   rates  of  metabolite  excretion  were  species-dependent  (for
example,  rats  > birds >  fish)  and dependent  on  the degree  of substrate
chlorlnation since  only  trace  levels  of   the  higher  halogenated  blphenyl
metabolites were detected.

    The in vivo  metabolism of Individual PCBs by  manna 11 an,  avlan and plant
species and by microorganisms has been reviewed (Matthews and  DedMck, 1984;
Schnellminn et  al.,  1985;  Safe. 1980;  Sundstrom et  al.. 1975a).  Numerous
studies have focused on delineating the  problems associated with  PCB metabo-
lism, and  these Include structure determination  of  PCB  metabolites,  evalu-
ation of  the effects  of  the position and number  of chloro substltuents  on
the sites, and  rates  of metabolism and determination  of  the  mechanism  of  PCB
metabolism (that Is. metabolic pathways).
 02340                                II1-36                           11/14/86

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   Figure III-2 summarizes the  structures  of  PCB  metabolites  that  have  been
Identified using  a diversity  of substrates and  blosystems  (Block and  Cor-
nish,  1959;  Hutzlnger  et al.,  1972;  Sundstrom et al., 1976a,b; Hsu  et  al..
1975;  Gardner  et  al..  1973;  Safe  et  al., 1975a,b,  1976;  Norback  et  al.,
1976;  Sparling et  al.,  1980;  Helancon and Lech,  1976;  Gh1asudd1n  et  al.,
1976;  Mass  et al.,  1977;  S1pes et  al.,  1980, 1982a,b; Schnellmann  et  al.,
1983,  1984.  Shlraada.  1976;  Jensen and  Jansson, 1976;  Hlzutanl  et  al.,  1978;
Bergman  et  al.,  1979,  1982; mo et  al.,  1976; Mlzutanl,  1978;  Baake  et  al..
1982;  Brandt  et  al., 1982; Brandt,  1986;  Preston  et al.,  1984; Lund  et  al.,
1985).   Invariably,  the phenolic  products  are   the  major  PCB  metabolites
although sulfur -containing  metabolites (for example,  methylsulfones), trans-
dlhydrodlols,  polyhydroxylated PCBs,  and  their methyl ether derivatives and
ring-degraded   mUroblal  oxidation   products  have   been   Identified.   The
effects  of  chlorine substitution patterns  on  the  sites of oxidation  have not
been  studied  systematically;  however,  examination  of  the results  In the
literature  suggest the following:
    1    Hydroxylatlon   Is  favored  at  the  para  position   1n   the  least
        chlorinated phenyl ring unless this  sHe  Is steMcally hindered
        (that is. 3.5-d1chloro substitution).
    2   In   the  lower  chlorinated  blphtnyls   the  para position of both
        blphenyl  rings  and  carbon  atoms  that are para  to the  chloro
        substHuent  are  all  readily  hydroxylated  (Sparling et al.,
        1980).
    3   The  availability  of  two   vicinal  unsubstHuted   carbon  atoms
      '  (particularly   C5   and  C4   1n   the  blphenyl   nucleus)   also
        facilitates  oxldatlve metabolism  of  the  PCB substrate  but Is
        not a necessary requirement  for metabolism.
    4.  As  the  degree  of  chlorlnatlon  Increases on  both  phenyl  rings
        the rate  of metabolism decreases.
    5.  The  metabolism of specific PCB Isomers by    "w"*1" can
        result  in  considerable variations  In  metabol
 02340
                                     HI-37                           03/06/87

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           Om-1   OH
         DochloHnotton
           Products
Thioettwrt
           a.
                          mro
                                     IN
                                    a,
                                        ON
                                                                a.  (OH),
Otols
                                                              MFO
                                                                    MAOMt
                                                                    OH
                                                           Ph«nol-conjugcte«
                                          a,

                                   atiydrodtols

                                  FIGURE II1-2

                                    of PCS HeUbollsa

                               Source:  Safe. 1980
02340
 111-38
       10/29/86

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   The mechanism  of  PCB metabolism  has  been delineated by results  obtained
from  several studies.   For  example the metabolism of 2,2',5,5'-tetra-CB by  a
variety  of  blosystems  gave  two  phenols,  2.2',5,5'-tetrachloro-4-b1phenylol
and  2,2'.5,5'-tetrachloro-3-b1phenylol  and  trans-3,4-dlhydro-3,4-d1hydroxy-
2,2'.5,5l-tetrachlorob1phenyl   as  major  metabolites   (Hsu   et   al..   1975;
Gardner  et  al., 1973;  Nor back et al..  1976; Ghlasuddln et al.,  1976).   The
latter  trans-dlhydrodlol suggested that  the metabolism may Involve  an  arene
oxide (Gardner  et  al..  1973).  Arene oxides  have  been  proposed as Intermedi-
ates  In the metabolism of  diverse  endogenous  and  exogenous  chemicals,  and
their  formation   requires   molecular  oxygen,  reduced  nlcotlnamlde-adenlne
dlnucleotlde  (NAOPH)  and  the mlcrosomal monooxygenase  enzyme system (Jerlna
and  Daly.  1974).   The high reactivity  of  these Intermediates  often precludes
their  detection   since  arene  oxides  characteristically  hydrate  to  give
trans-dlhydrodlols  and   other   rearrangement   products.    However,   using
[»H]-2,2' .5.5'-tetra-CB and  an  l£ vitro  mlcrosomal enzyme system,  the pro-
posed arene oxide Intermediate  from 2,2',5,5'-tetra-CB  has  been Identified
(Forgae and Allen. 1982).

    Arene  oxides   also  spontaneously   rearrange  to  phenols  with  the con-
comitant !,2-m1grat1on  of  substltuents   (e.g.,  aH,  »H.  Cl,  Br  and CH3)
from the site  of  hydroxylatlon  to the adjacent carbon atom  (the  MIH shift).
The  metabolism of  4-ch1oro[4'-*H]b1phenyl  (Safe  et  al..  1975a),  4.4'-d1-
chloroblphenyl (Safe  et al..  1976;  Hass  et al.,  1977;  Slpes et al.. 1980)
and  a.Z'^^'.S.S'-hexachloroblphenyl  (Slpes  et al.,  1982a; Schnellmann  et
al.. 1983; Sundstrom  et  al., 1976b)  all  featured the MIH  shift of  Cl  (or
 02340
HI-39                           11/14/86

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»H)  and  the results  were consistent  with metabolism  by  arene oxide  \nter-
medlates.  Thus,  the  detailed metabolic  studies  of selected PCS  Isomers and
congeners suggested that  arene oxides  play a  major  role In  their metabolism.

    Metabollcally  mediated  cytotoxldty,  mutagenlclty  and  cardnogenldty
have been associated  with the in vivo formation  of  electrophlllc  species and
their subsequent  alkylatlon  of  critical  cellular  macromolecules.    Arene
oxides  are  potential  electrophlles  and  thus  their formation  and  subsequent
cellular  reactions can Involve the formation  of  both  detoxification products
(for example,  metabolites,  glutathlone  conjugates,  other  phase  II  conju-
gates),  which  are excreted, and  potentially   toxic  covalently   bound  sub-
strate-macromolecular  adducts.   The   Vn  vivo   and in  vitro formation  of
PCB-proteln,  RNA  and  DNA  adducts  have been  reported  In  several  studies
(Uyndham and Safe. 1978;  Uyndham et al.,  1976;  Hesse and  Wolff,  1977; Hesse
et al., 1978;  Shlmada and  Sato, 1978;  Stadn1ck1 et al..  1979; Hong et al..
1979; Morales  and  Matthews, 1979).   The in  vivo  binding  of  2,2'.4.4'.5.5'-
and  2,2'.3.3l.&,6l-hexa-CB  to hepatic protein.  RNA and  ONA 1n nice has been
reported (Morales and Matthews,  1979).   Moreover,   the In vitro metabolism of
numerous PCB  Isomers and  congeners by  rabbit,  rat,  mouse and monkey liver
•krosomal  enzymes results  In the  formation of  hydroxylated  metabolites and
covalently  bound  PCB-«acro»olecular  adducts  (Hyndham and Safe. 1978; Wyndham
et  al.,  1976;  Hesse  and Wolff.  1977; Hesse  et  al..  1978; Shlmada and Sato.
1978).

     In  vitro   studies  using mammalian   cells  In culture  have confirmed  DMA
damage  mediated  by   PCB  congeners  and  their  metabolites.   Incubation  of
2,2',5.5'-tetra-CB.   2,2',5.5'-tetrachloro-4(3)-b1phenylols  (4:1   mixture  of
 02340
                                     HI-40                           11/14/86

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the 4  and  3  phenolic  products,  respectively)  and  3.4-d1hydro-3.4-epoxy-
2.2'.5,5l-tetrachloro-b1phenyl  with 1-929  cells  was conducted.  The  ONA  was
Isolated  and examined  for strand  breaks  by centrlfugatlon  techniques.   All
the test  compounds  were capable  of  Inducing  single-strand  breaks In  L-929
cell  ONA;  however,  the  arene  oxide  was  clearly the  most  potent  agent
(Stadnlckl  et al.,  1979).   Another Yn vitro  assay  of DNA  damage was reported
using 4-chlorob1phenyl  as  a substrate with Chinese  hamster ovary cells  (Wong
et al., 1979).   Incubation of  the cells  with  4-[»H]C8 resulted  In  metabo-
lite  formation  (that  Is.  hydroxylated  products),  which  was  accompanied  by
binding to  protein,  RNA  and  DNA.   Horoever,  the  specific  activity  of  the
substrate-ONA fraction  was higher  than  that observed for binding  to  protein
or RNA.   In  parallel   experiments,  a  ONA  repair  assay  confirmed   the  DNA
damage  by  a  significant  Increase  In the  uptake of [*H]dT  after  incubation
of the  cells  with 4-CB.

   The toxlcologlc  significance  of PCB  metabolism  Is  unknown.   However,
most  studies  suggest  that  the parent  hydrocarbon  Initiates  most  of  the
cowmen  toxic responses  by  Initial  binding to  the  cytosollc  receptor  protein
(Safe  et al.,  1982; Safe,  1984;  Poland  et al.,  1979. 1983).  The  role of
metabolism In the genotoxldty of PCBs has not been delineated.

   Because of  their  llpophlUc  and  relatively stable nature,  PCBs  rapidly
bloaccumulate  In biota  and  the  tissues  of humans.   PCBs  are effectively
absorbed  following  oral,  dermal  and  Inhalation  exposure.    In most animal
species that have been  Investigated there  Is  an Initial  uptake of PCBs  into
the liver  and  muscle because  of high perfuslon 1n the  liver and the rela-
tively  large muscle volume.  Subsequent redistribution of  PCBs into adipose

02340                                III-41                            03/02/87

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 tissue  and  skin  reflects  the  high  affinity  of  the  PCBs   for  llpophlllc
 tissues.  At "equilibrium the  elimination  of PCBs  from all  tissues  will  be
 dependent  on   the  structure-dependent  metabolism  rates  of   Individual  PCB
 congeners.   For example, biological  half-lives  1n  the  rat  range  from 0.15
 days for 2.2'-d1-CB  to -460 days for 2.2',4.4',5,5'-hexa-C8.

    Metabolism 1s  apparently  the primary rate limiting  event regulating the
 ellnlnatlon  of PCBs  from mammalian  systems.   The  \t\ vitro metabolism of PCBs
 has been Investigated  1n liver  mlcrosomes  from the  human, monkey,  dog, and
 rat.  The data suggest  that the human metabolism  of PCBs would most closely
 resemble that   of  the rat.   Therefore, the  rat  should  be a  good  model for
 predicting the disposition of PCBs In humans.

    The position  and degree of  chloMnatlon  substantially Influence the rate
 and extent  of  PCB metabolism.   As  the  degree  of  chlorlnatlon  Increases  on
 both phenyl  rings the rate of  metabolism decreases,  though  there  1s  also a
 selectivity  with  respect to  type  of  substitution  for  Isomers.   The  avail-
 ability of  two vicinal  unsubstUuted carbon  atoms  facilitates metabolism of
 the  PCB substrate  but   Is   not a   necessary  requirement   for  metabolism.
 Although phenolic  products  are  the  major  PCB metabolites, sulfur-containing
metabolites,  trans-d1hydrod1ols,  polyhydroxylated  PCBs  and  their  methyl
ether derivatives  have  been  Identified.   The presence  of trans-d1hydrod1ol
metabolites  strongly  suggests metabolism  through  an  arene oxide Intermedi-
ate.  Arene  oxides  have been Implicated In  cellular  necrosis, mutagenldty
and carclnogenlclty;  however,  the  role of metabolism  In the  genotoxlclty of
PCBs has not been  delineated.
02340                                III-42                           03/02/87

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   Studies  1n  laboratory  animals  clearly  demonstrate  that  PCBs can  cross
the placenta!  barrier and  accumulate In  the  fetus.   Another major  route  of
exposure occurs by  lactation In which the highly  I1poph111c  PCBs  are readily
transferred  from  maternal milk to  the  neonate.  The  latter  route represents
the tnst Important  route  of  PCB exposure for  the young.

   Preferential  structure-dependent  bloaccumulatlon  of  PCB  congeners  has
been   observed   1n   human   liver,   adipose   tissue.    serum   and   milk.
2,2l,4,4',5.5l-hexa-CB,    2,2',3.4,4',5'-hexa-CB,   2,2',3,3',4,4',5-hepta-CB
and 2,2' ,3,4,4' ,5,5' -hepta-CB  are  major components of both  a  high molecular
weight  commercial PCB mixture  (Aroclor  1260)  and human milk.   On the other
hand.  2,4.4'-tr1-CB.  2.4,4',5-tetra-CB,  2,2'.4.4',5-penta-CB,  2.3',4,4'.5-
penta-CB  and  2,3,3',4,4',5-hexa-CB  are  Identified   as  major  components  of
human  milk  extract,   while  representing only minor  components  of  Aroclor
1260.   Human studies  also  clearly Indicate  the  Importance of  lactation  as
the  aajor   route  of  Infant  PCB  exposure, as  well  as  representing  a major
route of depuration for  highly exposed mothers.
02340
HI .43                           03/02/87

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                             IV.  HUMAN EXPOSURE

    Humans  may  be exposed  to  PCBs  from a variety of  sources  Including  food,
ambient  air, occupational  settings  and consumer  products.  This  section  Is
United  to  water,  food and ambient air because  these  media are considered  to
be sources   common  to all  Individuals.   Evidence of  human exposure to  PCBs
from finished  drinking  water  1s   limited.   The  bulk  of  the  Information
relates  to  the  years  1984-1986.

Hater
    United  States.   The  National Organic  Monitoring  Survey  (NOMS)  was  con-
ducted  1n 1976 to determine  the frequency of occurrence of specific organic
chemicals (Including PCBs) In  finished  water supplies of  113 cities nation-
wide (U.S.  EPA. 1977).-  Data  from three phases  (referred  to  as NOMS I.  NOMS
II and  NOMS III)  of  the study were collected over  an 11-month period (March
1976 to  January 1977) to reflect any long-term or seasonal variations.

    PCBs were  not  found In groundwater  supplies sampled  In  NOMS I (minimum
quantifiable  limit   .  0.12  yg/l).   Only  a  single   finished  groundwater
sample  In  each of NOMS  II and  NOMS III contained  detectable levels of PCBs
(-6% frequency  of   occurrence  for  'both   phases).    Concentrations of  0.1
wg/l were  reported  for  the NOMS  II  and  NOMS  III samples  (minimum quanti-
fiable  limits ranged fro* 0.1-0.2 wg/l. respectively).

    During  a groundwater study In the state of New  Jersey, Tucker  and  Burke
(1978)   examined  163 wells  In  all  nine  counties of  the  state.  Including
public  and  private drinking water  wells,  and wells near Industrial  sites  and
02350
IV-l                             03/02/87

-------
landfills.  Thirty-two  of  the  163 wells  contained  PCBs with  concentrations
ranging  from   0..06-1.27   vg/i.    (The  minimum  reportable  concentration  was
0.06  ug/l«)   The  highest  concentration   reported,   1.27   uq/l.   was   from
a well  In Mercer  County,  NJ.   Many of  the wells  sampled  were from highly
populated.  Industrialized  areas.   The  levels  of PCBs  detected 1n  drinking
water from these sources were thus  In  the  very  low vg/i  range.

   PCBs  were  detected   1n finished  surface  water  supplies   In  all   three
phases of NOMS.   In  NOMS  I, concentrations  of  two samples  observed were 0.13
and   1.4  wg/l  (mean  =   0.77   wg/l.  frequency   of   occurrence   = 2.2%).
For  NOMS II,  two  samples contained  0.1  wg/i and  one sample  had a  level
of 0.2   yg/l  (mean  *   0.13  yg/i,   frequency  of   occurrence   - 3.3X).
Only  a  single  sample 1n  NOMS  III contained  PCBs  at  a level  of  0.2  tfg/l
(frequency of occurrence  >  1.1X).

   PCBs  were found  1n  the water  of  a small  upstate New York  public  water
supply  system  near  the  heavily  polluted  section  of  the  Hudson   River
(Brlnkman et  al., 1981).   The  Impounded  water contained a  uniform level of
Aroclor   1016   congeners   (Oorlty   Reservoir,  70-130  ng/t;  New  Reservoir.
110-120  ng/l;  Distribution system,  69-100  ng/l) while the levels In  rain
water  were  much  higher  (1300  ng/l).  Low concentrations  of  Aroclor  1254
congeners  (up  to  36 ng/t) were  detected  In  the  New  Reservoir  only.   The
high  levels of PCBs  In   the  Hudson River  (360 ng/l) near  Port  Edwards were
thought  to  be responsible  for high  Impounded  water  levels.   Finished tap
water  did  not  show evidence  of  Aroclor  1254  congeners   (<12 ng/l).   The
•edlan  concentration of  Aroclor 1016  congeners was  85 ng/l In finished tap
wter.   One sample  at  the chlorlnatlon site  was 30% higher In Aroclor  1016
congeners than at  a  household tap.
02350                               IV-2                             04/04/88

-------
   The  Aroclor  1016  origin  was  confirmed  by  identifying  at  least  five
specific surrogate  congeners  by  retention time  from a  possible  19  congeners.
The  19   congeners   were:    4-C1-CB/2.2'-C12-CB   (also   Aroclor   1221);
2,4'-Cl2-CB    (also    Aroclor    1221);     2,2',5'-Cl3-CB;    2,2',4'-C13-CB;
2.2'.3'- and   3,2',6'-Cl3-CB;  4.2' .S'-C^-CB;   two   unidentified   Cl3-CBs;
a.S'.S'-Clg-CB;    3.2'.4'-Cl3-CB;   2,4,4'-C13-CB   (also   Aroclor    1221);
2.3',4'-Cl3-CB;   2,5,2',5'-C14-CB   (also   Aroclor  1254);   2,4,2',5'-Cl^-CB
(also  Aroclor  1254);  2.3.21,5'-C14-CB   (also  Aroclor   1254);   2,4,2',4'-
Cl -CB   (also  Aroclor  1254);  2.3,2'.S'-C^-CB  (also  Aroclor  1254);  and
two  unspecified Cl.-CBs   (one   of  which  also arose  from  Aroclor  1254).
Thus, 10  of  the 19  congeners were unambiguously  from Aroclor 1016,  with 6
being  resolved  specific  congeners.    In  this  study,  60  congeners  were
utilized to  Identify  the  possible presence of  Aroclors  1221, 1016, 1254 and
1260.  Each  peak chosen  provided an Independent  estimate of  the quantity of
the Aroclor  using  the appropriate response  factor for  each congener.  The
concentration of the  Aroclor  was calculated as the average of  the concentra-
tions by  each  of  the five  chosen peaks.  Representative  samples were con-
firmed by  GC/HS.  The  detection  limit  was 50 pg, equivalent to  a 12 ng/i
(12 ppt) concentration 1n 2 I of  water  subjected  to the  analysis  technique.

    In  raw   tap  water In the Waterford,  MY  treatment plant, which also  has
the  Hudson  River  as  Us source,  mean  PCB  levels  In   1976 were 0.12  wg/l
 (range:   0.05-0.24)  (Schroeder  and Barnes, 1983).  The  average efficiency of
PCB  removal  was 80-90%  at   high  and  low  flows wHh  levels In  the  treated
drinking water  seldom exceeding  100 ng/l.
 02350
                                     IV_3                             03/02/87

-------
    PCS  measurements   In  water   samples   from  various   rivers   at   several
different  U.S.  geographical locations  have Indicated their detection  at  low
ppb levels (Interdepartmental Task  Force, 1972).  for  example, in the  Great
(Mart  River,  OH (5.7 ppb),  Pestlgo  River. UI  (0.31-0.38  ppb), Oconto  River,
UI  (0.16-0.45  ppb).  Milwaukee River  (0.02-2.07  ppb).  Lake Michigan  (0.013
ppb),  South  Florida (<0.02  ppb).  Escant la  River  and Bay,  FL   (<0.1  ppb).
Green  Bay, UI (0.04-0.07 ppb).

    PCBs  1n the  Hudson River were  first  detected In 1969.  but  It was  not
until  1975 that  a  problem was  deemed to  exist  (Brown  et a!.,  1985).   In
1975,  two  capacitor-manufacturing  facilities  at  Fort   Edwards  and  Hudson
Falls  were Identified  as  the major  sources  of PCB pollution.  It was estl-
•ited  that 14  kg  PCB/day  had been  discharged over a  30-year  period,  mostly
as  Aroclors  1016  and  1242.  The  discharges  were decreased  to  1   g/day  by
1977,  and the  306 km section of  the riverbed from Hudson Falls  through New
York Harbor was  left  as the  major  site  of  PCB  contamination.  Contaminated
sediments   removed  from  the  river  as  part  of  maintenance  dredging  were
deposited  1n  several  upland disposal  sites  during 1974-1977.  By  1978, the
Hudson River  system  was   estimated  to  contain   the  following   PCB budget:
Mverbanks, 63,500  kg; upper river,  134,000  kg;  lower river,  91.000 kg.
fish,  aquatic macrolnvertebrates  and river/sediment water have been analyzed
for PCBs since 1977 and zooplankton between 1978  and  1981.  Since 1982, only
the upper  river  has been  sampled with emphasis  on  high  flow events such as
the spring melting of  snow.   Comparison of  the  relative concentrations of
Aroclors  1016  and 1254 1s  suggestive of  a  decline In less chlorinated con-
geners over  time  as  reflected  also  In  biological  samples.   The  geometric
•tan  In  waters   collected  at   Stlllwater  and  Schuylervllle  from  Hay   to
 02350
f_4                              11/13/86

-------
September  each  year  declined  from  0.68  wq/l   \n  1977  to  0.11   ug/l  ^n
1982.   PCS  transport  declined  below  rWer  flows of  400 m'/second.  During
low flow conditions,  most of  the  PCB  penetrates  a 0.45  urn filter whereas
this  1s not  so  at  high  flow.  Also,  the  less chlorinated  congeners are
present  In  greater  proportions  In  the filtrate than  In  the  nonfllterable
residue.  At  high flow,  the more  chlorinated congeners  dominate 1n whole-
water  samples.   In  the late 1970s,  waters  from the tidal  Hudson  contained
generally   0.1-0.2   wg/l  as   dissolved  PCBs;   In   1982,  the  range  was
reported  as 0.05-0.10 wg/i.   Particle  size  and organic  content appear  to
control  PCB content  In the Hudson River.

    Bush et al.  (1985a)  Identified the PCB congeners  1n  Hudson  River  water
saw? led on  July  6  and August  15.  1983 at  Roger's  Island, Thompson's  Island
and StUlwater  (Table  IV-1).   The  respective  total  PCB  concentrations  1n
My were  100,  532  and  266  wg/l. respectively;  In August,  the concentra-
tions  were  331, 586   and  243  ng/l,  respectively,  mostly  as  Aroclor  1221.
1242,   1254  and  1260.   A specific  congener  analysis  1s  presented  In  Table
IV-1 for  the  three  sites.   The levels  primarily   reflected  dissolved PCBs
since  very  Uttle sediment was  present  In all samples.  A surprising feature
of the results  was  that half of the  transport appeared to  be caused by only
three low chlorinated PCB congeners  (2-,  2.2'-  and 2,6-PCB).   The  levels of
•ore chlorinated Aroclors did not vary greatly  from site  to site,  but those
of Aroclors 1221 and  1242 did.

    Baker  et  al. (1985)  reported  that resuspenslon events In midsummer  in
Western Lake  Superior waters  resulted 1n  a 50* Increase  In PCB residues  in
 the period  Hay to  October,  1983.   The seasonal cycling  of PCB  congeners  at
 12 sampling sites  was  strongly dependent  on  their  degree of  chloMnatlon
 02350                                IV-5
                                                                      04/04/88

-------
                                                          TAftLf  IV -I


                    Mean Mater Concentration (ng/t) of Chlorinated Blphenyl Congeners In Hudson River Mater

J=»                        at Roger's Island (Rl). Ihonpson's  Island  (Tl) and Stlllwater  (ST)  in 1983
w
in
o
 o
 u>

Congener
?
2,2'
2,6
• t ^
2.3'
"• f **
2.4'
2, 2', 5'
2, 2', 4'
2,2'.3'*3,2'.6I
4, 2', 6'
* 9 •* • ^
4.4'
2, 2', 4', 6'
3. 2'. 5
2, 4, 2', 6'
™ • * 9 fc f
3.2'.4(

4, 2', 3'
2, 5, 2', 5'
* t ** • *• t "
2, 4, 2', 5'
2. 3. 2', 5'
»•**•* F "*
2. 4. 2'. 4'
C14C
C14D
2, 3. 2', 3'. 6
2, 5. 3'. 4'
2, 4, 3', 4*
2. 5,2'. 4', 5'

Aroclor
1221
21/42
21/42
21/42
21/42
21/42
1242
1242
1242
1242
21/42
1242
1242
1242
1242
1242
42/54
42/54
42/54
42/54
54/60
54/60
54/60
54/60
54/60
54/60

Rl
0.5b
2.8b
3
0.6b
1.2b
2.0b
3.1
0.95b
1.0
5.1
ND
0.6b
0.8b
2.5b
3.3
2.2
2.3b
2.0b
2.1
1.2b
2.2
2.6
0.5
2.0
1.2
1.0
July
TI
145b
147b
150C
3.6b
33b
14b
11
6.2b
3.3
17
10
1 .lb
7.5b
13b.
0.1
5.0
10b
8.1b
1.6
7.4b
6.8
9.2
1.0
3.7
2.7
1.9

ST
5.5C
73C
73t
1 lc
17C'
4.9C
8
4.3
2.3
15
13
2.6'
6.7
9.7
5.8
3.2
7.0
6.4
3.3
4.9
4.9
6.1
0.8
2.6
1.7C
3.1

Rl
38
4b
4
NDb
0.8b
2.1
2.6b
0.6b
1.0b
1.6b
1.8
0.4
0.5
1.8
5.8
1.0b
2.9b
1.5
3.5b
0.9
2.2
2.7
NO
1.2
1.5
0.6
August
TI
20
44b
50
0.5b
9.7b
4.7
6.4b
2.1b
6.0b
5.5b
3.6
1.6
15
11
6.7
2.6b
6.3b
2.3
9.5&
4.5
3.9
4.8
3.6
5.9
2.7
3.7

ST
2.6
37
40
ND
8.9
ND
5.6
2.2
1.9
6.7
2.1
1.5
3.6
2.4
10
3.1
7.4
2.2
11
1.6
3.9
5.3
0.7
3.5
1.7
0.1

-------
                                             TABLf IV-1 |cont.)

Congener
2. 4. 2'. 4'. 5'
2. 3.2'. 4', 5'
2, 5, 2'. 3'. 4
2. 4,2', 3'. 4'
2. 3. 2'. 3'. 4'
2. 5. 2'. 3'. 5'. 6'
2. 3, 2', 3'. 51, 6'
2,3,4,2'.3',6'
3, 4.3'. 4'
2, 3. 6, 2', 3'. 4 .6'
2,4,5.2'f4',5
2. 3, 4, 2', 4', 5

2>,3',4,2'',3li4
2. 3.6. 2', 31, 4 .5'. 6
3. 4. 2'. 3'. 4'. 5'
2.3.4.5.2'.3'.5'.6'
Total PCB

Aroclor
54/60
54/60
54/60
1254
54/60
54/60
54/60
54/60
1254
54/60
54/60
54/60
54/60
54/60
54/60
54/60
1260


Rl
1.2
1.0
0.4
1.6
2.4
0.6
NO
0.2
0.8
0.5
ND
2.8
1.6
1.7
NO
9.4
0.03
100
July
TI
2.9b
i!o
0.9
1.5
2.5
0.5
NO
0.7
0.7
0.6
NO
1.9
1.6
1.4
ND
9.4
0.5
532

ST
5.7b
K9
1.1
1.6
2.6
1.9
0.2
0.9
0.7
0.7
NO
0.4
0.5
1.0
NO
11
0.3
266

Rl
14
1.6
8.0
2.6
0.7"
0.3
3.3
1.3
3.5
1.8
0.9
2.3
2.8
1.0
120
0.2
0.2
331
August
TI
4S
1.6
2.9
4.4
5.5
0.7
6.7
2.5
28
2.3
1.2
2.2
1.7
0.8
85
0.2
0.4
586

ST
6
0.6
1.8
1.3
2.0
0.4
0.0
0.9
2.0
2.3
0.3
1.0
0.3
0.04
50
ND
0.1
243
^Source:  Bush et al.. 1985a
^Probability that sites Identical <0.005
NO 
-------
«Hh  the  heavier  chlorinated  congeners  lost from  the water  column  (range
0.33-0.77 ng  PCBs/l) with  a half-time  of  17-28  days at  two  sites.  Total
PCB  concentrations  (range  0.57-1.1  ng  PCB/l)  In  the   benthlc  nephelold
layer were  maintained over  the summer  by  transport  of  lighter chlorinated
congeners from  the  underlying  sediments.   Though  atmospheric  and  riverine
Inputs  tc the Great Lakes  have decreased  In  recent years (water  concentra-
tion  ranges  were  0.5-2.0  ng/l  1n  1978;  3.2-3.4  In  1979;  0.4-2.1  In  1980),
the  seasonal  processes  of  lake mixing and sediment resuspenslon do  Increase
PCB and other residues.  The soluble PCBs In this  study were sorbed  by XAD-2
resin  and  analyzed  by  capillary   GC  with  »»H1  electron  capture detection
after  Soxhlet  extraction,   sulfurlc  add  treatment,  and  Florlsll   chroma-
tography  (recoveries  of  Aroclor   1254  and 1242  were 85%).   In  the  1983
samples, Aroclor  1242 made  up  -70% of the  sediment residues  and  90%  1n  the
dissolved phase.   Resuspended  particles were estimated to  contain  concentra-
tions between 100 and  300  ng/g,  and  were enriched In Aroclor  1254  relative
to Aroclor  1242 In general.  The  lighter chlorinated PCB  congeners  migrated
from  the pore waters of surflclal  sediments to the overlying  benthlc  nephe-
lold  layer at an approximate rate  of 27  ng/mVday  during  stratification.

   Capel et al.  (1985)  have reported  also  on   the  concentrations  of  PCB
congeners  1n a Lake  Erie  sediment at  a  depth  of  8-20  cm.   The  congener
levels  were  In   ng/g:   Clj.  2.18;  C13,  13.13;  C14,  32.06;  Clg.  33.2;
CK,  26.69;  Cl,.  14.33;  Cla.  1.68.   The  sum  was  123.2 ng total  PCB/g.
  o/o
This  was compatible with a composition of 24.  42  and 34% Aroclors 1242,  1254
and  1260  at  a  r»  of  0.91,  as  calculated  using  least squares  multiple
regression.   The  same technique applied  to  Lake Superior  water samples taken
In 1979 showed  an Aroclor 1242 composition of  between 37 and 56%  for  concen-
trations  between  0.5  and  8.5  ng/l  using a  50  peak  analysis.   In  Lake
02350                               IV-8                             04/04/88

-------
Superior  sediments  taken in 1982,  a  similar analysis showed  an  Aroclor  1242
composition wh.lch  varied between 15 and 21% {the  rest  being Aroclor  1254)  at
Aroclor 1242  levels between  1.5  and 1.9  ng/g sediment.

    In  a  laboratory  experiment  (VHkus  et al..  1985). 208  mg of  applied
Aroclor  1254  In wastewater  Influent was  diluted  to  a biochemical  oxygen
demand  (BOO)  of 200  ppm so that  the Aroclor  1254  concentration was  1  ppm.
After  treatment with a  lab-scale,  fixed  blomass  for  up to 17 weeks,  54%  of
the PCB  was  recovered 1n effluent  plus  blomass.   At 1  ppb levels, all of the
Aroclor  was  recovered In  the  effluent  plus  blomass.   Volatilization (30-39%
of that  applied) also accounted for  substantial  loss  of the Aroclor at the 1
ppm level.  The chemical  oxygen demand (COO)  and BOO  removal even  at 1 ppm
Aroclor   1254  remained  between  80  and  100%  after  week  3.   There  was  no
toxlclty  to  the blomass even at exposure  levels  of up  to 100 ppm for 2 days.
The U.S.  EPA   has   estimated   that   Industrial   and  publlcally-owned  waste
treatment facility   effluents  are  responsible  for an annual  discharge  of
110.08x10* kg   of  PCBs  Into  U.S.  waters,  and this   has  resulted  1n PCB
levels   of 100-3000  ng/l  In  waters and  2.0-160  i»g/kg  1n  sediment.   The
sedimentation  process   1n  wastewater  treatment   plants   primarily   removes
settleable particles that  contain  high  levels  of  adsorbed  PCBs   (Garcla-
Gutlerrez et  al..  1982;  Nclntyre et al..  1981).

    PCBs  (Aroclor 1260) have  been  detected  1n rainfall,  street  partlculates,
run-off  and  basin  soils  (4/11  samples) of  the  Fresno  Metropolitan  Flood
Control   District,  California,  which relies on  aquifer recharge basins  for
storiMater retention (Salo et al..  1986).
 02350                                IV-9                             04/04/88

-------
   Table  IV-2  summarizes  the  PCS content  of bulk  deposition  (rain, snow,
fog,  dew  and cloud water)  as contained 1n  a  review by Mazurek and Slmonelt
(1985).   VUleneuve  and  Catt1n1  (1986)  have  also  detected  Aroclor  and
specific  PCB  congeners  in  rain  (both  partlculate  bound  and dissolved)
sampled In  the  western Mediterranean.   Dry  deposition of Aroclor 12S4 (18.2
ng In  12  days),  and  2,2' ,4,5'-Cl4-CB  (78.6  ng  1n  12  days)  was   also
detected.   PCBs  have been  found  In  precipitation from all  over  the world  In
urban and rural  areas.   Long-range  aerial  transport  of  PCBs has thus  been
demonstrated.   The more  chlorinated  Aroclors tended  to  be  associated  with
partlculates  but  the   less  chlorinated  congeners  predominated   In   the
dissolved aqueous  phase.   Drinking  water  fed  from rainwater may  therefore
contain PCBs.

   Voudrlas  et al. (1986) detected  hydroxychlorlnated blphenyls as  a result
of chlorlnatlon  or  chloroamlnatlon  of phenol  adsorbed on granular  activated
carbon.   Since   hydroxychlorlnated  PCBs  are  In. vivo metabolites  of  PCBs,
analysis  of these  hydroxychlorlnated blphenyls quantUates both chlorlnatlon
effects   and  any  partial  metabolism  of  PCBs.   High  levels of  trlchloro-
hydroxybtphenyls were  also present after chlorlnatlon of phenol adsorbed on
granular  activated carbon.

    V1l1en*uve   and Cattlnl  (1986)   have  also detected  Aroclor  and  specific
PCB  congeners  1n rain (both partlculate  bound and dissolved) sampled 1n  the
western HtdHerranean.   Dry  deposition of Aroclor  1254 (18.2 ng  In  12 days),
and 2,2',4,5'-C14-PCB  (78.6  ng  In 12 days)  was also detected.
 02350
                                     IV_10                            04/04/88

-------
              Table IV-2.   PCBs  in  Rain  and  Snow Around the World
Concert-
PCB tratlon
Total 0.1 g/m?
-day-107
n.d. 130 ppt
50-230 pptb
97.5-229 ppt
21 ng/1b
29 ng/1»>
21-28 ng/lb
29 ng/lb
14-138 ng/lb
Sample
Type
Bulk deposit;
unfUtered
Bulk deposit;
unflltered
Snow;
unflltered
Snow;
unflltered
Rafn;
unflltered
Snow;
unflltered
Rain;
unflltered
Snow;
unflltered
Rain, snow;
aqueous, par-
Sample
Bulk collector -
glass sheet coated
with mineral oil
Unknown
Unknown
Unknown
Bulk collector -
stainless steel •
w/glass reservoir
Bulk collector -
aluorfnu* sheet w/
Manual packing Into
containers
Bulk collector -
stainless steel
funnel w/glass
reservoir
Manual collection
bulk sample
(1) Bulk collector
- galvanized steel
Collection
Period
Event basis;
2/71
Variable weekly
monthly periods:
7/74-11/74
Event basis:
1974-1976
Event basis;
1974-1976
Event basis;
5/76 - 11/76
Event basis;
winter 1975-76
Event basis;
5/76-11/76
5/77-11/77
Accumulated
snowpack; fall
thru winter,
1975-76
Event basis;
1975-1978
Location
Suburban
La Jolla,
CA, USA
Chesapeake
MO, USA
Remote,
urban Lake
Superior, USA
Remote, urban
Lake Michigan
USA
Rural Great
Lakes, Canada
Rural Great
Lakes, Canada
Rural Great
Lakes, Canada
Rural Great
Lakes, Canada
Rural, urban
Lakes Huron &
9-158 g/kn2
               tlculate;       funnel with
               wet only       partlculate filter
                              and adsorbent cart'
                              Hdge ; ^n_ situ
                              extraction IT?)
                              Auto, wet-only
                              collector (HASL)

               Bulk deposit;  Bulk collector -
               unflltered     metal cylinder
Monthly samples
1975-1978
                                                                       Superior, USA
Rural,  urban
Lakes Huron &
Superior,  USA
02350
                                    IV-11
                                                                      11/13/86

-------
                                   Table IV-2  (cone.)
  Concen-
  tration
  Sample
   Type
      Sample
CoHaction
  Period
"tocatlon
  Unknown
Rain
Unknown
Unknown
   Unknown
  10-100 ng/1
  1-61 ng/1
Rain;
unflltered
Unknown
Rain; aqueous; Auto, wet-only col-
               wet only
 0.3-4.1 ppt
 <1.0-6.7 ppt
 620-10,510
 ng/nr-wonth^
Rain; snow;
part 1culate
Rain; snow;
aqueous
Bulk deposit;
unflltered
lector - Teflon
coated stainless
steel funnel with
adsorbent cart-
ridge; jn situ
extraction

Bulk collector -
aluminum 50-1
can

Bulk collector -
aluminum 50-1
can

Bulk collector -
nylon net Impreg-
nated w/s111cone
oil
5/75-12/75
Event basis;
b/81-8/81
Event basis;
1973-1976
Event basis;
1973-1976
2-3 month per-
iod; 1970-71
   Rural Ontario
   Canada

   Urban, rural
   Ontario,
   Canada
   Rural, urban
   Norway;
   network

   Rural, urban
   Norway;
   network

   Rural  south-
   ern Sweden
 1400 no/fir?
 -month6
 5 g/gxloU
Snow;
unf11tared
Snow;
unflltered
 160-1000 pg/1 Snowpack;
               unflltered
 220 pg/1
Snowpack;
unflltered
Unknown
Bulk collection -
manual trimming of
1ce blocks with
melting Into glass
containers

Manual collection
with polyethylene
containers
Manual collection
with polyethylene
containers
1972
Accumulated
5-10 yr snow-
pack; sampled
1969
Accumulated
snowpack 1980
era; collected
5/81

Accumulated
snowpack 1960
era; collected
5/81
   Urban, subur-
   ban Uppsala,
   Sweden

   Remote Hal ley
   Bay,
   Antarctica
                                                           Remote
                                                           Japanese.
                                                           Antarctica
    Remote
    Japanese
    Antarctica
02350
                      IV-12
                                                                       11/13/86

-------
                                    Table  IV-2  (cone.)
m
total
Concen-
tration
Unknown
- Sample
Tyoe
Rain;
unflltered
•
Sample
Unknown
Collection
Period
Event basis
Location
Urban Lake
Zurich.
Switzerland
  178-6010 ng/  Rain;
  rn'-l00 days   aqueous
  1300 no./I
  39-57 ng/
  10,c
Bulk deposit:
unflltered
Rain;
aqueous
  16-31/no,/
  ]b,c
Rain;
part1culate
  41 ng/
  1/bc
Snow;
aqueous
  33 ng/
  lb,c
Snow;
part1culate
  <0.6
  <3-24 ng/kg
  rain
 Rain;
 unf11tared
 Rain;
 unf11 tared
Bulk collector -
aluminum funnel «/
adsorbent cart-
ridge; Iji situ
extraction

Automatic
Wong Sampler
Bulk collector -
galvanized steel
funnel w/part1cu1ate
filter & adsorbent
cartridge; in, situ
extraction

Bulk collector -
galvanized steel
funnel w/part1cu1ate
filter & adsorbant
cartridge; in, situ
extraction

Bulk collector -
galvanized steel
funnel w/part1cu1ate
filter & adsorbant
cartridge; .in situ
extraction

Bulk collector -
galvanized steel
funnel w/p«rt1cu1ate
filter & adsorbant
cartridge; in situ
extraction

Bull collector -
Stainless  steel
funnel with  glass
reservoir

Bulk collector  -
stainless  steel
bowl
                                      3-mo. period:
                                      6/75 - 5/76
Weekly collec-
tion or 30-day
composite sample

Event basis;
7/75-1/77
Event basis;
7/75-1/77
 Event  basis;
 7/75-1/77
 Event  basis;
 7/75-1/77
 Event basis;
 4/79-8/79
 Event basis
 spring/fall
 1977-1979
                    East coast
                    United King-
                    dom; network
Urban Fort
Edward. NY
USA

Rural, urban
Lake Michigan
USA
Rural, urban
lake Michigan
USA
 Rural,  urban
 Lake Michigan
 USA
 Rural,  urban
 Lake  Michigan
 USA
 Remote
 Enewetak
 Atoll,
 Pac.  Ocean

 Coastal
 SC,  USA
02350
                     IV-13
                                        11/13/86

-------
                                         Table  IV-2  (coat.)
PCB
Aroclor
1254
Concen-
tration
35-49 ng/
lb,c
Sample
Type
Rain;
aqueous
Sample
Bulk collector -
galvanized steel
funnel w/particulate
filter & adsorbent
cartridge; j£-sltu
extraction
Collection
Period
Event basis
7/75-1/77
Location
Rural, urban
Lake Michigan
USA
         30-46 ng/
         lb«c
              Rain;
              paniculate
         24
              snow.
              aqueous
         76
              Snow;
              partlculate
Aroclor
1260
         
-------
                                            Tabl* IV-2 (cont.)
pro
Aroclor
1260
1 CUV



Concen-
tration
11 ng/1°«c




Sample
Type-
Snow;
aqueous




Sawle
Bulk collector -
galvanized steel
funnel v/pertlculate
filter ft adsorbent
cartridge; 1n-s1ty
extraction
Collection
Period
Event basis
7/75-1/77




s
Location
Rural, urban
Lake Michigan




            24 ng/1b'c
               Snow;
               parti oil ate
Poly-
chlorin-
ated
terphenyl
(PCT)
Unknown
Rain
Bulk collector -
galvanized steel
funnel v/pertlculate
filter ft adsorbent
cartridges 1n-s1tu
extraction

Unknown
                                    Event basis;
                                    7/75- 1/77
                                                               Unknown
Rural,  urban
Lake Michigan
USA
                                                                       Unknown
•Source:   Mazurek and Slawnelt,
       concentration
          02350
                                    IV-15
                                                                               11/13/86

-------
    ruh»r   Countries.   PCBs  at  concentrations  of  10-100  ng/i  have  been
detected   In  tap  water  froa  Kyoto,  Japan  (Panel  on  Hazardous  Trace  Sub-
stances.   1972)  and  0.33  ng/i In  a  Swedish  tap water  sample  (Ahllng and
Jensen,  1970).

    PCB  levels  In River Nile water 1n Egypt were decreased  (Aly and Badawy.
1986)  by  coagulation  with Nalco  (0.5  ng/i)/a1un1niM  sulfate (SO  ng/t)  to
the extent  of 19-41* for Arodors 1221, 1232. 1242,  1248,  1254 and  1260.  If
ferric  chloride was  used Instead  of alwIniM sulfate.  the  removal  percentage
was 27-34%  for  these Aroclors. Aluminum, sulfate did not remove  Aroclor 1248
efficiently  (19% removal).   The  chlorine content of  Aroclor  1221 only was
Increased by  conventional chlorlnatlon Methodology;  the chlorine contents of
the other Aroclors  were not affected  by chlorlnatlon.   Levels of Aroclors In
the  canal  water  and  wastewaters,  near  the  River  Nile,  have  also  been
reported  (Badawy  and Aly,  1986).

    The  PCB  pollution of  waters  of  the National Park of  Donona In  Spain
(Baluja et  al..  1985) and of  the  River Po and  Adlge  In  Italy  (Galassl and
Prov1n1.  1981)  have been reported.

     The levels  of PCBs In water have probably  been underestimated  since less
chlorinated PCBs  will  preferentially  solublllze so  that the  PCB congener
composition in  water  can  be greatly different from  that of Aroclor  stan-
dards.  Specific congener analysis  Is essential as discussed In Chapter  II.

Food
     Dietary PCB  Intake has been  reported for  adults,  as well as Infants and
 toddlers.  In the Food and Drug Administration's (FOA) Market Basket Studies

 02350                                IV-16                           04/06/88

-------
for fiscal  year 1979  (FDA,  1982a.b).  The relative  dally  Intakes of PCBs are
presented  for  FY74 through FY79  in Table IV-3.  There Is no apparent trend
in  intake levels  over the  years  for  which  Information was obtained.  Total
dietary   Intake  of  PCBs  for  adults  In  FY79  was 0.0133  wg/kg/day  (FDA,
I982a).   [This includes an estimated 0.0053 »g/kg/day fro* dairy products,
0.0075  wg/kg/day  fro* Mat,  fish  and  poultry, and  0.0005  wg/kg/day  from
oils  and  fats.]

    No  PCBs  were  detected  for Infant  and  toddler  dietary studies by FDA In
FY79  (FDA,  1982b).   Total  dietary  Intakes  of  PCBs for  Infants and  toddlers
1n  FY78  (as  reported In  FDA, 1982b) were  11.3 and 98.5 no/kg/day, respec-
tively.   Information on the Individual  food groups, which Included the total
intake values, was not obtained.  The FDA  calculations assume that the aver-
age  infant  weighs 8.2 kg  (6-month-old) and the average toddler (2-year-old)
weighs 13.7  kg.  No  comparisons of Intakes  of  PCBs by geographic region were
presented In the FDA Market Basket  Studies.

      Bloaccunwlatlon  of  PCBs  In  fish  and other  aquatic life is a major  route
 of exposure to humans.
     PCS Residues  in Aouatlc L1*» "*  the  Unity) frtatM and Canada.  The PCB
 pollution in the  Hudson River  In the  United States has been  discussed (Brown
 et  al..  1985).  The monitoring  of PCB levels In fish In 1977 showed that a
 PCB  contamination problem existed (the levels were w«n above the then FOA
 temporary tolerance level of  5.0  ppm).   Since 1977, not only fish but net-
 spinning  caddis fly larvae  iTrichoDtera:^™"*^*"* have  been "°nUored
 from   June   through   September.  Zooplankton  (e.g.,  6ammirus.   5«2fin!l.
 Leptodera and  Cranqon)  have also been monitored.   Levels are higher  in  the

 02350                               IV-17                           04/04/88

-------
                                  TABLE IV-3

      Estimated  Dietary Intake  of PCBs for Adults,  Infants and Toddlers3
                                  (tig/kg/day)

FY79
FY78
FY77
FY76
FY75
FY74
Adult
0.0133
0.0269
0.0164
T*
T*
0.0056
Infant
NO
0.0113
0.0253
T
T

Toddler
NO
0.0985
0.0301
NO
T
~
^Source:   FDA, 1982a.b

bln  the  FOA  report  that lists  the  Intakes  {FOA,  1980a.b).  values  for the
 adult  in  FY75  and  FY76 were reported as 0.0000 tig/kg/day.  These values
 indicate that only  trace amounts of PCBs were detected m  the market basket
 studies.
NO .  Not detected

T  -  Trace

— -  Data not obtained
 02350                                IV-18                           11/13/86

-------
upper  river  than  those In  the  lower  river and  have  been  steadily  declining
ever  since  remedial actions  have been completed  In  1977.   Mean  total  PCB
concentrations  1n  fillets  from  largemouth  bass  (Hlcrooterus  salmoldes)
collected near  SUllwater  declined  from 145.3  yg/g  In  1977  to 10.2  ng/g
in  1981; at  Catsklll  In  the  estuary,  the residues decreased fro»  29.5  vg/q
in  1977  to  <1.0  wg/g in  1981.   PCB concentrations  In Median striped  bass
(Morone   saxatlllsl  declined  from 9.9  »q/q  In  1978  to  2.6  wg/g  In 1982.
During   the   same  period,   the  fish showing levels below  the FDA  temporary
tolerance level  Increased from 11-75X.  In 1983, only 10% of the  fish  were
below  the current FDA  limit of 2.0 ppm.

    A  strong correlation  between  PCB  and  llpld  concentrations was observed
for  all   Hudson  River  resident  species  but not  for  anadromous  (river-spawn-
Ing)  species.   For  example, mean  llpld-based  PCB concentrations  In yearling
pumpklnseed  (Leoomls  albbosusl  declined  from  1079  wg/g  1n  1979   to  36
wg/g   1n 1982.    Similarly,  mean  llpld based PCB  concentrations  In brown
bullhead (Ictalurus nebulosus).  goldfish (Carasslus auratus).  and largemouth
bass   (Hlcrooterus  salmoldes1  declined  from  2.51, 6.76  and 6.01 rng/g  to
0.428.   0.310  and  1.000  mg/g,  respectively.   Between  1978  and 1981.  a
progressive  decline In  PCB levels  also generally occurred  In  zooplankton.
especially In Gammarus spp.  In samples of resident and anadromous  fish, the
pattern   of  decline  In total  PCB concentration  Is  dominated  by  the decrease
in  Aroclor 1016.   For  example. In SamMrus spp,  the mean was 1.5 ppm  In  1979
and  0.76 ppm in 1980.   During 1977-1982 In the  summer, the water PCB  concen-
trations correlated well  with the PCB concentrations In yearling pumpklnseed
collected In the  fall  at  Stlllwater.  Though  less correlated, the PCB levels
in  other  fish species and In  macrolnvertebrates are still correlated In the
upper  Hudson River.
02350                                 IV-19                          04/04/88

-------
    More  recent  work  has Implicated  PCB  contaminated  fungi  like  FusaMum
nxysporuro  as  a- route  of  exposure (mostly  in the gut) responsible  for  high
PCB  levels In  Garomarus tlqrlnus In the Hudson River (Plnkney  et  al.,  1985).
After  a period of  144 hours,  57% of the accumulated "C-Aroclor  1254  was
eliminated In  l£ vitro  experiments.   Gammarus  Is a major component  of  the
diet  of  striped  bass  (Moron*  saxatlllsl  and  Atlantic  tomcod  (Mlcroqadus
tomcod),  and also  eats mlcrozooplankton. algae and detritus.   After  exposure
to  7 ng  14C-Aroclor  1254/g  for 24 hours,  the apparent distribution coeffi-
cients   at  24 and  48  hours  were  1.3x10*  and-  1.14x10*.  respectively.
Maximum accumulation  occurred  between 9 and 24 hours.

     The presence  of  74  specific  PCB congeners  was detected (Bush et  al..
1985a.b)  in  caddis fly  larvae  from three sites  In the Hudson River, Roger's
Island. Thompson's Island and StWwater (Table  IV-4).  The data reveal that
selective  uptake  of  different congeners  by the various species  occurred.
Hvdropsvche   leonardl  appears  the  most  representative species  for  PCB
exposure   (Table   IV-5)   since the  bloaccumulatlon  factors  appeared  to be
constant  at  each  distinct site.   However,  the factors were  different at
different  sites.    PCBs 1n  striped bass  (Morone saxatlllsi have been reported
by  White  et  al.  (1985).  PCB levels In  standard  fillets Ug/g net  weight)
were  assessed  using  peak-to-neak   summation  of  representative congeners:
 40.0-44.9 cm  length.  1.1-5.8 ppm (13  fish); 45.0-49.9  cm  length.  1.3-21.3
 ppm (18  fish); 50-56 cm.  1.2-40.3 ppm (19 fish).  It Is possible  that  the
 bloaccunulatlon  of  PCB  congeners depends on bloaccumulatlon along the food
 pathway as well as at the  PCB-ln-water/flsh level.

      Lake  trout ranging  In age  from 6-12 years  from  Cayuga  Lake In Central
 New York  were examined  In 1978  (Wszolek et al.. 1979).   The levels of PCBs
  02350                                IV-20
                                                                      04/04/88

-------
                                            TABLE IV-4

                 Chlorinated Blphenyl  Congener Concentration (yg/g net weight)
                         In  Caddlsfly Larvae taken froa the Hudson River*
Roger's Island

2
2.2'
2.3'
2.4'
2.2'. 5'
2.2'. 4'
2.2'.3'+3.2'.6l
4,2'. 6'
4.4'
2.2'. 4', 6'
3.2'. 5'
3,2'. 4'
3.2'.3'+4.2'.4t
4,2'. 3'
2.5.2'. 5'
2. 4.2'. 5'
2.3.2'. 5'
2. 4.2'. 4'
CL4C
CL40
2.3.2'. 3*. 6'
2. 5,3'. 4'
2.4.3'. 4'
2. 5.2'. 4'. 5'
2.4.2'. 4'. 5'
2. 3,2'. 4'. 5'
2.5.2'. 3*. 4'
2.4.2'. 3'. 4'
2. 3,2'. 3'. 4'
2.5.2'. 3'. 5*. 6'
2.3,2'. 3'. 5'. 6f
2. 3.4,2', 3'. 6'
3.4.3'. 4'
2.3,6.2'. 3'. 4'. 6'
2.4,5.2'. 4'. 5'
2,3.4,2'. 4', 5*
3.4.2'. 3'. 4'. 6*
2.3. 4,2'. 3'. 4'
3. 4.2'. 3'. 4'. 5'
2.3.4.5.2'. 3'. 5'. 61
n. i<
HMD
.08
.03
.03
.04
.02
.06
.04
.1
.06
.1
.06
.1
.2
.4
1.2
.5
1.1
.3
.5
.6
.07
.8
.5
.2
.2
.1
.3
.2
.3
.01
.003
.05
0.
.2
0.
.2
.03
.03
.02
.02
*SI
.05
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.01
.008
.01
.03
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.02
.1
.1
.2
.5
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.5
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.1
.8
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.003
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0.
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0.
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.006
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.01
.007
CM*
HtM
.07
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.1
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.1
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0.
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.7
2.3
1.0
2.3
.7
1.4
1.8
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1.6
1.1
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.6
.4
.7
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.01
.1
.004
. .4
0.
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SE
.04
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Q.
.1
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.1
.9
.1
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.004
.03
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.08
0.
.06
.008
.00
.007
.002
THOMSON'S Island1
•£.'"» li1
.6
3.
.06
.5
1.2
.7
0.
2.0
.3
1.1
1.0
1.6
.7
2.6
7.4
1.8
12.
1.6
2.5
3.7
.5
2.6
1.6
.9
.5
.6
1.3
1.4
1.8
.3
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.4
.06
1.0
.3
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1.6
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.1
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.3
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.05
.004
.1
.06
.01
.3
.2
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0.3
.2
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.05
.1
.05
0.
.1
.2
.06
0.
.4
.09
.2
.7
.2
1.7

!l
.3
.05
.4
.5
.1
.2
.1
.1
.2
.2
.02
0.
.06
0.
.2
0.
.1
.03
.04
.004
.01
JUv*
SE
0.1
.09
.008
.02
.05
.02
0.
.04
.02
.02
0.
6.0
.05
.08
.1
.04
.07
.02
.05
.06
.02 .
.03
.05
.01
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.02
.02
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0.
.01
0.
.03
0.
.02
.006
.005
.002
.006
•05=i
Ntaii
.3
.8
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.1
.4
0.
.8
.8
1.3
3.1
.8
3.5
.6
1.2
2.0
.4
1.2
.5
.6
.5
.4
.5
.7
1.3
.2
.1
.4
.002
.7
0.
.5
.2
0.3
0.1
0.1
9 SE
.04
.04
.002
.01
.03
.07
0.
.02
.05
.03
0.
.03
.1
.05
.1
.06
.1
.03
.03
.06
.03
.03
.01
.005
.006
.009
.1
.004
.02
.01
.1
.003
.002
.1
0.
.05
0.1
.04
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0.1
5t1 1 iMtcr
P.
MMA
.004
,7
.07
.01
.08
.03
Q.
.08
.3
* w
.03
.05
.7
.06
.1
.5
.1
1.2
.1
.06
.2
.02
.2
.1
.07
.06
.07
.08
.2
.1
.01
.004
.04
.01
.2
.3
.1
.02
.03
.002
.008.
*"*
.002
01
• w •
.002
.002
.004
.007
• JrW «
o.
.004
.009
.004
.05
.2
.03
.03
.04
.01
.2
.01
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.003
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.02
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.01
.02
.03
.01
.003
.002
.01
.006
.02
.3
.006
.002
.008
.002
00002
Tot«]
H-
                      9.6    4.     22.    5.
                               Ch«ao
-------
o
rvj
U)
                                   IABII  IV S


Bloaccumulatton factors* of Hacrolnvertebrate Species  In the Hudson  River*
1 '
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in  the  flesh  of  the  12  year-old  fish  were -13 ppm relative to wet  weight,
about  the  same levels as  In aged  trout  taken  from  the same lake  In  1970.
The  PCB  resembled  Aroclor  1254 but contained  a  higher proportion  of  more
highly   chlorinated   Isomers  (higher  Cl&- and  lower  Cl4-PC8s).    The  PCB
accumulation  In  the  flesh but  not  1n  the liver Increased  with  fish age  (3
fish/age):    6 years,  4.1-4.8  ppm;   7  years,  5.2-6.1  ppm;  8 years,  7.4-8.8
ppm;  9  years.  7.5-11.7 ppm; 10 years,  S.3-11.6 ppra;  12  years, 12.8-13.5  ppm
(2  fish).

     Fish are not  the only edible  animal  known to accumulate PCBs  from  the
Hudson  River  drainage area.   PCBs  have been measured 1n the subcutaneous  fat
and breast  muscle  of 55  waterfowl collected   1n  New  York  State  along  the
Hudson  River and near  Long Island  during 1981  and 1982 (Kim et  al., 1985).
Waterfowl  have relatively  large  amounts  of  fat.  so  1t  Is  possible that  the
FDA  tolerance  level  for   domestic  poultry  (3.0  vg/q)  might  be  exceeded.
Fifty-five  waterfowl  were  examined  for  maximum  PCB  residues  1n  terms  of
ug/g wet  weight:   11  Canada  geese  (Branta  canadensls)  0.63-15  (subcuta-
neous fat),  0.05-0.33 (breast muscle), and 0.08 (1  liver);  13 mallards (Anas
platyrhynchos)  0.34-14  (subcutaneous  fat),  0.07-1.1   (breast  muscle),  and
0.23 (1  liver);  18  black  ducks  (Anas rubMpes)  0.59-20 (subcutaneous fat),
0.05-0.69   (breast  muscle),  and  0.16-0.29  (2 liver);  1  green-winged teal
 (Anas  caro11nens1s)   0.81  (subcutaneous   fat)  and 0.27 (breast  muscle);  1
 hooded  merganser  (Loohodytes  cacullatus)  124  (subcutaneous  fat)  and  6.3
 (breast  muscle);   1  shoveler  (Anas  clypeata)  8.8 (subcutaneous  fat), 0.30
 (breast  muscle), and 0.21  (liver); 5  canvasback  (Avthva vallslnerla)  0.98-13
 (subcutaneous  fat)  and  0.11-0.66  (breast  muscle);   and  4  woodduck  (Alx.
 spousa)  0.64-9.0  (subcutaneous  fat)  and 0.08-0.12  (breast  muscle).   Levels
 In  genera]  were lower  than  1n 1979 and 1980  samples.   Sex  and age  were  not
 02350                                IV-23                           04/04/88

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factors,   This confirms widespread PCS contamination  in the birds' migration
region  and  H.  points  out  the possibility  of  humans  Ingesting  PCBs while
consuming  gam* birds.

    PCBs  In  10  mussels (HytHus edu!1s|.  each from 10 sites  In Long Island
Sound,  CO, have  also  been reported  (Grelg and  Sennefelder, 1985).  The mean
maximum PCB  levels ranged  from 0.049-0.115  ppm as  wet  weight.   These are
below  the  5 ppm Hm1t set by FOA for  PCBs In fish and shellfish.

    The maximum  PCB  residues  1n 547  flnflsh  from  the Chesapeake Bay  and Its
tributaries during 1976-1980 have also been  reported {Elsenberg and Topping,
1985).   The  concentrations  In  flesh  were as  follows  (In  ppn):  In 1976, not
detected   to  0.98 (145);  In  1977, 0.030-0.51  (40);  In  1978, 0.06-4.64  (51);
In  1979,  0.01-1.60  (98);  and 1n 1980, 0.003-1.45  (24).  There  was clear
evidence   of  accumulation In fish roe  and perhaps  In  the  gonads of specific
fish  species.

     Snapping  turtles  (Chelydra serpentlna)  from the contaminated  Hackensack
Meadowlands  of  New Jersey and  an "uncontamlnated* area 1n Maryland have been
analyzed  for evidence  of PCB  residues (Albers et al.. 1986).   At the con-
taminated  sUe. mean  maxima  PCB levels  1n visceral fat were (In terms  of
ppffl  11p1d)  29U305  (8 males),  34+16  (3  females),  and 23±11  (8 males from
freshwater).   In the "uncontamlnated site,"  the concentrations  were  4U37  (7
males) and  36*81  (6  females).

     Table   IV-6  summarizes  PCB  residue  data  for   freshwater  fish  tissues
 (Schmltt  et  al.,  1985).   Residues  In freshwater  fish  (obtained by GC/MS)
appear  to  be declining  steadily from the  data  of  107 stations  operated  by

 02350                                IV-24                            04/04/88

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                                  TABLE IV-6

           PCS Residues  In Freshwater Msh  in  the United Statesa«b
                                                    Geometric Mean of PC8
                                                        Concentration
PCB Type
Aroclor 1248


Aroclor 1254


Aroclor 1260


Total PCBs


Sample Site/Years
107 U.S. stations
(freshwater)

107 U.S. stations
(freshwater)

107 U.S. stations
(freshwater)

107 U.S. stations
(freshwater)

76/77
78/79
80/81
76/77
78/79
80/81
76/77
78/79
80/81
76/77
78/79
80/81
Wet Weight
(ppm)
0.14
0.14
0.11
<3.48
0.46
0.24
0.37
0.37
0.25
0.88
G.85
0.53
Llpld Weight
(ppm)
0.6
0.8
0.8
4.3
5.0
2.1
3.4
3.6
2.6
8.3
9.6
5.4
aSource:   SchmHt et al., 1985

Between   1976 and  1981,  935  samples  were taken  representing
 1980  and 1981, 315 samples were taken  representing 48 taxa.
                           62 taxa;  In
 02350
IV-25
                                                                     04/04/88

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the  U.S.  Fish  and wildlife  Service  on  key  rivers  of the United States;  in
the  years  1976-1981  continuous  data  have  been  obtained  for  97  of  these
stations.   PCBs  have  been  reported at  94%  of  the  stations  since  1976.
Although  levels  for  Aroclors  1254  and  1260  decreased  In  1980  and  1981,
residues  for  Aroclor  1248 remained the  same.   In  1980  and  1981, the  highest
PCB  concentrations  (>2  wg/g  net yelght)  were  1n  the  Northeast   (Hudson,
Merrlmack,  Connecticut  and  Delaware  Rivers); Lakes  Michigan,  Huron,  Erie and
Ontario;  Lake  City,  Minnesota;  the  Ohio  River System  and  1n the  Cape  Fear
River,  North  Carolina.   Aroclor  1260 was  the most widespread  Aroclor,  unlike
In 1978 and 1979  when Aroclor  1254 was  more widespread.  However,  this  could
be caused by  the change  from  packed column GC technology to  caplllary-GC  In
1980  and  1981.   The  Aroclor  1248  levels Indicated  either recent Inputs  of
this  Aroclor   or  the  degradation of more  persistent  Aroclors.   Total PCB
levels  proved   to  be  more reliable  than  the  levels  of specific Aroclors  In
Intercollaboratory  studies.

     Composite   fish   samples  were  collected   during a  separate  monitoring
program  1n  1980  and  1981 fron  Great Lakes  harbors  and tributary mouths and
analyzed for   PCBs  by  GC  and  GC/HS methods (DeVault,  1985).   The  Sheboygan
River   In  Wisconsin  was  still  severely contaminated (63-98 mg  total  PCB/kg
wet  weight  as  compared with 10-750 mg/kg In  1978), mostly as Aroclors 1248
and  1254.  Moderate  PCB  pollution  (<5  pom  wet weight)  was  also found In the
Ashtabula River (OH),  the Milwaukee River (HI), the  Klnnlckklnnlc  River, and
the  Fox  River  above and below  DePere  (still  about  the  same  level,  2-21  mg
total   PCB/kg   wet  weight,  as  measured   In  1978).  Low   levels  of  PCBs
(0.40-0.66 mq  total  PCB/kg  net  weight)  were found  1n Chequamegon Bay In Lake
Superior.  PCB levels  have  also been reported 1n  fish  (<0.30  mg total  PCB/kg
wet  weight)   from  the  San  Joaquln  Valley  1n  California  1n  1981  (Salkt and

02350                                IV-26                           04/04/88

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SchmUt,   1986),   from  the  Atchafalaya  River  basin   in  Louisiana   In   1981
(Winger  and Andreasen, 1985) and Prom Lake Verret,  Plaquem1re-8rule and  East
Franklin  1n Louisiana In  1978 and 1979 (Oowd et al., 1985).

    Few  PCB  levels  1n salt  water  fish  have been reported  for U.S. waters.
Uptake   of   1*C-2,2I,4,5,5'-Cl5-CB   by  adapted  Juvenile  Atlantic  salmon
(Sal mo  salar)  1s  -3-fold more efficient from freshwater than from seawater
(Tulp  et  al.,  1979).   The generality of  this  finding  still  remains  to be
proven.

    Countries  Outside of  the United  States  and  Canada.  PCBs  were  first
detected  In  1967  1n fish and wildlife In Great Britain and the  Netherlands.
PCBs  have  been  found In  fish caught  1n  and  near  Finland 1n 1982  (Vuorlnen et
al.,  1985),  and Norway during 1972-1982 (Skare  et  al.,  1985).   Game  animals
1n  Spain  In  1982-1983  (Hernandez et al., 1985),  In  West  Germany  (Brunn et
al.,   1985)  and  1n Sweden  (VHIeneuve  et  al.,  1985) have  been  shown to
contain   high PCB  levels.   Birds and animals eating  earthworms  contaminated
with  PCBs will  accumulate  PCBs (Dlercxsens, et al., 1985).

A1r
     Information  on the  potential   inhalation exposure  to PCBs is  sparse.
Even   though  PCBs  exhibit  low  vapor  pressures  they  have  been  detected  In
ambient  air,  In   Indoor  air and  1n occupational  environments.   Samples  of
ambient  air collected using an  ethylene-glycol  Inplnger sampler  In suburban
 locations  In Florida, Mississippi and Colorado  In  1975  contained PCBs at all
 locations  (Kutz and Strassman, 1975).
 02350                                IV-27                           04/04/88

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    PCBs  were detected  In effluents from combustion  of  coal/refuse  at  Ames,
IA  at  levels  'of  2.0-10.0 ng/m«  (Harkov, 1986).   Murphy et al.  (1985)  have
also  detected  PCBs  In  Incinerator  emissions  after  burning municipal  refuse
[40±45   (n-5).   and  360   ng/raa]  ana  sewage  sludge  [2000  ng/m3  (n«2);  and
430  ng/m3  (n«2)l,  mostly as  Aroclors  1248  and  1254.   The  PCB  content  In
sanitary  landfill  gases   ranged from  37-390 ng/m» (7  samples).  Bldleman  et
al.  (1986)   separated  ambient  airborne  PCBs  Into   partlculate   and   vapor
phases.   The   levels were  1.5,  0.45,   9.3  and  0.067  ng  total   PCB/m1  at
Columbia,  SC;  Denver, CO; New Bedford,  HA (landfill); and Stockholm, Sweden.
respectively.    The  PCB  was  Identified  as  Aroclor   1254.  The  fraction  of
particulate/vapor  components  depended  on  the ambient temperature.   In  the
highly   contaminated  Hudson   River   basin.   Purple   Loosestrife   (Lythrum
sallcaMa)  absorbed  PCBs  from ambient air  containing  a  PCB concentration  of
141  ng/m»  (Bush et  al.,  1986).   When  the ambient air level was low, a  con-
taminated  plant  emitted  the most  volatile PCB congeners (e.g.,  2-chloro-  and
2,2'-dlchloro-blphenyl).   Specific  PCB  congeners  also  were  absorbed  from
PCB-contamlnated  soil  by  the  plants, and this was  the major  source  of  plant
PCB.   Levels  between 1.6 and 15  ng/m»  of 31  specific  congeners  were  found
in  ambient  air.   Cash  crops  such  as  broad bean, bean,  tomato and  cucumber
can  accumulate  PCBs from  PCB-contamlnated   soils,   and  probably  also  from
airborne  PCB (Bacd  and Gaggl, 1985).

    The  potential  presence  of PCBs  In  Indoor  air appears to  be greater  than
outdoor  air  (Benolt  et  al.,  1984;  Oatman and Roy,  1986).   Air,  whether  In
commercial. Industrial  or  residential buildings, can  contain  levels of  PCBs
at  least 1  order of magnitude higher than  outdoor levels.  The average  level
of  PCBs  (as  Aroclor  1242 plus 1254)  found outside of an Industrial  research
building  was  <0.02  yg/m»,  while  the  level Inside  was  5  times higher,
02350                                 IV-28                           04/04/88

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0.10   ug/ms-    Inside  laboratories  the  level  was  10  times   higher   than
ambient,  averaging  0.21  ug/m3.   Comparing  outside to  Inside  air  of  homes
on  the  same  day,  the   levels  were 0.004  ug/m*  and  0.31  ug/m3,  respec-
tively.   In a  room  containing a bu-ned-out  light  ballast,  PCS  levels  1n  air
were  50  times  higher than  normal  (11.6 vs. 0.2  ug/m3)  for  that  room  and
remained  elevated for several  months afterward.   Airborne  PCB  levels  In  nine
homes   ranged   from   39-580   ng/m»   with  the  higher   levels   occurring   1n
kitchens  with  pre-1972  fluorescent  lighting.   Another  source  of  PCB  emis-
sions  such  as  video   display  terminals  (VOT)  has  been reported (Benolt  et
a!.,  1984;  Olgermes  and  Astrup,  1982)  In  the foreign  literature.   Levels
ranging  from 46-81   ng/m»  were found  In  offices  containing  VOTs,  whereas
the  outside  air  levels  were 0.5-1 ng/it*.   In   three  buildings  with  PCB
transformers  In Minnesota (Oatman and  Roy,  1986)  the  air  levels of  Aroclor
1242   and   1254  ranged   from  192-881   ng/m«.   Surface  levels  ranged  from
0.05-1.47   wg/100  cma.   Four  buildings without PCB  transformers  contained
air   levels  ranging  from  78-384  ng/ra«,  and  surface  levels  of  0.05-1.00
vg/100  cm3.   In  another  building  where  Improper  Incineration  conditions
for  Askarel  had been  used,  PCB air  levels   In  31  buildings  ranged  from
0.14-3.2  yg/m»   (53   samples)  with  surface  levels   ranging  from  <0.01-4
mg/m2  (Thompson  et  al.,  1986).

     Since most  people spend 16-17 hours/day In  buildings (Chapln, 1974), the
potential  exposure  contribution from  PCBs  In  Indoor  air  becomes  Important
relative  to outdoors.   Because there  are  few  data on  PCB levels  In Indoor
air,   the  total  exposure  and  fractional  contribution  from  Indoor  air  to
exposure for  humans  remains difficult to assess.
 02350                                IV-29                           04/04/88

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    Large  exposures  In  the  occupational  environment  have  occurred  (NIOSH,
1977,  1986).   Air  levels of  Aroclor  1242  have  ranged  as  high  as 2.2 mg/m3
(Quw  et  al.,   1976).   NIOSH  has  documented  many  occupational  exposures  to
PCBs  1n  Us NIOSHTIC  data  base  durln-g PCB  production,  handling,  foundry  work
(decachloroblphenyl  Is  used  as  an  Investment casting wax),  railroad  building
and  maintenance,  capacitor  and transformer manufacturing and  maintenance.
and  handling of  older  types  of  carbonless  copy paper (3.4% PCB content).

     In   1976,   a  NIOSH  evaluation  of  the Honsanto  manufacturing  facility
revealed  PCB   levels  (Aroclors 1016, 1242 and  1254)   In the  breathing  zone
ranging  from  20-86  yg/'™*-   At  two capacitor  manufacturing  facilities  1n
1977 breathing  zone  levels ranged  from  24-1260  ng/m».   Plasma  levels  of
PCBs In  workers In a  U.S.  capacitor manufacturing facility  In 1976 ranged
from 0.03-850  ng/mt  plasma  (Wolff et  al., 1982a).   Personnel  In  a Massa-
chusetts  machine  shop  company (Chrlstlanl  et  al.,  1986) showed  PCB  serum
levels  of  2.0-20  ppb  (office males),  3.0-97  ppb  (production males)  and
1.0-8.0  ppb (office  females)  In year 1.   In year  2, the levels  were  4.8-13.0
ppb  (office males),  3.1-65  ppb (production  males), and 2.0-15.0 ppb (office
 females).   The  PCB  levels  exposing  Italian electrical workers between 1949
and  1965  varied  between 48  and   275  vg/»', «Hh  blood  PCB levels between
 41  and  1319  wg/kg  of  blood.  These  levels  were correlated  with adverse
 effects   1n  the  liver  and  chloracne   (Maronl  et al.,  1981a,b).   Similar
 effects  were  also observed In three cohorts of  Japanese  workers  (Takamatsu
 et  al.,  1985).

      Another  source of  large  exposure  to PCBs  Is  during  and after  PCB  fires
  (e.g.,  Stockholm.  1978.  1981;   Blnghamton,  New York,  1981;  Surahanmar,
  02350                                IV-30                           04/04/88

-------
Sweden,   1982;   Imatra,   Finland,  1982;  Hal Istahammar,  Sweden,  1982;  In   a
Swedish  locomotive, 1982; Skovda,  Sweden, 1982 and Klsa, Sweden, 1983).

other  Exposures
     In  addition  to  the  occupational  exposures  and  the  large  exposures
characteristic  of  PCB  fires  and  point-source  environmental  pollution, the
Yusho  and  Yu-Cheng  Incidents  In  Japan  (1968)  and Taiwan  (1979),   respec-
tively,  have  also caused  large PCB exposures  by Ingestlon  of contaminated
rice  oil  (Hsu  et  al.,  1985; Yoshlmura  and  Hayabuchl,  1985;  Chen  et  a!.,
1985;  Mlyata  et al.,  1985;  Kashlmoto et al., 1985; Kara, 1985).  In  Japan,
the  rice  oil  samples  contained 151-968 ppm  Kanechlor 400/500; Yu Cheng oil
contained  between  22  and 113  ppm  (Hlyata  et  al.,  1985).   The  congener
contents are  known along  with  the  PCQ  and PCDF  levels.   The  health  effects
are  dealt with  1n  Chapter  VI.

     PCB  residues  as  Aroclor  1260  1n Louisiana  showed PCBs  1n 1980  from  8
donors  to  range between 0.59 and 2.33 ppm Upld, and  1n  1984  from 10 donors
to   range between  0.65 and 1.96 ppm  llpld (Holt et al.,   1986).   These were
among  the  highest  concentrations  and occurrences reported by  previous U.S.
EPA  National  Human  Monitoring  Programs.   Residues  In  the breast tissue  of
females  tended to be  high.   Two hexachloroblphenyl congeners  were determined
on   autopsy In  tissues  from  seven  people who had resided on  the  Texas Gulf
Coast  (AnsaM  et  al.,  1986).  The levels for  2,2' ,4,4'  .S.S'-C^-CB  In  the
anterior  abdominal wall ranged from 98-276 ppb adipose tissue, <5-251 ppb  1n
 the   axillary  fossae,  and  109-231  ppb  In the  oaentum;  the   levels  for
 2,2',3,4,4',5  Cl.-CB   1n  the  anterior   wall   ranged  from  211-1625  ppb,
                   o
 <5-1166 In the axillae, and  221-1161 ppb In  the  omentum.   Since fat contents
 ranged  between  7.5 and 20% among the different tissues  examined,  only fat

 02350                               IV-31                           04/04/88

-------
from  the anterior  abdominal wall was analyzed In 109 cadavers.   The levels
increased   with,  age:    0-4  years.,  22+.12  and   67+03   ppb   (n=3)   of
2,2' ,4,*' ,5.5'-C16-PCB    and   2.2'.3,4.4',5'-Cl5-PCB,   respectively;   4-9
years,  30+10  and 77+25  (n-2);  10-19 years,  212+131  and  19+19 (n-3); 20-29
years,  82+17 and 146*29  (n»15);  30-39 years,  163*61 and 253+61 (n»12J; 40-49
years,  136+41  and  340+110  (n»15);  50-59  years,  154+24  and  586+130  (n»16);
60-69   years,   153+28  and  296+56  (n«24);  70-79   years,  128+17   and  296+73
(n=14);  and  80-89  years,  198+97 and  641+372  (n=5).   There  were no gender
differences In  the  60-69 year age group.   Safe has found the  burden  of  PCBs
In  human  fat  to range  between  500  and  1500  ppb (Safe,  1984).   Klrabrough
(1985)   In  a  review  has asserted  that mean  blood  PCB levels  1n  the  U.S.
population  are -5-7  ng/mi  with  adipose tissue and human milk  levels being
100-200 times  higher with PCBs  tending  to accumulate  with  Increasing  age and
Increasing  fat content  of  tissues.  Wolff  et al. (1986) has reported  that
the  PCB  pattern  1n  serum for   people  exposed  through  the  food  chain  1s
different  from  that  characteristic of  'directly  exposed  persons,' which
tends  to   resemble   Aroclor  1260,  using specific  congener markers.   Similar
PCB  residue  data   In  fat and serum  samples  have been reported  from Israel
(Pines  et  al.,  1986). Denmark  (Unger et  al., 1984);  Italy  (Focardl  et  al.,
1986) and  1n  Japan  (Ando et al.. 1986).

     Human  nllk samples  In  the  United States  can  contain high levels  of  PCBs
 (Bush  et   al.,  1985b; Safe,  1986).   In the  highly contaminated  Hudson  River
area  (Bush  et  al.,  1986),  whole  milk total  PCB from 40  samples  based on
 specific   congener   analysis was  26.5+2.5  ng/g  (standard  error)  with  the
 corresponding  internal  blood   levels  being   3.5+0.1   ng/g  (standard  error).
 The  major congeners In  74  samples  of milk were 2,2'.4,4',5,5'-hexa-CB (12%);
 2.2',3,3',5,6-hexa-CB (9.4%);   2,2' .3' .4,4' ,5-hexa-CB (7.8%);  and  2,3',4',5-

 02350                                 IV-32                           04/04/88

-------
totra-C8  (6.6X)-   The  corresponding percentages  In  maternal  blood  were  8.8,
8 07  and   not  detected,  respectively.    While   the  milk/blood  ratio   for
specific  congeners  was  between 3.5 and 10 for most congeners,  the ratio for
2,2, ,3' ,*.*' ,5-hexa-CB  was  >7500,  and  2,3,3' ,4,4' ,5-hexa-CB,  20.  Inhalation
exposure  In  the Lake Ontario  and  the  Hudson River areas may  also contribute
to  maternal  exposure (2.8^0.5  ng  PCB/re»  (n«6)  at Oswego,  NY).   Safe  et al.
(1985a)  quantHated 80  specific  congeners  of  Aroclor 1260  1n  a  human  milk
sample  and  found the 2.4.4'-tr1-CB; 2,4,4',5-tetra-CB;  2.2'.4.4',5-penta-CB;
2,3' .4.4' ,5-penta-CB;      2.2'.3.4,4'.5'-hexa-CB;     2.2',4.4',5.5'-hexa-CB;
2.2' ,3,3' .4.4' ,5'-hepU-CB;  and 2,2',3,4,4',5,S'-hepta-CB  congeners predomi-
nated,  unlike in the original formulation.

     Similar   results  (noncorrespondence  of  abundant congeners  1n human milk
 compared  with   the exposing  PCB)  have  been  found  1n  recent  studies  from
 Yugoslavia  (Krauthacker  et  al.,  1986),  Israel  (yelsenberg et al.. 1985)  and
 Japan  (Yakushjl et al.,  1978;  Ando  et al., 1985).

 Estimated  United States  Exposure
      Table   IV-7 presents  estimates of the  total  amount  of  PCBs  potentially
 received  by  an  adult  U.S.  male  from ambient  air,  food and drinking water.
 Seven  separate exposure  levels  for drinking  water and three  levels  for  air
 and food  (representing a probable  range of exposure  levels  based on the data
 presented  In  the  Exposure Estimation section)  are shown in the table.  The
 actual  contribution   of  air  exposure  Is  not  precisely  known.   Indoor  air
  levels  may  play  an  Important  role  In  exposure  with preliminary   findings
  indicating   levels  of   up  to   0.580   u9/»«   In  normal  settings   such  as
  residential  homes.   Occupational  sources and  PCB fires  may  also contribute
  :o  the  total  exposure.   The  data  presented  represent possible  exposures

  02350                                 IV-33                           04/04/88

-------
LT>

O
                           UBU l\i  I



(ttlMted Intake at PCBs fro* the US  Environment  by  Adult  Hales
lotal Intake In
food:
Drinking Water
(,,g/l> AU:
0
0.04
0.10
0.20
0.40
1.00
1.40
Intake AstiMpttons:


0.002
0.007*
0.008
0.010
0.013
0.018
0.036
0.047

0.04 v
O.I
0.2
O.S
1.0
1.4
(0)
(17)
(29)
MS)
(78)
(81)
(84)

9/t
0.
0.
0.024
0.026
0.028
0.03)
0.039
0.054
0.064
«*!?£_
0.0014
0.0029
0.0047
0.014
0.029
0 04
004
02
(0)
(M
(10)
H»)
(36)
(S4)
(62)

wQ/kq,

0.20
0.204 (0) 0
0.206 (O.I) 0
0.208 (1) 0
0.211 (3) 0
0.219 (6) 0
0.234 (12) 0
0.244 (16) 0

'day 0
0
0

itg/kg/day (X fro* drinking water

0 002
.0)2
0)3
01S
018
026
040
042
002
02
2
(0)
(10)
(19)
(32)
(44)

-------
based  on  the  occurrence data  and  the  estimated  Intakes.   The values pre-
sented  in Table  IV-7 for air and food levels  of  PCBs, as well  as  the  values
for  drinking  water  levels,  represent a  range from the  values found  In  the
PCB  monitoring data  (see Drinking Water, Air and Food Sections).   The  Intake
from  ambient  air   may   be  0.05  ug/kg/day  assuming  0.20  i»g  PCB/m3   and
time-activities  of  16 hours Indoors.  Assuming the Intermediate  food  Intake
of  0.01  wg/kg/day  and   the  Intake  of 0.02  ug/kg/day  from  air to  be  repre-
sentative, drinking  water would be  the  predominant source of PCB  exposure 1n
the  adult male  when  drinking  water levels  exceed  1.0 jig/l.   An accurate
assessment of  the number of Individuals  for which  drinking water  Is the pre-
dominant  source of  exposure cannot be  determined  from  the current data  but
H  1s  likely that persons  In  the Hudson River Valley, the  Great Lakes Region
(except  for  Lake  Superior), the Ohio Valley,  the  upper Mississippi, and the
Cape Fear River  1n  Morth Carolina  have a higher  potential  for PCB exposures
 than others.

     The  relative  source contribution data  are based on estimated  Intake and
 do  not account  for  a possible differential absorption  rate for PCBs by route
 of  exposure.   Eschenroeder et  al.  (1986)  have  estimated  the  possible expo-
 sures  and  the  resultant health risk after  PCB spills.  Since PCBs  tend  to
 penetrate down  only Into  the  first  2  cm of  soil, plants and vegetables  with
 shallow  root  systems  will  be predisposed  to PCB contamination.   As  prefer-
 ential  volatilization  of  the less chlorinated congeners also   occurs,  the
 more chlorinated congeners will bloaccumulate.

 Suamary
      The  major exposure routes  to  humans are  through food  and  drinking water,
  and by  Inhalation.  Dermal exposure Is also Important  In  occupational expo-

  02350                               IV-35                            °"04/88

-------
sures,  for sw^""61"3  In polluted waters and 1n cleaning up PCB spills  or  1n
hazardous  waste  sHes  containing  PCBs.   In  all  cases,  total  PCB  levels must
be based on specific  congener  analysis  or direct perchlorlnatlon  rather than
In  terms  of  Aroclors  because the  congener patterns  In  environmental  media
and  biological  tissues usually do  not  match  those  In Aroclor  fluids  unless
massive contamination has occurred (typical of spills and some occupational
situations).   Thus,  predictive models  based  on  specific  congener  data must
also be utilized.

     The  less  chlorinated  congeners  predominate  In air  samples  from known
contaminated  areas and  In  water  and  wet  deposition  samples with  temperature
and   the amount  of  sediment  1n river and water samples being Important co-
variables.   In  contrast,  the more highly chlorinated  Isomers  with  substUu-
ents at the 2.4,5-  or 2' ,4' t5'-pos1t1ons  tend  to bloaccumulate 1n  some crop
 vegetables,  game animals,  fish and 1n  human  tissue  samples.   PCBs  In  contam-
 inated  soils  can  be  absorbed by plants  and vegetables with  shallow-root
 systems to  PCB contamination,  although  volatilization In this  situation  Is
 also   favored;  erosion  of  such  soils  will  also  cause  contamination   of
 sediments.  The more chlorinated congeners  dominate  In  soils and sediments
 and the  resident  biota (cash crops,  vegetables,  fish,  aquatic  life).   The
 absolute  levels 1n any  situation  depend on  which of  the competing processes
 dominates as  estimated 1n  Table  IV-7.
  02350                                 IV-36                           04/04/88

-------
                         V.  HEALTH EFFECTS  IN ANIMALS

    Commercial  PCB mixtures vary 'in PCB Isomer  and  congener composition, and
Impurities.   In general, PCB mixtures produce  low  to moderate acute toxldty
1n mammalian species,  but  produce pronounced  subacute and chronic toxldty.
In  contrast.   Invertebrates  exhibit  greater  acute toxldty  to  PCBs  (LC5Qs
<1  mg/t)   (NAS,   1979).    In  addition, as  reported  for  other   halogenated
aromatic  hydrocarbons,  PCBs exhibit  significant  Interspedes variability  In
toxldty.    In   considering  the  health effects of  PCBs  In  animals,  It  1s
Important   to  consider  the 1so»er  and  congener   composition of  the  PCBs,
potential    Impurities,  the  length   of  exposure  and   the   species   under
Investigation.

Acute ToxUUy
     Representative  toxlclty  data following a single  exposure  to PCBs  are
 summarized   In   Table V-l.   Single  oral  dose   L05(Js  of  commercial  PCB
 mixtures  In rats  ranged from  1.01-11.3 g/kg bw (see  Table  V-l).  The data do
 not  establish  a  consistent relationship between  commercial  PCB  formulations
 and   reported  L05()s.   Sow   of  the variability  1n   reported  L05()s  for
 specific  PCB  mixtures  has been  related  to   differences  In  the observation
 period,  strain and solute concentrations. There appears  to be no significant
 sex  differences  1n the acute toxldty for  the PCB mixtures studied;  however,
 Aroclor  1254  was found  to  be slightly  more toxic  to  immature than  mature
 rats (Llnder  et  al, 1974; Grant and Phillips  1974).
  02360                                V-l                            °4/04/9S

-------
                                                                            lAblt  VI

                                                                     Atute  loxUtty  ol PCHs
                                                                        (single exposure)
o:
CT
C
          Species/ ^
          Strain
Sex/No.
Source at KB
                                Houte
                                                                                     nts
                                                                                                                Heterence
        Guinea
        Hartley
        tiutnea  pig/
        NK
        Hal/Wtslar
                         tut
                         MH/M
 i
re
        Hat/Sh*r«an
M/42

1/4?

NX 4^

»/42


1/60 80
        Ral/Sprague-
        Uawley
        Rat/Ulstar
 o
 tr
 o
 tr
N/NR
I/NH
N/NR
f/NR
            3.4.5 sy«.
            hem LH
            NH; ~4» II
                                     Aroclor
                                                         oral
                                                         oral
                                                         oral
                                     Aroclor 1244
                                 l.v.
            Kanechlor  400
            Kanechlor-400
            Kaneihlor  300
            Kanechlor  300
                    oral
                    oral
                    oral
                    oral
                               I 39 i«ol/k<| bw
                               (U •) ag/ky)
                               1.3 g/kg bw
                               (30 days old)
                               1.4 g/kg bw
                               (30 days old)
                               1.4 g/kg bw
                               (bO days old)
                               1.4 g/kg bw
                               (bO days old)
                               1.0 g/kg bw
                               (120 days old)
                               ?.S g/kg bw
                               (120 days old)

                               3S8 «g/kg bw
NR/60-HO
N/60 HO
N/60-aO
N/NR
Aroclor 1264
Aroclor I2b0
Aroclor 1264
Aroclor 1260
Aroclor 1242
oral
oral
oral
oral
gavage
4 10 g/kg bw
l.29i g/kg bw
1 .314 g/kg bw
4.26 g/kg bw
1.30 M/kg bw
1.14 M/kg bw
1.16 g/kg bw
1.06 g/kg bw
                                                                  Single dose
                                                                  Half ot the anlMls died wllhtn JO
                                                                  days (10SO)

                                                                  Iwo bl mq dotes / days apart
                                                                  Mortal Ity II 29 days; ctntrl lobular
                                                                  liver necrosis and fatty Infiltration

                                                                  Single doses
                                                                  iNMturt seeoed «ore susceptible
                                                                  than older rals. sex did not see* to
                                                                  to be a factor; Majority died within
                                                                  3 days
                                                                HcConnell and
                                                                tUKInney. IS/H


                                                                Nlller. 1944
                                                                                                           Urant and Hhllllps,
                                                                                                           1914
                                                                  Adult; single dose;  death  In  b  110
                                                                  •In; dyspnea, depression,  salivation.
                                                                  diarrhea
                                                                  Adults,  single dose

                                                                  Uvanllngs.  single dose:  diarrhea.
                                                                  depression,  salivation,  death 1-3 days
                                                                  Weanlings:  diarrhea,  depreiilon.
                                                                  salivation,  death 1  > days

                                                                  14 day ID.,0
                                                               Under  el  a>..  19/4
Bruckner et a I.,

et ai.. 19)8

Motor augh et al.
19 /«

-------
                                                                         I ABU VI (conl.)
o
ro
to
Species/
Strain
                         Sex/No.
Source of PCS
Route
CoMMents
Reference
Hdt/NR






Rat/SherMn

Rat/Osborne-
Nendel

Rabbtt/NR






Rabbits
NIce/CH

NIce/CH
Ntce/dd
NK






(/NR

N/NR
M/NR
N/NR







NR
N/NR

f/NR
f/NR
Aroclor l??l
Aroclor 123?
Aroclor 1?4?
Aroclor 1248
Aroclor 1260
Aroclor 1262
Aroclor 1268
Aroclor 1221
Aroclor 1262
Aroclor 1254
Aroclor 1254
Aroclor 1254
Aroclor 1221
Aroclor 1232
Aroclor 1242
Aroclor 1248
Aroclor 1260
Aroclor 1262
Aroclor 1268
NR
Kanechlor 400

Kanechlor 400
2'. 4' dl-CB
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
derMl
dec M)
derMl
derMl
derMl
derMl
derMl
NR
oral

oral
oral
3.90 
-------
                                                                        I ABU  V-)  (tool  )
Spec les/
Strain
NUe/CBA
Nlre/AlAS
NIce/BAlB/CJ
Ntte/CSf
•ajiltulatus*
Nlnk /Pastel
Sex /No.
NR
NR
NR
NR
NR
NR/81
Source
Aroclor
Aroclor
Aroclor
Aroclor
Aroclor
of PCB
1264
l?54
1264
1264
12S4
Route
l.p.
Ip.
IP
IP
IP
Aroclor 1221. gavage
1242. 1264
eao
1200
IOBO
1000
9)0
600
..so
Mj/kg bw
•g/kg bw
»,.Kg bw
•g/kg bw
•g/kg bw
4000 «g/kg bw

6
&
6
6
6

day
day
day
day
day
Single
COM
observation
observation
observation
observation
observation
doses
ten Is
per tod
per lod
period
period
per 1 od

Referee
lewln et al . ,




Auler Ich and
Ringer. 19/7
       •f leld aouse
       NR  . Not  reported
cx>

-------
    LD5Q   values  from  dermal  application  of  commercial  PCB  mixtures   In
rabbits  ranged'from  0.794-3.169 g/kg (see Table V-l).   There was  no  associa-
tion  of  degree  of   toxlclty  with  chlorine  content.   In  addition,  the data
suggest  that  PCBs are  readily  absorbed  following dermal exposure,  although
no  comparative  data are  available  on  toxlclty in  rabbits  following oral
exposure.    Several   reviews  (Peakall,  1972;  Nelson  et  al.,  1972; Flshbeln,
1974;  Klmbrough,  1974;  NIOSH,  1977;   Klmbrough  et al.,  1978;  McConnell,
1980a)  report  both  L05Q data and a  further  discussion  of  the ac .te toxic
effects  of PCBs.

    As  mentioned previously, the toxlclty of PCB mixtures  can vary  because
of  a  number  of  factors.  Including the  content  of specific  congeners  and
Isomers.    Klmbrough  et  al.  (1978)  reported  Increased  toxlclty  1n mice
exposed   to  PCB  congeners  containing  greater  chlorine  substitution.  The
structural  requirements for biological  activity (AHH Induction) and  toxlclty
of  this class  of compounds has been recently reviewed  (Poland and  Knutson,
1982).   One  of the  structure requirements for AHH Induction,  and  apparently
toxlclty,   1s an unsubstHuted carbon atom In the ortho position.  These PCB
congeners   produce biologic and toxic activities related  to that  produced  by
chlorinated   dlbenzodloxlns  and   dlbenzofurans.    3,3',4,4'-tetra-CB  and
3,3',4,4',5.5'-hexa-CB    {Blocca   et   al.,   1976;   NcKlnney,   1976)  and
3,3',4,4',5-penta-CB (Safe, 1984)  are highly toxic.  The 3,3',4,4'-tetra-CB
1s  found  1n cownerdal  PCB mixtures  (Albro and Parker, 1979).

Subchronlc  Toxlcltv
     Multiple   exposure   studies  are  summarized  by species  and  route   of
exposure  1n Tables  V-2  to V-5.   As  with acute toxlclty, attention  must  be
given  to   the  type   of  PCB, species, and the route  of  exposure  employed  in

02360                                 V-5                             04/07/88

-------
                                  I ABIE V 2

Acute. Short tera and Subihruntc loiUUy of Orally Administered PCBs to Bats
o
fSi
CJ
er
o Sl/aln
Spr ague
Dawley
Spr ague
Dawley
Ho It /man
f 1st her
Spr ague -
Dawley
o» Utstar
HI star
long -[vans

Sr«/Ni>.
f/56
N/16
1/25
ft/42
N/12-16
f/40
ft f/144
ft/ 124.
1/24

Weigh I/ Age
200 300 g
250 300 9
sexually
mature
weanlings
200 250 g/
7 weeks
1 year
30. 60 or
120 days
4 weeks

Source of PCBs/Vehlc le
Aroclor 1244/dtel
Aroclor 1244/corn oil
Aroclor 124 4 /pea nut
•11
Aroclor 1254/dtel
Aroclor 1244/mtneral
oil
Aroclor 1254/corn oil
Aroclor 1244/corn oil
2.4,2',4' tetra Cl/
corn oil

Dose/Duration
0 900 ppm
for 10 days
50 mg/kg bw
for 7 days
0 64 mg/kg day
for ) days
0. 71. 1)1. 347. 421.
700. 1400 ppm for
14 days
0. 0.04. 0.24. 0.4
t/kg bw dally for
21 days
0. 12.5. 25.0. 50.
100. 400. 800 mg/kg
bw dally for 7 days
0. 5. 10. 20 mg/kg
bw/day for 7 days
0. 0.5. 1.0. 1.5.
2.0 g/kg bw. single

Animal Effects
>300 ppm: weight loss. Dei reaped
placenlal protein, glycogen, partial
anorexia.
Increased acid phosphatase in testl
cular Interstitial cellt.
64 mg/kg/day: Increased liver weight.
Depressed rate of gain, food Intake;
Increased liver weight.
>0.04 g/kg bw/day: decreased rate of
gain to frank weight loss; depressed
feed Intake; depressed water Intake;
depressed body temperature.
>400 mg/kg: mortality; >100 mg/kg:
Increased liver fat percent (p<0.05).
All doses: Increased liver weight
|p<0.05).
All doses: Increased liver weights.
Increased aniline hydroiylase activity.
>I.O g/kg: heavy mortality; thymlc
hemorrhage; atrophy; liver and kidney

Herer em es
Spencer, 19B2
Otkshlth et al
19)4
Sager. 1963
Carter and
fiercer. 1983
Komlves. 19)9;
Kumlves and
Alayoku. 1980
Grant and
Phillips. 19)4
Grant and
Phillips, 19)4
Allen et al..
19)5
                          dose


0
o
~J
^
CD
Hooded
Spr ague
Dawley
Spr ague -
Oawley


H/N* 1BO-200 g Aroclor 1244/dlet
l/fc 200 240 g *H labeled
2.5.2'.4'-tetra-Ca/
corn oil
f/24. 300 g Phenoclor DPt/dtet
N/24


240 ppm for 14 days
0. 1.7 g/kg bw.
single dose i
i
i
0. 100 ppm for 8 days 1
i
1
1

enlargement; splenic and lymph node
regression.

Increased thyroid activity.

Intracellular vacuolltatlon; veslcula
lion, fragMniallon of •!», enlarged,
varlfled cytoplasm; altered mltothon-
drlai conformation; AlPase Inhibition.

Decreased phenobarbltal sleeping lime.
Increased liver weight and protein con-
tent; males more greatly arfeiled than
females.
                                                                                             Bastomsky, 19/4

                                                                                             I In el al.. 19)9




                                                                                             Narbonne, 19)9

-------
                                                                            lAbl I  V I (lont )
O
r\>
CJ
CT»
O
Strain
Sex/«o    Weight/Aye   Source of PCfls/VehIc le
            Sprague      N.I/4H
            Day ley
                       adult and    Phenotlor OPb/dtel
                       34 days
                                                                Dose/Outat Ion
                                               13 p|M adult
                                               ?4 pp« young
                                               tor B days
                                    AnlMl (freili                    References
                        liver weight elevated equally In both      Narbonne,  IS/9
                        sexes; elevated liver protein and rat
                        •ore noticeable In adults.
            I !•. (her
            CO
                         H/SO
             m/
             yroup
            Long tvans    H/12
                       34 days      Aroclor l2S4/dlet
                       4 mono It/
                       cottonseed ot I
                       130 g
                                                Aroclor 1246/dlet
0. ?0 i>i*» for I, 2.
4. B, or 14 days

30 »g/kg bWday on
days B. I). 13, IS.
18 ot pregnancy

0 or 100 ppa for
4 weeks
Hepatomegaly by day 4.
[ levated Intestinal •onoaatne oxtdase.
serun sorbHol dehydrogenase and
alkaline phosphatase.

Hepatomegaly (4 4bX of by), obvious
increase In SIR.
                                                                                                                  Carter. 1983
                                           Uolden et al..
                                           1982
                                                                                                                  Allen et al..
                                                2.5,2'.S' letr* CB
                                                                                    HepatoMgaly  (3.3M of by), less
                                                                                    obvious  Increase  In SlH.
            WtsUr
            Osborne-
            Mende)
            bunn
            Osborne-
            Nende1
             N.f/3a    MR
                                                Aroclor )2S4/dtet
             H/b/
             group
             H/12/
             group

             H/NR
          B weeks      Aroclor 1244/dlel




          300-400 g    Aroclor l?S4/dlet


          8 weeks      Aroclor 1254/dlet
                                               1000 pp« for 14 or
                                               30 days
0. S. SO. SOO pp«
for 4 weeks
SOO ppa for 4? days
0. SO. SOO ppa for
4 or 1? weeks
At >I4 days. 30  >2» reduction In rate      HI Ing el al..
of gain; at 30 days. ?9X reduction In      I9f8
food  Intake; no  change In liver weight.
Altered cholesterol, fatty acid syn-
thesis.

>S ppa: enlarged thyroid, reduced          Collins and
follicle size, folllcular lu«en            Capen. )9BOb
reduced, papillary projections and
cytoplas«lc projections,  diluted RtR.

Ihyrold folllcular  cells  More toluwiar.     Collins  and
diluted HEM, vatuola led Mitochondria.       Capen,  )9BOd

>SO pp«. by 4 weeks: enlarged              Collins  et  al.
thyroid, folllcular cells more             191)
columnar,  vacuoled  cyloplasa,  papillary
projections, cyloplas«lc  processes.
Dilated RIB. Golgl  apparatus  «ore pro*
tnenl. larger  nuober  of enlarged lyso-
so«es.  Reduced seriw thyroxln;  after
36 -week recovery  period Ihyiolds re
seahle those of controls, serun thy
roxln nor«a).
 O

 •v»
 O
 oo
 CB

-------
                                                                             IABH V 2 (tont )
o
             Strain
Sex/Mo.    Height/Aye    Source of PCBs/VehUle      Dose/DuralIon
                                                                          Animal  tffecli
                                                                                                                                                Hefeiencev
             Sprague      N/40
             Daw ley
            Ho It/«an     N/t  Ik/
                         groups
           100  130 g     Kanethlor  SOO/iMel      100 ppa for 4 weeks
          2SO g
             Aroclor 12S4/dlet
                        0. S. SO or  SOO pp*
                        for 2. 3 or  S weeks
            Sprague-
            Dawley
N/10/
group
weanlings
Aroclor 1254 or
diet
                                                                 )?MX
0 or 20 pp» for
28 days
             Mtstar/      H/10/
             Neither berg   group
           100 g
             Clophen A SO/ollve
             oil
                        0. ?, 10. SO. ISO or
                        ?SO «g/kg bw. twice
                        weekly for k weeks
o
•^
v.
O
             tut
N/IO
                                      Months
             •PCBs IZZIVethyl
             alcohol
                        ?SO «9/i In drink
                        Ing wdter for 10
                        weeks
 No effect on food Intake,  water  Intake.    OUM el al ,
 urinary volume.   Slightly  enlarged         19/8
 brain, spleen and liver.   Heaatologtc
 values unchanged.  Serua protein,
 cho)etl«>ro). chollneslerase elevated;
 seru* trlglycerlde reduced

 SOO ppa:  weight  lost.                       Garlhoff el al .
 >S PPM:  hepatomegaly.                       I9/?
 SOO ppa:  slightly Increased slie of
 kidney,  testes;  decreased  adipose.
 SO SOU ppa:  liver - Increased content
 of fat;  decreased protein.  RNA.  DMA.
 SO SOO ppa:  blood - glucose reduced.
 •UN.  cholesterol, protein  Increased.
 S ppa: awlnopyrlne deaethylase activ-
 ity Increased.   SO SOO pp«:  p-nltro-
 benioate  reductase. pentobarbltal
 hydroiylase  activity Increased.

 No effect  on food Intake, weight gain or    Chu el  al..  H//
 liver  site.   Moderate  liver  lobular pat-
 tern with  pertportal perlnuclear halos
 and per I venous cyloplasatc ballooning;
 anlsokaryosls. Moderate falty  liver
 degenerations.   Ihyrold changes  (see
 Collins et al..  1977).  Reduced  SGOt;
 Induced Mined function oxldases.

 >SO ag/kg: decreased bw; slightly In-      Baunann et al..
 creased food  Intake; Increased liver       1983
 weight.
 >1SO *g/kg: elevated SGOT.  SGPT.
 >SO «g/kg: Increased seru* btllrubln.
 protein, trlglycerIdes; Increased urin-
 ary porphyrln precursors.
 >2 «g/kg:  Increased seru* cholesterol;
 hepallr coagulation focal  necrosis. PMN
 Infiltration, fatty degeneration.
 enlarged (functional) nucleoll.

f levated plaiM cortlcoslerone; hyper       Kasseraan
activity of tona  fasclculata of adrenal     et  al..  19/3
cortex.
CO
CD

-------
                                                                              IAHII V 2 (cent
co
er
o
Stialn       Sex/No.   Melght/Acje   Source of PCBs/Vehkle      Dose/Duration
                                                                                                              AntMl  tfteiti
                                                                                                                                   Heferentes
Sprague
Daw ley
                          N/NN
                       100 g
Aroclor I,'48. I?S4 or   0 or 1000 pp* up to
l?60/dle(                6 weeks
Ulstar
                          f/8
                       112 130 g    Phenoclor 006/dtel
             Sprague-
             Dawley
             Holt**an
             N.f/4/
             group
             N/30
                                    NR
                                    Ctophen A SO/ollve
                                    oil
                                    Aroclor l?54/dlet
             Ho It man     N/30
                        NR
                                    Aroclor l?S4/dtet
o

o
 CD
 00
             NH . NoI reported
                        ?000 fftm up to
                        Sb days
                        0 or 100
                        1 ttM/w*ek for ?
                        weeks
                        0. •>, SO. SOO
                        for 5 weeks
                        0.  4.  SO or 500 pp*
                        for 6  weeks
 Reduced  rate  of  gain:  Aroclor  1248 >       Allen and
 I?M  >  I?b0.  Moderate elevation of Hb,    Abrahamon.
 CIV   Relative neulrophllla.  ly^iho
 cytopenta.  (nlarged  llvei. decreased
 thyMus,  fatty liver degenerations,
 cystic areas  and focal necrosis with
 Infiltration  of  inflaoMtory  cells.  IR
 proliferation, veslculatIon of 8(8,
 Increased nunber of lyso/y«es.  In-
 creased  hepatic  protein,  RNA.  phospho-
 llpld; decreased DMA.  cholesterol.  In
 duclton  of  N  deaethylase, nllroreductase.
                                                                                                                                                         H/l
 >3 weeks.  UV  fluorescence of  Incisors.
 s*all  Intestine  (porphyrta).  Hepatic
 enlargement with centrDobular degenera-
 tion.   Splenic degeneration with dis-
 appearance of while pulp, reduction In
 red pulp, evidence at  slderosls.

 N: Increased  liver percent of bw fro*
 ? fc :!.:«.  Pretence of AlPase deficient
 Islands,  f:  Increased liver percent of
 bw fro* 2.9-3.6X.  Greater presence of
 Alfase  deficient Islands.

 >SO ppa: hepatoaegaly. fatly degenera-
 tion, hepatocellular hypertrophy and
 cytoplasalc vacuolltattun.
 >S pp«: enlarged SIR; decreased number
 of Bltochondr la, lysosows;  Increased
 Golgl apparatus.
 >bO pp«: Golgl apparatus  decreased.
>5 ppa: enlarged thyroid,  reduction  In      Kas/a  et  al.
folltcular slie. hyperplastlc  cells  with    19)8a
papillae and cytoplasslc  processes ex
tending Into luaenal colloid;  folltcular
cells More columnar. •Itochondrla vacuo
lated with disrupted crlstae,  accuMila
tlon of colloid, Increased nuober of
lysosones.
Vos  and Koe«an,
19/0
Oe«l and
Oeslerle.
Kas/a et al.
19/Bb

-------
                                  TABU  V 3



Acute. Short term and Suttchronlc loxtclty of Orally Administered PCBs  to Nice
o
rvi
CO
O*
° Strain Sex/Mo.
NHJil f/llb

NMtl f/108


HHRI f/4S


CD 1 M/fc/group


CD-I f/NR


i
0 CBH l/IO/group

ICR M/S/group





CD 1 H/9/group


Swiss N/IO/group
Albino




o
•V
O
—J
00
00

Weight /Age Source of PCBs
sexually 2.4'.S Irl CB
mature
sexually 2. 2'. 4. 4'. 5. 5'-
mature hexa-CI

sexually Clophen AM)
mature

19-24 g Aroclor 12S4


»0-«0 days 3.3' .4.4' .S.S' -
hexa-CB


12 weeks 2.2' .4.4' .S.S' -
hcia -Cl
adult Aroclor 12S4





2S-2* g Aroclor 12S4


23 4J g 2.4.S.2'.4'.S'
hexa CB











Vehicle
peanut oil

peanut oil


peanut oil


tmulphor :
sallne(l :8)

cottonseed
oil


peanut oil

diet





[mulphor :
sa1lne(l:8)

peanut oil












Dose/Duration
0. O.OS. O.S
mg/day
0. 0 OS. O.S
mg/day for
b days
0 or 0.02S mg/
mouse dally for
b2 days
0. 10. 30. 100.
2SO or SOO mg/kg
bw, single dose
0-lb mg/kg/day
for 10 days


0. O.S mg/day
for 1 or 13 days
0. b2.S. 2SO.
1000 or 4000
ppm for 14
days


0, 30 or 100
mg/kg bw/day
for 14 days
0. 200. SOO.
1000 mg/kg
bw/day for
28 days









Animal iffects
O.SO mg/day: Increased cytochrome P 4SO

>0 OS mg/day: Increased cylochrome P 4SO
(p8 mg/kg/day: decreased weight gain.
lethargy, vaginal bleeding of pregnant
females

Increased liver weights; reduced sensi-
tivity to stressful stimuli (moving)
4000 ppm: total mortality by day 1.
1000 ppm: death of 3/S by day IS.
2SO ppm: hepatomegaly, depressed food
Intake, decreased pentobarbltal sleeping
time.
b2.S pom: elevated serum cortlcosterone.
Prolonged penlobarbttal -Induced sleep
time at both doses.

No significant effect on body weight.
food or water Intake. fecal or urinary
output. 1000 mg/kg: decreased kidney
weight; SOO mg/kg: Increased liver
weight. Brain, testes, spleen; no
change. PCV: no change. Hepatocytes:
enlarged cytoplasn and nuclei; fatly
Infiltration, reduced glycogen. In-
creased StH; ?00 *y/kg: Increased
lyiosomet. mitochondria. RIR. No
deficits In neuronusi ular coordination.


Reterem e
Orbery. 19)8




Or berg and
Kthlstrom.
19/3
Rosin and
Martin. 1981

Narks et al.
1981


Hat tsion
et al.. 1981
Sanders
el al.. 19/4




Rosin and
Nartln. 1983

Carter and
Cameron. I9//











-------
                                                                             IAHU  V  3  (cunt  )
o
*J
O>
O
Weight/Aye
                 Source  at
                                       Vi'hlc It-
                                      Dose/Duration
                                 Animal ttrei
                                                                                                             lowest exposure (ppM) to cause:
                                                                    He I ec em e
                                                                                                        tnlarqed
                                                                                                         (Iyer
                                                                                         Hedui ed
                                                                                          Spleen
                                                                                         1m i eased
                                                                                          lestts
                                                                  Btocia  et al
                                                                  nut
     ISJBI/6J    H/Vgroup
IB ?0 «.
4 weeks
3.4.4 syM  hexa CD
2,4.6 syM  hexa CB
?,4.S iya  hena Cl.
2,3> »»•  h«»a C8
                                                                      diet
0. 03. t. 3.
10 or 30 pp»
diet lor 28 days
0. 10. 30, 100
or 300 p|M
dtet for 28 days
     BAIB/tJ     «/  IJ/group     18 20 g
               Aroclor  124?
                                                                      dtet
                                     0 or  \bl ppm
                                     for b weeks
o
4»
>v
O
.03
 100
.  30
.  NR
                                                                                                        300
                                                                                                         3.4.4
                                                                                                         2.4.6
                                                                                                         2.4.6
                                                                                                         2.3.6
    10
   300
   300
    NR

tevell tn
 Adipose
   10
   NR
   NR
   NR

levels In
                                                                                          4329
                                                                                          1923
                                                                                           ?BO
                                                                                           1344
                                                                                           1022
                                                                                            631
                                                                                             i2
                                                                                                        30 ppa 3.4.S hena CB depressed serua pro
                                                                                                        letn. caused UV fluorescence of liver.
                                                                                                        teeth, sternua.  ilver.  10pp«3.4.4
                                                                                                        h«Ma CB caused liver *tcroabscesses to severe
                                                                                                        fatty degeneration and necrosis at 30 pp«
                                                                                                        Other tsoaers: sa«e lestons at 300 ppa
                                                                                                        IhyMis:  3.0 ppa 3.4.S he«a CB caused
                                                                                                        •oderate to Barked Involution at  30 ppa;
                                                                                                        300 pp« 2.4.6 he«a CB caused Barked Invulu
                                                                                                        tton; 300 ppa 2.3,6 hexa CB caused sllyhl
                                                                                                        Involution   Spleen:  3.0 30 pp* 3.4.S
                                                                                                        hena CB.  300 pp« 2.4,6 he«a CB caused
                                                                                                        •oderale depletion of  lymphocytes.   3,4,!>
                                                                                                        he>a CB:  enlarged speraalaqonta.   2.4.6
                                                                                                        hexa CB:  cardlo»yupalhy  and passive con
                                                                                                        yestlon  of liver,  lung
                    Increased |p<0 04)  Mortality  caused by
                    ^'•ynella (yphpsd  endotoxln  at  6  weeks.
                    Increased |p<0 OS)  Mortality  caused by
                    ?i'!9°
-------
                                                                             I ABU  V 3 (cont )
CO
o>
      Stialn
     BAiB/lJ
                    St-x/No
«/  li/gtoup     10  ?0
                                                 Source of CtBv
                                               Aroclor 124?
                                                      VehU le      0'i  fold reduction  In prlury and seiuiid
ary splenU plaque tor«lny cells In
response  to sheep  HBC, decreased serua
iMMjnoylobulln.  Decreased Metwry cell
function  and seru* lyA when iMuntied
with  sheep HBC  3 weeks before b week
exposure  to Aroclor  )?4<'.

Increased (p<0.0?>) Mortality caused by  S.
ilphosa endotoxln.   (Mo difference be
tween Aroclor  lOlb or 1242.)  Increased
(p<0 OS)  Mortality caused by p.  berjhet at
3 weeks.  (No difference between Aroclor
I (lib or 1242.)  No htstopalhologtcal
changes In lung, IhyMus. Mesenterlc lyaph
nodes, spleen.  Hlstopatholoylcal exa« of
Mver revealed hepatocytlc hyperplasla.

Splenic cells fro* treated «lce  Injected
Into neonates elicited greater  graft vs.
host response.  Indicating Arotlor  lOlb
May act Wat e donor lyMphocytes.

PCI residues (pp« adtposa) I.I.  109.
399.  1330, 3/bO respectively at  3 weeks.
No decreased food  Intake or  other  signs
of toitclty except usual hepalocellular
alterations.

At 4* days post Inoculation with  live
SalMonella !u»hl««urJUM,  treated  Mice  had
greater  nwttSers of  live  organises  In
liver and blood.

Apparently dose-related  Increase In Mor
tallly due to S.  ilfihlSSirlas endotoxtn.

Depressed  feed  Intake, hepatomegaly
                                                Heterenie
                                                                 loose el a I
                                                                 SI Ikworlh and
                                                                 loose,
                                                                        and
                                                                 Hlnsdlll. ttlti
                                                                 lanlMura
                                                                 et dl ,  ISHO
 O
 .»»
 •^
 O
      HN -  Nut reported
 CD
 00

-------
                                        TABH  V 4



Acute. Short tar* and Subchronlr loilclly of PCBs Administered by Routes Other  than  Oral
o
0 Species/
Route Strain Sex/Mo.
s c Guinea pig/ MR/S4
MR
sc. Guinea pig/ MR/10
MR
si Rat/MR Ml/30
s.c. Rabbit /MR MR/3
MR/ 3
7- Derail Guinea pig/ MR/11
" MR
NR/lfc
s c Nlce/ddV f/NR
l.p. Rat/MR M/NR
Inhalation Rat/NR H/S. I/&
O
0
00
00

Source of
Weight /Age PC 8s Vehicle
MR NR; 4«C Cl None
MR MR; ~4» Cl Mineral
oil
MR MR; -4?X Cl Hone
MR NR; -42» Cl None
MR NR; -4» Cl Mineral
oil
NR MR; ~4» Cl None
NR NR; -4W Cl Mineral
oil
IB weeks Kanechlor HO IMt
elhanol -
NR Aroclor 1244 NR
NR Decachloro NA
blphenyl




Dote/Dura (Ion
69 690 aq.
single dose
345 «g.
single dose
M or MO my.
single dose
MO or IJBO *g.
single dose
34S or MO *g.
tingle dose
34. S *g/day
for 11 days
3.S 11 «g/day
for I or 15
days
0-10 *g/day
for 10 days
100 *g/kg/
day for »
days
2.S4 g/»*
for 6 hours




Aftltul iffecls Referenu-s
local Injection necrosis to fibrous Miller. ISM
encapsulation. Hepatic: cenlr llobular
necrosis, atrophy, tatty Infiltration.
splenic iynphold hyperplasla. pulmonary
congestion, •orlallty.
As above; complete wirtallty 13 days;
pulmonary congestion mart severe
fatly liver degeneration; splenic
hypertrophy; local Injection fibrous
encapsulation
Death In 14-7? days (as above, except
Itver contained fine droplets of fat).
Death In 4? 3bO days (as above, except
liver contained fine droplets of fat).
Death within 21 days. (Derm*) epllhe
Hal destruction, teslons In Internal
organs as above. )
Killed ? days after last dose: Uatanabe and
Mortality >4 ag/day Sugahard.
1981
Aatnolevullnlc acid (At A) synlhetase
activity Increased. AIA dehydralase
activity decreased. •lcroso«al he*e
and cytochroae f 450 Increased
Blinking and ineeilng. reversible; Bertiy
14 day observation, no effects on el al . 14/4
appetite or growth. Gross pathology.
no lesions.




-------
lAllt  V 4 |cont  )
o
CJ
o
















1
a*














o
o
CO
CD

Spec lei/
Route Strain Sex /Ho
Inhalation Ral/HR HR/4




Inhalation Rat/HR HI/3


l.p. Ral/UtsUr N/l
Uoodlyn




l.p. Rat/Wtstar N/NR


l.p. Ral/long N/NR
Ivans

t.p. Rat/Sprague It/24
Bawley

t.p. Rat/Spragu*- N/NR
Bawley

l.p. Rat/Sprauue N/NR
Bawley









Source of
Uetght/Age PCBv Vehicle
Solvol HA




Solvol HA


young pur* extno .
dl . telra-.
heia-. octa CIs
pur* e»*o ,
dl-. lelra-
tsoMrs of Kit
young Aroclor IOI». Peanut
1221. 12)2. oil
1242. 1241.
I2S4. t?M
3 weeks Aroclor I2S4 Com oil
or 21 purl-
fled tsaaeri
adult Aroclor I2S4 Corn oil
,

1&0-200 g Aroclor I2&4 Rtng*r'i
solution

100-120 g Aroclor I2S4 HR











Dove/Our at ton
10 g/««
for 3 hour i



04 «/••
for II
exposures
SO *g/kg bw
dally for 1
days
100 Mi/kg bw
dally for I
days
SO M/kg/
day for 3
days

SOO i^Ml/fcfl
bw 1 Itew

Control, corn
oil. or
1 g/kg bw
0. 2i. SO
•g/kg

100 ag/kg/day
for 4 dayi

100 ag/kg
once weekly
for » weeks






Anlovil llretti
All uncoordinated, coeuloie, dead U
24 hours. Hvpallt necrosis, tally
Infiltration, renal lubulet cloudy
swelling. Heart and spleen congested.
splenic necrosis.
I death, necropsy tleillar to above.
signs less marked. Hyperplasla ol
Kupfer cells.
Hepatocyttc proliferation of SIR.
changes In RIR. focal necrosis.
cytoplasatc vacuoltiallon.
Nor* pronounced hepatic changes;
fatly Infiltration, cenlr 1 lobular
necrosis, biliary proliferation.
Induction of aany hepatic eniynws.


Increased liver weight, decreased
thy»tc weight; Induction of various
cytochroae f 4iOs
•typical* liver lesions; no effect
on plaseta corltcoslerone

HepatoMegaly, elevated cytochroew
P 4SO. various hepatic eniye* systems
Induced or Inhibited.
f levaled AIA synthelase. •Icrosoetal
heew. cyloihroae P t40. Depressed AIA
dehydration.
f levaled total porphyrlns. •tcrosomal
he**, cylochroew P-4SO. Depressed AIA
dehydration, ferioihelatase.






Referent e\
Ruianova,
1)43






Hansel! and
tiobtchon.
DM



Icubtchon.


Parkinson.
el al .
l«H3a
Dunn el a 1 . .
19V]

Hlnlun
el al . I9(U

Alvares and
Kappas. 19/1









-------
                                                                                TABU V  4  (cool  )
o
ro
CJ
0*
o
loule
        IP
        t.p.
I

LTt
        t  P.
Spec lei/ Sour ic of
Strain Sei/Ho Weight /Age Ptli VehUU Dose/Ouratton
JUI/Sprague a/13 Ml Aroclor 124? Peanut 100 wj/kg few
Daw ley "II (wtit weekly
for k weeks,
out* weekly
for an add)
1 tonal «
weeks
lal/Sprague H/24 200 MO g Aroclor 1242 Peanut 0. 1. S. 2S,
Mwley otl SO or 100
••/kg bw.
N/»/tre4ied NK Aroclor 124? PeAnut tln«le 4o»e
9TMi». V all 0 or 100 «fl/kg
control few. tlofle eote
f/OMO
l«l/WtiUr N/IM 2SO f CloplMn A SO Com oil 0 or 100 o>g/
kg bw. tln«U
eo t* 4 weeks
ootcrvJllo*
An\«ul (ffeiii
lady weight luiv. hepii U •lUiunil
tudanophlltc vjcuollKt Ion. focal
ncirotti, dtUllon of reru) tubulei
with prolttn^ccouv tittt. Detreaied
PCV. lit, hwwgloUIn, neulrophU
Increjted teru* Iron, decreased
corttcoiterotdt *nd blood glucote.
Increated urinary protein tugar.
coproporphyr In.
tlevaled hydroiyUlton. H oeaelliyl
etlon, cytochroM P 4iO
fiMilMllont of •Urotoeu) eniyae In
duct Ion «l 1. i, 10. ?0. 40 days poil
Irealewnl Indicated •inlau* Induttlon
it i day», toe>e retloual Induction at
20 oays. Hydroiylallon ewil draovill
cally elevated.
CylochroM P 4SO Inrreaied 3 to
4 fold. mt»\mm In 1 week. n»OPH
activity doubled. t> nttroantsoU
0 deMlkylate Induced • to Mold.
        Ip
             NIce/tAII/CJ
M/4 IO/
troop
                                                               Aroclor 124?
Cor* oil
1000 ag/kg
bw single
dote
-4 fold after I ownlh.  ANH activity
Increased 1 told, down to noreul -I
•ontfc.  Nlcrosoeul epoitde hydratate
Increased 2.S fold at I week,  per
stsled at least 4 weeks.  Clutathtonc
S-lransferave Increased at I  day
regained al  these levels.   Htcrosuoul
OOP glucuronosyllransferase activity
Increased 2.S fold In I week,  per-
sisted 4 weeks.

Splenomegaly:  significant  by day b.
peak  by day  t.  gone  by day 13.
Cellulailly:  significant reduction  In
lymphocytes  days  i 10.
                                                                                                                     Heleiem t\
                                                                                                                                                  Irutknei
                                                                                                                                                  et  al  .
                                                                                                                                                  ISMb
                                                                                                                                                  •rucknvr
                                                                                                                                                  el  al  .
                                                                                                                                                  19Mb
                                                                                                                                                 Parkkl
                                                                                                                                                 el al..
                                                                                                                                                        Carter and
                                                                                                                                                        Clancey.
 O
 -4
 CD
 CD

-------
                                                                               Ullt V 4 |tont.|
        •oul«
       OKI tut
                     Speiles/
                     Strain
Kabbli/New
/ealand
Whit*
               Sen/Mo.
f/u
              U*tghl/Ao.e
Source of
  PCBi
     JOSO    Phenotlor DPb
g/S Months   Clophen A bO
             Aroclor
Vehicle


Isopro
                              Dove/Duration
                                                                        An I Ml  HfecU
i
or-
                    HaMttt/Mew
                    Zealand
                    Milt*
                                    f/U
                             2.S
                                lbt
2.4.4.2'.4'.4'-   Isopro-
heia Cl           panol
Aroclor I2M
                            1)8 •g/djy.        All  PCIt:  Gr^duil wetghi  Imi, mui\*\
                            &  dayi/week        tty  beqlnHtng 4t d.
        MR . Not reported
 QD
 00

-------
                                                                                 I ABU V S

                                          Aiule, Short tera and Subchionlc  loxtctty of  Orally Administered KB*  to Other Species
O
ru
CJ
cr
O
     Spei tes/
     Strain
     Monkey/
     rhesus
     Rabbit/
     Mew /ealand
     While
Sex/No.     Weight/Aye     Source of PCBs    Vehicle
                                                               Dose/Duration
                                                                               Animal IHeits
             adult
f/20. li/20   MR
                            tetra Cl
                          Aroclor 1221.
                          Aroclor 1242
                          Aroclor 12S4
                                                                   torn oil
                                                                   corn oil
     Rabbit/MM
                    f/lt
                                 adult
                                               Aroclor  I2S4
                                                                   corn  oil
     Rabbi I/New
     Zealand
     UMte
H/7/group    -2
                                                Aroclor  1254
                                               diet
 oo
 00
      Guinea ply/
      Dunbar/
      Haitley
 1/5 H/
 group
SOO 600 q/
8 10 weeks
                           Clophen
                           Z^.i.Z'
                           hexa CB
                                             peanut oil
                                                             0.18 My/kg bw
                                               0 or 300 m) 1 I l«e
                                               week ly for 14 weeks
                                                             0.  1.0.  10.  I?.4.
                                                             ?S.  SO aq/kq bw
                                                             dally  for  ?8 days
                                               0.  3.7.  ?0.0.  4S.t
                                               1)0 pp> diet  for
                                               8 weeks;   0.18.
                                               0.9?.  ?.l  or  6.44
                                               •q/kq  bw/day.
                                               rcspetlively
?i or  100 «q.
lotal  dotes over
Moderate proliferation of SIR, slight
decrease of  liver DNA, Increase  In
cytochrome P 440.

Aroclor  1242.  I2S4: elevated SGOI.  SWI .
Aroclur  1254:  slight  transient  Increase
In  serum cholesterol, reduced rale  of
gain,  severe hepaI omega Iy.  uterine
atrophy.  No differences  In hematologlt
parameters. RUN.  serum protein fractions.
Htstopathology. Aroclor  1254: vacuolaled
and granular enlarged hepatocyles,
centrllobular  necrosis and  flbrosls.
•allooned RfR.  lesions  less obvious  In
Aroclor  1242-txposed, absent In Aroclor
1221-exposed.

No  effect on lotal number of fetuses,
number of viable fetuses, number of
resorptton sites or number  of abortions
at  doses of 1.0 or 10 mg/kg bw/day.
liver weights  In the dams were slgntfl
canlly Increased al the 10 mg/kg bw/day
dose,  fffecls on fetal viability as well
as  other maternal effects were seen al
doses of 12.S or greater.

No  effect on feed consumption,  growth
rate, visceral pathology  except  hepato
megaly which was statistically  stgnlft
cant (p»0.OS) al the highest two doses.
No effect on hemalologtc  parameters.  No
consistent  Immune log I
-------
                                                                             IAHII V S (conl.)
ro Species/
•-> Stialn
a-
o
Guinea ply/
MM

Sex/No


H/40

                                 We Iyhi/Aye     Source of I'tlh     Vehicle
                                 3 4 weeks/    Clophen AbO
                                 ~?2S «
                                               diet
                                                               Doie/OuratIon
                                               0,  10.  SO,  ?M)
                                               ppm  tor 4 weeks
                                                                                Aritmal t HIM !•>                        Defer em e
                                                                      ?*>0 ppm: BOX mor Id Illy; <SO ppm.  >10 ppm: dose related reduc
                                                                      lion tn hemayylutInatIon tilers and
                                                                      tetanus anlltuiln pioduitng telK  tn
                                                                      puplUeal ly«|>h nudes following tetanus
                                                                      I oxo I (I  (MMinliat Ion.
                   1/40


                   1/40


                   1/30
34 weeks/    Clophen AbO
~2K g

34 weeks/    Aroclor l?fcO
                           Ctophen AbO
i
CD
    Guinea pig/
    albino
     Pttj/
     Vorkihtre
     Monkey/
     rhesus
NH/tl
             4 weeks
14 days
                                               Aroclor 12bO
              Aroclor  I?S4
              S  b  k»/J  10    Aro.lor  1248
              years
                                                                  dtel
                                               diet
                                               diet
                                                                  dtel
                                               condensed
                                               •Ilk  added
                                               to diet
                                                                  diet
                                               0,  10. SO pp>
                                               for 6 weeks

                                               SO  pp« for
                                               b weeks

                                               0.  SO. 2SO pp*
                                               for I weeks
                                                             0.  10.  SO of
                                                             for  • weeks
0. 1? S. 7S. SO,
100 »q/kfl t»w up to
3S days
                                               0. ?S fpm for
                                               ? Months; total
                                               Intake of
                                               ?kO 4 SO ag
                                                                                                       SO
                                                                                            Clophen: Increased liver weight .
Significant reduction of tetanus anil
toxin  tilers, circulating  leukocytes and
lymphocytes and  ihywis atrophy with both
PCii.  SO ppa.  I (MIX •urtallty at ?SO ppa.
•educed tuberculin skin reaction,  thyaus
atrophy, leukopenla at SO pua level.

SO pp«i: reduced  rale gain, hepato-
megaly, reduced  weight of kidney.
adrenals.  10 pps: splrnlc atrophy;
reduced popliteal lynph node. gao»a
globulin-producing cells.

All  levels: partial anorexia, reduced
weight gain, diarrhea (*elena or  blood
at >SO •g/kg). abdualnal  distension.
gaslrltls,  colitis,  enlarged thyroid.
thy*1c and splenic atrophy, liver and
kidney enlargement.

Alopecia;  edemi of lips,  eyelids, tur,
pustules Involving hair  follicles;  prut
Its;  necropsy of  the  animal consuming
4SO mg: severe weight  loss, subcutaneous
edema, acute hyperplasllc  gastritis with
focal hemorrhage, ulcerallon.  liver:
local necrosis,  enlarged hepatocytes,
llpld accumulation.   HypocellularIty of
bone  marrow.
                                                                                                                               Vos and van
                                                                                                                               Gender en.  tin
                                                                                                                  Vos  and  Je  Uolj.
                                                                                                                  Nlnlats  el  al  .
                                                                                                                  19/B
                                                                                                                  Allen  et al. .
                                                                                                                  l-JMb
 O
 4k

 O
 CD
 00

-------
                                                                            IAHII y 4  (conl  )
o
r\J
CJ
Spec les/
Slidln
    Monkey/
    rhesui
 Sex/No.


H/l
Uelghl/Age     Source of PCBs    Vehicle
                                                                                  Dose/Duration
                            9 ? kg/adult  2.4.?'.i'
                                          tetra CB
                                                                  corn ot I
0 or
                                                    16 Mg/kg bw.
                                                      dose
    Monkey/
    rhesus
                   NR
                            adult
                           Aroclor 1246
                                                                  dtet
                                               100 or 300 ppM
                                               for 2-3 Months
    Monkey/
    rhesus
               M/2
               r/2
             2 • 3.k kg    2.5.4' trICI
                                 dtet
& ppa for 84 days
(historic controls)
     MR - Nut  reported
 O
 *»
 v.
 O
                                                                                                                Animal  Hret Is                        Heft-feme
 •No obvious illnhdl effeiti '  No          Allen el al
 (hanije  In  heaalology   levels (14 day.)     I9IS
 ot tetra CB: ddlposa.  Id. adienaU. 33;
 lung  and hurl, 9;  liver ind skin. 4;
 thyroid. ? n9/fl tissue.  Mliiosroptc
 ally, all  tissues normal.  Hepatic ultra
 strucllve: proliferation ot StH. elevated
 cytothroae P 4SO.

 Gradual weight loss, alopecia lacrlva       Allen.  IS/S
 tlons. conjunctiva) congestion, facial
 •dema. coaedones, laiyp Intrafolllcular
 keratin cysts.  Heaatology: gradual de
 crease  In  PCV. Ht>;  lyaphocylopenta and
 concoaltant neutrophl Ha.  Reduced serua
 proteins.  Itptdt. cholesterol,  trtgly
 cvrldes.   Ihlckened gastric Micosa with
 •uctn filled cysts. Moderately Invasive
 gastric hyperplasla.  Iwo fold hepato
 Megaly. enlarged hepatocytei with In
 creased SIR; decreased liver DMA.  RNA.
 Increased MfO.

 Host organs: Increased blood voluae.         lalropoulos
 Increased relative  liver,  brain weight       el al..  I9I/
 (Males).  Microscopically.  venous  con
 gesllon In Many tissues.   Adrenals:
 hemorrhages and cellular  changes In  tona
 fatctculata.  Renal  cortical and medulary
 degeneration,  lubal  colloid,  liver:  con-
 gestion, fatly Infiltrations.   CNS:
 parenchyMal and mesenchymal degeneration,
macroillal  piollferalIon. gltosts. swell
 Ing of Purklnje eel Is.
 CD
 CD

-------
these  studies.  Various  routes  of  administration of  PCS  to  many  spedes have
produced  similar  signs  and symptoms of toxIcHy.  Some  spedes, such as the
guinea  pig, appear  to be more  sensitive to the effects  of  PCBs  (Vos and van
Genderen,   1973).    In  the  following  section,  the  pathological  effects  of
short-term  PCS  exposure  will   be  described.   The  studies  discussed  1n the
following  sections  are  also summarized 1n Tables V-2 to V-5.

    Hepatic  System.   The majority  of  the toxldty studies  have  evaluated
the  effects  of PCBs  on  the  liver.  Grant and Phillips  (1974)  administered
Aroclor  1254  by  gavage  to male  and female Hlstar  rats.   In both sexes,  5
mq/kg  bw/day  for  7  days  significantly  Increased Hver weights.

    Longer  exposure  to  PCBs   produced  hepatoxldty.   Allen  and  Abrahamson
(1973)  fed  diets  containing up to  1000 mg Aroclor 1248, 1254 or 1262/kg diet
to  male  Sprague-Oawley  rats  for   6 weeks.   Liver  weights at  the end of  6
weeks  were  Increased >3-fold;  the livers  from  the Aroclor  1262-exposed rats
were   most  enlarged  and   livers  from  Aroclor 1248-exposed rats were  least
enlarged.    More  recently,  Baumann et  al.  (1983)  reported  that  male  Hlstar/
Neuherberg  rats  treated  with  2-250 mg/*g °f  Clopnen A-50  by  gavage  twice
weekly for  6  weeks  exhibited  liver damage at  levels as low as  2  mg/kg  bw.
Liver   damage  was  characterized  by Increased liver  size,  congestion,  fatty
degeneration  and focal necrosis.   Lin et al.  (1979)  did not  report Increased
 liver   size,  but   found  considerable  ultrastructural  damage  (Intracellular
 vacuollzatlon  fragmentation  of RER,  altered  mitochondria! conformation)  in
 200-500 g  female Sprague-Oawley rats  that were treated by  gavage with single
 doses  of  1.7  g 2,2' ,5,5' -tetra-CB/kg bw.
 02360                                V-20                           04/07/88

-------
               i  hepatic alterations  were  described by Kasza et al.  ('978b;.
Four-wees-old male  Holtzman rats received  0,  5,  50 or 500 mg Aroclor  1254/kg
In  the  diet   for   5  weeks.   The  animals  experienced   hepatic  alterations
consistent with  those previously described  In  this section.   Additionally,  a
dose-related  Increase 1n the  number of  ilposomes,  as  well  as  Upld droplets
and an  Increase  In  the number of Golgl apparatus at the 5 ppm exposure  level
and  a  modest  reduction  1n Golgl  apparatus  In  the  50  and  500 ppm  exposed
groups.    Laminated   cytoplasmlc  Inclusions  or membrane  whorls  were  seen  In
hepatocytes from rats exposed to 500  ppoi.  The  observations  from  this  study
Indicate   that  a blockage  occurred 1n  the mechanism by which  hepatocytes
discharge  Uplds.

    PCBs   have been  used  widely  to  Induce  hepatic  enzymes,  often  In  studies
with  other cherolcals.  In  these studies,  large  doses  of PCBs are  often  given
by  l.p.  Injection or gavage to obtain  maximal  enzyme  Induction.

    The rapidity In  which  certain  hepatic  enzyme activities  are  Induced  and
their  persistence  In  the  Induced  form was  demonstrated In a study by Parkkl
et  al.  (19^7).   A  one-time l.p. administration  of 100 mg Clophen  A-50/kg bw
to  male   Wlstar  rats elicited  profound  biochemical  changes  In   the  liver.
Cytochrome P-450 levels  Increased  3-  to 4-fold with a maximum achieved In 1
week.   NAOPH  cytochrooe  c  reductase activity doubled, and p-n1troan1sole-o-
demethylase  activity  Increased  6-  to  7-fold and declined to -4 times normal
activity  at   the   end  of  the   4-week observation  period.   AHH  activity
Increased  3-fold Initially and  had  returned to normal by  the end of 4 weeks.
Mlcrosomal  epoxlde  hydratase  activity had  Increased  2.5-fold  at  1 week  and
persisted  at  this   level.   Glutathlone-S-transferase  activity  had Increased
°y  1  day  and  remained elevated  for  4 weeks.
G2360                                V-21                            04/07/88

-------
    Similar  evidence  for  rapid  onset  of  enzyme  Induction was  demonstrated  *n
Sprague-Oawley- rats   fed  diets  containing  Aroclor  1248,  1254 or 1260  for  6
weeks.   This  treatment resulted In many enzymes systems  being  Induced  after
1 week  of exposure to all of the Aroclors  tested.   Hicrosomal n1 troreductase
activity  Increased  initially  and  declined  to  near  normal  values  by  the
second  week.   Activity  continued  to decline except 1n  livers  from  Aroclor
1260-exposed  rats.  N-demethylase  activity  persisted at high  levels  through-
out   the   6-week  period,  whereas,  AHH,  glucose 6-phosphatase   and  esterase
activities  decreased  during  the  study.   An Increase  In  the  amount  of  endo-
plasmlc  retlculum  correlated with  the  occurrence  of  enzyme  Induction with
 this  phenomenon.   By  6  weeks,  degenerative changes such  as  veslculatlon  of
 the  endoplasmlc retlculum, dissolution of membranous whorls and accumulation
of  numerous  llpld  droplets  had occurred.   This  degeneration  was accompanied
by  a  decrease In  hepatic enzyme activities  (Allen and  Abrahamson, 1973).

     Few  studies  have been  designed  to  define  minimum effective  oral  doses
 required  to  Induce  hepatic  enzyme  activities.  Chu  et  al.  (1977)  reported
 Induction   of  MFO activity  In  male  weanling rats  exposed to  20  mg Aroclor
 1254 or  Aroclor  1260/kg  In  the diet  for  28 days.   Similarly, Garthoff  et al.
 (1977)  reported  that 5  pp« of Aroclor 1254 In  the diet  for  3  weeks resulted
 In  Induction of  hepatic a«1nopyMne demethylase  activity;  exposure  at the
 same  dose  for  5 weeks  produced  a   significant  Increase  in  liver  weight   in
 male Holtzman rats.

      Effects  on  the  livers  of  mice   are strikingly similar to  those observed
 ^n rats  (Carter  and Cameron, 1977;   Orberg, 1978;  Sanders et  al.,  1974; Loose
 et  al..  1978a.b).   Levels  of  0.3-1.0 ppm  of 3,3',4,4',5,5'-hexa-C8 diet  for
 28  days  resulted  in liver enlargement; fatty  degeneration  and  formation  of

 02360                                 V-22                            04/07/88

-------
mlcroadscesses  were  found at  doses  >I.Q  ppm  of  diet  (Blocca et  al.,  1931;,
This  study  used  groups  of   five  C57B1/6J  male  mice  to  test  the  relative
potency  of  four  symmetrical  isomers of hexa-C8.  The other isomers  tested
elicited   similar  responses  at the  30-300  ppm  diet  level.   Mattson et  al.
(1981)  observed  hepatomegaly in groups  of female C8A  mice  that were  exposed
to  2,2',4,4',5,5'-hexa-C8  1n  peanut  oil at  levels of  0.5  mg/mouse/  day  for  1
days.   Higher  levels  of commercially available PCB products  are necessary  to
elicit  these   hepatic   responses.    Loose  et al.   (1978b)  exposed  groups  of
male/BALB/CJ  mice to a  diet  containing 167 ppm  Aroclor 1242 for  6 weeks  to
demonstrate  hepatocytlc  hypertrophy.   Sanders   et  al.  (1974)  demonstrated
hepatomegaly  1n groups  of  five adult male  ICR mice exposed  to dietary levels
of  250  ppm Aroclor 1254 for  14  days.

    Other    species    have   demonstrated   variable  alterations    In   hepatic
parameters  upon exposure  to  PCBs.   Oral  administration of   levels as low  as
3.7 ppm Aroclor  1254 In the diet  (0.18 mg/kg  bw/day) for  8  weeks  to male  New
Zealand  rabbits  failed  to produced hepatomegaly  (Street and Sharma,  1975).
Guinea  pigs treated  with a 250 mg Clophen A-60/kg diet for  4-7  weeks  experi-
enced  hepatomegaly with 'liver  damage* (Vos and  van Genderen, 1973).

    Skin  — Only  one  study  was  found  that  Implicated PCBs (Aroclor  1254)
In  dermatitis In rats  (Zlnlcl,  1977).  Alopecia  and a crusty dermatitis  with
serum  ooze  developed  first  on the  ears,   then the dorsura of the nose,  tall
and feet  of  female CD  rats after  10 weeks  of  exposure  to  100  pom  Aroclor
1254  diet.

    Signs  of   toxlclty   In monkeys  acutely  exposed to  PCBs  closely  parallel
those  reported In other species  with  a few notable exceptions.   Frequently,

02360                                 V-23                            04/07/88

-------
the  first  obvious  sign  of  PCS  Intoxication  1s  the development  of  facial
lesions,   facial  and  palpebral  edema  followed by alopecia and development  of
comedones  was  reported  In  female rhesus monkeys exposed to  25  ppm Aroclor
1248  in  the  diet  for  2  months  (Allen et a!.,  1974b;  Allen,  1975).   Total
Aroclor  1248  Intake was  calculated on  the basis of  known food  Intake  to  be
260 mg.   Within  1  month,  all the PCB-exposed animals suffered from alopecia.
subcutaneous  edema,  purulent  ocular  discharge  and  acneform  lesions.   These
signs  progressed to  generalized  subcutaneous  edema,  pruritus  and  alopecia.
As described In  more detail  1n  the Chronic and Subchronlc Toxlclty Section,
chronic  low  level  toxUHy  studies  by  NcNulty et  al.  (1980)  resulted  In
lesions  identical  to those reported  for  rhesus  monkeys  fed  higher  doses  of
Aroclor  1248.

    Imroune Systeti -- Imraunotoxldty  of  PCBs  appears to  be  dependent  upon
the expression  of the  aromatic hydrocarbon (Ah) receptor  and on  the ability
of  the  PCS  to  bind  to  the  receptor.   As  stated   previously the  receptor
binding  affinity of PCBs Is  dependent on  the molecular  conformation that  Is
determined by  the  chlorine  substitution pattern.   Two  tetra-C8s,  3,3',4,4'
and 2,2',4,*',  were found  to have  different enzyme   Inducing  capabilities  as
well  as  differing  potentials  to Induce 1mwunotox1c1ty; that  1s,  3,3'4,4(-
tetra-C8  was  1mmunotox1c  while  2,2',M'-tetra-CB  was  not.  In  addition,
this  immunotoxlclty  appears  to  be  dependent  upon   the  presence  of the  Ah
locus  In  the test  animal  studied (Sllkwortn  and Grabsteln,  1982;  SUkworth
et al.,  1984).

    Mice  have  been  used as  a model  to  demonstrate the effects of  PCBs  on
suppression  of   the  Inwune  system.   Loose  et al.  (1978a.b)  demonstrated
1mmunosuppress1on as measured  by Increased  mortality  to Salmonella typhosa

02360                                V-24                            04/07/88

-------
endotoxin  and  Plasmodlum  berqhel  In  groups  of male BAIB/CJ mice  that  were
treated  with  167  ppm  Aroclor  1016  or  1242 In the diet for 6 weeks.   These
treatments did  not result  In  hlstologlcally-demonstrable  lesions  In  thymus,
spleen  or  mesenteMc  lymph  nodes.   Thomas  and H1nsd1l1  (1978)  demonstrated
decreased  mortality  of S. typhlmurlum 1n groups  of  outbred  female  mice that
were  given  1000  ppm Aroclor  1248  1n  the  diet for  5 weeks and  an  apparent
dose-related  Increase  In mortality  caused  by S. typhlmuMum endotoxin  at
levels  of  100 and  1000 mg/kg diet.

     Male  C57B1/6J mice exposed to one  of  four  symmetrical hexa-CB  Isomers
exhibited  thymlc  Involution especially with 3,3' ,4,4',5,5'-hexa-CB.  Concen-
trations  of  3.0  ppm  1n  the  diet  for  28  days caused moderate  depletion  of
splenic lymphocytes  {Blocca et al., 1981).

     The  guinea pig  demonstrated  Iramunosuppresslon  resulting  from  a  4- to
 7-week  exposure of  groups of female albino guinea pigs to 50 ppm of Clophen
 A-60  or  Aroclor  1260   In  the diet  (Vos  and de  Rolj,  1972;  Vos  and  van
 Genderen,  1973).   In  this  same laboratory,  guinea pigs were exposed to <250
 ppm  of  Clophen   A-60  In  the  diet  for  4-7 weeks  experienced  atrophy  of
 lymphold  tissue  and  reduction  1n tetanus antitoxin  tHers following  Injec-
 tion  with  tetanus  toxold  (Vos and  van  Genderen, 1973).  However,  recently
 Brunstroem et  al.  (1982) reported that all  animals 'seemed unaffected  by  the
 treatment' In  a  study that exposed pregnant  females  to total  Clophen A-50 or
 2.2' ,4,4' ,5,5'-hexa-CB awunts  of  100  ag over a 55-day period.

      Dermal  applications  of  120  mg  of  either  2,2',4,4',5,5'-hexa-CB  or
 Aroclor  1260,  5  times weekly for  4 weeks resulted  In moderate thymlc atrophy
  ^n  rabbits  (Vos  and  Notenboom-Ram,  1972),  the most  severe of  which was pro-

  02360                                rf-25                            04/07/88

-------
duced  by  the  hexa-CB.   These  results  indicate  that  both  PCBs had  potential
for cell  mediated  Immunosuppresslon.

    PCBs  have  been shown to cause  splenic, thymk  and  lymph  node  regression
In  rats  (Allen et  al.,  1975;  Allen and Abrahamson,  1973; Parkinson et al.,
1983a).    Slight  splenic enlargement  was  reported  for  some  workers  after
occupational exposure to PCBs (Miner, 1944;  01sh1  et  al., 1978;  Carter and
Clancey,  1980).

    Endocrine  System — The thyroid  has  been Implicated  as  a  site  of PCB
toxldty  and  thyroid dysfunction  as  the  cause  of  many  of the PCB symptoms.
The  first  study  to  report  thyroid  toxldty  was conducted using  young male
Osborne-Mendel  rats  (Collins et al.,  1977).   In another  study,  Kasza et al.
(1978a) reported  that 4-week-old HoHzman  rats fed diets containing 5,  50 or
500  ppm  of  PCBs   diet  for  5 weeks  produced  ultrastructural  changes  at the
lowest dietary PCB level.   Aroclor 1254  at  levels  as  low as  5 ppra 1n the
diet  for  4 weeks  has been shown  to cause considerable  change In  the micro-
scopic and  ultrastructural appearance of  the thyroid gland 1n groups of six
male  8-week-old Osborne-Mendel  rats  (Collins and Capen,  1980b).   The  Inves-
tigators  noted  that Aroclor   1254   Interfered  with  thyroid  function and
reduced thyroxlne.

     Reproductive    Svstea — PCBs   have   been  Implicated  in   reproductive
system  dysfunctions  1n  a  variety  of  experimental  situations  (see Reproduc-
tive and  Developmental  Toxldty Section).   Dietary  administration  of  300 ppm
Aroclor  1254 1n the  diet for 10 days  to female Holtzraan  rats (Spencer,  1982)
has been  associated  with  decreased levels of placenta! protein  and glycogen
content.   Gavage  treatment of  male  Sprague-Oawley rats (250-300  g)  with  50

 02360                                V-26                            04/07/88

-------
mg  Aroclor  1254/kg  bw  for 7  days  resulted  In  Increased add  phosphatase
activity   in  te.st1cular  Interstitial  cells (Olkshlth et al..  1975).   These
studies    indicate  that  PCBs   may   Indirectly  hasten  steroid   catabollsm
(Spencer, 1982).

     Gastrointestinal   Systea —  Development  of  gastritis  progressing  to  a
moderately  Invasive gastric hyperplasla In the  Individuals were described In
the  rhesus monkeys after consuming -260 ing Aroclor  1248  over  2 months (Allen
et  al.,  1974b) and  1n six  male monkeys exposed for  3  months  to  a  diet con-
taining  300  mg Aroclor  1248 diet (Allen  and  Norback,  1973).   Upon necropsy,
edematous  thickening  of  the  stomach  wall  accompanied  by glandular  hyper-
plasla  was  observed.    Glandular  cells accumulated  mucus, resulting  In  the
formation  of  large,  mucus containing  cysts.   Alterations of  the  glandular
epithelial  cells  and  their nuclei accompanied  by  Inflammatory processes  and
 Invasion of  the muscularls were observed.

     Urinary   Systea —  Rabbits   exposed   to   PCBs   responded  In  a  manner
 similar   to  other  species   (Vllleneuve et  al.,  1971a,b)  with  the exception
 that  dermal  application of any  of three  commercially  available PC8 products
 resulted In  severe renal  damage (Vos and  Beems, 1971).  Applied  at 118 rag, 5
 times  weekly  for 27  applications (38  days), Phenoclor OP6,  Clophen A-60 and
 Aroclor   1260  all  resulted  In  hydropic  degeneration  of  convoluted  tubules,
 destruction  of  tubular epithelial   cells  «Hh  resultant  tubular  dilatation
 and protelnaceous  casts.   No  mention of  such lesions was made In a  subse-
 quent study  by  this  laboratory  using a  total  of  20  such applications  (Vos
 and Notenboom-Ram, 1972).
  02360                                V-27                            04/07/88

-------
     Other  Observations - Many  reports  have  Indicated  that  the nutritional
status  of  animals  may  be  altered  with PCS  treatment.  Dally  gavage with
0.05  g  Aroclor  1254/kg  bw  to  groups  of male Sprague-Oawley  rats  (weighing
200-250 g)  for   21   days   resulted   In  depressed   food  and  water  Intake,
depressed  body  temperature  and reduced rate  of   weight  gain   or  absolute
weight  loss   (Komlves, 1979;  Komlves and Alayoku,  1980).   Similar  results
were  obtained  by  Kllng   et  al.  (1978)  and  Garthoff  et  al.   (1977)  using
similar doses of  Aroclor  1254 In the diet.   Other  workers (Chu et al.,  1977)
however,  reported that exposure of  male Sprague-Oawley weanling   .ts  to  20
mq  Aroclor  1254  or  Aroclor 1260/kg diet for  28  days  did not  reduce feed
Intake  or rate  of weight gain.  Similarly, Olshl et  al. (1978) reported that
a 100 mg  Kanechlor  500/kg  diet  failed to reduce feed or water Intake In  rats.

     Depressed food  Intake  and rate of weight  gain  and lethargy were reported
In  mice  treated with  PCBs  (Tanlmura  et  al.,  1980;  Sanders  et  al.,  1974).   A
dose  as  low  as  8 mg  of  3,3',4,4',5,5'-hexa-C8/kg bw/day given  by gavage  for
10  days to pregnant CD-I  mice also caused the above-described effects  (Marks
et  al., 1981).   Dietary  exposure of male ICR  mice  to  250 ppm Aroclor  1254  1n
the  diet  for  14 days  also resulted In depressed  food  Intake (Sanders  et al.,
1974).    Carter   and  Cameron  (1977),  however,  observed  no  effect  on  body
weight  or food  or water  Intake  1n groups of  male Swiss albino mice  that were
exposed by  gavage  to 1000  mg  of 2,4,5.2',4' ,5'-hexa-CB/kg bw dally for  28
days.

     In  general,  blood and  urine che«1str1es  appeared to  be  affected  by oral
administration  of various  PCB  products  (Olshl et  al.,  1978;  Baumann et al.
1983),    Blood  levels  of  glucose  were  reduced and blood  levels  of  urea
nitrogen, cholesterol and  protein  were  Increased  by  50  ppm  Aroclor  1254  In

02360                                 V-28                           04/07/88

-------
the diet  fed  for  2 weeks  to  groups of male 250 g HoHzman rats (Garthoff et
al.,  1977).    Baumann  et  al.   (1983)  found  Increased  levels  of  urinary
porphyrln  and  porphyrln   precursors  In  groups  of  ten 100 g  male  Wlstar/
Neuherberg  rats  following treatment by  gavage  with 50  mg Clophen A-50/kg bw
for 6 weeks.

    latropoulos  et al.  (1977)  exposed  male  and female rhesus  monkeys  to  5
ppm of  2,4',5-tr1-C8 diet  for  84  days.  No  mention of total  PCS  Intake was
made.   They  reported  a  generalized Increased  blood  volume of  many  tissues
apparently   resulting  from dilation  of  arterloles,  capillaries and  veins.
Hemorrhages   and   cellular  changes  1n  the  adrenal  cortex  were  observed.
Parenchyma 1  and mesenchymal degeneration 1n the brain was also reported.

Chronic  Toxldty
    Chronic   toxldty  studies discussed 1n  this  section  Include  those >90
days  1n  duration.   These  studies are summarized 1n Tables V-6  to V-9.

    In  contrast to  acute  toxldty  Induced  by  commercial  mixtures  of   PCBs.
chronic  studies clearly Indicate differences In  the relative  toxldty of the
commercial   PCB  mixtures.  A 14-week oral  exposure (300 mg.  once  a   week)
study evaluated  the  relative  toxldty of  Aroclor 1221, 1242 and  1254 1n
rabbits  and  found that Aroclor 1254 was the  nost  toxic and that Aroclor  1221
was the  least  toxic  of  the products tested  (Roller and Zlnkl,  1973).   Simi-
larly,  male  8ALB/CJ mice  fed  diets  containing  Arodors 1221,  1242  or  1254
resulted in  the determination that Aroclor 1254 was more toxic  than Arodors
1242  and 1221 (Koller, 1977).
 02360                                V-29                            04/07/88

-------
                                                                                 unit v b

                                                             {Meets of Chronic Or*l  fxposure  of  Rats  to  PCBs
er
o
     Strain
     f 344
     Utstar
     Sprague
     Dawley
     Spr ague
     tawIcy
     CO
Se«/No.


N.f/191



1/400




H/MO





M/fc/group



N/M




i/300
Source of PCI Vehicle
Aroclor 1244 diet


Aroclor 12M» diet



Kanechlor 300. diet
KanecMor 400
or Kanechlor
400

Aroclor 124? diet


Aroclor 1?4«. diet
Atoclor 1244
or Aroclor
Dural tun
Dosage Schedule of Study
0. ?S. 40. 100 ? years
ppei for 2 year •>

0 or 100 ppei for 21 Months
?l Months


0. 400 or 1000 ppM 1 year
for 2/42 weeks



0, 4 or 24 ppM for i. 4 or
2, 4 or fc Months t Months

0 or 100 ppM Ii4 weeks
for 42 weeks

Ant Ml tffecU
Reduced body weight. Stomach: "Inlesl Ina 1" Mela
plasla. dose related; adenoiarc tnoma of glandular
stomach.
Ho effect on food Intake; reduced body weight.
tlrvaled Ian liver Modules (I/0/IB4). nepalocel
lular carcinoma (26/184).. Other areas: hepatic
disrupt Ion.
Heavy mortality. Hepatomegaly, oval cell and bile
duct proliferation, fatty liver Infiltration.
Cholanglof tbrosls at 1000 ppm level of all three
Kanechlors. nodular hyperplasta. Depressed final
body weight.
flevated hepatic mlcrosomal en /yew activity, lip Id
content, flevated urinary coproporphyr In levels.
Present after 2 months at 4 ppm.
Increased hepatic protein, KNA and llpld; decreased
DMA. Increased mtcrosomal total protein and cyto
chrome P 440. Induced M demethylase nltroreduc tase.
Kefereiu e
Hor yan e 1 d 1
1SH)

Klmbruuijh
el dl . I1*/',


Mo el al .
19/4



Iruckner
el al.. 19/44

Allen and
Abrahamson.
19/9
                               Aroclor  1244
     Donryu
N/14.
1/14
Kanechlor 400
diet       0. 10. 30 or 100      20 we^ks
           ppei for up to
           ?0 weeks
diet       total Intake          4W) days
           440 1400 ppei over
           149 460 days
SeruB cholesterol, beta globulin Increased, gaeau      30 ppa:
leduced rate of fain, hepatomegaly, cardloaega ly
(dose-related).  >IO ppei: Hepatic porphyrlnlc
fluorescence. >IO pp»: trytheeia. crustiness.
hyperkeratosls. perIkeratosls on ears,  dor SIM of
nose and feet. tall.

All treated rats: fatty liver degeneration.             Ktexira and
feaales 1200-1400 Big: Multiple adenoeMtous nodules.     Baba.  IS/:i
All rats >)00 «g: hepatoewgaly.  tung and Intra
cranold abscesses suggested lopalred resistance
to Infection.
O
-j
OD
CD

-------
                                                                            IABI t V 6  (conl  )
O
CO
->
                !>r*/No.
              Source  of  KB    Vehicle    Dosage Schedule
                      UuralIon
                      of Study
                            Anl«dl  Illftli
                                                                      Keterenie
    Sprdcjuc*
    Daw ley
f/b/group    Aroclor  1242
                                              did
    Sherman
i
CJ
    Sprague-
    Dawley
H/IO. f/10
per group
                H/10. F/IO
                per group
                H/96
                             Aroclor  1264
                             Aroclor  1260
                               diet
                               diet
              Aroclor  124B.
              Aroclor  1264
              or  Aroilor
              1262
                                               diet
0. I'j or 110 pp*
toi  B or 3b weeks
36 weeks
0. 20. 100. 600
pua for 8 months
0. 20. 100. 600.
1000 ppa for
a aonthi
0 or 100 ppa for
62 weeki
                                                                                8 »onlhi
                                                                                B aonlhi
                                                                                6S
Both  leveh: lusstve venous enyorye»ent of liver       Jonsvuri
with  (harailerUlli darkening, narked total neuro      et al  , I4UI
sis and reyeneralton. enlarged hepatocyles; «any
• Itoses and Mill (nucleate cells. auiMulat Ion of
plijMent adjacent  to veins, heaviest In Kupfer
cells; accuMilat Ion of  Itptd droplets In cytoplas*.
sane  wltfi areas  suggestive of  Itpld cholesterol
coaplexes; Barked  S(R proliferation; deposits of
lion, granular degeneration of Mitochondria, many
hepatocytes contained whorl like *e«liranous bodies.

Mortality (3/20)  and reduced rate of gain at 600       Klrtrouyh
pp*.  Hepatomegaly, enlarged hepatocytes with          et a).. 191?
foa«y cytoplasn  containing Inclusions at >20 ppn.
AdenofIbros Is and  plgaenl accu«ulalton at >IOO pp«.

Mortality 1/10.  2/10. fl/IO of fevales In 100. 600.
1000  p|M groups. Decreased rate of gain at >600 ppni.
Nepaloaegaly. Bale and  female at >20 f>f», discolored
liven with UV fluorescence,  enlarged hepalocyles
with  foaay cytoplasM-contalnlng Inclusions.
Increased Itptd  content at >IOO pp>.   Ptyaenl accu
•ulattons al 600 ppa.  AdenofIbrosIs  al  >IOO ppo.

Nor Ml appetites,  appearance,  weight  gain.  Hb.  PCV.    Allen et al .
MBC,  sertMi protein. A/G ratios,  flevaled seru*        19/b
total llplds. cholesterol.  Iota) Itptd and If I
glycerlde spiked very high peaks on Aroclor 1264
(only) at 62 weeks.  Cholesterol levels  persisted
at 66 weeks (13 weeks off exposure).   Irlglycerlde
levels fell less than controls  by 66  weeks.  Hepato-
megaly:  focal degeneration and  necrosis  by  13 weeks.
 o
 >
 v.
 o
 CD
 OO

-------
                                                                                 IABII  V /

                                                             Effects at Chronic Oral fxposure of Mice to PCBs
O
ro
            Strain     Sex/Mo.      Source of  PCBs
                                            Vehicle
            Nlce/dd   N/M4
                       Kanechlor 300.
                       KanecMor 400
                       or Kanechlor
                       400
                                                     diet
            BAII/CJ   H/24/group
                       Aroclor 1221.
                       Aiotlor 124?
                       01 Aroclor
                       1244
                                                     diet
i
CJ
to
                       f/63


            BMI/CJ    It/200
Swiss
Albino
             ddN
                       1/60
Aroclor 1244


Aroclor 1244



•CIP"
                                                     diet
                                        diet
                                        olive or rice
                                        bran otl
 o

 o
                                 Dosayt  Schedule
                    Duration
                    of  Study
                                 0.  100.  240  or
                                 SOO ppm  for
                                 3? weeks
                                 0. 3  /S.  31.S or
                                 3»i ppB  for
                                 t Months
?00 ppa for
?3 weeki

0 or 100 ppa for
6 or II wtnlhi
0. 0 Ml V/V CBP
in olive otI or
IfcOO »9/k
-------
 o
 1-0
                                                                                 I ABU  V  B

                                                              I (lei Is of Chronic  Ixposure of Monkeys to PCBs
Strain    Sex/No       Source of  HCBs
                                                 Vehl( le
                                                      Doidye
                             DuratIon
                             ot  Study
                                                                                                                                IMeili
                            Aroclor  1246
                                  diet
               N/NR
0.  ?  S or  i  0  ppM  fur     31  b Months
  IB Months
     Rhesus     1/30         Aroclor )?48

               M/10         Aroclor 1248
                                  diet

                                  diet
i
CJ
CJ
t/a/group    Aroclor  1248
               t/24
     Rhesus    NK/i
                            Aroclor  1016
             Aroclor  1248
                            Aroclor  1248
                                  diet
                                                diet
                                  transpla-
                                  cenlal  or
                                  •other's
                                  •Ilk
                                  transpla
                                  cental  or
                                  •other's
                                  • Ilk
0. 2 S or SO p|M

0 or VO pp« (or
-16 aonths
0.5 or 1.0 ppa
3 tlMes weekly
for -16.6 Months
                                                0.02S.  0.?S or
                                                1.0 ppM
Mothers exposed to
HCfls 6 Months before
to yeiIjI ton ihrouyh
gestilIon and 3 4
•onths of nursing

Mothers reMovt'd fro*
exposure to CCBs for
22 84 weeks before
concept Ion
                                                                                   16 Months
                                                                                  lotal Intake
                                                                                  90 or 180 ppM
                                                                                  by fetMles In
                                                                                  b Months
                                                                                  -16  6  Months
                                                                                  lota)  Intake  -B
                                                                                  or  Ib  Mg after
                                                                                  7 Months

                                                                                  MR
                                                                                      Up  to  Infant
                                                                                      age of ?4
                                                                                      Months
 Males  |'j  0 ppM  level only): Moderate       Batsuttl  ami
 etytheMa  and  perlorbltal ede»d .             Allen.  I'US
 leMalev   More severe skin  lesions
 (alopecia,  aine),  eitreMe  wulyht  loss.
 irregular  Menstrual tytle  length,  de
 pressed seruM progesterone   Consider
 able  lM|>roveMent after  I year  recovery
 period.

 Skin  lesions  as above;  ISX weight  loss      Bartolll.
 In  feMales.   Nor Ma I heMlograMS    After     el  a)..  nib.
 b Months:  seruM lotal llplds reduced,       Allen el at ,
 shift  In  A/t  ratio, elevated SGPI           ISISU,
 Menstrual  cycles lengthened.  SeruM
 progesterone  and estradlol reduced.
 After  12 Months. seruM cholesterol and
 Irlglycerlde  reduced.

 Mo  Irregularities  In Menstrual cycle,
 or  seruM eslradlol. progesterone or
 reproduction  success.   Infants smaller,
 skin hyperplgMentaled.

 No abnormalities of (llnlcal,  gross or     Barsolll and
 reproductive paraMeters  In adults.          van Miller.
 1.0 ppa:   Infants  born  In the  1.0 ppM      1984
 group were slgnlfliantly sMaller  than
 controls.

 Significantly  Increased  locoMotor  be       Bowaan el al
havlor  (hyper act Ivlty).   Significantly     19/B,  I'lHI
retarded  learning ability.
                                                                                                    Mothers exposed to
                                                                                                    activity.
                                                                                                                               S Mg/kg: hyper
 CO
 oo

-------
                                                                            IABI I  V 8 (cont. )
o
ro
OJ
cr
O   Strain
Sex/Mo.
              Source of  PCBs
                                 Vehicle
      Dosage
    Duration
    of Study
                                                                                                          Anltal  Iffecis
                                                                                                                           Meter cm e
    Hhesus    H/J/yroup
3.4.3'.4'  or       diet

leUatl

Control
M/4 S/group  3.4.3*.4'- or        diet

             telra CB

             Aroclor 1242
                                               3 pi* (days  I ??)
                                               reduced  lo  I ppa
                                               (days ?3  49) reduced
                                               to 0.3 pp*  (fro* day
                                               SO) .  lor one ant»a)
                                               eleven)  to  I ppa
                                               (fro* tUy 104)

                                               I pp* for 38 d«yt
                                               or 133 d*yi. then
                                               contiol diet

                                               I ppa for 133 days
                                               S «q/kg additional
                                               ? aunlhs
Up lo ?IS days
                                                                                       190 days
                                           Mortality of all three by day ?IS In
                                           3. 4. 3'. 4' letra CB eiposed groups.
                                           emaciation,  skin lesions, nat) bed
                                           hyperplasta.  loss of nails, thywjs
                                           atrophy, gastric lesions as described
                                           (Allen.  19/4)   2.S.2'.4  letra CB:
                                           no  signs of  toxic Ity, no gross or
                                           hlstologlc  lesions.
                                           I death: necropsy findings as above.
                                           Others:  squaaous «elaplas« of sebac
                                           eous glands.

                                           Ho  evidence  of loilclty.
                                                                                                                                      NtNulty
                                                                                                                                      el  al  .  14111)
    Hhesus    N/b
                            Aroclor  124?
                                                diet
     Cyno-
     •olijus
     Cyno
     •olgus
               f/4
                            Aroclor 1264
             P KC 400*
             V PCBb
                            Pt-PCi1

                            control
                                               0. 3. 10. 30 or
                                               100 pi* diet
                                 corn oil.     0. 100. 100 or
                                 gelatin.      400 wi/kg bw/day.
                                 apple juice   3 days/week
                                  ollwa oil
                                  In banana
 O
 -j
 v,
 CO
 05
S ag/Monkey/day
S or 10 mt/
•onkey/day

b •g/aonkey/day

NA

All above treat
•ents qlven b
days/week
Up to ?4S days     All PCi enpoied aonkeys: palpebral         Becker «l d
                   SMclllng. erylhetila; weight loss, rough    ms
                   hair coal, reduced Hb. leukocytes Is .
                   Norlallly of 4/6 by day ?4S.   Gastric
                   lestons: hyperlroph»i gastric  aucosa
                   consisting of elongated hyperplasllc
                   glands, destruction of parietal and
                   lyaogentc cells.  Only specific region
                   along greater curvature affected.

Up to 73ft days     tost fingernails,  fetal toxlctty.  Sub     Iruelove
                   stanllally reduced antibody production     r\  al  .I9H?
                   lo SftBC antlyen.

?0 weeks           Death of 10 ag V PCB dosed  aonkeys  by      Hoi I et a I. .
                   a weeks.  WeighI loss of  P  KC  400 and      I SB?
                   & *g V PCI dosed Monkeys.   V PCB  dosed:
                   alopecia,  acne,  hyperplgaenlatlon,  perl
                   orbital ede*a.   All  treatments: reduced
                   antibody production  lo SRBC.   Hlslopalh
                   ology V PCB:  enlarged hepatocyles with
                   enlarged SIR.  focal  necrosis,  bile  duct
                   proliferation    Dilated renal  tubules
                   with casts,  epithelial  vacuoles.  He I
                   boaIan cysts,  skin hyperkeratosIs.
                   Hlslopalhology  P KC  400 and PY  PCB:
                   lesions  In liver, kidney as above, but
                   •urealld.   Peiloibltal skin:  no  lesions.

-------
                                                                             I ABU V 8  (conl  )
o
N)
Shdln    Se»/Mu
          M/6
                            SOUK e of PCBi       Vehicle
                                                                Dosage
                            "PCU"
                                           saldd oil     0  or  0.4  •ij/k.j  bw
                                           In bdiidiid     ( /•)  <• JM b  wj)
PCOI
                                           (Mel
? 4 pp« by PtO(
    *H KC 400 - lUneihlor  400 with KOtl rMoved

    bY PCB was prepared  (roa Kanechlor  400. contained -400 ppa PCOFs

    CPY PCI - V PCI with PCDfi rMK>v«d

    HA . Hot available
                            Duration
                            ol Study


                        Up to 4 Months
                                                                                                                         Animal  iMeiti
                                                                                                                   u»  d 1 1  ttedted
                                                                                                          dlupecld,  pdlpebidl  ede»d.  dtnefor*
                                                                                                          erupt loni.  \qiidnuus  •etaplas Id  o»
                                                                                                          •elbiMitdn
                                                                                                                                                       ttereiemr
                                                                                                                                                     OhnUht  and
                                                                                                                                                     Kuhno.
OD
00

-------
CJ
0>
o
                                                            IABK V 9

                                    litre !•. of Chronic Oral fxposure of Other Spec lei (o PCBs
    Strain
    Ntnk/
    Pastel
Sex /No.
H. 1/104
Duration
Source of PCIs VehUle Dosage Schedule of Study
Aroclor 1242 diet 0. S. 10. ?0 or 40 6 months
PP»
Animal Itfec
Aroclor l?42 at S or I
reproductive failure.
•Ink on >20 pom.
Is
0 pp«: covplete
Mortality of ill
Referent es
Bleavlni el al
I960
    Ntnk/MR
f/) or •/
group
                                 Aroclor  lOlt      dltt
Aroclor 1016.     dUt
Aroclor 1221.
Aroclor 1242 or
Aroclor 1264
                                            0 or  20 pp»
0 or 2 pp*
              Aroclor lOlfc (20 pp»):  death of  3/12  (2SX)
              of femjlei.   Necropsy:  eaucUllon, complete
              absence of  body fat.  gastric ulcerallon.
              reproductive performances  reduced.

10 ewnthi     Aroclor 12S4:  Interference with  reproduc-
              tion.   All  Aroclors  tested: no significant
              differences  In body weight gain. he*o-
              glooln. PCV.   Aroclor  1016 (200 ppa): no
              effect  on reproductive  parameters, kit
              growth, and  adult  and kit mortality.
Auler l(h and
Hlnyei. 191)
    MM - Not reported
 O
 00
 CD

-------
    It  is  readily apparent  that  the  toxIcUy  of  PC8  congeners  1s  dependent
on  the  degree  and positioning of chlorine on the blphenyl  molecule.   From a
5 wee*  exposure  study  Blocca et  al.  (1981) determined the toxic  potential of
various  hexachlor inated  blphenyl  isomers  in mice and ranked them relative to
their  toxic  potency:   3.4,5-syra-hexa-CB  »  2.4,6-sym-hexa-C8  >  2.4.5-sym-
hexa-CB  >  2,3,6-sym-hexa-CB.  Blocca  et  al.  (1981)  also reported the  same
ranking   for   the   relative  persistence  of   the   hexa-C8   Isomers,   with
3,4,5-sym-hexa-CB  having  the highest  levels  In  adipose tissue and  liver.
Another  example  of  a structure-toxlclty relationship for  PCBs  Is reported In
the  study  by  HcNulty et  al. (1980).  Administration of a diet  containing
0.3-3.0   ppm  3,3'.4,4'-tetra-CB  caused chloracne,  weight loss  and death In
rhesus  monkeys  In  1-6  months,  while similar  feeding of 2,2',5,5'-tetra-CB
produced no  clinical or pathologic lesions.   Toxldty appears  to  be  related
to  the  ability of the congener to bind to a  receptor  and Initiate subsequent
genetic   expression  resulting  In  plelotrophlc responses (Poland  and Knutson,
1982) .

     Species  differences  In  sensitivity to PCB  toxldty have been Identified
 In  chronic  exposure studies.   The  monkey appears  to be  more  sensitive  to
PCBs  than  rodents.   Sprague-Dawley rats  did  not  exhibit excessive mortality
when  exposed  to 100 pp«  dietary  levels  of  Aroclor  1248 for  65 weeks;  how-
ever,  rhesus monkeys fed  diets containing 25,  5 and 2.5  ppm produced morbid-
 ity and  mortality  after  consuming these diets for  2 months and <18 months,
 respectively  (Allen  and Abrahanson,  1979;  Allen  et al., 19746; Barsottl  et
 al.,  1976).    In  addition,  the mink appears to be one of  the more  susceptible
 species  to PCB  toxldty.   Studies have shown that as little as  2  ppm  Aroclor
 1254  in  the  diet   for  10  months resulted  In  complete  reproductive  failure
 (AuleMch  and Ringer, 1977).  A  subsequent study Indicated that the «1nk was

 02360                                V-37                            04/07/88

-------
more  sensitive  to  both  Aroclor 1016 and  1242  than  the  genetically  similar
ferret  (Bleavlns  et  al.,  1980).  The reason  for the apparent large variation
in  species  sensitivity to  PCBs has  not  been elucidated  but  cannot  be fully
accounted for by  a  difference  In the rate of  PCB metabolism.

     Although  many responses reported 1n animals exposed to  PCBs  are  highly
spedes-speclfic.  there 1s  a  similarity  1n  the  toxic  responses  produced  by
PCBs  and  other  halogenated aromatic  hydrocarbons (HAHs) (Poland and  Knutson,
1982) .

     Hepatic   System — As  with  acute   and   subchronlc  exposure  to  PCBs,
chronic  exposure commonly  produced  hepatoxldty.  Several  reviews mentioned
at  the beginning of this  section are recommended  for a  general discussion of
PCB-induced  hepatotoxldty.   Hepatomegaly  has  been reported  In male rats and
to  a  lesser  extent In the  livers of female rats  exposed  to 20.  100,  500 or
1000 ppm Aroclor  1260 In the diet  or 20,  100  or 500 ppra Aroclor 1254 In the
diet  for 8  months  (Klmbrough et al.,  1972).  Grossly, the  livers were soft
and discolored and nodules were seen 1n a number  of  Hvers.   Sprague-Oawley
rats  fed diets containing  100 ppm  Aroclors  1248, 1254  or  1262  1n  the diet
 for  52  weeks  were reported  to have livers as much as 3  times the normal
 size.   In  addition,  focal  degeneration and necrosis were  evident (Allen et
 al..  1976;  Allen  and Abrahamson,  1979).   Discoloration from  congestion was
 also  noted  1n  livers of  rats treated with 75 or 150 ppm of Aroclor  1242 In
 the diet for 36  weeks (Jonsson et al..  1981).

     Two   studies  using  rats,   one employing  dietary  Incorporation of  Aroclor
 1260  or   1254 (Klmbrough et al., 1972)  and the other Aroclor 1242 (Jonsson et
 al..   1981)  described   the  microscopic  and  ultram1croscop1c   changes  that

 02360                                V-38                            04/07/88

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occurred   with  dietary  exposure  to  tnese commercial   PCB  mixtures.    3otn
studies  confirmed  that the enlargement In livers  of  PCB-exposed  animals was
1n  part   due  to  hypertrophy  of  individual   hepatocytes.   Other  findings
Included  focal  necrosis,  hepatocytk  regeneration, mitoses and multlnucleate
cells,  cytoplasralc  vacuollzatlon  and Iron deposits  In  perlvascular  macro-
phages,  Kupfer  cells  and  hepatocytes.

     Ito  et  al.  (1973)  exposed  male dd mice for 32 weeks  to 100.  250  or 500
ppm  Kanechlor  300, 400 or 500  In  the diet. They  reported hepatomegaly,  oval
cell  formation  and  bile  duct proliferation with  Increasing Incidence  appar-
ently  related to  the  degree  of chloMnatlon of the Kanechlors.  A«ylo1dos1s
occurred with a greater  Incidence when smaller  doses of  less heavily chlori-
nated  Kanechlors  were  fed In the  diet.  Klmtarough and Under  (1974) reported
hepatopathology In  male  BALB/CJ  nice fed 300  ppm Aroclor  1254  In  the  diet
for  6  or 11  months but made no mention of  a«ylo1dos1s.

     Exposure of   animals  to pure PCB congeners  elicited  similar  signs  of
hepatotoxldty.     The    2,4.5,2',4',5'-hexa-C8;    2.4,6,2'.4'.b'-hexa-CB;
2.3,5,2'.3',5'-hexa-CB   and  2,3,4,5,2',3',4',5'-octa-CB  congeners  produced
alterations   in   rat   livers   detectable   by  conventional  hlstopathologlcal
procedures;   these Included  hepatocytes with vacuolated cytoplasm and focal
necrosis  (Hansell and  Ecoblchon,  1974).

     Hypertrophy  of  Individual  hepatocytes has  been  sho>.n to be  due to  an
 Increase  1n the  smooth  endoplasmlc  retlculua (Allen and  Abrahamson, 1973;
 Hansell  and  Ecoblchon,  1974;  Jonsson et al..  1981;  Klmbrough  et  al.. 1972).
 L1p1d-contaln1ng  vacuoles w«re also observed  1n these  studies with  concen-
 trically  arranged   membranes   surrounding  the  I1p1d-conta1n1ng  vacuoles.

 02360                                 V-39                            04/07/88

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Koller  and  Zlnkl  (1973) administered 0 or 300 mg Aroclor  1221,  1242  or  1254
by  stomach  tube,  once weekly  for  14  weeks, to Mew Zealand White rabbits  and
reported   similar  ultrastructural  alterations  In  livers  from Aroclor  1254-
treated  and  to a  lesser  extent  from Aroclor  1242-treated  animals.   Livers
from Aroclor 1221-exposed  animals  did not differ  from  those of controls.

    PorphyMa.  evidenced  by  UV  fluorescence,  occurred  frequently   1n  PC8-
treated  rats.   Fluorescence was  most  pronounced  In  the  liver, with  occa-
sional  fluorescence  of  bone, serum or urine or both  (Klmbrough et al., 1972).

    Persistent  biochemical  alterations  Including  elevations of N-demethylase
and   nUroreductase  activities   and   reduction  1n  glucose  6-phosphatase
activity   were  demonstrated In male  Sprague-Oawley  rats  exposed  to  diets
containing  up  to  100 ppn Aroclor  1248.  1254  or  1262  for  1  year  (Allen  and
Abrahamson.  1979).   Partial  (70%)  hepatectony  was  performed  periodically
throughout  the  exposure.    At  the end  of  52 weeks,  animals were  put on  a
control  diet  for  13  weeks before  being killed for final examination.   Ratios
of  hepatic  prote1n/DNA and  RNA/DNA remained  elevated throughout the  52-week
exposure  period  to  any  of  the  three  Aroclors  tested.   Levels  returned  to
near  control  levels  by  65 weeks.  Liver  llplds  Increased  throughout  the
52-week  exposure  period  but had  decreased  toward control  levels after  13
weeks  on  a  control  diet.  Aroclor  1248  produced the highest llpld  content
following  52 weeks  of  exposure, while  exposure to Aroclor  1262  had the least
effect.

     Skin  -- Skin  lesions  are a  species-specific  sympto*  of  PCB  exposure.
Skin  lesions were  first  reported  In nice exposed to  1  ng of an unidentified
 "CPB"   (N1shlzum1,   1970).   The lesions were  eczematous and  ulceratlve about

02360                                 V-40                            04/07/88

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the  head  ana nuzzle.   Another  study  (Bell,  1983)  reported  Initial  lesions
consisting of  thickening and erythema of the pinna 1n mice  exposed  to  a  200
ppm Aroclor 1254 diet.

    As  in  the  case with acute exposure to PCBs,  monkeys exhibit skin lesions
when  exposed  chronically to  PC8s.  Hale  rhesus monkeys exposed to  3,  10,  30
or  100  ppm Aroclor 1242 diet for up  to 245 days  exhibited palpebral  swelling
and  erythenva.   Similar  toxlclty was  observed  In male  and  female  rhesus
monkeys   fed  diets containing  2.5  and 5.0 ppm  Aroclor 1248  for  18 months.
The  fenvales   had  more  severe  skin   lesions such  as  alopecia  and  chloracne
(Barsottl et al .  1976).

     These  same  lesions,  however, were  produced  In animals  exposed  to PCBs
devoid   of PCOFs.    When rhesus  monkeys  were exposed to 3,3'.4,4'-tetra-C8
(PCDFs   <1  ppm)   1n  the  diet,  large-scale  mortality followed.    The  skin
lesions  consisted  of  squamous  metaplasia  of  sebaceous glands  and  cystic
formation  In the  eyelids.   Nail  beds were  hyperkeratotlc  leading to shorten-
ing or   loss  of  nails  (NcMulty  et  al.,  1980).   In this same report, other
monkeys   exposed  to  3,3',4,4'-tetra-CB  were allowed  to  recover  from  PCB
exposure  for 76 days  at  which time the animals  exhibited normal regeneration
of the  skin.   In  a  study  with  cynonolgus donkeys, HoM  et  al. (1982) found
that PCBs devoid  of PCOFs  did  not produce typical  skin lesions.

     Immune  Systeti —  Chronic  studies  using  rhesus  monkeys  have  Indicated
an  apparent  effect  of  PCBs on  the liwune system.   HcNulty et  al.  (1980)
 found  that  3.3' ,4.4'-tetra-CB  produced  thymus  regression.   In another  non-
 human  primate  study  utilizing  PCB  mixtures  with  or  without  PCOFs,  HoM  et
 al-  (>982)   found  that  all  conpounds  tested depressed  Immunocompetency  as

 02360                                 V-41                            04/07/88

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 evaluated by  tilers developed against  sheep  red  blood cells.  There appeared
 to  be  no difference In Inwunotoxlclty between PCBs  with or without PCDFs.

     Gastrointestinal   Svstea  -- Rats  exposed  to 0.  25,   50  or  TOO  ppm  of
 Aroclor   1254   of   diet   for   2   years  developed  Intestinal  metaplasia  or
 adenocarclnoma  at  the Incidences of 3/47 (6.4%). 5/48 (10.4%).  8/48 (16.7%)
 and  17/48  (35.4%)   In   the  control,   low-,  medium- and  high-dose  groups,
 respectively.   There  appeared  to  be  no  differences  In  Incidence  between
 sexes,  and incidence  appeared to  be dose-related (Morgan et al. 1981).

     Nonhuman  primates were susceptible  to gastric  lesions upon PC8 exposure.
 Becker  et al.  (1979)  exposed male  rhesus monkeys to 0,  3, 10,  30 or 100 ppm
 Aroclor  1242  in  the  diet  for  up to 245 days.  Gastric  lesions  1n exposed
 subjects included  hypertrophlc gastric  mucosa consisting of elongated  hyper-
 plastic  glands  with destruction of  parietal  and  zymogenlc cells.   In a study
 employing 3,3' . 4,4'-tetra-CB  1n  the diet of  rhesus  monkeys, HcMulty  et  al.
 (1980)  found  at  necropsy that the gastric mucosa was severely disrupted,  and
 large mucus  cysts  and loss  of parietal and zynogenlc  cells developed.

     Urinary   Syste* « Few  reports  exist  on  the urinary  system as  a  target
 for  PCB  toxlclty.   One study In nonhutun pM«tes  that employed PCS  mixtures
wUh  or  without  PCOFs found  that  kidneys  were enlarged  because  of dilated
 renal  tubules.   The  tubular  epithelial  cells  were enlarged  and  vacuolated.
Kidney   tubules  contained casts.   These  microscopic  changes were  present  In
all  experimental animals  studied  (HoM et al..  1982).

     Other   Observations  —  A   large  number   of  observations  and  determina-
 tions have been  recorded 1n animals exposed  to  PCBs  Including gross  changes.

02360                                V-42                            04/07/88

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alterations In  body weights,  hematologlc, urlnalysH  and clinical  chemistry
parameters.

    Hale Sprague-Oawley  rats  were fed diets containing 100 ppm Aroclor  1248.
1254  or 1262  for 52 weeks  (Allen et al.,  1976; Allen and Abrahamson,  1979).
Observations  continued   for   13  weeks  following  treatment.   Appearance.
appetite  and  weight gain  were  normal  In all  rats  throughout  the  study.
Hematologlc parameters  and  serum protein and  albumin/globulin ratio remained
normal.  Total  serum llplds and cholesterol remained elevated throughout  the
52-week experimental period and serum cholesterol remained elevated 13 weeks
after   exposure  was  terminated.   Serum  trlglycerldes  from all  treatment
groups ranged from  20-40% below control  levels.

    Morgan  et  al.   (1981) reported  on the  toxldty of feeding diets contain-
ing  Aroclor  1254  to male  and  female  F344  rats* for  2 years.    Rats were
exposed  to levels  of  0, 25,  50 or  100  ppm of Aroclor 1254 1n  the  diet.
Mortality  occurred   In 8  and  33.  17 and  21, 42 and 17. and 54 and 29% of  the
males   and  females,  respectively.  1n  these  respective  groups.  Nean  final
body  weight of  all treatment groups were lower than the body weight  of  the
control groups  with the  exception  of  the low-dose group males.  Beginning at
72 weeks   for  the  high-dose  group  and  104 weeks  for  the medium-dose group
rats,  alopecia, facial  edema,  exophthalamos.  cyanosis and  amber  colored
urine  became  noticeable.

     Long-term  studies  1n  nonhuman primates  have provided  Information on a
variety  of alterations  In clinical  parameters.  Clinical determinations in
rhesus  monkeys  (Barsottl et  al.. 1976; Allen et al.,  1979a; Barsottl. 1981)
after  16  months of exposure  to 2.5 and 5.0 pom Aroclor 1248  In the diet

02360                                V-43                           04/07/88

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Indicated  normal  hematograms.   Six  months  of exposure resulted  In  reduced
total  I1p1ds,  elevated  SGPT, and  a  shift  In the  albumin/globulin  ratio.
Serum  cholesterol  and  trlglycerlde were also reduced after  12 months  of
exposure.

     In  another  laboratory.  Becker  et  al.  (1979)  exposed  six male  rhesus
monkeys  to levels  of  3,  10,  30 or 100  ppm Aroclor 1242 In the diet for up to
245  days.   Mortality  of all monkeys exposed to >10 ppm In the diet occurred
by  day  245.   All  exposed monkeys exhibited palpebral swelling and erythema.
weight  loss, rough hair coat,  reduced hemoglobin and leukocytosls.

     McNulty  et  al.   (1980)   also  Investigated  the  relative  toxlclty  of
S^.S'^'-tetra-CB;  2,5,2',5'-tetra-CB  and  Aroclor  1242.   Groups of  male
rhesus  monkeys  were  exposed  to 3 ppm  of  3,4.3'.4'-tetra-CB  or 2,5.2',5'-
tetra-CB  1n  the  diet or a  diet without added PCBs (control).  The dosages
were reduced to  1 ppm  and  again to  0.3 ppm because of rapidly developing
morbidity  In the  three  monkeys  exposed  to  3,4.3',4'-tetra-CB.  Mortality of
two subjects in  this  group had occurred by day 62.  Mortality of the third
subject  on  day 215  terminated  this  experiment,   necropsy  revealed severe
emaciation with a total absence of  adipose  tissue.   In a  second  experiment.
groups  of young  male  rhesus  monkeys  were  given diets containing  1  ppm of
3,4.3'.4'-tetra-CB,  2,5.2'.5'-tetra-CB or Aroclor  1242 In the diet  (McHulty
et  al..  1980).  At  the end of  the 133-day  trial,  all  control  animals, those
exposed  to  2,5,2',5'-tetra-CB  and  those exposed  to  Aroclor 1242  appeared
 normal.   One of  th«  3.3'.4.4'-tetra-CB  subjects died on day 33.   Findings
 upon necropsy examination of  3,3',4.4'-tetra-C8-treated animals  w«re  similar
 to  those  reported above.
 02360                                V-44
                                                                      04/07/88

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    As  mentioned previously,  minks are  sensitive  to PCB Intoxication.  A
study  (Aulerlch and  Ringer.  1977) indicated that 2  ppm of Aroclor  1016,
1221.  1242 or  1254  In the diet had no effect on  body weight gain,  hemoglobin
or  hematocrlt   In  nlnk.   In  another study  (Bleavlns  et  al., 1980)  Aroclor
1242  and   1016  were  fed  to  male and  female  pastel mink  for  -8  months.
Aroclor  1242 was fed at 0, 5,  10. 20 or  40  ppm  In the diet and  Aroclor 1016
was  fed at 0  or  20 ppn In the diet.  Aroclor 1242 at levels >20  ppm In the
diet  resulted  In 100% mortality.   Aroclor 1016 at 20  ppn  In  the diet result-
ed  In  mortality of  25X  (3/12)  of the  females   exposed.   Necropsy revealed
emaciation, an almost complete absence of body fat and gastric ulceratlon.

     Roller and  Zlnkl  (1973)  administered 300 ppm Aroclor 1221.  1242 or 1254
 by stomach  tube,  once weekly for 14  weeks, to New Zealand White rabbits.
 Blood samples  were taken every 2 weeks  from the five miles  and five females
 in each  group  for determination  of blood  cnemls'tMes.  After  2 weeks SGPT
 and  SGOT   levels were elevated 1n  Aroclor 1254-treated miles. Females  devel-
 oped  elevated SGPT and SGOT  at  4 and  8 weeks,  respectively, after exposure.
 Aroclor  1221  failed to elevate  serum levels of  either enzyme throughout  the
 study.    Total serum protein,  protein fraction levels and BUN did not  differ
 from controls  during the  study.  No   hematologlc  differences  were  noted
 between  control and treatment  Individuals.  Serum cholesterol  was elevated
  significantly In males treated with Aroclor 1254 as early as 7 weeks.

  Developmental and aaprodiictlv* Toxicology
      Developmental toxicology  Is  the study  of adverse effects on  the develop-
  ing  organism  that  may  result   fro.  exposure   prior  to conception  (either
  parent), during prenatal development,  or  postnatally to the time of  sexual
  saturation.   Adverse developmental effects iy be detected at any point In
                                       u je                           04/07/88
  02360                                v'45

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the  llfespan  of  the  organism.   The major manifestations of  developmental
toxIcHy   Include:    1)  death   of   the  developing  organism,   2)  structural
abnormality,  3) altered   growth,   and  4) functional   deficiency.    Several
studies  have  Investigated the developmental  toxlclty of  various mixtures  of
PCBs.   Little evidence of gross abnormalities was  found.  Most reports  deal
with  the  developmental   toxlclty  potential  of  PCBs  and their  ability  to
Interfere  with  expected  levels of  fertility  In  many manmallan  species.  The
more  pertinent studies are summarized In Table V-10.

    Rats.    One  of  the  first  reports  (Vllleneuve et  al.,  1971a)  examined
the  developmental  toxlclty of Aroclor 1254 In  the HI star rat.  Aroclor  1254
In corn oil at  doses up to 100 mg/kg bw/day was administered on days 6-15  of
pregnancy to Ulstar  rats.  This exposure failed to produce maternal  toxlclty
(evaluated  as body weight gain, fertility  and  Utter  size)  or  developmental
toxlclty  (evaluated  as  number of  litters, average litter  size,  resorptlon
sites/litter,  average  litter  weight,  skeletal  or  visceral  abnormalities).
Exposure  did  result  In  a significant decrease  1n average fetal  weight, but
since  the  total  number  of  fetuses  per Utter  was Increased,  there was  no
effect on total litter weight.

     Spencer  (1982) Investigated the reproductive  toxlclty of Aroclor 1254 In
female Spr ague -Daw ley rats.  Rats were fed diets  containing Aroclor 1254 at
levels  up  to 900 ppm diet  from days 6-15 of  pregnancy.   Dietary  levels  of
300, 600  or 900 ppm  led  to  a  significant  reduction In  dally feed Intake.  Mo
effect on the number  of Implantations  was observed on days 6 or  12 of  preg-
nancy.   Average  fetal weight/Utter at birth  was significantly  reduced at
dietary  levels of  >1QO ppm.   Fetal  toxlclty In  the 600 and  900 ppm dosage
 groups   precluded   this   measurement.   Percentage  live births/litter  was
 02360                                V-46
                                                                     04/07/88

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                                                                              Uttf  V-10

                                         SuoMry:  leratogenetlc. feloloitc and leproducttvo Iffects of Orally Administered Kit
or>
o
Species/
Strain Source of PCIi
Dosage level and
Duration of Irealaent
Maternal Responte
Progeny Response
Reference
      •at/Mlstir
                      Aroclor  1244
Arocler 1254
                      Aroclor  12S4
                    t.  J.fl, 10.0. 12.5. 2S.O.
                    SO  ej|/k| few/day on days  1-21
                    •f  pregnancy; 25 *g/k| kw/day
                    M  dayt 7-21 of pregnancy
0. ».2S. 12.S.  2S.O. M,
1M o*/kg few/day on dayt
fc-li of gestation

0. 1. t. 20,  IM. MO pp»
4let fro* 3-4 wtokt of •«•
to teratMlte*  of 1- or
2-fCMr«ttM
                                •ott >2S M/fc| few: Mitr-
                                M! 4e«tk. Mlfkl lots;
                                >10.0 aoykf ten: Moa(«-
                                •efily; 2S of/kf kw **yt
                                1-M: roOHceo* r«to of flo.
     reported
                             >I?.S of/kg few/day: fetal «ealk.
                             resorptlMi, akorttont.
 MOM reported
                                                                                f ij SM ppa: reduced Utter  site;
                                                                                100 ppa: reduced Utter stxe;
                                                                                fib IM ppa: reduced survival at
                                                                                weanlngj 20. IM ppa: reduced
                                                                                Utter die;
                                                                                »24 IM ppa: reduced Utter  «tte
                                                                                aid reduced survival at weaning;
                                                                                20 ppa: reduced Utter (lie;
                                                                                f M 20. IM ppa: reduced Utter
                                       vtlleneiivt el t\ .
                                                                                                                                            Under et al..
                                                                                                                                            1914
                      Aroclor 12M
                      Aroclor 1254
       Kat/Spr»floo-    Aroclor 1254
       Oawley
       Ntce/COi
1
-j
i
 3.3'.4.4'.S.S«
 fcOM-CO
                    •. S. M. IM. MO opt
                    tftot fro* 3-4 nook* of
                    lo teratMtlo* of 1- or
                    0.  IB. M, IM BV/kf bw/tfcy
                    rfotoi on 4ayt }-lf of
                    0.  24.  U. IM. MO. 3M.
                    Mtt. MO »»•
                    **y» »-lS of
«. 0.1. 1.0.  2.0. 4.0. 0. U
•o/kf kw/oty. on «ay« fc-U
of 90
                                                                                   tetf
>MO ppo>:  (M
«oor««U «M|
                                                   Ion.
>0 «l/kt kw/«\iy:
Mte of ««U. Ulk«r«y.
                                                                                                     f)4 MO ppa: reduced  Utter ttie
                                                                                                     MM reduced *«r«lval  at weaolof.
                                                                                                     f|B MO ppa: reduced  Utier il»e.
                                                            f i IM •fj/kf kM/day: redeced Utter
                                                            (lie.
>3M ppa: fetal deatk at delivery.
>1M ppo): reduced Utter Mel
>4 *i/kf kw/day: fetal Mortality.
reierptioMi
>2 oi/kf few/day; Increased Incidence
of cleft palate;
>4 «|/ke kw/day: tncreated tncldeoce
of kydronepfcroilsi
>1 e>t/k« kw/day: Increased Incidence
of creM colored lUtr;
>1 •oykf kw/day: Increased Incidence
of un4ertli«4 renal
                                                                                                  Spencer.  IM2
tbrks et  al.. IMI

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                                                                       TAIlf ¥-10 (cant.I
o
i





I


o
1
£
Spec »«/
Strain
Mtce/ddV
Rat/Sprague-
Oawley
Rat/Mlstar
Htce/NMRI
NUe/CM
RabbU
Mink
Monkey/
cynoaolgus
Monkey/
rhesus

Source of PCBs
Kanechlor 500
Aroclor 1221
1242 or 1260
Aroclor 1254
ClophenA..
2.2'.4.4«.
S.5'-bexa-CR
Aroclor 1221.
Aroclor 1254
Aroclor 1242
Aroclor 1016
Aroclor 1254
Aroclor 1240
Aioilor 1241
Aroclor 1016
Dosage tevel and
Duration of Trealaent
0, 1.0, 2.0, 3.0. 4.0. 5.0
ag/day/aouie; days 6-15 of
gestation
0 or 30 ag/kg bw. days 14-20
of pregnancy
0 or 70 ag/l drinking water
(6.4 ag/kg bw/day); 9 weeks
0 or 0.02S ag/aouse/day;
72-76 days
0 or 0.5 ag/aouse/day; days
5-11 or 5-lR of pregnancy
0. 1.0 or 10 ag/kg bw;
first 20 days of pregnancy
0-40 ppa diet; 0 aontht
20 ppa dtet; 0 aontht
0. 100 or 400 pg/kg bw/day;
continuous starting at 60
days of pregnancy
0, 2.5 or 5.0 ppa diet;
10 aontht starting 6 aontht
pregettattonal
0. 2.5 or 5.0 ppa dtet;
off treatment for 1 year
0.025. 0.25 or 1.0 ppa diet
Maternal Responte
Mortality In high dose
Mot exaalnod
Mortality at 7 weeks
Lengthened estrus cycle
Mepateaegaly
"~
>10 ppa: significantly
Increasing aortaltty;
>5 ppa: coaplete repro-
ductive failure;
25ft aortaltty. reduced
fertility.
fingernail lost; tnauno-
loglc Inceagetence.
facial edeaa. cacbexta.
hair lots, hyperptg-
aentatton, lengthened
aenstrual cycle
Persistent chloracne
Hone
Progeny Retponte
>1.0 ag/aouse/day: cleft palate
None
fetal resorptlon
fetal resorptlon
Hon.
Hone
Increased aortaltty; decreased
litter bloaass
Increased preweanlng aortallty.
decreased body weight by 4 weeks.
fetal aortaltty; tnaunologlc
Incompetence.
fetal death. Infant facial and eye-
lid odea*, lott of facial hatr.
facial hyperptgatntatton. gattrtc
hyperplasla and voalttng. lyaphotd
degeneration, bypocellular bone
aarrow. fatty liver.
Reduced neonatal weight, hyper -
ptgaentatlon. hyper activity.
retarded learning ability.
Infants born to the 1.0 ppa dtet
group were significantly saaller
than controls.
Reference
Matanabe and
Sugahara, 198)
Gellert.and
ytlson. 1979
laker et al., 19);
Or berg and
Klhlstroa. 1973
Ma It ton et al..
1901
Vtlleneuve et al..
197lb
•leavlns et al.,
1900
Truelove et al..
1902
larsotlt. el al.,
1976; Allen
et al.. 1979b.
1900
•arsottl and
van Miller. 1964
NA . Hut applicable

-------
significantly  depressed at  the  300 and 600 ppm  level.  There were  no  live
deliveries at the 900 ppm  level.

    Baker  et  al.  (1977)  administered Aroclor  1254  to Wlstar rats  through
drinking  water  to  study  the  toxlcoklnetlcs of  this commercial  Mixture  of
PCBs.   Drinking  water  contained  70 ppm Aroclor 1254 enulslfled with 0.15X
Tween  80.   Dally  Aroclor  1254 consumption was  6.4  ng/kg bw  for  9 weeks.
Fetal  resorptlon  and Increased maternal  mortality  were  reported during  this
exposure.

    An  extensive  study  on  reproductive effects of PCBs In rats was  performed
by  Under  et  al.  (1974).  In a  1-generation study,  pathogen-free female
Sherman  rats  were fed  diets  containing  either  Aroclor  1254 or Aroclor  1260
at  levels  of 100  or 500  ppm starting  at 3-4 weeks  of age and  terminating
exposure after  the weaning of the  F..  litter.  Aroclor 1254 at the  500 ppm
level  resulted  1n reduction of the number of  litters born, and Utter  size
was  reduced.   Aroclor   1260  appeared to  cause a significant  decrease  In
Utter   size  In  F,   rats  at  the  500   ppm  level.   F.   survival  was   also
significantly reduced at the 500  ppm level.   Aroclor 1260  failed to  produce
evidence of reproductive toxlclty at a  level  of 100  ppm.   Similarly. In the
2-generation  study  In which  pathogen-free  mile  and female  Sherman  rats  were
fed  diet  levels  of up  to  100  ppm Aroclor  1254  or  Aroclor  1260. F2a  litters
were  reduced  In  size at the  100  ppm level of  Aroclor 1254.  f^ litters  In
Aroclor  1254-treated animals were reduced In size at  both the  20 and  100 ppm
level.   These  reductions In  litter  size  were  significant at the 0.5% confi-
dence  level  with the exception of  the F2a 20  ppm  litter,  which was  signif-
icant  at  the  5.OX confidence level.  Ability  of animals to wean was  reduced
by  Aroclor  1254  1n both  studies.    Survival  at  weaning was  significantly

02360                                V-49                             04/07/88

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reduced  1n  Flb  niters  at the 100 ppm treatment level In  the  1-generatlon
study.   F2a  1uters   also experienced a  significant decrease  In  percent
survival  at weaning at the 100 ppm treatment level.   Dietary levels of  5  ppm
Aroclor  1250  and 100  ppm Aroclor 1260 had no effect  on reproduction  In rats
exposed  through  two generations.

     In   a  postlmplantatlon  exposure  study,  100-day-old   stock  rats  were
treated  with  Aroclor  1254  In  peanut oil by gavage at levels of 0,  10, 50  and
100  mg/kg bw/day on days 7-15 of  gestation.  A reduction  In pup survival  was
observed only at the  100  mg/kg bw/day level  (Under  et al..  1974).  Repro-
duction  and pup  survival were not affected following exposure  to 10 or  50 mg
Aroclor  1254/kg  bw/day  or 100 mg Aroclor  1260/kg  bw/day  on days 7-15 of
gestation (Under et al.,  1974).

     Using  a  low level  (30  mg/kg bw) of  Aroclors  1221,  1242 and 1260  and
various  chlorinated  pesticides.  Sellert and Wilson  (1979)  Investigated  the
effects   of  prenatal   exposure on  reproductive  functions  of   FI  males  and
females.   Speculating that PCBs may have  estrogenlc  qualities  that  could be
expected to Interfere with subsequent reproduction,  Sprague-Oawley rats were
treated  by  gavage on days  14-20 of pregnancy.  At  6  months  of age.  FI
females were  examined for persistent vaginal  estrus  and  anovulatlon,  indi-
cators  of  prenatal exposure  to estrogenlc substances. Although no signifi-
cant  Increase  In these parameters was found,  the  Incidence seemed to be
 Inversely   related  to  the  degree of  chlorine  saturation of  the  Aroclor
 tested.   Male  F.  rats at  6  months  of   age  were  mated  with  known  stock
breeder  females and then  necropsled.  The offspring were  normal, and exami-
nation  of  adrenals,   testes.  epldldymus   and  ventral prostates  of the FI
males revealed no lesions.
 02360                               V-50                            04/07/88

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    Olkshlth  et  al.   (1975)  examined the  effects  of Aroclor  1254 on  rat
testls.    Mature  male  Spr ague -Oaw ley rats  were  treated  by  gavage  for  7
consecutive days  with  50 mg/kg bw  Aroclor  1254.   At the end of  the  7-day
treatment period,  the  rats were  allowed  a period  of  recovery.   No signs of
morbidity were  observed.   Necropsy examinations were performed on three rats
from  each group on days  1. 7,  15 and 30 days  of  recovery.  The  body  weight
of  rats  examined by  necropsy at  30  days was significantly reduced compared
with  controls.   Testlcular  and  epldldymal  size  and  Mstologlcal  features
were  normal  In  treated  rats  with  the  exception  of  a  slight  Increase In
testlcular  Interestltlal  tissue with  Increased acid phosphatase activity.

     One recent  study on early postnatally-admlnlstered PCBs to male rats was
undertaken  to determine effects on their subsequent reproductive performance
(Sager,  1983).   Dams received 8.  32 or 64 mg/kg bw Aroclor 1254 by gavage on
days 1-3, 5,  7 and  9  of lactation.   At  130 days  of  age, 3 or  4 males from
each  treatment  group were   randomly  selected for  observation   of  mating
behavior  and fertility.   PCS treatment at  all  levels  tested  Interfered with
mating  behavior  and  fertility as  evidenced  by  a reduction In  numbers of
 females  Impregnated.   Testlcular  weights were significantly Increased In the
 32  and   64  mg/kg  groups.    Testlculomegaly  and   subnormal   development  of
accessory  sex  glands  was taken  as  evidence  that  PCBs  administered  in the
 early  postnatal period Interfered with circulating  levels of androgens.

     Nice.   A commercial  mixture of  PCBs.  Kanechlor   500. Induced  formation
 of  cleft palate  1n mice  (Watanabe and Sugahara,  1981).   Pregnant  ddY  strain
 mice  were  Injected daily on days 6  through 15 of gestation with PCB at  1.0.
 2.0,  3.0,  4.0 or 5.0  mg/mouse/day.   Maternal  mortality  was  increased  in the
 n:qhest  dose  group.  The   Incidence of  cleft palate  In  live  fetuses  was

 02360                                V-51                            04/07/88

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significant and  dose-related.  Additional  experiments  were  performed  on two
other  groups  of  mice.   One  group  received  5 mg/day Kanechlor 500 on  days
6-10  of  gestation  (25  mg  total),  and  one  group received 10 doses of  5 mg
Kanechlor  SOO/day  before  mating (50 mg  total)  and an additional  10 dally
doses  during  days  6-15 of gestation (100 mg total).   Severe  mortality was
observed  in  the  100 «g group.   The  occurrence  of  resorbed  or  dead fetuses
and  cleft  palate Increased with the amount of PCBs  received.  Five Instances
of  brachydactyly,  four of syndactyly  and  one of  cleft  lip  In PCB-treated
fetuses were reported (Uatanabe and Sugahara. 1981).

     Using  a   low  chlorinated  PCS,  2,2'-d1-CB,  Tor ok  (1978)  reported  an
increase  in  fetal  resorptlon and retardation of  fetal  development.  Pregnant
NMRI mice  were dosed orally with 375, 500 or 750 mg/kg of this  PCB dally for
3 days  following appearance  of  the  vaginal  plug.  Similarly,  another group
was  dosed orally  with 250 mg  PCB/kg/day for 6.days.   The author reported
 that  the  375  mg/kg dose Increased fetal   resorptlons and  that  doses  >500
mg/kg caused delayed Implantations.

     In  a  study  designed to evaluate the effects of the specific PCB  Isomer.
 2.2'.4t4'.5.51-hexa-CB. Nattson et al.  (1981) were unable to Increase fetal
 resorptlon In CBA mice mated  syngenelcally  to  CBA or  allogenlcally  to mi
 male  mice.   Animals were  treated  with hexa-CB at  the  level of 0.5 mg dally
 for  either  days  5-11  or  5-18 of  gestation. All  mice were killed  the day
 following the last  treatment  except for five control  and  five treated mice
 from  the  second  trial,  which were allowed  to give birth to permit examina-
 tion  of  offspring.   Treatment  with PCB at this  level did  not result  1n
 significant  Increase In fetal  resorptlon.
  02360                                V-52                            04/07/88

-------
    Marks   et  al.  (1981)  clearly demonstrated gross malformations  in CO-1
mice  resulting  from treatment  with  3.3'.4.4' ,5.5'-hexa-CB.   This isomer was
chosen  for  these  studies  because  It  was found  to  be  more  toxic  and more
readily  bloaccuraulated,  and to  have  a  more pronounced toxic effect on liver.
thymus  and spleen  than other Isomers tested  (Blocca et al., 1981).  Pregnant
mice  were  administered  0.1-16  mg/kg  bw/day hexa-CB by  gavage  from day  6
through  day  15  of gestation.   Although  no deaths  occurred  1n exposed dams,
lethargy  and  vaginal  bleeding  were observed  In  dams  exposed  to >8  mg/kg
bw/day.   Dams  In  the  8  and 16 mg/kg bw/day groups  suffered  a  significant
reduction   1n  weight gain.   Average  numbers  of live  fetuses/dam  In  the PC8
groups  demonstrated a significant  reduction  In  a dose-related  fashion  at
doses  >4 mg/kg  bw/day.  The average number  of Implants  was  reduced  In the 8
mg/kg  bw/day  group  and  fetal  resorptlons were  Increased in  the  8 and  16
mg/kg  bw/day  groups.  A significant dose-related  Increase  In  the Incidence
of  cleft palate occurred  In groups  dosed at >2 jig/kg bw/day.  An Increased
Incidence  of hydronephrosls was also found to be dose-related.

    In  an   effort  to demonstrate that PCBs may Induce mlcrosomal  hydroxylat-
1ng  enzymes  that  catalyze  the breakdown  of  steroid hormones,  Orberg  and
Klhlstrom   (1973)  Investigated the ability of Clophen A-60  to  affect  repro-
duction  in mice.   NNRI   strain  sexually mature  female  mice were fed  0.025
rag/day  Clophen  A-60 for  72-76  days.  Clophen A-60  was found  to lengthen the
estrus  cycle and to  reduce  the rate of nldatlon.

    Orberg  (1977)  failed to demonstrate  any  effect of pre- and postnatally-
admlnlstered PCBs  on the reproductive  performance of mice.  2,4',5-Trl-CB  or
2,2',4,4'.5,5'-hexa-CB was  fed  at levels of  0.05 mg/day  from day 5  of preg-
nancy  to weaning at post par turn day  22 to WWI strain mice.  The males and
02360                                V-53                             04/07/88

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females  exposed  to PCBs  In  utero and by lactation were mated.   No signifi-
cant differences were found  In conception rates and litter size.

    Orberg  (1978)  further  Investigated  the  effects  of 2.4' ,5-trl-CB  and
2.2',4,4'.5.51-hexa-C8  fed at two different dosage levels on reproduction 1n
mice.   NMRI  mice  were  treated with  0.05 or  0.5 ng tr1-C8/dayt or  O.OS or
0.50 rag hexa-CB/day beginning on  the first day of vaginal  plug and continu-
ing for 6 consecutive days.   Animals  exposed  to  the high dose of either con-
gener  had significantly lower frequencies  of  Implanted  ova  than the control
females.    Furthermore,  the  exposures  at  both  levels  had no significant
effect  on the frequency of  pregnancies or the number of implanted ova/preg-
nant female.

    Rabbits.   Vllleneuve  et al.  (1971a) found  rabbits  to  be  sensitive to
Aroclor 1254.  In  three  separate experiments, pr.egnant  rabbits  were treated
with  Aroclor  1254  at levels up  to 50.0 mg/kg bw/day by gavage  for  the first
28  days of  pregnancy.  An additional group of  four rabbits  was treated with
25  mg/kg  bw  on  days  7-28 of  pregnancy.   Dead fetuses,  resorptlons  and
abortions were Increased for groups treated with  Aroclor 1254 at doses >12.5
mg/kg  bw/day  for  the  first 28  days  of  pregnancy.   Rabbits treated  on days
7-28  of pregnancy with 25.0 mg/kg bw experienced fewer dead fetuses, resorp-
tlons   and abortions than what  were observed  In  50.0 mg/kg bw/day exposed
animals.  Two fetuses  from  dams  In the  12.5  ma/kg bw/day group had subcuta-
neous   cephalic  hemorrhages  and  cranial asymmetry.  Maternal   toxlclty  was
manifested  as death  of two  dams  in  the 50.0  mi/kg  bw  group and one dam in
the 25.0  mg/kg  bw group.   Other  evidence of miternal toxlclty consisted of
weight  loss  in  dams receiving  25 or 50 «g/kg  bw and  hepatomegaly In dams


02360                                V-54                            04/07/88

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receiving 10. 25  or  50 rag/kg bw.   Dams  treated with 25 mg/kg bw on days 7-28
of pregnancy exhibited decreased weight gain and hepatomegaly.

    Another  study  from  the  sane  laboratory  (Vllleneuve  et al.t   197lb)
reported  no  evidence  of   developmental   toxlclty  to  orally administered
Aroclor  1221  or  1254 at levels  of  1.0 or 10 mg/kg bw In  rabbits.   Nature
dams  were  exposed  to the  Aroclors for  the  first 28 days  of  pregnancy.
N1dat1on,  fetal  growth  and  development,  litter size and placentatlon were
all  similar to  control  rabbits.

     other  Species.   Mink  are especially  sensitive  to  the toxic  effects of
PCBs.    Feeding mink  levels  of  Aroclor 1242 as low as 10 ppm In the diet  for
8  months  resulted In  high mortality, while exposure at 5 ppm  caused  25X
mortality  and  reduced fertility of females (Bleavlns  et  al., 1980).  By  4
weeks,  Utters experienced  Increased mortality aod decreased litter blomass.
No teratogenlcUy was  observed.   Reproductive toxlclty  was  related to feto-
 toxlcUy rather  than Interference with ovulatlon  or nldatlon because fetal
 resorptlons were  found at  all stages of gestation.   In another  experiment.
 dietary  exposure  to  Aroclor  1016 at  20 ppm  produced  25% mortality  and
 reduced reproductive function  (Bleavlns et al.. 1980).  Kits  nursed  by dams
 fed Aroclor 1016  at  20 ppm had significantly lower  body weight at 4 weeks of
 age.   In addition,  higher  kH  mortality between  birth and 4 weeks of  age was
 also  noted.

     Aulerlch and Ringer  (1977) exposed mink to Aroclor  1254 1n the diet at  a
 level   of  2 pom  (see Table  V-9).  They observed a  reduction  In reproductive
 function  with  no apparent maternal  toxlclty.  In another  experiment,   dietary
  02360                               V-55                           °"07/88

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exposure to Aroclor  1Q16 at 2.0 ppra for 10 months had no efect  on reproduc-
tive parameters, kit growth, and adult and kit nortaUty.

    A  comparison  of  the  developmental  toxic  effects of  Clophen A-50  and
2,2',4,41.5,5f-hexa-C8  1n  guinea  pigs was performed  by Brunstroem et  al.
(1982)   In  three  separate  trials.  In the first trial,  groups  of  pregnant
Dunk In   Harley guinea  pigs were exposed to Clophen A-50 at  2.2 mg/day  for
days  16-60  of gestation.   Exposed animals received a  total dose of 100  mg.
In  the  second trial, groups of guinea pigs were exposed to a total dose of
25 mg  hexa-CB distributed over  days 16-60  of gestation.  In the  third  trial,
guinea   pigs  were  exposed to a total  of  100  mg hexa-CB over days  22-60 of
gestation.   All  dams were unaffected  by  treatment.   Significant  numbers of
abortions  and  dead  fetuses were  found  In  the  Clophen  A-50  group.   Mo
abortions occurred In the  other  treatment or control  groups.  According to
the  authors,  the  hexa-CB used  In these  trials contained <0.5 mg/kg  PCOFs.
They  suggested  that  PCBs  other  than hexa-CB  or possibly  PCDFs  or  other
contaminants  In  Clophen A-50  accounted  for  the developmental  toxlclty In
guinea  pigs.

    Hansen  et al.  (1975) Investigated the effects  of PCBs on swine  repro-
duction.   Sows  of  mixed breeding were fed rations containing 0  or 20  ppm
Aroclor  1242  throughout gestation  and nursing.  This study  indicates  that
exposure  to  Aroclor  1242 apparently  reduces  the  number   of   live  pigs
delivered/Utter.

     Two  laboratories  reported studies on PCB  toxlclty In nonhuman primates.
Truelove et al.  (1982)  dosed 60-day pregnant cynomolgus monkeys  with Aroclor

02360                               V-56                            04/07/88

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1254  at  TOO or  400 wg/kg  bw/day  continuously until a  termination of  preg-
nancy.   Monkeys  dosed at  the  100  ug/kg bw/day level delivered  term,  still-
born  Infants.   The monkey  dosed at the 400 wg/kg  bw/day level delivered  a
live  Infant  that  subsequently succumbed at 139  days  of age to  pneumonia.
Maternal   toxldty  was evidenced  as  fingernail   loss  and Impaired  Immuno-
competence  as   evaluated  by  tlter  developed  to  tetanus toxold  and  sheep
erythrocytes.

    A  longer-term and more  Intensive  study examined the  effects  of  Aroclor
1248  on reproduction  In  rhesus monkeys (BarsotH  et al.. 1976;  Allen  et al..
1979b,  1980).   Aroclor 1248 was fed to groups  of eight mature female  monkeys
weighing  -5.6  kg  at  levels of  2.5 or 5.0 ppm In  the diet  for  -18  months
starting  6  months before breeding  to  untreated males.   On the basis  of food
intake, the  total  Aroclor 1248 intake  was calculated to be 270+25  and 498+50
mq  for  the  2.5 and  5.0 ppm  diet groups,  respectively.   Analysis of  this
batch of  Aroclor  1248 revealed -1.7 ppm PCDFs.  This would have provided 4.4
and  8.7   yg  PCDFs/kg  In the  2.5   and  5.0  ppm Aroclor 1248  diets,  respec-
tively.   Treated  females  experienced  weight   loss  and  lengthened  menstrual
cycles  accompanied by altered levels of progesterone and estradlol.   Concep-
tions  were  normal  for both groups.   Monkeys  receiving 2.5  mg/kg delivered
five  live  Infants and experienced three  early  abortions or fetal  resorp-
tlons,   and  only  one  monkey  receiving  5.0 mgAg  delivered  a  live  Infant.
Adult  females  exhibited  signs  of  toxlclty.  Live  Infants had reduced  birth
weights and, after 2 months of nursing, exhibited facial edema,  hyperplgmen-
tatlon and  hair loss  and  palpebral edema and  acneform lesions  more severely
than  their  mothers.  Within the first  year, 3 of these  6 Infants had died.
 02360                               V-57                            04/07/88

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    Removing  treated  monkeys  from  treatment  for  1  year  allowed  them  to
recover  body weight  and permitted facial  lesions to heal.  Menstrual  cycles
had  returned  to normal.   These monkeys were  then  retired  to  control  males.
No  problems 1n  conceptions were encountered.   Full-term live Infants weighed
less  than  Infants  born  to control animals.  After  nursing  for 4  months.
Infants   from  previously  exposed  mothers  developed  focal  areas of  hyper-
pigmentation.

    Three surviving  Infant monkeys  from the first study (Barsottl and  Allen,
1975;  Allen and Barsottl.  1976; Allen  et al.. 1980} were subjected  to loco-
motor  activity and  learning ability tests from  6-24 months of  age (Bowman
and Helronomus. 1981).  These animals were Infants  of dams exposed  to diets
containing  2.5  ppm  Aroclor 1248  for  at least  6  months  before  breeding.
through  gestation and  3 months of nursing.   All PCB-exposed  infant monkeys
exhibited  hyperactlvlty  and  retarded  learning  .ability  when compared  with
offspring  (4)   of control  females.   Hyperactlvlty continued to  Increase  with
Increasing  age.   These  same  three  PCB-exposed  monkeys  and  3/4  control
monkeys  were retested  for hyperactlvlty  at  44 months  of  age.  At  this  time
the three  PCB-exposed  monkeys showed  significant hypoactlvlty  when  compared
with the controls.

     After  the  original  females had been removed  from  Aroclor 1248-contalnlng
diets  for  periods  of 6-18 months,  they were  rebred (Bowman and  Helronomus.
 1981).   No further  exposure to PCBs was allowed. Infants  from these females
also showed hyperactlvlty  when subjected to testing  at 12  months of age.
 02360                                V-58                           04/07/88

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    In  another study  (Allen  et  al.,  1979b), exposure of eight female monkeys
to  0.5  or  1.0 ppm  of Aroclor  1248  In  the diet  3  tines weekly  for  7 months
resulted  1n  total Intakes of -8  or  16  ppm of  Aroclor  1248  {see Table V-8).
These animals  showed  no Irregularities  of  menstrual  cycle or  alterations  In
serum estradlol  or  progesterone, and had normal fertility when  bred.   This
exposure  produced sow  fetal  loss.  Infant birth  weights  were  reduced and
nursing Infants developed focal areas of hyperplgmentatlon.

    Subsequently.  24  adult  female monkeys were  exposed to  diets containing
0.02S.  0.25  or 1.0 ppm Aroclor 1016  (Barsottl  and van Miller.  1984).  After
consuming the  PCS diets  for  6 months, the animals were bred 1n the 7th month
of  the  experiment.   Animals  continued consuming PCB diets  throughout gesta-
tion  and 4  months  of nursing.   The author reported observing  no abnormali-
ties  of  clinical,  gross or  reproductive parameters.  Infants  from  females
exposed to 1.0 ppm  diet exhibited significantly (<0.01) reduced birth weight.

HutaqenlcUy
    Hutagenlclty  studies  of  PCBs  In Salmonella tvphlmurlum are  summarized  In
Table   V-11.   PCBs  have  not  shown positive  results  by  themselves, but
evidence exists  that metabolic activation may  result 1n mutagenlc  metabo-
lites   which  may have  potential  activity with  DMA resulting  In  mutagenlc
responses  (Wyndham and  Safe. 1978; Wyndham et  al.. 1976; Hesse and Wolff,
1977;   Hesse et  al.,  1978;  Shlmada  and  Suto,  1978;  Staln1ck1 et al.,  1979;
Wang  et  al..  1979; Morales  and  Mathews,  1979).   Evidence also  exists  that
the position  of the chlorines  on  the blphenyl ring Influences  potential
mutagenlclty.   In  addition. It  appears that  S-9  fractions from  different
strains may  cause different  results.

02360                                V-59                            04/07/88

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o
IV>
LO
O»
O
                                                                               1ABK V II


                                                     SuMMry  of HuUqenUHy Assays of PCBs In Salaonella typhlnurlu*

lype of
Assay
Plate
Plate
Plate

Plate










Plate



Type of S 9
Activation
none
non Induced
Aroclor 1254
Induced
none
PCO*

3HC*
corn oil*
PCIC
3HC«
PCIC
3HCC
PCfC
3NCC
rabbit liver
•UresoMl
preparations

Results for
PCB Source PCI Dose
Aroclor l?44 0 4 400 pt/plate
Aroclor 1254 0.5-500 pi/plate
Aroclor 1254 0.5-500 »t/plate

4-«M»o-Ct 1-200 n9/plate




3.4.3'.4'-tetra- 5-200 nf/plate
CO
2.4.2'.4'-tetra- 5-200 n«/plate
CO
2.4.». 2'. 4'. »•- 5-200 m/plate
ke«a-CR
4-vono-CI 10-200 nf/plate

Aroclor 1221
2.2'.5.5'-tetra-C»
Aroclor 1254
IAI53?
-
-
•

NR»
.
NA
NA
NA
NA
NA
NA
NA
NA
NA
NR

NR
NR
NR
JAI439
•
-
„

NR
NA
.
NA
NA
NA
NA
NA
NA
NA
NA
NR

NR
NR
NR
S. typhlaurlua strains
1A98
-
-
0*

NR
NA
NA
NA
-
NA
-
NA
-
NA
-
NR

NR
NR
NR
Reference
1AIOO 1AI438
NA Stltoeny et al..
19/9
NA
NA

NR Schoeny. 1982
NA
NA
-
NA
-
NA
-
NA
-
NA
NR »• Mymtna* el al..
1976
MR •
NR
NR
             •At 0. 10. SO and 100 nt/plate

             •MM teil 414 not iMllcale Mnat strains Mere tested  for MUgenlclty without S-9;  results were reported as ne9atl«e.

             CSO nt/plate

             NA » Not applicable; NR » Not reported

             » . Positive; - ' MegatI**
 OB
 OD

-------
    Scnoeny  et  al.  (1979)  tested  Aroc'ior  1254  for  mutagemcUy  at  eignt
concentrations  ranging  from  0,5-500  iil/plate In  strains  TA1535,  TA1537,
TA98  and  TA100  of  S.  tvphlmurlum.  Aroclor  1254  alone,  activated by  S-9
hepatic   fractions  From  untreated  or  Aroclor 1254-lnduced  Sprague-Dawley
rats,  failed  to manifest  mutagenlclty.  Subsequently,  this  same laboratory.
recognizing  the  heterogeneous  nature  of  commercial  Aroclor,  conducted  a
study  of  the mutagenldty of four  separate PCB  congeners  (Schoeny,  1982).
Using  materials  of  99%  purity, eight doses  of  4-chloroblphenyl  and  five
doses   each  of  3,4,3',4'-tetra-CB; 2,4,2',4'-tetra-C8 and  2.4.6.2'.4'.6'-
hexa-CB  were tested  for  mutagenlclty  In  S.   typhlauMun (see  Table  V-ll).
Mutagenlclty was  not demonstrated with  any  of  these PCBs with or without the
addition  of  hepatic S-9  fractions.  In this sane study, the author likewise
failed  to demonstrate mutagenlclty of dlbenzofuran or  various polychlorl-
nated dlbenzofurans,  often considered commn contaminants of PCBs.

     Myndham  et  al. (1976) have  attempted  to relate  degree of mutagenlclty to
degree  of chlorine  substitutions on the  blphenyl  moiety.  Using  levels  of
 10.  50,   100   or  200 tfg/plate of  the   4-mono-CB,  Aroclor  1221  [average
 chlorine  content  1.15 (2  Cl/molecule)],  2,2',5.5'-tetra-CB (4 Cl/molecule)
 or  Aroclor  1254  (average  4.96 Cl/molecule),  these  authors  demonstrated  a
 pronounced mutagenlclty  (>2000  mutant  colonies/plate) of 4-mono-CB compared
 with  the more highly chlorinated PCBs.

     Heddle and  Bruce (1977)  examined  the  mutagenlclty of Aroclor  1254 1n a
 group of 61 potential mutagens  and compared mutagenlclty  with the  production
 of  cytogenetlc  effects   In  mice.   Aroclor  1254 was  found to be nonmutagenlc
 1n  the S. tvph1mur1um bloassay  and negative In both cytogenetlc evaluations.
 02360
v.61                             04/07/88

-------
S.  typhlmurium strains TA1535. TA1537, TA98 and TA100 dotn «Hn and -Uncu'.
S-9 activation were  tested.

    One  study examined  dominant   lethality  in rats  attributable  to  PCBs
(Green  et  al.,  1975b).  Mature,  random-bred  Osborne-Mendel  male  rats  were
given  Aroclor 1242 by gavage  In single doses of 625, 1250 or 2500 mg/kg bw.
In  a  second  study, Aroclor  1254 was given by gavage at levels of 75,  150  or
300  mg/kg/day.   Treatment   groups   consisted  of 100  animals  each;  negative
controls  were  treated  by gavage with corn  oil alone and positive  controls
were  treated  with  a  known  mutagen.  TEM.   Significant  fetal loss  occurred
only  In  TEN-treated  positive controls.    Similarly,  a  feeding  trial  with
Aroclor  1254  at  levels  of  25 or  100   ppn diet  for  70  days  produced  no
significant fetal  loss.   Positive controls were not used.

    Nllsson  and  Ramel  (1974)  reported  briefly  on  a  study  to  determine
clastogenlc effects  of  PCBs  1n Drosophlla  reelanogaster  carrying  sex-linked
color  markers.  Clophen  A-30  (30% chlorine) or Clophen  A-50 (50% chlorine)
was  Incorporated  Into  the  media at  250  or 200 mg/i,  respectively.  Treat-
ment  was given  during the  entire  larval period  or  during  1 week  to  adult
flies.   These levels were chosen on  the  basis  of  the results of preliminary
trials  using  levels  of  62.5,  125,  250 or  500  mg/i  substrate  of Clophen
A-30  or  levels  of  25. SO.  200  mg/i  substrate of  Clophen  A-50  to determine
the  toxic  effects of  these  PCB  products  on larval development.  Differences
between  the  Clophen A-30 group and  Its  controls  were not significant.  The
incidence  of  XO  males 1n  the Clophen A-50  treated  group was significantly
(p<0.01)  greater than Us controls.   A  larger  Clophen A-50  trial was  there-
fore  performed using  20  mg/i substrate  larval  treatment of parental  males.


02360                               V-62                             04/07/88

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These  authors  concluded  that  the products  tested  did not  indicate  c'.asto-
genlc  effects,  but  pointed out  that  these  products  differed  from  conrner-
clally  available PCB  products  In that the  Impurities ordinarily  present  in
commercial  products  were  not present  here.

    A  cytogenetlc  study  of Aroclor  In rats was performed  by Green et  al.
(1975a).   Aroclor  1242  was given orally  1n single doses  of  1250,  2500  or
5000 mg/kg bw or at multiple doses of  500  mg/kg/day for  4  days  to groups  of
eight  male,  random-bred Osborne-Mendel  rats.   Aroclor  1254  was orally admin-
istered  at 75,  150 or 300 mg/kg/days  for  5  consecutive days  to  groups  of
eight  rats.   The  animals were sacrificed  24  hours after the  last  dose  was
given.   Aroclor 1242,  the more  toxic  product,  did not  produce cytogenetlc
damage  in spermatogonla or In cells  from  the  bone  marrow.   Aroclor 1254  did
not  show any  evidence of cytogenetlc  damage In  the bone marrow cells.   The
effects  of this product  on spermatogonla were  not  evaluated.   The number of
bone marrow cells  observed In  mitosis appeared  to  be depressed (p<0.05)  In
the  Aroclor 1254 groups  at the mid  (150 mg/kg/day) and high {300 mg/kg/day)
treatment  levels.   Mitosis  In   bone  marrow cells  of  Aroclor  1242-treated
groups  did not appear  to be depressed, but spermatogonlal mitosis did appear
to  be  reduced  In  the  500  mg/kg/day  for  4 days  (p<0.01) and  the 5000 mg/kg
(p<0.05)  groups.  A later cytogenetlc study of bone marrow and spermatogonla
1n  male   Holtzman  rats   (Garthoff  et  al.,  1977) confirmed   the  negative
findings  of the previously cited  study.

     Likewise,  OlkshUh et  al.  (1975),  In a more comprehensive study of  the
effects  of orally administered  Aroclor 1254 on rat testls, found no signifi-
cant  evidence  of  chromosomal  aberration caused  by PCBs.  Aroclor  1254  was


02360                               V-63                             04/07/88

-------
administered by  gavage to 18 mature, male Sprague-Oawley rats at  ine  
-------
    PCBs  have  been tested for cardnogenldty In rats and  1n mice  by  Incor-
poration  of  particular  commercial  PCB  preparations  Into  the  diet.   Eight
separate  PCB  feeding  studies and  one  study of  topical  application to  the
skin  are considered.   Studies  in which  the  PCB preparations were  adminis-
tered  1n  conjunction with other agents are also discussed In this  section.

    Carc1noqen1c1ty.   The  feeding  studies  demonstrate  the  cardnogenlcHy
of  some  commercial  PCB preparations although 1t  1s  not  known which of  the
PCB  congeners  In  such preparations,  or which  of  their  metabolites,  are
responsible for  the  cardnogenlcHy demonstrated  by  the  tests.   The  liver
appears   to  be  the primary  target  organ  that  exhibits  a  tumorlgenlc  and
carcinogenic response  to PCB exposure.   The studies reviewed had. In varying
degrees,  shortcomings  that  modify the meaning of the results and the contri-
bution the study made  to the overall assessment  of  PCB cardnogenlcHy.

     Rat  Studies  « PCBs have  produced  a  variety  of oncogenlc  effects  in
the rat  liver.   Historically, adenoflbrosls  was  the first  hepatic lesion to
be  described  In animals chronically exposed to PCB  mixtures  (Klmbrough et
al..  1972;  Klmura  and  Baba.  1973).   Klmura and  Baba  (1973)  studied Kanechlor
400 Incorporated  Into  the test diet of male  and  female Oonryu rats fed diets
 Initially  at  38.5 ppffl  and  Increased periodically to an upper  limit  of 616
ppm to  keep pace with  body weight  gain.  The upper  level  resulted 1n  severe
 body weight loss  and  was accordingly reduced to 462  ppm  for  the  remainder of
 the  trial.   The  duration   of  the  study ranged  from 159-538  days  for the
 different  animals, but  there were two  Intervals  of 4 weeks each  during which
 02360                               V-65                             04/07/88

-------
the Kanecnior  feeding was stopped so that the total feeding of Kanecnlor  »a;
-400 days.   Female rats consumed 700-1500 mg and male rats consumed 450-1800
mg Kanchelor 400  by  the end  of  the  trial.

    Adenomatous  nodules In the liver were found  In 6/10 female rats that  had
consumed  >1200 mg of the Kanechlor  400.   The females that had received <1200
mg Kanechlor  400 and the males had  no such lesions.  All treated animals, of
both sexes,  showed fatty degeneration of  the liver.

    It  Is  Important 1n  evaluating  this study  to consider the  weight  data
reported  by  the Investigators.   These data  were  sufficient to determine that
the treated  animals  showed weight  losses of  >20%.  Such decreases In weight
gain may  Indicate that  the  MTD was  exceeded.   Table V-12 shows the percent-
age of weight  gain for  various  doses and  for controls.

    It  1s clear from these weight data that In all cases the treated animals
received  doses of  Kanechlor  400 that exceeded the MTO  as  judged by current
criteria.   Toxic  symptoms not  only  Included failure of  rats  to gain weight
at a  normal rate  but 80% of the females and 10% of the males showed deplla-
tlon;  70% of  the  females and 60% of the males had lung abscesses;  30% of the
females  and 10%  of  the males had 1ntracran1al  abscesses; fatty degeneration
of  the adrenal  was  also  found In  treated animals.  These  lesions were  not
reported  1n the control animals.

    In summary,  the study was too short and the  exposure  level  too high to
provide  a good  experimental  basis  for  the  determination of the carcinogenic
potential of  the PCB preparation used.


02360                                V-66                            04/07/88

-------
                                  TABLE  V-12

    Change 1n Rat Body Weight Following  Chronic  Exposure  to Kanechlor 400*
PCB 1n Diet
   (ppm)
                      No.
                    Animals
             Initial
             Weight
               (q)
               Final
               Weight
                (9)
 Percent
01fference
     450
     900
   >1200
  Control
1
1
8
5
HALES

  199
  192
  210
  205
                                                     309
                                                     273
                                                     259
                                                     462
    +55

    +23
   +125
'Source: Klmura and Baba, 1973
                                   FEMALES
700
1100
>1200
Control
1
3
6
5
158
160
196
196
137
162
196
323
-13
0
0

02360
                                    V-67
                                             04/07/88

-------
    Ito  et  ai. (1974)  have  Investigated  Kanecrnors  3CO.  4GC  and  500 •" na  e
Wlstar  rats by administration  of  100,  500 or  1000  ppm of each  of  the test
preparations  1n the  diet  for 28 weeks  to  1  year.  The  Initial  weights for
each group  and their  respective  weight gains are given  1n Table V-13.

    The  figures Indicate  that  the  weight gain was  Inversely related to the
dose  of  Kanechlor used  for  the  40- and 52-week  exposure groups.   In all
cases  (for  52-week  exposure) the average  percentage  weight  gain  was  below
that  observed  with  controls,  but  only  marginally below  controls  for  the
lowest  dose groups of  100  ppm.   The  weight  figures  Indicate  that at 100 ppm
for  52 weeks,  Kanechlors  300 and 500 did  not  produce  a  toxic manifestation
represented In weight loss.  At  the 100 ppm  level  the liver  weights were
(expressed  as  percentage  of  body  weight) 2.4%  for  controls, 2.9% for the
Kanechlor   300  and 3.7%  for the Kanechlor  500.   There was  no amyloldosls,
cholanglofIbrosls   or  flbrosls  at  100  ppm  for   these  two  Kanechlors.   At
higher  doses oval cell proliferation, bile duct proliferation, fatty changes
and  cellular hypertrophy were seen.  Since the 100 ppm level  did not seem to
produce other  toxic  manifestations  the  finding  of hepatic  nodular  hyper-
plasla,  which the   Investigators  considered  to  be  preneoplastlc.  In 3/25
animals treated with Kanechlor  500 and  1/22  animals  treated with  Kanechlor
300  1s  noteworthy.   The  study  does  not provide  data  on  the progression of
preneoplastlc to neoplastU effects since 1t  was  terminated after 52 weeks.

     In  the case  of  Kanechlor 400, all  three of   the dietary  levels produced
apparent abnormal  weight  changes,  as an  Increase of  23%  In  weight over  the
40-week period  Is lower than would  be  expected.   At  the  highest  dose,  3/10
of  the animals  showed nodular  hyperplasla  and  at  100   ppm  2/16  cases  of


 02360                               V-68                             04/07/88

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                                  TABLE  V-13

            Change 1n Rat  Body  Height Following Chronic Exposure to
                        Several  Kanechlor Formulations*
Product

K-500
K-300
Control

K-400
Control

K-400
Control
ppm

1000
500
100
1000
500
100
0

1000
100
0

500
0
Initial
Weight Gain
Average
5 2 -Week Exposure
126
123
124
128
135
125
130
40-Week Exposure
163
175
NA
28 -Week Exposure
188
NA
Percent
Increased
Average
Cases
129
207
300
228
239
304
325
Cases
23
129
NA
Cases
53
NA
No. Animals

13
16
25
15
19
22
18

10
16
NA

8
NA
'Source: Ho et al.,  1974

NA = Not applicable
02360
V-69
04/07/88

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nodular  hyperpiasla  appeared.   These  findings  were  made at 40  weeks.   T.,S
study  was flawed  wHh  respect  to short duration  and small  number  of animals
used  1n  the  experiment.

    While the  Investigators  considered hepatic  nodular  hyperpiasla  to repre-
sent  preneoplastlc  lesions and. therefore,  the tumorIgenUHy of  the  Kane-
chlors,   the  experiment  falls   short  of  demonstrating  tumorlgenlclty.   The
study  1s Inconclusive  because  of the  short  duration, small starting numbers
of animals  1n  each group and still smaller numbers  of animals  at risk.   How-
ever,  the nodular hyperplasla  that appeared as early as 40 weeks  precludes
adding this  study to a negative finding.  In addition,  effectiveness  of  the
Kanechlor 1n producing tumors  was not a function of the level  of  chlorlna-
tlon  of  the  PCBs  In the mixture.

    Klmbrough  et  al.   (1975)  was the  first   to  report that  Aroclor  1260
unequivocally  produced  hepatocellular  carcinomas  In  female Sherman  rats  when
100  ppm  dietary  level  was administered  for  21 months  (630  days).   In  this
study,  complete  hlstopathology  on all major  organs was  performed  on 200
treated  rats.   There was  a slight but statistically  significant decrease in
weight gain  after 3 months  1n the treated  group.  The  difference  1n weight
gain  was not  large  enough to  consider  the  dose  level  to  have exceeded the
MTD.   There  were  no other  definite dose-related signs of toxldty.

    Hepatocellular carcinoma was found In only  0.58% of  the controls  (1/173)
and   1n   14%   (26/184)  of  the  treated  animals.   In  addition, while  78%
(144/184)  of  the treated animals developed  neoplastlc liver  nodules, no
control   animals  did.   All  1n all,  there was <1%  Incidence  of neoplastlc
liver lesions  In  controls  as compared wUh 92% (170/184) 1n treated  animals.
02360                               V-70                             04/07/88

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          only  a single  dose  was  selected  and on', y femaie an'roa's emp  oye:,
the  study  demonstrates  hepatocardnogenlclty  of  Aroclor  1260  In   female
Sherman  rats.   Klmbrough et  al.  (1972),  using  10 animals of each sex  given
each of  three doses  (100.  500  and  1000  ppm)  of  Aroclors 1260 and 1254.  did
not  produce either  neoplastlc  ncjules or  hepatocellular  carcinoma   In  this
same strain  of  rat  when the study ran less  than  a year.   In  this preliminary
study Aroclor  1254  produced adenofIbrosls  In 10/10 male  rats.   This  finding
suggests  that  hepatocellular  carcinoma results when  the dose Is  low enough
to permit  the  study to be run for a sufficient  length of time without Inter-
fering  toxlclty.   The  14%  Incidence of  hepatocellular  carcinomas   1n  the
large  experiment also  explains why  It  would be unlikely to have  detected
this  cancer In  experiments  run  on a  small  number  of  animals:  14X  of  24
animals  would  be 3-4 animals  and  hepatocellular carcinoma  would only have
appeared  after  about a  year.  Experiments  that  reduced  the  number  below 24
before  the earliest  time  to  tumor would not be  expected  to  yield a  detect-
able carcinoma  Incidence.

    Even  though this experiment  Is probably  an  adequate animal  study to use
for  risk assessment.  It also  has  a  problem 1n  that a  mixture  of compounds
was  tumoMgenie.   The  active  Ingredlent(s)  In  the  mixture  Is  most  likely
limited  to a few of the molecular species.  A tumor yield of  14X,  which Is
due  to  the presence  of  a molecular species that constitutes only a   fraction
of the  composition  of the administered material,  would be considered  potent.

    The cardnogenldty of PCBs was Investigated 1n a study sponsored  by NCI
(1978).    Groups  of  24  F344  rats  of each  sex  were   fed  diets containing
02360                                V-71                             04/07/88

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Arodor  1254  at 25. 50 or  100  ppm  for  104-105 weeks.   Proliferate  '.85'C'--.
1n  the  liver  were  not  found  In  controls  but  were  found  in  the  treated
animals as shown  in Table V-14.

    The  data  Indicate a  dose-related nodular  hyperplasla  In both  sexes  and
three  cases  of  hepatocellular carcinomas among treated males at  the  100  ppm
dose.   Although the  Incidence  of hepatocellular  carcinomas was not  statis-
tically significant.  1t Is  Important to consider  the following points.

    In  a  preliminary study  using 10 Sherman rats of each  sex,  Klmbrough  et
al.  (1972)  did  not produce  hepatocellular carcinomas with  doses  of 100,  500
or  1000 ppm  administered for a  duration  of less  than  a  year.  But  In  the
other  study   {Klmbrough et  al.,  1975),  which lasted 2  years,  female  Sherman
rats  had  a 14% Incidence of hepatocellular carcinoma as a  result  of  treat-
ment  with 100  ppm Aroclor  1260.   In the  NCI  (1978) study  the  Incidence  of
hepatocellular  carcinomas   In  males at  100  ppm  group  was  3/24; only  20
animals  survived.   Since  Incidence  1s more  precisely  expressed  as  the ratio
of  the  number of  animals  with tumor/number of animals at risk, the figure Is
probably  closer to 2/20  or  10%.   In either  case, the Incidence of 8-10%,  or
even  14%, as was  found 1n  the  Klmbrough  et al.  (1975) study,  would  not  be
statistically  significant  with  group  sizes of  24  animals.   The  test  was
simply  not sensitive enough to detect statistically significant differences
at  this level  of  potency.   The  lack of statistical significance In the NCI
study  has to be  understood 1n  terms of the highly  Insensitive nature of the
assay  used.  A system that employed 24  animals  per group  would  require a
true  difference  In  Incidence between controls and treated groups  of 35% In
order  to have  a  90%  chance of being significant at the p»0.05  level.  A 90%
chance of  finding a  significant  difference at  the  p-0.05  level  when the

02360                                V-72                            04/07/88

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                                  TABLE V-14



     Proliferate Lesions of the Liver 1n Fischer Rats Fed  Aroclor  1254*
Hales

Controls
25 ppm
50 ppm
100 ppm
Hepatocellular
Carcinomas
0
0
1/24
3/24
Hyperplastlc
Nodules
0
5/24
8/24
12/24
Females
Hepatocellular
Carcinomas
0
0
1/24
2/24
Hyperplastlc
Nodules
0
6/24
9/22
17/24
'Source:  NCI,  1978
02360                               V-73
                                                                    04/07/88

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difference  between  controls and treated Incidence Is of  tne  oraer  of  9%.  =5;
H 1s  In  this study, would require  117  animals  each  for  control  and  treated
groups.   It 1s therefore a  question of  biological significance,  rather  than
statistical   significance.   In  determining  whether   an  8-10%  cancer  yield
represents  a  positive  finding.  Although  this  yield could  not  be used  to
demonstrate the  carclnogenlclty of  the  test agent,  1t is  Indeed  consistent
with  the  14% yield obtained  by Klmbrough  et al.  (1975) and  lends  support  to
that  finding.

    The  NCI  (1978)  data  were re-examined  by  Morgan  et  al.  (1981)  with
respect  to  gastric  adenocarclnomas  that  occurred   In  the  rats.   All  191
stomachs  of rats from  that study were  available  for further sectioning and
examination.   Sectioning  at  the  pylorlc  Junction  revealed  "lesions*  upon
gross  examination  1n 3/47, 5/48, 8/48 and 17/48 of rats fed diets containing
0, 25, 50  or  100  ppm Aroclor  1254, respectively.  There  did  not  seen to be
sex-related differences 1n the Incidence of these lesions.  Hlstologlcally.
adenocarclnomas  were  found  In 1,  3  and  2 of  the  stomachs  Identified  as
having lesions In  the  25.  50 or 100 mg/kg  Aroclor 1254 diet groups,  respec-
tively.   None were detected  In  the controls.  Remaining lesions were Identi-
fied  as  "metaplasia,* the  significance  of which was  not stated.  Determining
the  occurrence of  gastric adenocardnoma In control  rats to be <2% (0/47),
the  authors  calculated the  likelihood of  six  carcinomas  occurring  In the
stomachs  of  144 treated  animals to be  <5%  1f occurrence  was random.   Morgan
et al. (1981) concluded that  Aroclor 1254 may produce adenocarclnomas 1n the
stomachs  of rats.
 02360                               V-74                            04/07/88

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    A  recent  paper  reevaluat*ng mis same  study  (Ward,  i985/,  c'tes  a  :ose-
related  depression  of  body weight  gain  for  both  sexes  and  a  decrease  in
survival  for  male  rats.   Increased Incidence  of. gastric  Intestinal  meta-
plasia  and adenocardnoma  was  confirmed.   Hepatocellular  adenomas,  carci-
nomas  and  eoslnophlllc  and  vacuolated  hepatocellular  foci  were usually  found
1n  dosed  rats  only and  in these  animals  their numbers  were significantly
Increased.   The  conclusion of  the author  was  that  the  appearance of  the
potentially preneoplastlc lesions  and  tumors  In  the liver  and stomach of the
PCB-treated rats  did not occur  spontaneously.

    The  hepatocarclnogenlc  effect  of  dietary   administration  of   100  ppm
Clophen  A-30 or  A-60  (Authors  stated that  Clophen  A-30  and A-60  did  not
contain  chlorinated dlbenzofurans) for 832 days was  tested In male weanling
rats   (Schaeffer  et al.,   1984).   Twenty-one percent  of  the Clophen  A-60
treated  animals  that died  In  the  first  800  days  experienced  hepatocellular
carcinoma, while only  2%  of  the animals  died  with  similar  lesions  m the
Clophen  A-60.  Preneoplastlc lesions were  first  observed  after day 500 fol-
lowed  by  tumors  after  700  days on the PCB diets.  An Increase In neoplastlc
nodules  and  hepatocellular carcinomas was observed  to  Increase with  time.
Statistically  significant  Increases   of   hepatocellular  carcinomas   were
observed In male rats  fed  Clophen  A-60.  However,  rat fed  with Clophen A-30.
had  a  statistically   significant   Increases  of  neoplastlc  nodules or/and
hepatocellular  carcinomas  together.  Interestingly,  the total  mortality rate
and  the Incidence  of   thymoma  and  Inflammation  of  the genital/urinary  tract
 In  the  experimental animals  was  reduced  when  compared  with the controls.
This   protective  effect   has   been  seen  In  other  halogenated   aromatic
hydrocarbons (Koclba et al., 1979).


02360                               V-75                             04/07/88

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    Two points  should  be  made  In  regard  to  this  study.   First, the itj-2/  -as
done  only  In males, and  females  appear  to  be more sensitive  to  the  tumoM-
genlc  effects  of PCBs  (Klmura and Baba.  1973;  Morback and  Ueltman.  1985).
Second, the  study  was  conducted In PCB mixtures  that are  apparently  free of
dlbenzofurans.

    In  the  Norback  and  WeItman   (1985)  study,  Sprague-Oawley  rats were
selected  because of  low  Incidence of  spontaneous liver  tumors.   Hale  and
female  weaning  Sprague-Oawley rats  Initially  weighing  100  g were  divided
Into  two  groups of  70  males  and 70  females.    They  were  fed   basal  diet
(Purina  rat  chow,  St.  Louis, MO)  mixed  with   corn  oil  (a  PCB mixture),
Aroclor  1260 (Monsanto  Chemical  Co.,  St. Louis,  MO)  at  a  concentration of
100 ppm  for  16 months and  50  ppm  for  an additional 8 months,  followed by a
control diet for 5  months.  A  control  group  received  a  basal diet with added
corn  oil   for  18 months  and  basal diet  alone  for  an  additional  5  months.
Both  groups  received  water  ad  libitum.   Sequential  morphological  changes
were  evaluated   to determine the  progress of liver lesions.   The  medial  and
left  lobes  of  the liver  of  10  etherized  rats  (2  male  controls, 2  female
controls,  3 male  PCB-treated, and 3  female  PCB-treated  rats  for each  time
period)  were   removed  at  1,   3,   6,  9.  12,  15  and   18 months.   Partial
hepatectomy  was performed  once per animals  In  these groups.  At 24 months
similar  groups  and at   29  months all   remaining  animals were   sacrificed.
Throughout the study moribund  rats were  sacrificed.  At  death all rats  were
necropsled.   Selected organs  were prepared  for  microscopy.   The sequential
morphologic  changes were evaluated throughout the study and results are pre-
sented In Table V-15.   In the  PCB-exposed group the following  hepatocellular
lesions  were  developed  In  sequence:   centrolobular  cell hypertrophy at 1
month, foci  of cell   alteration  at  3 months, areas at  6 months, neoplastlc

02360                               V-76                            04/07/88

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o
to
                                                      I ABU  V 15



                Progression of Preneoplastlc and Neoplastlc  Hepatocel lular Lesions In Male and lemale

                                    Sprague Dawley  Rats  Exposed to Aroclor  l?60a'b
Number of Livers with Lesions
Lesion

Focus
Area
Neoplastlc
nodule
Trabecular
carcinoma
Adenocarclnoma
1 Month
M
0
0
0

0

0
F
0
0
0

0

0
3 Months
M
2
0
0

0

0
F
»
0
0

0

0
6 Months
M
3
1
0

0

0
F
3
0
0

0

U
9 Months
M F
3 3
? 1
0 0

0 0

0 0
of Each Ihree Sampled
12 Months
H
3
0
f>

0

0
F
3
3
1

0

0
l!> Months 18 Months ?4 Months
M F M F M F
33 33 33
1 3 0 :< :» 1
u 'j o :i i i

01 0 2 0 ?

U U U U U
     ^Source:  Norback  and Ueltman.  198b



     blhese lesions  were not  present  In sequentially  sampled  control  liver,
oo
oo

-------
nodules  at  12 months, traDecular carcinoma at  15  montns.  and adenocar:'"oma
at  24  months.  These  lesions  were  not present  in  sequentially  sampled  con-
trol liver..  In  addition,  simple and cystic chloangloma at 18 and 23 months.
respectively,  and  adenofIbrosls at  22 months were  present.   HHh the excep-
tion  of  hepatocyte  hypertrophy and  adenofIbrosls,  all   lesions  contained
cells  that were  positive  for  gamma glutamyl  transpeptldase  activity.   The
percentage  of  animals  with  hepatocellular neoplasms  occurring  In  animals
that survived for  18 months or  longer  are presented In Table V-16.   Females
had  the highest Incidence  of  hepatocellular  neoplasm;  >95X developed tumors
(45/47,  1/49.  p<10~«).   Few  males developed  tumors   {7/46.  0/32.  p=0.02).
neoplastlc  nodules were present  In 11X and hepatocellular  carcinoma  In 4%.
Only  one hepatocellular  neoplasm occurred 1n  female  control rat and  there
was  none In male control animals.  The Incidence of hepatocellular neoplasms
1n  females  was strikingly greater than In males.  In conclusion. Norback and
Weltman (1985)  found positive hepatocellular  carcinomas  In  male and female
Sprague-Oawley rats  fed  Aroclor 1260 In  the diet for a  period  of  2 years.

     House   Studies — Kanechlors  500,  400 and  300  were administered to male
dd  mice for  32  weeks at dietary levels of 500. 250 and 100  ppm  (Nagasaki et
al.,  1972).  The nine different  experimental groups had 12  animals/group and
the controls had 6 animals/group.   All of  the  animals  survived  the  entire 32
weeks   of   the  test  and  there  was  no  apparent  weight  difference  between
control and  treated animals  although  liver  weight as a  percentage of  body
weight was elevated  1n all treated groups.

     In  the first  report of this experiment by  Nagasaki et al. (1972) results
were given as grossly observable nodular  hyperplasla  1n  7/12 (58.3X)  of the
animals fed  500 ppm of the Kanechlor  SCO.  Microscopic examination revealed

 02360                               V-78                             04/07/88

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                                 TABLE V-16
           Incidence of  Hepatocellular Neoplasms 1n Male and Female
                 Sprague-Oawley  Rats Exposed to Aroclor 1260a
                                 % Incidence  In              % Incidence In
                                 Treated  Animalsb            Control Animals0
Number of Animals
M F
46C 47d
M
32C
F
49e
Trabecular carc1nomaf           4(2)        40(19)            0       0

Adenocarc1nomaf.9               0           51  (24)            0       0

NeoplastU nodule only         11 (5)         4 (2)             02 (1)

Negative                       85 (39)       4 (2)            100      98 (48)


^Source:  Norback and  Weltman. 1985

t>F1gures  1n  parentheses  denote number of animals that survived >18 months.

clncludes 8  animals  that had  received a  partial  hepatectomy  during  the
  first  18 months.

dlncludes 7  animals  that had  received a  partial  hepatectomy  during  the
  first  18 months.

elncludes 10  animals  that  had  received  a  partial  hepatectomy  during  the
  first  18 months.

fAn1mals  containing neoplastlc  nodules plus  carcinoma  were  only  Included
  In the carcinoma category.

9An1mals  with  trabecular carcinoma  and adenocardnoma were  only  placed In
  adenocarclnoma category.
 02360                               V-79                             04/07/88

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5/i2  (41.7%)  of  these animals nad  hepatomas.   There *ere no  tumors  'n  :^e
control  animals  or  other  test groups.   In a  more  detailed report  of  this
experiment  Ito  et al.  (1973)  gave  the  yield of liver tumors as 7/12 (58.3%)
liver nodules and 5/12 (41.7%) hepatocellular carcinomas.

    This  study   demonstrates  that   Kanechlor   500  Is  capable  of  producing
hepatocellular  carcinoma 1n male dd mice when  given  at  500 ppm 1n the diet.
The  carcinogenic potential of the Kanechlor 500 1s qualitatively demonstrat-
ed  but  quantitative application of  the Information obtained  requires  some
considerations  not  Immediately  obvious  from  a statement  of  exposure level
and  tumor  yield.  The  composition  of  the Kanechlor 500  was  given  as  55%
penta-CB,  26.5%  tetra-CB,  12.6%  hexa-CB and 5.0% d1-CB.  Kanechlor products
contain other halogenated  aromatic hydrocarbons Including PCOFs.  The conse-
quences of these contaminants on the process  of  cardnogenlclty of the PCB
mixture Is unknown; however,  the findings  of hepatocellular carcinoma in the
study of Clophens  A-30 and 50 (devoid of  PCOFs) 1n  rodents (Shaeffer et al.
1984)  Indicates  that  PCB  mixtures  alone  are  capable  of  producing  hepato-
cellular carcinoma 1n rodents.

     Klmbrough  and  Under  (1974)  fed   Aroclor  1254  to  two groups  of  male
BALB/CJ mice.    There  were 50 mice  per treatment  group and  two  groups  of
control mice (50 animals each).  The  treated groups  each received  300 ppm of
Aroclor 1254 1n their  diet;  one group received the PCB-contalnlng diet for
 11 months  and  the second group  received the PCB-contalnlng diet  for 6 months
 followed  by  a  5-month recovery period  1n  which  they received  a  normal  diet.
 There  were a large number of deaths 1n the experiment  that were a  result of
 02360                               V-80                             04/07/88

-------
 animal  housing  conditions  and  were not due  to toxlcity.   At  the  end z~  "'
 months   the  surviving  animals  were  sacrificed.   Only  those  animals   that
 showed  gross abnormalities  were  examined microscopically.

     The livers of animals  treated  with  the  Aroclor  congeners were enlarged.
 Control  animals  had  liver  weights  that  were, on  the  average, 6X  of their
 body  weight.  Treated animals  had livers  that were 7.5X of their body weight
 for  the group  exposed for  6 months and  25.5X of  their  body weight for those
 exposed  for  11 months.  Livers  of  treated  animals  showed  multiple abnormal-
 ities  Including  abnormal  porphyrin metabolism as  Indicated by  UV  fluores-
 cence.   Adenoflbrosls,  a possible  premallgnant lesion,  was also found among
 treated mice.

    At  the  end  of  11 months  the surviving animals were  sacrificed  and  the
 Incidence  of tumors of the liver was  noted:   0/34  and  0/24 for the two con-
 trol  groups and  9/22 (40.1%)  (10  hepatomas  1n  9  animals)  In  the  11-month
 exposure  group;  1/24 (4X)  of  the animals In  the 6-month  exposure group  had
 hepatomas.  It  should be  noted  that the 8AL8/CJ mouse  has  a  low spontaneous
 Incidence  of hepatoma strain.

    The  experiment  provides positive  evidence that Aroclor  1254  Is  capable
 of  producing a 40% Incidence  of hepatoma  In  male  BALB/CJ mice at  a  dosage
 level of  50 rng/kg/day given for  11  months.   The  study provides confirmatory
 evidence of  the  carclnogenlclty  of  commercial  PCB mixtures In mice.   In this
 case  300  pptn  Aroclor  1254 produced  a 40X  incidence  of  hepatoma In male
 BALB/CJ  mice In 44 weeks,  and  1n the Ho et  al.  (1973)  study  Kanechlor  500
at  500  ppm  in  the diet for  32 weeks produced  a  40X  Incidence  of  hepato-
cellular carcinoma  1n male  dd mice.
02360                               V-81
04/07/88

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     The  mouse studies, therefore, give  strong  evidence  of  ?C8 care •nogeri % ;-
 Uy.   Table  V-17  summarizes the  findings  on  the  PCS  feeding  studies  with
 respect  to  liver tumor1gen1c1ty and carclnogenlclty.

 Summary  and Conclusions
     Several  animal  bloassay studies were of  adequate quality  to  assess  the
 carcinogenic  potentials  of  specific  commercial  PCS mixtures.    The  early
 bloassay studies of  PCBs  conducted by  Klmura  and  Baba (1973),   Ito  et  al.
 (1973)  and Klmbrough  and  Under  (1974) were  all  Inadequate  to  assess  the
 carcinogenic  potential of  PCBs  because of  small  group  size or  period  of
 exposure extending  for  <1  year.   In  particular, the Ito  et. al. (1973) study
 In  which dd  male  mice fed  Kanechlor  500 at  550 ppm for  32  weeks produced
 hepatocellular  carcinomas.   The   study  by  Klmbrough and  Under  (1974)  in
which  50 BALB/CJ male  mice were  fed  diets  containing  300  ppm Aroclor  1254
 for  11   months was  suggestive that  Aroclor  1254 was  producing a carcinogen
 effect  1n  liver.  Of  the  22 animals surviving PCB  treatment  for  11 months.
 all  had  areas  of  adenof 1bros1s  1n  the liver,  and  7 had  hlstologlcal ly
 Identified  heptomas.    In  a  long-term  study  by  Klmbrough  et. al.  (1975),
 Sherman  strain female  rats  fed  100 ppm Aroclor  1260 1n their diets  for  21
months   Induced   statistically   significant   Increases   of  hepatocellular
carcinomas  (26/184)  and neoplastlc  liver  nodules (144/184).  Only  1  of  173
control  animals  developed  a  carcinoma; no neo-  plastic nodules were observed.

     In  the cancer  bloassay (NCI, 1978)  study, where 24 male  and 24  female
 Fischer  rats/group were  fed diets containing  0,  25. 50 or  100  ppm Aroclor
 1254,  although  dose-related  Increases 1n  the  nodular  hyperplasla  were
observed,  there  was   no  statistically  significant   Increases  of  neoplastlc


02360                                V-82                            04/07/88

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o
f\J
CO

o
                                                                            I ABU  VI)

                           Effects on liver Tumor Igenes Is  and Carclnogenesls:  feeding Studies Using Various Cummer tU) PCB Preparations
           Species/
          Strain/Sex
  Agent
  Duration
Exposure
 (PM-)
                                                                        No.  AntMals
             Results and CoMent
                                                   Reference
         Bats/Sherman
         IN
Aroclor
1760
90 weeks
                                                               100
             200/group
OB
         Rats/Sprague-
         Dawley  (Mf)
         Rats/Fischer
         344  (Wf)
         Rats/Oonryu
         (NU)
Aroclor
12M
Aroclor
12S4
Kanechlor
40Q
29 months
 100 for     70/group
 It Months.
 SO for
 8 aonths.
 none for
 S Months
                                         104-10S weeks
                      100
                       SO
             24/group
                                         22-77 weeks
                   38-4*2      10/group
Hepatocellular carcinoma 14X (26/184) com
pared with O.S8X (1/173) controls.  78X neo
plastic nodules compared with 0  In  controls,
no other treatment-related toxicIty, study
well done but limited to single  dose and to
females: shows carctnogenlclty  In female
rats of Aroclor 12kO.

95X hepatocellular tumors In female rats
45/41, IS* In Male rats 7/4k
In Mies at 100 pp«. 8-10X hepatocellular
carclnoM.  Not statistically significant
but study design would have required  3SX or
greater Incidence for statistically signifi-
cance.  Results consistent with Ktatorough
et al. (197S) and supports effect  In  Males.

Excessive toxlclty. HID exceeded,  adenomatous
nodules In fMales with total dose of  1200
Mg or More; test too short, too few ant Ma Is
at risk, excessive toxtctty.   lest Inadequate.
Rats/Utstar
IN)


Nlce/dd (M)



Kanechlor s 28-52 weeks
500
400
300
Kanechlorj 32 weeks
500
400
300

1000
500
100

500
250
100
22 257/group Nodular hyperplasla with Kanechlor 500 and
Kanechlor 300. not statistically significant.
duration of study too short, excessive
toxtclty. lest Inadequate.
12/group Nepalocellular carcinoma with Kanechlor 500
at 500 ppn 41 . 7» (5/1?) and liver nodules In
58. » (7/1?). demonstrates carcinogenic lly
In Male Mice.
                                                  Klmbrough
                                                  et al.. 19/5
                                                  Norback and
                                                  UeltMan. 1S8S
                                                 NCI.  1978
                                                                               KlMura and
                                                                               •aba. 1973
                                                                                                                                          (to et  al..
                                                                                                                                          1974
                                                                                                                                          Mo et .al..
                                                                                                                                          1973
CO
00

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                                                                              1ABII  VI)  (cont.)
0*
o



4C
1
Species/
Strain/Sex
NIce/IALI/CJ
<")

ftat/Mlstar
("I

•AntMl deaths

Agent
Aroclor
1?54

Clophen
A 30
AM
were not dm

Duration (xposure
(PP-)
1) 44 weeks 300
2) 24 weeks »
5 Mnths
recovery
118-119 weeks 100
111-119 weeks 100
i to toilclty but to housing tea

No. AnlMls Results and Coment
SO/group Hepatoaa 40. IX (9/2?)*. none In controls In
44 -week group

lS2/group Statistically significant (p<0.04) Increases
of neoplastlc nodules and hepatocellular
carclnoMs.
Ml/group Induced statistically significant (p
-------
lesions.   In  addition,  adenocardnomas  were observed  \n stomacn, jejunum :•
cecum  1n  treated  animals.   Morgan et al.  (1981),  In a  later  review of tissue
specimen   (NCI,  1978)  detected,  three  additional  adenocardnomas   of   the
stomach  at sites  of alkaline phosphatase (AP) positive.  The NCI (1978)  and
Morgan  et al. (1981) results  are especially  Important  In light of the  fact
that the  sample sizes used by NCI were  unusually  small.

    Saeffer et al.  (1984)  tested Clohen  A-30  and  Clophen  A-60  In Wlstar  male
rats  by  long-term  feeding  over  a  period  of 118-119  weeks.    Clophen  A-60
Induced  a  statlscally  significantly  Increased Incidences of  hepatocellular
carcinomas 1n rats.  However,  Clophen  A-30  Induced statistically significant
Increased  Incidence   of  neoplastlc   nodules,   carcinomas   alone  were   not
significant.

    In  a  more recent  study of Norback and Ueltman (1985) where 70  male and
70  female Sprague-Qawley  rats  were  fed  a  diet  containing  polychlorlnate
blphenyl   mixture  (Aroclor  1260, 100  ppm  for  16 months and  50 ppm  for an
additional 8 months)  for  2 years  followed  by  a control diet  for  5 months,
Aroclor   1260  Induced  highly  statistically  significant  Increases  of   liver
tumors  In  female  rats  (45/47 treated  vs.  control 1/48).   In  males,   liver
tumor   Incidences   were  statistically   significant but  less  striking   (7/46
treated  vs.  control  0/32).  These results  strongly  support earlier hepato-
cellular   tumor evidence In Sherman rats fed  Aroclor 1260 In the Klmbrough et
al.  (1975) study.  Polychlorlnated blphenyl  Aroclor 1260 Induced significant
hepatocellular carcinogenic  effects  In  two rat  studies  {Klmbrough et  al.,
1975;  Norback and  Heltman, 1985).   Kanechlor 500  Induced statistically  sig-
nificant  Incidences  of liver tumors  1n dd mice  fed  550 ppm for 32 weeks.


02360                               V-85                             04/07/88

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Aroclor  '254 also produced carcinogenic effects  in  mice  \8AL3/C-i a^c -a:s
(Mscher  344),  and  results  are dose-related  but not statistically  signifi-
cant.

    This  level  of  carcinogenic evidence  In  rat and mice  for some  commer-
cial  PCBs  (Aroclor   1260.  Kanechlor  500  and  Aroclor  1254)  constitutes  a
"sufficient"  level  of carcinogenic  evidence  for  PCBs  In  animals, using  the
EPA's  Guidelines  for Carcinogen  Risk  Assessment  (U.S.  EPA.  1986c).   The
multiple  studies  with Aroclor  1260  and  one study with  Clophen A-60  provides
a  sufficient  animal cancer  evidence.   The  bloassay  results  for  Kanechlor
500,  Arochlor  1254   and  Clophen A-30,  when  viewed  Individually have  only
limited  animal evidence;  their not being multiple assays  or species  with
clear  statistical significance.   Taken  collectively however,  along  with an
argument  for  a  hypothesis  that  sturcture-actlvlty-relatlonshlp  provides  a
basis  for   recommending  that  PCB  mixtures  of  any composition should  be
regarded  as having  the  potential  to be probable  human carcinogens  and thus
1n  the  we1ght-of-ev1dence  category of  Group  B2.   Obviously,  the  mixture
components  of  the five  commercial  PCB preparations  have  common  characteris-
tic^}  which  Influence  animal carclnogenldty.  The decision to regard all
PCB's  as Group 82 compounds  has uncertainty  since with present  knowledge  H
cannot  be   verified,  alblelt  the  decision  1s Judged to  a  prudent public
health  choice at  the present time.

     The conclusion  that  PCBs  are carcinogenic  to  rodents  1s reached by the
 International  Agency for Research  on  Cancer  (IARC).   In  Its evaluation  of
 the Carcinogen Risk  of Chemicals  to Humans,  it 1s  stated  that "Kanechlor 500
 and Aroclor  1254 are carcinogenic  In mice,  and  Aroclor 1260 Is  carcinogenic
 1n rats."
 02360                               V-86                             04/07/88

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     The  question arises as  to how  to  use  tnese  studies  for  risk  asses
It  Is  difficult  If  not In  fact  Impossible  at present  to  scientifically  to
assess  the  toxic  nature of the mixtures  of  the majority of  the commercial
preparations.   The  biological  significance  of  this  heterogeneity  1s  that
each  of  the  Isomers  has   Us  own particular  toxlcoklnetlc,  metabolic  and
enzyme  Induction profile that  1s  as  much  a  function of the position of  Us
chlorine   substltuents  and  the  total  number  of   chlorine  substltuents  U
contains.    The  extent  to  which  any particular  Isomer contributes  to  or
antagonizes   the  carcinogenic  process   Is  not   known.    The   resultant
carc1nogen1c1ty  observed when  the  mixture  Is  administered may  be  the work of
one  Individual  Isomer.  present  1n a small   quantity,  or  of another  Isomer
present to a larger extent,  e.g.. 25X of the composition of  the mixture.

Other Related  Studies
    Promotional  and  Ant1promotional  Studies.   Long-term  exposure  to  mixed
commercial  PCBs  has  been  associated  with the development  of  hepatocarclno-
genlc  effects In  mice and  rats.   There  Is  little evidence to suggest  that
pure  PCBs are  mutagenlc or  otherwise genotoxlc.    The  role of  PCB-lnduced
liver mlcrosomes  as  potent  activators of  many chemicals  to  mutagenlc deriva-
tives has  been established.   Recent evidence  Indicates  that  PCBs  may also be
protective against other carcinogenic events.

    Promotion  —  Ito  et al.  (1973) evaluated  Kanechlor 500  in  combination
with  BHC  (Table  V-18).  These  data show  that  when male dd mice  were  given
Kanechlor  500 (250 ppm) 1n  their  diet for  32 weeks with or  without one of
the  BHC  compounds, they responded   by  yielding a higher  Incidence of hepato-
cellular  carcinoma than  when either the BHC or the Kanechlor was given alone.


02360                               V-87                             04/07/88

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                                  TABLE  V-18



         Action of Kanechlor  500 and a-. 0- or y-Benzene HexachloMde*
Test Compound(s)
(ppra)
a-BHC (250)
a-8HC (250)
a-BHC (100)
a-BHC (TOO)
a-BHC (50)
a-8HC (50)
B-BHC (250)
S-BHC (250)
B-BHC (100)
B-BHC (100)
B-BHC (50)
B-BHC (50)
Y-BHC (250)
-T-BHC (250)
Y-8HC (100)
Y-BHC (100)
T-8HC (50)
T-BHC (50)
PCB (250)
Controls
» PCB (250)
» PCB (250)
* PCB (250)
* PCB (250)
<• PCB (250)
* PCB (250)
+ PCB (250)
* PCB (250)
* PCB (250)


Nodular Hyperplasia
(%)
23/30 (76.7)
21/30 (80.8)
0/26
8/25 (32.0)
0/28
9/30 (30.0)
0/26
16/29 (55.2)
0/26
5/30 (16.7)
0
0
0
0
0
0
0
0
0/20
0/20
Hepatocellular Carcinoma
(%)
8/30
15/30
0/26
1/25
0/26
2/30
0/26
6/29
0/26
1/30
0
0
0
0
0
0
0
0
0/20
0/20
(26.7)
(57.6)
(4.0)
(6.7)
(20.7)
(3.3)






'Source: Ito et al.. 1973
02360
V-88
04/07/88

-------
    In  a  brief  communication  of  a  short-term study,  Ito  et  al.  (~'9'8j  ae<7icr-
strated  the ability of  PC8  {mixture  not stated or  characterized)  and  other
organic  compounds  to  enhance nodular  liver  hyperplasla Induced by  feeding
2-FAA,  a known  liver  cancer  Inducer,  to  rats.   Hale Fischer  rats  weighing
155 g^  were  used.   Two  groups  of control rats were  fed  diets  containing  200
ppm 2-FAA for  the  10-week trial;  one group  was partially  hepatectomlzed  in
the third week of  the  study.  There  were  two PCS  treatment  groups,  both  fed
a  diet containing  1000  ppm  PCB  for  the entire  10-week  experimental  period.
and  one  group  partially hepatectomlzed  In the  third  week  of the  study.
PCB-fed  rats had livers  containing  significantly  (p<0.05)  more hyperplastlc
nodules/10   cm2  than   control  rats.    Partial   hepatectomy  significantly
(p<0.001)  Increased  the  Incidence of  nodular  hyperplasla   In  the  treatment
groups.

    The  data  show  that  while each  agent  alone  produced some  reduction  In
growth compared with controls, the combined effects  were substantial.   It is
not  possible  to  tell from  this experiment  whether  the  effects  observed on
tumor  growth  were   due  to  a  general  systemic  debilitation or  whether  the
effects  represent  specific  drug-related  responses.   The overall toxlclty of
the combined agents was not adjusted so that It would be no greater than the
level  of  toxlclty of each alone.

    A   report  published  by   OIGIovannl  et  al.  (1978)  1n  which 100  »g  of
Aroclor  1254  was  applied to  the skin  of  CD-I  mice  followed by repeated
applications  of  the  phorbol ester  promoter,  OHBA, stated  that  the data
showed weak  Initiator  activity with  only  0.2  papllloraas per  mouse.  The
tumor-promoting  activity of  Aroclor 1254  was  Investigated  1n a  study by
Berry  et al.  (1978).   Groups  of 30  female  CD-I mice were  used.  The  animals

02360                                V-89                             04/07/88

-------
were  Initiated with  0.2 g  DMBA,  1  week later  a positive control  receded  C
wg  TPA  and   an  experimental  group  received.  100  jig  Aroclor  1254.    The
promoter  and   the Aroclor  applications  were  made  twice weekly  for  30  weeks.
TPA promotion resulted In  92%  of the animals  with paplllomas  while none  of
the Aroclor  1254 treated  animals  developed  tumors.  It  was  concluded  that  at
the dose  of  Aroclor 1254  used 1n  the study  of  the preparation was not  a  skin
tumor  promoter  1n  this system.   General  toxlclty precluded  use of  larger
doses  1n  the  experiment.

    Ant 1 tumor 1qen1c —  In   the  study  of Haklura  et   al.  (1974)  Kanechlor
500,  at 0.05% In  the diet for 24  weeks,  did  not produce  detectable  tumors
for the 24 weeks  of the  experiment.  When  this regimen was  modified  to add
3' -methyl-4-d1methylan1noazobenzene  (3'-MeOAB),  2-FAA  or  d1ethyln1trosam1ne
(DEN)  at  carcinogenic levels  the  combined effect  was  to reduce the Incidence
of  tumors to  zero.  The  tumor  Incidence  1n Sprague-Oawley  rats  with  these
three  agents  was 65X (3'-MeDAB).  54% (2-FAA) and  92% (DEN) liver tumors.  In
paired combination 3'-HeOAB  and DEN  produced 92%  liver  tumor  Incidence.
which  was reduced  to 7.7% when PCB  was also given.   When  2-FAA and DEN were
given  together the  tumor  yield was  82% and 1n  the experiment with these two
agents plus  PCB  the yield was  zero.   The  combined  agents produced  extreme
toxlclty  as  shown  by the weight records, shown  1n  Table V-19.

    Nlshlzuml  (1980)  demonstrated  the ability  of  placentally  transferred
PCBs   to  Inhibit  OEN-1nduced  hepatomas.   Groups  of   ten  10-week-old  female
Ulstar rats  were  treated  with  200  or  40 mg/kg bw/day Kanechlor 500  (Ito et
al.,  1973) by gavage on days 5,  10  and 15  of gestation.   A group  of 10 olive
oil-treated   rats  served   as  vehicle controls.    At  28 days  of  age,  one FI
offspring from each  Utter  was killed  for   quantltatlon of  liver  PCBs.

02360                               V-90                            04/07/88

-------
                                  TABLE  V-19

             Percent Weight Change In Kanechlor  500 Exposed Rats*
Welaht Change X Uelaht Chanae X Uelaht Chanqe X

Control
3-MeDAB
OEM
2-FAA
PCB

+180 Control +180 Control
+150 PCB + 3-MeDAB +107 PCB + 3-MeOAB + OEM
+137 PCB + DEN +73 PCB + 2-FAA + DEN
+116 PCB + 2-FAA +100
+112

+ 180
+65
+52


'Source: Adapted from flaklura et al., 1974

MeDAB   =   3'-methyl-4-dlmethyl-amlnoazobenzene;   DEN
2-FAA = N-2-fluorenylacetaralde
                     DlethylnUrosamlne;
02360
V-91
04/07/88

-------
Remaining  f-\  offspring were  exposed  to  50 mg/DEN In drinking water  cont'n-
uously  for  5  weeks.  At  16,  20  and  24 weeks after  the start of exposure  to
DEN.  for  6-8  F^  rats  from  each  treatment group,  liver weight was  recorded
as percent  of  body weight and livers were sectioned  and grossly  examined  for
"tumors" >5 mm  diameter.

    Dams  showed no  signs  of maternal  toxlclty during gestation or  the  fol-
lowing  6  months (N1sh1zum1,  1980).   There was  no  evidence  of fetal  toxldty;
average  Utter  size was 6.2, 6.5 and  7.1  In  the  400, 40 and 0 mg/kg groups.
respectively.   The  500   mg/kg  groups  experienced  several  losses  of   f}
progeny  {numbers  not reported) and  slight depression 1n rate of  weight  gain
(body weight not  given) before weaning.

    The  authors  reported  that almost  all  liver nodules  >5 mm  In  diameter
were  h1stolog1ca11y  hepatocellular  carcinomas and  that  some nodules >5  mm
were  neoplastlc  nodules  (number  not report)  (N1sh1zum1.  1980).   The number
of  nodules >5  mm  diameter was  therefore chosen as  the endpolnt  Indicator of
hepatocardnogenlc  potency.   The  result  of  this   study  are summarized  in
Table  V-20.    Liver  weight   as  percent  of  F,  body weight did  not  differ
statistically   between  treatment  and control  groups.   Although  liver weight
and  average number of liver  tumors/rat were reported as separate figures for
male   and  female  F,  progeny,  It  was  unclear   1f  statistical  analysis
compared  treatment animals  with control  animals   by  sex  or  collectively.
Significant (p<0.05)  reduction  In  number  of liver  tumors after  20 weeks
occurred In both sexes of  rats  In  the  high-dose group,  and In the  low-dose
males.
 02360                               V-92                             04/07/88

-------
 o
 IV)
 O>
 er
 o
                                                                                TAIlf ¥-20


                              The Liver  and lody Height •alto and the Muter  of Liver Toners Produced In Offs
and In* Muter  of Liver TMaori Produced In Offspring lals fiposed  to PCS  through
Their lam  and  treated with MM after Weanlng'>b
o
.»
v.
o
Group
Mo.

1

2

3

Treat*

IM
PCI 200/ag/kg
3 tlaes
PCI 40/ag/kg
3 tlaes
None

•nt

Offspring
MM SO pp*
S weeks
MM SO pfM
S weeks
DIM SO ppB
S weeks
Se« of
Offspring

•ale
female
•ale
feMle
•ale
fe«ale
Liver Height as Percent
ftOfitf Mttoht

20 week
S.3 »
S.I »
S.3 »
S.S »
».0 »
.1
.3
.2
.1
.4
5.4 » .3

24 week
4.4 » 0.3
0.2 » 0.2
4.3 « O.S
S.I » 0.2
l.S » O.o
4.1 » 0.4
Awfffgf lfyBt>*r of |.tver Tuaors l>4 Bml/ijl

20 week
1.0 » p04c (4.4.4)
0' (0.0.1)
1.3 » 0.4C (10.4.1)
0.4 .0.3 (4.4.11
3.0 » 0.1 (?1.4.1)
I.I ±0.4 («.S.I)

24 week
2.0 » 0.7* (I4.&.7)
0.4 ± 0.3 (3.2.1)
2.1 • 0.7 (17.6.4)
0.? ± 0.4 (i.3.)J
4.4 » 0.7 (17.8.8)
1.4 ± OS (10.4,7)
              'Source: NtsMiuat. 1100

              •Ike  data  are expressed as Mans » SI.  Hwdters In parentneses are tke total
               luaors. and  the nMher of rats sacrificed,  In that order.
                                     of liver Iwwrs/group.  the  ntmtotr  of  rats  bearing  liver
              'Significant at the SX level as conjured with group 3.
oo
CO

-------
    At  the  24-week  examination,  significant  (p<0.05)  reduction  in  tumor
Incidence  occurred only  1n  high-dose  males  (see  Table  V-18).  The  authors
reported  11-ver  PCB values  In  28-day-old  FI  Individuals  of  360*30, 18*7  and
<1  ppm  for  high-dose,   low-dose  and  control  groups,  respectively.   They
therefore  suggested  that placental  transfer of  PCBs  protected  rats  from
DEN-lnduced  tumors.

    A  recent study was  conducted  to  evaluate the mechanisms  of PCB  modula-
tion  of  2-FAA-1nduced cardnogenesls  by  2-FAA.   The  results  of  the  PCBs
tested     {2,2',4,4'-tetra-CB,     3.3.',4,4'-tetra-CB.     2.21.5,5'-tetra-CB
2.2',4,4',5,5'-hexa-CB and  the Aroclor  1254)  Indicated  that  In  spHe  of
predictable  Inducer specific  opposite  Influences  of the different types  of
PCBs  on  cytocldal  toxlclty  of   2-FAA,  all  PCBs  similarly  reduce  nodule
selection  by 2-FAA Initiated  livers.   This ability  for  reduced  growth  of
nodules  correlated  with  the  ability  of  all PCBs  to  consistently  enhance
regenerations of   liver  mass.  Indicating  antlpromotlng activities  against
m1to1nh1b1tory carcinogens.

    Cocarc1noqen1c1ty  — A  study  of  the  cocarclnogenlc  effect of  PCB  on
3-methylcholanthrene  (3-MC)  Induced  cervical cancer  was  performed  1n  mice
(Uchlyama  et al..  1974).  Adult virgin female dd mice were  fed control diets
or  diets  containing 10  ppm  for 15 weeks  or 100 ppm for  8 weeks of  Kanechlor
400.   Cotton thread  Impregnated  with 3-MC  was Inserted  Into the  cervix and
through the anterior  horn,  and  left  1n  place  for 4  weeks.  PCB  did  not
Increase   the  Incidence  of  cervical  epithelial  change   Induced  by  3-MC.
although  effective  numbers  surviving  the experiment were  small (20  mice 1n
each  PCB-fed group).    A  simultaneous  study using  10  ppm  and 100  ppm DOT
showed considerable  tendency  to  Induce  cervical  carcinoma, which  may be

02360                               V-94                              04/07/88

-------
considered  a  positive control.   In  this  trial  using  sma'l  numoers anc  a
short  experimental period,  the authors found  that  PC8 fed at  these levels
did not effectively enhance  3-HC-1nduced cervical carcinoma.

    Considerations   in  Evaluating   the   Carcinogenic   or   Antlcarclnooenlc
Potency  of  the  PCB   Preparations   Tested.   The manufacturing  process  for
commercial  PCB  products,  such as  the Aroclors,  yields  products  composed  of  a
mixture  of  20-60  different  polychlorlnated blphenyl  molecules.   Individual
lots of Aroclors  of  the same average chlorine  content  differ greatly 1n  both
their  components  and  amounts of each component.   The extent to  this variable
composition  can be seen  from  the  analyses  of three  different  Aroclor  1260
preparations  carried   out  1n different  laboratories.   One  preparation  con-
tained  26  PCBs, another  48  different PCBs and the  third was only partially
analyzed.   The  number  of  Isomers  found 1n  the  preparations  for  each level  of
chlorlnatlon  Is shown  In Table  V-21.

    In  addition  to  the   variability  1n  polychlorlnated   blphenyls  1n  the
commercial  PCB preparations,  there  are also a  number of  Impurities In  the
products.   Among   the  Impurities  are PCOFs, which  are highly toxic  and are
under  test  for  carclnogenkUy.

    Several  points concerning  the  Interpretation  of   cardnogenlclty  data,
and  risk  assessments  based  on the  data,  hinge  upon the recognition of  the
qualitative  and quantitative  variability among commercial preparations.
    1.  Data  on  purified  Isomers  show  that  the  toxic, metabolic  and
        pharmacoklnetlc  behavior  of  the  different  component  molecules
        varies  not only with the degree of  chlorlnatlon,  but also with
        the  position of the  chlorine atoms.
02360                               V-95                             04/07/88

-------
                                  TABLE V-21

                Number of Isomers  at  Each  Chlorinated Level for
                  Three Different Aroclor  1260 Preparations*
Chlorlnatlon
Level
Dlchloro-
TMchloro-
Tetrachloro-
Pentachloro-
Hexachloro-
Heptachloro-
Octachloro-
Nonochloro-
Decachloro-
Total
Albro, 1976
0
0
2
8
5
6
3
2
0
26
Slssons and Ueltl. 1971
7
7
3
7
8
5
7
3
1
48
Tas and Vos. 1971
NR
NR
NR
NR
4
3
NR
NR
NR
7
'Source: Adapted from NIOSH, 1977

NR = Not reported
02360
V-96
04/07/88

-------
    2.  Metabolism  of  purified  isomers nas  been  extensively  stucpea.
       The  hydroxylated  metabolites  of  some  18  different  individual
       PCBs  were  analyzed.   It appears  that  predictable  patterns  of
       hydroxylatlon  occur  mat  Indicate that  the major  pathway for
       most  of the molecules  Involves  direct  hydroxylatlon.  At  least
       three  different molecules  among those studied produced products
       that   indicated  utilization  of  an  alternate  pathway.    These
       three   compounds   were   4.4'-d1-CB,  2,2'.5,5'-tetra-CB   and
       2,2',4.4>,5,5'-hexa-CB.   The alternate pathway  for  these  three
       compounds  Involves the  formation  of  arene oxide  Intermediates.
       Such   Intermediates  would  be  expected   to  be  carcinogens and
       mutagens  based  on studies  on  well known  carcinogens.   If the
       cardnogenldty of  the  commercial preparations  was  due solely
       to  these components  the potency  of  the  preparations  could  be
       calculated  on the amount of these  Isomers present, the percent-
       age  of parent compound that utilized this alternate pathway and
       the  pharmacoklnetlcs  of the Intermediates  formed.   Table V-22
       shows  the  results  of  analyses  of  three different Aroclor  1260,
       and  three  different  Aroclor  1254  preparations  for the presence
       of  these  arene oxide-forming compounds.

       Since  only  a small fraction of  the parent compound utilizes the
       arene  oxide  pathway. It  Is highly  unlikely that the carcino-
       genic  potential of  PCS  mixtures  Is  due  entirely to this  geno-
       toxlc  reaction.   Indeed,  the genotoxlclty  of  the products and
       even  these  specific Isomers Is  In  doubt  as  judged by short-term
       mutagenldty  tests.   If the cardnogenldty observed  with the
       Aroclors  Is due to the  Initiating  activity  of epoxldes that may
       be  formed  as  metabolic  Intermediates,  then the  activity In the
       preparations  1s  too low  to be detected  in vitro,  or  requires
       other  in  vivo conditions to be expressed.

       The metabolic  data,  along  with  the  Information  on  chemical
       analyses, and the in vitro  tests  all suggest that  1f these com-
       ponents do  act as Initiators their  role  1n the  cardnogenldty
       may be  contributory but  Is unlikely to  be the  sole  mechanism
        Involved.   Recent findings  Indicate that  short-term  exposures
        to  2,21.4.4',5,5'-hexa-CB,  2.2',4,4'-tetra-CB  and Aroclor 1254
        during liver  cell proliferation  do  not   show  Initiating action
        In  an  1_n  vivo  assay that  detects both  hepatic  and nonhepatic
        initiating carcinogens  (Hayes  et  al.,  1985).   It Is.  therefore,
        unsatisfactory  to   calculate   the  potency on   the  basis  of
        exposure to  'possible*  active  components,  or  to calculate the
        potency  on the  basis  of  exposure to  any  of  the other  compo-
        nents, some of which are scarcely metabolized at all.

    3.  One of the most striking  findings concerning the variability of
        the  components  of  the commercial  products   Is the  differing
        enzyme  Inducing  capacities  of  particular  Isomers  even  at  the
        same  level  of chlorlnatlon.   The enzymes  Induced  range  from
        those  that are  Involved  In  metabolism  of PCBs themselves  to
        others that  have been Implicated  as  activators  and  Inactlvators
        of  other  procardnogens  or   carcinogens,  respectively  (Cyto-
        chrome  P-450   and   P-448  associated  monooxygenase  systems).
02360                               V-97                             04/07/88

-------
                                  TABLE V-22
   Analyses of Three Different  Aroclor  1260  and  Three Different Aroclor  1254
        Preparations for the Presence of PC8 Isomers Known to Utilize,
   to Some Degree, A Metabolic  Pathway  that  Forms Arene Oxide  Intermediates3
Aroclor
1260
(Albro)
1260
(Slssons)
1260
(Tas)
1254
{Albro)
1254
(Slssons)
1254
(Willis)
4,4'-D1chloro- 2,2' .5,5' -Tetrachloro-
absent absent
minor peak minor peak
b/ b/
absent 8%
minor peak major peak
absent minor peak
2.2',4,41,5,51-Hexachloro-
<4X
major peak
minor peak
4%
major peak
minor peak
aSource: Adapted  from NIOSH,  1977
^Probably  not  analyzed
02360
V-98
04/07/88

-------
       The mixed nature of  the PCBs would  be  reflected  in  Tilxed  enz/rne
       Induction,  some  of  which  will  be  capable  of  reducing  the
       carcinogenic  effect  and  some   of  which   will   Increase  the
       carcinogenic effects.

   4.   The'se examples show  why the test  data  on  the carclnogenlclty of
       PCBs  generated  by  use  of commercial  preparations  such  as  the
       Aroclors  and  Kanechlors  can provide  only a net  effect picture
       of  the  many  and varied  effects of  the  Individual  components In
       the   preparations.    The  carclnogenlclty  that   1s  manifested
       reflects  the  sum  of vectors   that  represent  partial  additive,
       synerglstlc  and  antagonistic   effects  of  numerous  Individual
       components.   Potency and  exposure are  basic  parameters used 1n
       risk  estimation.

   5.   It  can  be  said,  however,  that  1t   Is  very  likely   that  the
       potency  of  any  commercial  PCS preparation  may  be considerably
       higher  or  lower  than  any  figure  obtained  by utilizing  the
       dietary  level of exposure as a basis for  calculation.
02360                                V-99                             04/07/88

-------
                         VI.  HEALTH EFFECTS IN HUMANS
General  Background
     Human  exposure  to PCBs  may come  from direct  contact  with  industrial
products,  accidental  contamination  of  foodstuffs  or from  association with
contaminated  environmental  components.  Whatever  the source. PCS exposure can
occur  by Ingestlon,  respiration or dermal absorption.

     Exposure  to  PCBs  results In  the retention of  certain PCB  Isomers  and
congeners  In  human  tissues  and  fluids  because of  Its  chemical  nature.  The
levels  of  PCBs vary  with  the route  of exposure,  geographical  location,  and
sex  and  weight of the  Individual.   In  humans  with no occupational exposure.
PCB  residue  analyses  have  shown  mixtures  of higher  chlorinated blphenyls
that exhibit  a  compositional  pattern differentiated  from that of the commer-
cial  PCB preparations.  Occupational  exposure leads to PCB GC  patterns  1n
most  cases  characteristic  of exposure  to  a  PCB  mixture with  54X chlorine
(Wolff  et  al., 1982*.b).   All  types of  exposure  lead   to  the  retention  and
bloaccumulatlon   of  specific  PCB   Isomers  and  congeners  based  on  their
chemical structure and  stability (Parkinson et al., 1980a).

    PCB  residues  In  humans  have  been  demonstrated  worldwide.   In  North
America,  the  majority of the general population has PCBs  In  adipose tissue
at  levels up to  2  pp«  (Yobs.  1972;  Grant  et al..  1976); however,  other
populations from  other  countries,  for example  Germany,  have been reported  to
have  higher  PCB   adipose   concentrations  (Acker  and  Schulte.  1970).   Few
studies  have  reported the composition of these total PCB residues.
02380                               VI-1                             03/02/87

-------
    The  Identification of  specific  PCB  structures  In  human  tissues  may  be
Important  not  only  for  assessment  of  long-term  persistence  but  also  for
evaluation of  potential  health  effects.   The  Importance of  the  latter  1s  due
to  the specificity  of toxldty and  Induclblllty of  mixed function  oxldase
enzymes by  these persistent PCB Isomers  and  congeners.  At  the  present  time,
the consequence of  the persistence  and bloaccumulatlon  of  these specific  PCB
congeners and  Isomers  Is  unknown.

Acute  and Short-Term Exposure
    Unlike  animal studies (Chapter  V), there Is little Information regarding
acute  or  short-term  PCB exposure   conditions  nor  any  reports of  possible
consequences  of  the exposure   In humans.  The  majority of the  data  on PCBs
and  humans  comes from  long-term  exposure Incidents,  that  Is. occupational
exposure  or  undetermined  exposure  duration  such  as  occurred with  direct
Introduction of  PCB-contalnlng material  Into  the  food chain  from contami-
nated  rice oil.

Chronic Exposure
     Because of  the  chemical complexities of PCBs and  the  nature of PCB expo-
sure  In  humans. It  1s  not  surprising that  data on the behavior of  specific
PCB Isomers  and congeners as  well  as on effects of contaminants alone or  1n
combination on  the  human  system do not exist.

     The problems associated with considering PCBs  as  one  entity Is  presented
 In  the literature  on human health  effects  of PCBs.  As  previously  pointed
 out.  Individual PCB Isomers and congeners as  well  as the contaminants of PCB
 02380                                VI-2                             11/13/86

-------
mixtures   vary   extensively   In   their  biologic,  ecologlc  and  toxicology
behaviors.   However,  for the most part,  reports on human PC8 exposure  do  not
consider  this  fact  and analytical data are presented as total PCBs.

    At  the onset It  Is Important to make the distinction as to  the type  of
PCB compound and the  exposure conditions that  have  generated  the literature
on  human  health effects.  The Importance of  clinical  and  toxlcologlcal data
obtained  from the  relatively large  numbers of  humans  exposed  to  PCBs  cannot
be  Ignored  but  must be placed In  proper perspective.

    Occupational  Exposure.   In the  past  60  years, large  numbers of workers
have  been  exposed  to  PCBs In  the manufacture  or  use  of  PCB-contalnlng
products;   however,  evaluation  of  any  health effects   1s  complicated   by
exposure  to other chemicals.  U1tn this consideration the following sections
summarize the  Information  on PCB  exposure and resultant health effects.

    Historically,  the  original  toxlcologlcal  data on PCBs  were  produced  In
occupational  settings.   Exposure to  PCBs  may  occur through  absorption  by
skin  or  respiratory  or alimentary  tracts.   These studies  were  reviewed  In
detail  by NIOSH (1977).

    Generally  speaking, symptoms associated with  PCB exposure  do not  corre-
late  with duration and  Intensity of exposure 1n the workplace.  However,  PCB
residues  In serum  1s  proportional   to that  of  the adipose  tissue  and had a
positive  correlation with exposure conditions and alterations In some clini-
cal  parameters,  such  as  elevation  of  SGPT  (Wolff  et al..  1982a,b;  Ouw et
al..  1976;  Naronl et  al.,  1981a,b;  Flschbeln  et  al..  1979).


02380                               VI-3                             11/13/86

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    Skin  — The  most  commonly encountered  dermatologlc  symptom  associated
with  PCB  exposure   Is  chloracne.   Chloracne  1$  produced  upon exposure  to
chlorinated hydrocarbons,  for example, napthalenes and blphenyls.   The  skin
lesion  manifests Itself  as  folllcular keratosls  with comedo  formation  and
acneform   eruptions.   At  first  the   lesion  was  thought  to   be  a  contact
phenomenon as  1t developed on skin not covered by clothing, but subsequently
It  has  been determined that  systemic  exposure  to  PCBs will also produce  the
dermatitis.

    Differences  1n   the lesions  occur  with the amount  of chemical  exposure.
patient  age and  lesion  site.  Although there  Is  one  report that correlated
time  of  exposure with severity  of  lesions (Schwartz, 1943).  other  reports
Indicate   that there Is no  good  correlation of  occurrence of  chloracne  and
Its  severity  with   duration  of  employment  (Flschbeln et  al.,  1979;  Ouw et
al..  1976).  Thus.   It appears that Individual  susceptibility to chloracne 1s
more  Important than duration and  extent of PCB exposure.

    Many   case studies  In  the literature  describe  varying  degrees  of chlor-
acne  as  a result  of  occupational exposure to PCBs.   Early case studies of
occupational  PCB exposure were reported  by  Jones  and Alden (1936). Drinker
et  al.  (1937).  Schwartz  (1943)  and  Nelgs  et al. (1954).   Jones  and Alden
(1936)  reported 16  cases  of  chloracne among workers employed  1n the  manufac-
ture  of  PCBs;  these are  summarized  In Table  Vl-1.  These  workers were  also
exposed to Impure benzene.

     PCB air  concentrations  have  been reported and related  to  the  occurrence
of  chloracne.   The  air   concentration of 0.1 mg  Aroclor/m"   was  associated


02380                               VI-4                             11/13/86

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                                  TABLE VI-1  .

        Summary of  the Symptoms 1n Sixteen Cases of Acneform Eruption*
 Case     Age              Duration
Number   (years)   Race    of Exposure   Type of Skin
                           (months)
                                        Type  of  Eruption
          22      white
          28      white
          32
           20
           19
           26
white
          36      white
           28      white
           30       white
Negro
Negro
Negro
NR
            10
            NR
NR
seborrhelc;
previous acne

average


seborrhelc



average dry



average
                      seborrhelc;
                      previous acne
          seborrhelc
          average
seborrhelc
diffuse comedones;
few cysts

diffuse comedones;
few cysts

diffuse comedones;
large cysts and
pustules

diffuse comedones;
large cysts and
abscesses

diffuse comedones;
few cysts on face
and neck

diffuse comedones;
deep abscesses on
neck; severe cysts

erythematous diffuse
comedones; few small
cysts

few scattered
comedones; occasional
cysts

diffuse comedones;
cysts; small
abscesses
10 37 white
11 56 white
9
NR
average
dry
scattered comedones;
occasional abscesses
scattered comedones;
occasional abscesses
02380
                  VI-5
                                       09/11/86

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                              TABLE  VI-1  (cont.
Case
Number
12
13
14
15
16
Age
(years)
20
37
23
22
20
Race
white
white
Negro
white
Negro
Duration
of Exposure
(months)
2
NR
12
NR
NR
Type of Skin
seborrhelc
average
average
seborrhelc
seborrhelc
Type of Eruption
few comedones;
occasional abscesses
occasional comedones
very few comedones
scattered comedones
diffuse comedones;
few cysts on back
and face
•Source: Jones and Alden. 1936
NR » Not reported
02380
VI-6
09/11/86

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with  seven  cases  of chloracne among 14 workers 19 months after Initiation of
exposure  (Melgs  et al.,  1954).   The  mean  length  of exposure was  14.3 months
for affected workers  and  11.4 months  for unaffected workers.

    Ouw  et  al.   (1976)   compared  dermatologlc parameters  of  34  electrical
Industry  workers  exposed to  electrical  grade (no Impurities) Aroclor  1242
with  those  of 30  control volunteers.  Major  worker  complaints consisted  of
burning  of  the  eyes,  face  and  skin.   One  worker  had chloracne  without
systemic  effects,  and  five  workers  had  eczematous  hand  and leg  rashes.
These  dermatologlc  effects   occurred  at  an  air   concentration  of <1  mg/m3
PCS.

    A  subsequent  study  of capacitor manufacturing workers  recorded  the  air
levels  (8-hour TWA)  of  PCBs as  0-11.0  mq/ra»  (F1schbe1n  et  al.,  1979).   The
clinical  study  surveyed a   cross-section  of  326  capacitor  manufacturing
workers  (168 males,  158  females; mean  years  of  employment,  >15)  exposed to
various  PCS  mixtures  (Aroclors  1254,  1242,  1016 and  1221).  Both  plants
surveyed  In this  study also  used chlorinated  benzenes.   The duration of  PCS
exposure  and age  distribution  by sex of the capacitor manufacturing  workers
are  given  in Tables  VI-2  and VI-3.  respectively.   Dermatologlc  symptoms,
Including   rash,   burning  sensation,   acne,   pigmentation   (darkening),   and
thickening  and discoloration  of  the  fingernails,  were reported.   The preva-
lence  of  these dermatologlc  symptoms  Is  given  In Table VI-4.

    Maronl  et al.  (1981b) reported blood  PCB concentrations  of  41-1319  ppb
1n  80 electrical  workers (40 male.  40  female)  employed 1n Italian electric
capacitor  manufacturing  and  testing  plants.   Of the  80  workers.  67  were


02380                               VI-7                            03/02/87

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                                  TABLE  VI-2
       Duration of PCB Exposure of 326 Capacitor Manufacturing Workers•
Duration
(years)
<5
5.0-9.9
10.0-14.9
15.0-19.9
20.0-24.9
>25.0
Number of Workers
33
68
57
37
95
36
Percent
10.1
20.9
17.5
11.*
29.1
11.0
'Source: Flschbeln et al.. 1979
02380                                VI-8                             09/11/86

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                                 TABLE VI-3
       Age Distribution of 326 Capacitor  Manufacturing Workers by Sex*
Age
(years)
<30
30-39
40-49
50-59
60-69
>70
Total
Total Number
Examined
49
61
88
93
25
10
326
Hales
33
41
48
27
13
6
168
Females
16
20
40
66
12
4
158
* Based on data from Mschbeln et al.. 1979
02380                               VI-9                            09/11/86

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                                  TABLE  VI-4

            Prevalence of Reported Dermatologlc  Symptoms Among  326
                       Capacitor  Manufacturing Workers*
Symptom
Rash
Burning sensation
Acne
Pigmentation (darkening)
Thickening
Discoloration of fingernails
Number
128
81
35
8
12
8
Percent
39.3
24.8
10.7
2.5
3.7
2.5
'Source: Flschbeln et al.t 1979
02380
VI-10
09/11/86

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exposed  to  Pyralene  3010 (a PCS mixture containing  42% chlorine)  and 13
exposed  to  Aplrollo  (a  PCS mixture  containing 42% chlorine).  The  mean  age
of the  workers  was 37^8  years,  and  the mean  duration  of  employment  was 12*6
years.   There  were six cases of chloracne among  the 80 workers,  as  shown 1n
Table VI-5.

    Reproductive  System — Quantitative and  qualitative  examination of  PCS
residues  In blood of  women occupationally  exposed  to  PCBs and their  nursed
children  were  conducted  (Kuwabara  et al.. 1978).  The  data obtained  indi-
cated  that   PCBs  are  retained  In  the children's body  for  many  years  after
breast  feeding  and a longer feeding  of mothers'  milk  Increased  PCB levels In
the blood of the  children.  In addition,  the GC pattern of  PCBs  present in
the mothers differed  from  that  of the  children.  The  health  Implications of
such an  occurrence Is  unknown.

    Clinical  Observations.   Exposure  to  PCBs  has  been  associated with  a
wide  variety  of  alterations   In  clinical  parameters,  both  subjective  and
objective.   The following  paragraphs give summaries of various studies  In a
historical  manner.

    Of  seven  workers  Intermittently exposed  to PCB  vapors who  developed
chloracne all  had normal  blood cell counts,   urlnalysls  and  blood pressures
(Helgs  et  al.,  1954).  Six of these  Individuals had  normal  liver  function
tests,  which Included direct and  total  blllrubln determinations  and 24- and
48-hour   cephalln  flocculatlon,  thymol turbidity  and alkaline  phosphatase
determinations.   The  other affected worker had borderline cephalln  floccula-
tlon and  thymol  turbidity, which was Improved 13  months later.


02380                                VI-11                            03/02/87

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                                 TABLE VI-5
         Clinical Features of Six Electrical  Workers  with  Chloracne*
Age at
Case Age First PCB
No. (years) Exposure
1 49 27




2 26 16




3 SO 20




4 43 28

5 38 24


6 49 42


Skin Lesions
Age at Current Findings
Onset
39 vermicular scars.
comedones, super-
ficial cysts and
suppuratlve fol-
llculltls
22 vermicular scars,
comedones, super-
ficial cysts, and
suppuratlve fol-
llculltls
23 vermicular scars.
comedones, super-
ficial cysts, and
supperatlve fol-
llculltls
40 vermicular scars

37 folUculHIs
(possibly chlor-
acne)
45 comedones with
erythema (possibly
chloracne)

Affected Regions
abdomen, thighs




face, neck




neck, shoulders
arms, back



arms, back.
legs
scrotum


neck, sternum


'Source: Maronl et al.t 1981a.b
02380
VI-12
09/11/86

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    Although  In  the  previous  study  PCBs  were  not  found  to alter  hepatic
function as Judged  by the clinical  tests,  Aroclor 1016 has  been  reported  to
alter drug  metabolism through  the mechanism  of  hepatic  enzyme Induction  in
exposed  workers  (Alvares  et  al.,  1977).   A  significantly decreased  mean
antlpyrlne  half-life  (10.8  hours)  In five exposed  workers as compared  with
nonexposed  control  subjects (half-life of 15.6  hours) was  reported.   There
was also  Increased  metabolic clearance rates  In  workers  exposed  to  Aroclor
1016.  Therefore, the author  suggests  that PCBs accelerate  the rate  of  drug
metabolism  In man.    No  systemic  toxic   effects  were  reported  among  the
PCB-exposed workers.

    In another  study, apparent  systemic  dysfunctions occurred.   Warshaw  et
al.  (1979)  reported  the  Incidence of  various  symptoms  In  capacitor  manu-
facturing  workers   to be:   pulmonary  and ocular  symptoms  as Indicated  by
cough  (13.8%),  wheezing   (3.4%),  tightness  In  chest  (10.IX)   and  upper
respiratory  or eye   Irritation  (48.2%).   There were  some  abnormal  results
found  In  biochemical  and hematologlc tests.   In  pulmonary function studies.
a decreased forced  vital  capacity was  seen In 34/243 workers examined (14%).
but no abnormalities  were seen In chest X-rays.

    Health  conditions of  80 electrical  workers exposed for many years to PCS
mixtures  who had  blood  PCB  concentrations   of  41-1319  pg/kg  were reported
(Maronl  et al.,  1981a,b).   Sixteen  of the  males  had  liver abnormalities.
including  hepatomegaly and hepatic dysfunction  (Indicated  by an  Increase In
serum  enzymatic  activities);  for 20%  of  these, the  blood PCB concentration
was  <200 ppb.   No liver abnormalities were reported among exposed female
workers.   There  were   two cases  of  bleeding  hemangloma,  one of whom also had
chronic myelocytlc  leukemia.

02380                               VI-13                            03/02/87

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Direct Introduction  of  PCBs  Into Foodstuffs
    Ynsho  Incident.   The  first  documentation  of human  effects  as a  result
of  Ingestlon of PCBs was  derived  from the  Japanese poisoning  Incident  that
occurred  In  1968.   In   1968,  the  victims  suffered  an  acute toxicosis  from
consuming  rice oil  contaminated with  an  Industrial  oil  (a  commercial  brand
of  PCBs),  Kanechlor-400 consisting of  a mixture  of  polychlorlnated blphenyls
(PCB).  polychlorlnated  dlbenzofurans  (PCOF)  and  polychlorlnated  qulnones
(PCQ).   The average total amount  of PCBs  consumed was estimated  to  be -2  g.
with  -0.5 g  being  the   least  total amount  consumed  by  an affected  group  of
some  325  people at  the  time (Kuratsune et  al.,  1972).   The  PCB  oil  that got
Into  the rice  oil  was   estimated  to contain  5000 ppm PCDFs. some 250 times
more  concentrated than  the  18 ppm found  In Kanechlor  500  by  GC/MS methods
(Nagayama  et al., 1976).   The presence of  the  potent toxicant  PCDFs  1n the
Yusho  oil  probably  contributed  to the overall  toxlcologlc  effects  seen  In
Yusho  patients.

    Yu-Chenq Incident.   A similar mass outbreak of a peculiar  skin disease
was  recorded  In  TaUhung  and Changhwa In  Central Taiwan.   The  cause of the
disease  was  later  Identified to  be the  Ingestlon of  rice bran oil contami-
nated  with PCBs, and   there  were >1900  victims.   Blood  PCB   levels  of  66
affected  persons ranged from  11-720  ppb  (mean 49 ppb) at -9-12 months after
consumption of the PCB-contamlnated oil (Chen  et al., 1980).

     The  presence  of  polychlorlnated quaterphenyls  and  dlbenzofurans  was
documented  (Chen et al.,  1981).   The PCOF levels In the  Taiwan  episode were
less   than   that  in   Japan.   The  rice oil  consumed  In  Taiwan  consisted of
larger percentages  of   penta-,  hexa-  and  heptachloroblphenyls  than did  that


02380                               VI-14                            03/03/88

-------
consumed  by  the   Japanese.   The concentration  of  PCBs   and  PCOFs  in  5u
different samples of the contaminated  oil  are given  in  Table  Vl-6.

    Prevalence  of  PCOFs  In  rice oil  and  1n  tissues  of  Yusho and  Yu-Cheng
victims  strongly  suggests  that PCOFs  are  the  resonslble  compounds  for
adverse  health-effects  In  these Incidents.  This  Is  substantiated  by  the
observations  that  PCBs  and  polychloMnated quaterphenyls,  (PCQ)  which  were
also  detected 1n  the  rice oil   samples from these  Incidents,  fall  to  cause
toxic  response  similar  to those of PCDFs  1n  experimental animals.   (Masuda
and  Yoshlmura,  1984;  Masuda et  al.,  1985;  KunUa  et  al.,  1984.  1985;
Klkuchl,  1984;  Chen  et  al., 1984.  1985; Mlyata et  al..  1985; Kashlmoto  et
al., 1985).

    Although  the  PCDF  concentrations  In  Yu-Cheng  Incident  rice  oil  were
lower  than  1n  the  Yusho  oil, 1t has  been  estimated that  the  average Intake
during  the  exposure period was  more  or  less Identical:   973.  3.8 and 586  mg
In  Yu-Cheng  (Chen  et al..  1985)  and 633, 3.3  and  596 mg  1n Yusho  victims
(Hayabuchl  et al., 1979)  for PCBs,  PCOFs and  PCQs, respectively.   The tissue
distribution  of   PCOFs   with  the  relative concentrations  of  the  various
Isomers   Indicates  that   1n  liver  and  other   tissues the  major  congeners
detected  were  1,2,4,7,8- and  2,3,4,7,8-PeCDFs  and  1,2.4.7,8-HxCDF.   Minor
quantify  of  2.3.7.8-TCOF  and 1,2,3,4,6.7,8-HxCDF  were also  found (Masuda et
al.,  1985;  Chen et al., 1985).

     All  the  PCOFs retained  had at  least  3 chlorine atoms  at  the 2,3.7.8
positions  and  no  vicinal  hydrogens  In  the  dlbenzofuran  ring.    Though
unhalogenated vlclnal-C-atom congeners were present  In the  rice oil no  such
unhalogenated  congenes  were detected  In  the  Yu-Cheng  patients  (Chen  and

02380                               VI-15                            04/07/88

-------
HHes,  1983).   Rappe et  al.  (1979) also  reported  similar observation  in  a
Yusho patient.

    A  correlation  between the  severity  of clinical symptomatology  In  Yusho
patients  and  the estimated contaminated oil  Ingestlon  (PCBstPCFOstPCQs) was
reported  (Kuratsune  et  al.,  1972;  Nagayama  et  al., 1976; Hayabuchl  et  al.,
1979).   However  there 1s much evidence to support  the  hypothesis  that  PCDFs
and  not PCBs  are  responsible for  the  disease.   Analysis of  the  concentra-
tions  of  PCDF and PCS In  the  liver  and  adipose  tissue  of Yusho patients and
of  control  subjects killed  In  traffic   accidents  revealed  comparable PCS
concentrations  1n  tissues of the two groups, but PCDF  (In the range of ppb)
only  In  the  organs of  Yusho patients  (Masuda and  Kurokl.  1982).   Other
evidence  of  the Importatnce of  PCOF  and  PCB  In  determining  the  Yusho and
Yu-Cheng  syndrome has been obtained more  recently.  Kashlmoto et  al. (1985)
compared   the blood levels  of  Yusho  (11  years  after   the  outbreak)  and
Yu-Cheng  patients with that of occupatlonally PCB  exposed workers  (19   years
after  termination)  and  unexposed  people.   In spite  of  high levels of PCBs 1n
all  the samples, detectavle amounts of PCDFs were only found  In the blood of
Yu-Cheng patients.    In  113  Yu-Cheng patients there was  a clear correlation
between  the  blood  PCDF  concentration  and  the severity  of  dermatologlcal
symptoms.   PCQs  were present  In the  blood  of  all the  Yu-Cheng  patients  6
months after  exposure  and  1n  54 of the  56 living Yusho patients 11   years
after  the outbreak.  The presence  of  PCQs In blood can be considered a good
marker of past Ingestlon of  contaminated oil.

     In the  blood of Yu-Cheng patients  there was  a sldtlnctlve PCB  pattern,
very different  from the  original pattern  (Hasuda et al..  1985) and richer  in
the more  chlorinated  Isomers  (for example, 2,3,4,5,3',4'-hexa-CB  Is   a PCB

02380                               VI-16                             03/03/88

-------
 that  is  highly  bloaccumulat1ve).  This  distinctive  chromatogram  has  now oeei
 adopted as one of the criteria for Identification of Yu-Cheng disease.

    Preliminary  data  1n the  three  Taiwan Yusho  patients  Indicated that  in
 the  first year  after  exposure blood  concentrations  of penta-  and  hexa-CDF
 dropped  20 and  15%,  respectively.  Thus,  the  half-time  of  highly-chlorinated
 PCDF  In  man appears  to exceed 1 year  (Rappe et al..  1983).   Rappe et  al.
 (1979) actually  detected  reliable levels  of  PCOF In blood of  Yusho  patients
 10 years  after  the  Intoxication.  Of particular  Interest  Is  the  detection of
 high  concentrations  (100-500 ppt) of  2,3,4.7,8-PeCDF   and  1,2,3,4.7,8-HxCDF
 In the placenta  1f Yusho women 5 years  after  exposure (Hong et  al.,  1982).

Noncardnoqenlc Toxic Effects Observed
    Sk^n.  Kuratsune  et al.  (1969)  reported  that the   roost  notable  symptoms
of Yusho  among  189  patients  Included  dark  brown pigmentation  of nails  and
 skin,  folUcular  accentuation,  acneform eruptions,   Increased  eye  discharge.
 increased sweating  at  the palms and feeling of  weakness.   The  percent dis-
 tribution of  symptoms  among 189 Yusho  patients  1s  summarized  1n Table  VI-7.
Acneform  eruptions  and pigmentations were most prevalent.  With passage  of
 time  these   dermal  symptoms  Improved   considerably  but  the patients  still
experienced  some dermal  conditions  after  several   years  (Urake and Asahl.
 1985).

    Similarly,  the  major clinical signs  of  contaminated  rice oil  1ngest1on
 In  the  Yu-Cheng  Incident  were  skin  disorders such  as   pigmentation  and
acneform  eruptions (Chang et  al.. 1980a.b).
02380                               VI_17
04/07/88

-------
    Immune  System.   PCB  exposure In the  human  has  been shown to affect
Immune  system.   Shlgematsu et al.  (1978) reported  that  human subjects  who
consumed  PCB contaminated  rice  oil  were  more  susceptible  to  respiratory
tract  infections.  Yu-Cheng patients had  lower  serum IgA and  IgM,  decreased
percentages  of  T cell subpopulatlons (111,  Y-C  and  Wu. Y-C, 1985, Chang et
al.,  1980a.b)  and decreased delayed type skin  hypersensltlvUy  response to
streptoklnase and streptodornase (Chang  et al.,  1980a,b, 1981).

    Reproductive  System.   The  maternal-perinatal  system also  appeared  to
be  affected  with the consumption of PCB-contamlnated  rice oil.  From  these
Incidents 1t Is  apparent  that PCBs  cross  the placenta  and can be  transmitted
In  mothers  milk  (Abe et  al.,  1975; Yoshlmura,  1974;  Kodama and Ota.  1980;
Kuratsune, 1976).

    Embryos, fetuses  and  neonates  (2-3  months  old) are a  subpopulatlon at
special  risk because of  Inherent  physiological  differences  from  the  adult
human.   This  subpopulatlon   usually  lacks   the  hepatic  mlcrosomal  enzyme
systems.  Including  the  glucuronldatlon  pathway, that are capable of  oxidiz-
ing PCBs  to facilitate the detoxification  and  excretion of  these  compounds
(Calabrese  and   Sorenson,  1977;  Gillette.   1967;  Nyhan.  1961).   Breast-fed
infants  are at  greater  risk also  because  of  a steroid  excreted  In  human
breast  milk, but  not In  cow's  milk,   that  Inhibits glucuronyl  transferase
activity, and thus  glucuronldatlon  and  excretion of toxicants  such as  PCBs,
by >20X (Calabrese and Sorenson, 1977;  Gartner and Arias, 1966).

    YamashHa (1977)  reported  four  cases of  Infants born  to mothers  who had
Yusho  during pregnancy.   The amount of  PCB-contamlnated  oil  consumed during
pregnancy was  -1.1-10.5 l.   Maternal  symptoms  Included  acneform eruptions.
02380                               VI-18
03/03/88

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                                  TABLE VI-6

          Concentration of PCBs  and  PCOFs  In  the Toxic Rice-Bran Oils
               That Caused "PCS Poisoning" In Talchung.  Taiwan*
Sample No.
1
2
3
4
5
6
PCB (ppm)
405
53
99
78
77
65
PCDF (ppm)
1.68
0.180
0.399
0.250
0.209
0.297
PCB/PCDF Ratio
241
294
248
312
368
219
'Source: Chen et al.,  1981
°2380                                VI-19                            03/03/88

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                                  TABLE VI-7



     Percent Distribution of Signs and Symptoms of Yusho Among 189 Persons*
Symptoms
Dark brown pigmentation of nails
Distinctive hair follicles
Increased sweating at palms
Acnel Ike skin eruptions
Red plaques on limbs
Itching
Pigmentation of skin
Swelling of limbs
Stiffened soles 1n feet and palms of hands
Plgmented mucous membrane
Increased eye discharge
Hyperemla of conjunctiva
Transient visual disturbance
Jaundice
Swelling of upper eyelids
Feeling of weakness
Numbness 1n limbs
Fever
Hearing difficulties
Spasm of limbs
Headache
Vomiting
Diarrhea
Hales
(n»89)
83.1
64.0
50.6
87.6
20.2
42.7
75.3
20.2
24.7
56.2
88.8
70.8
56.2
11.2
71.9
58.4
32.6
16.9
18.0
7.9
30.3
23.6
19.1
Females
(n.100)
75.0
56.0
55.0
82.0
16.0
52.0
72.0
41.0
29.0
47.0
83.0
71.0
55.0
11.0
74.0
52.0
39.0
19.0
19.0
8.0
39.0
28.0
17.0
'Source: Kuratsune et al.. 1969
02380                               VI-20
03/03/88

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folllcular  accentuation;  dark brown  pigmentation  on  the  skin,  mucous
branes and  nails;  and hypersecretlon of  the  melbomlan gland.   Three of  tne
four  Infants,  Including  one  full-term (40 weeks  gestation),  one  premature
(36 weeks gestation),  and one 2 weeks later  than  term (42  weeks  gestation),
were  smal1-for-gestatlonal  age  (both weight  and  height).   Other  clinical
features  among the four  Infants  Included  dark brown  pigmentation  on  the  skin
and  mucous  membranes,  glnglval  hyperplasla.  eruption  of  teeth  at birth.
spotted  calcification  on the parleto-occlpltal  skull  and  the  large or  wide
fontanels and sagittal suture, facial edema and  exophthalmic eyes.

    Hsu  et  al.  (1985)  reported  39  Infants  showing  hyperpigmentation  were
born from poisoned mothers In Yu-Cheng Incident.

    Kuratsune et al.  (1969)  summarized four studies  (Yamaguchl et  al..  1971;
Tak1 et  al..  1969; Funatsu  et  al.. 1971; Klkuchl et  al..  1969)  of  10  live
and  3  stillborn  births  from  February  15  to January  31, 1968. to  11  females
with  Yusho  during  pregnancy and 2  wives of  males  with  Yusho  during  the
female's  pregnancy.   The  amount  of  Kanechlor-contaminated   oil  consumed
during pregnancy  was  0.3-2.6 l  (Yamaguchl  et al., 1971).   Of 10  live  and 2
stillborn births,  9  had unusually grayish,  dark-brown  stained  skin.  5  had
similar  pigmentation  of  the glnglva  and nails and most   had  Increased  eye
discharge (Yamaguchl  et  al.,  1971;  Takl  et al., 1969;  Funatsu  et al., 1971).
Of  the 13  Infants, 12 were described as  smaller  than the  national  Japanese
standards and  4 as small-for-dates  babies (Yamaguchl  et al..  1971;  Takl et
al.. 1969).
02380                                VI-21                            04/07/88

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    YosMmura  (1971)  compared  the  growth  of  42  school-aged  children *Hn
Yusho  (23  males.   19   females)  with  that  of  719  sex-matched  classmates
described  as  being  "healthy."   For  the  years  1967-1969,  the  height  and
weight gains  of  girls  with Yusho were unaffected, while boys with  Yusho  had
significant height and weight gains.

    Clinical  Observations.   The Initial  Yusho  symptoms,  reported  among  136
patients,  are summarized In Table VI-8.   Based on the estimated  amounts  of
Kanechlor-contamlnated  rice  oil  consumed  1n   Table  VI-9  and   the  clinical
severity  of  resulting  effects  In  different  age  groups   1n  Table VI-10.  a
qualitative  dose-response  relationship was prepared (Kuratsune et a!., 1972).

    The  clinical abnormalities displayed by Yu-Cheng patients were decreased
red  blood cell counts. Increased total  white cell counts  and decreased he«o-
globln.   The  patients  presented  with swelling of  the  eyelids  and Increased
discharge from  the  eyes,  headache,  nausea and  numbness  of  the limbs  (Chang
et  al.,  1980b).

     Clinical  parameters evaluating liver  function were suggestive  of  hepatic
dysfunction  1n  both  the  Yusho and  Yu-Cheng  patients.  Inverse  correlation
between  serum  blllrubln  concentration  In  Yusho  patients  and  blood   PCB
 levels,  with mean serum  blllrubln concentrations  of  0.48^0.26 mg/100 mi  In
 121  Yusho  patients  and 0.87*0.33 mg/100 mi  In  257  healthy  adult  controls
 have  been noted.   Increased serum trlglycerlde concentration was  observed In
 Yusho patients.  Similarly,  Increased  tMglycerldes and  elevated activities
 of   serum  transamlnases   and alkaline   phosphatase  were  recorded  1n   the
 Yu-Cheng patients (Chang et al.,  19BOa).

 02380                               VI-22                           04/07/88

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                                  TABLE  VI-8



                 Initial  Symptoms  of  Yusho Among  136  Persons*
Initial Symptoms
Swelling of upper eyelids. Increased eye discharge
Acne-form eruption, folUcular accentuation
Edema tous swellng of limbs
Langulshment
Disturbances In digestive canal
Numbness and other neurological signs
Pigmentation of skin
Total

No.
52
45
9
4
4
9
13
136
Patients
X
38.3
33.1
6.6
2.9
2.9
6.6
9.6
100.0
'Source: Goto and Hlguchl, 1969
02380
VI-23
                                                                      03/03/88

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                                  TABLE VI-9

        Relationship Between the Amount of  Kanechlor-Contaminated Rice
                 011 Consumed and Clinical  Severity of Yusho*
Estimated
Amount of 011
Consumed
<720 ml
720-1440 mi
>1440 ml
Nonaffected

No.
10
0
0

%
12
0
0
Light

No.
39
14
3
Cases

X
49
31
14
Severe

No.
31
31
18
Cases

X
39
69
86
Total

No.
80
45
21

X
100
100
100
*Source: Kuratsune et al.. 1972
02380
VI-24
03/03/88

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                                 TABLE VI-10
           Relationship Between Clinical Severity of Yusho and Age
                            of Affected Persons8
Number of Patients By
Estimated
Amount of
011 Consumed
<720 ml



720-1440 ml

Age
(years)
<12
13-29
>30
Total
<12
13-29
>30
Total
Nonaffccted
No. X
3
2
5
10
0
0
0
0
16.7
8.3
13.1
12.5
0
0
0
0
"L1ght"b
No.
13
7
19
39
5
1
8
14
%
72.2
29.2
50.0
48.8
50.0
6.7
40.0
31.2
Clinical SeverHv
"Severe"0
No.
2
15
14
31
5
14
12
31
%
11.1
62.5
36.9
38.7
50.0
93.3
60.0
68.8
Total
No.
18
24
38
80
10
15
20
45
X
100
100
100
100
100
100
100
100
aSource: Kuratsune et al., 1972
bC11n1cal  severity was  classified  as  'light"  or  "severe."  as  defined  by
 Goto  and  H1guch1  (1969);  further details enumerating  clinical  features  of
 this classification scheme were not reported.
02380
VI-25
03/03/88

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    PCB  exposure  in  experimental  animals Is known to  cause  abnormal  urinary
excretion of heme  precursors,  thus  the  urinary  excretion  of  these precursors
were examined  1n  both  the  Yusho  and Yu-Cheng patients.  PCB  poisoning caused
an  Increased  excretion of delta-amlnolevullnlc add  (0.72-1.00  mg/24 hours)
and  uroporphyrln  (13.6-41.2  pg/24 hours),  but   not  In  the  excretion  of
porphobl llnogen or coproporphyrln  (Chang et  al.,  1980b).   Similar studies  on
Yusho  patients failed to reveal  any  differences  1n porphyrln  metabolism;
however,  the  studies  were conducted  long  time  after  the  Incident  (Strife  et
al., 1979; Nonaka et al.. 1979).

Human Cancer Studies (Inhalation and Dermal Contact)
    Two  brief  reports  In  the literature have noted an Increased  Incidence  of
malignant melanomas  In workers heavily exposed to PCBs.   Bahn et al. (1976.
1977)  reported  two   malignant  melanomas   In   31  research  and  development
employees  (6.5%)  of  a  New  Jersey  U.S.  petrochemical plant  that had  used
Aroclor  1254  for  9  years (ending  In the  late 1950s).   Quantified exposure
levels  or concentrations  are not  given.   This  Incidence was  significantly
greater  than  expected (p<0.001),  based on  a  person-year analysis and  com-
parison  with  the  Third  National  Cancer Survey Incidence  rates  (NCI, 1975).
Only  0.04 malignant melanomas would  be expected  among 31  persons for a rate
of  0.13%.   In a  second  group  of 41 refinery workers exposed to   "low" levels
of  Aroclor  (quantified  exposure levels not  reported),  one had  a malignant
melanoma.   Exposure to other potential and known carcinogenic substances was
not evaluated  although they  were believed  to be present (Lawrence,  1977).

    NIOSH  (1977)  expanded  upon   the  report  on  New  Jersey  petrochemical
workers  by noting  that  eight cancers  were observed  In the study  population
of  51  research and   development employees  and 41  refinery plant employees

°2380                                VI-26                            04/07/88

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known  to  have  been exposed to Aroclor  1254 followed  to  January  1,  1976  while
5.7  were  expected when  compared  with  that of a  similar  sample of  the  U.S.
population.   Of the  eight,  three were melanomas  while two were  pancreatic
cancer.   Both  were significantly  Increased over expected  cases  according to
the  authors,  although no figures  were  provided  of  expected cases.   PC8  expo-
sure histories were  based upon  recollections of  two company  employees.   A
more extensive Investigation  was reported by NIOSH  to  be In progress  by  a
B.N.  Klghtllnger   In  a  written communication  to NIOSH.   However,  to  date we
have been  unsuccessful  In  acquiring  Information  about this more extensive
Investigation.  Details about  this  study are  sketchy  at best  In all  three
reports.

     Oavldorf and  Knupp  (1979) calculated  the Incidence  of ocular melanoma on
a  county-wide basis In  the  State  of   Ohio  over   an  11-year period  from
1967-1977.  This  survey was  prompted  by  reports of an  association of cutane-
ous  melanomas  with  ultraviolet  radiation or exposure  to  PCBs.  The authors
identified  counties  with Industries  that might use PCBs and  counties with
known high  concentrations of PCBs determined by  level  of PCBs  found in  fish
as well  as  location  of  Industries known  to produce  PCBs.   The  purpose was  to
evaluate  the  Incidence of  ocular  melanomas  with  respect  to proximity  to
areas  of high concentrations.    Information on  primary  choroldal  melanomas
was  obtained  from 'Institutions,"  such  as  hospitals and tumor registers  in
 Ohio  and adjacent states  who may have had adult residents as patients.   Some
 698 white Ohio patients were Identified  from this endeavor.

      Over the 11-year period, an average  Incidence of 1.09 cases/100,000/year
 were  found.   This   Incidence  did not differ  significantly  with  any  single
 year's   Incidence.    The  authors  did   note,  however,   that  other  studies

 02380                              VI-27                           04/07/88

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reported  an Incidence of 0.6  cases/100,000/year (Scotto et  al.,  1976).   The
authors  attribute the difference to the use of  medical  records  at hospitals
and  not just  tumor registry  data.   The  county Incidences  over  the  11-year
period  also did  not  reveal  any pattern of distribution  that  was correlated
with  areas  of high PCB  occurrence.  The authors suggest  this  may In  part be
due  to  small population sizes  In certain  areas  they  thought were clinically
over-represented.   This was  compounded by the  fact   that  fewer  persons  In
poorer  rural  areas  tend  to seek early medical  care.

     Brown  and Jones (1981) conducted a retrospective  cohort mortality study
on  2567 workers  who  had completed  at  least  3  months of employment  at  any
time  In any  area  of  two capacitor  manufacturing  plants  where potential  for
exposure  to  PCBs  existed.   PCBs  had  been used at  the  facilities  for  >30
years before the cut-off date of the study on January 1. 1976.  Aroclor 1254
was  used first  but changed over  the  years to  Aroclor  1242  and finally to
Aroclor  1016.  Workers exposed to trlchloroethylene (TCE) were excluded from
the  cohort.  Time-weighted  average  (THA)  personal air  samples   In  the  two
plants  ranged   from  24-1260  wg  PCB/m3.   Vital   status  ascertainment  was
98%  complete.   Observed deaths were  contrasted with expected  deaths based
upon  U.S.  white male and female  deaths.   All  cause mortality was lower than
expected  1n  plant  1  (73 observed  deaths  vs.  76.7 expected) as  well  as 1n
plant 2 (90 observed vs. 105.6 expected). Combining two cohorts produced a
nonsignificant   excess  risk  of liver  cancer   (3   observed  deaths vs.  1.07
expected)  and  a nonsignificant  excess risk  of  rectal  cancer  (4 observed
deaths  vs.  1.19 expected).   This excess risk  of rectal cancer was  limited to
females of  plant 2  (3  observed vs.  0.5  expected).
02380                                VI-28                           04/07/88

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    No  apparent  pattern of  response  In  liver  cancer was found  according  to
the  years since  first  employment  (presumably  first exposure).  All  deaths
from  liver .cancer occurred before the 20th year of  latency.   A slight,  non-
significant  excess  risk of  cirrhosis  of  the  liver was found  after  the  20th
year  of latency  (3  observed  vs.  1.49 expected) as well as  a  nonsignificant
excess  risk  of  cancer of the rectum (2 observed vs.  0.36 expected)  after  the
20th  year of  latency.

    The  authors  point  out  that  because  of the relative number  of  deaths  In
this  cohort,  conclusions drawn from the study  are only  tentative.   Although
1t appears  to be a  rather  large  cohort,  relatively  few deaths were reported
to have occurred.   Indeed,  1n the group of workers who have  reached  the  20
year   latency  period,  eight  cancer  deaths   occurred  while  13.24  were
expected.   This  may be an  Indication that the  cohort consisted  of  either
mostly  youthful  employees  or  else older  employees who  only  recently  had
their first  exposure (first  employment).

    Recently,  the author  provided an unpublished update  of  his 1981  study
(Brown,  1986)  In which he  added an  additional  7  years of  follow-up,  thus
Increasing  the number  of deaths  to  295.   This was still lower than expected
at  318.  Cancer  mortality  totaled 62 deaths  vs.  80 expected.  In  the later
draft the authors noted a statistically significant  excess risk of  cancer of
the  liver and  biliary passages   (5 observed vs.  1.9 expected; p<0.05).   The
excess  chiefly  occurred 1n women  employed  In one  plant.   The author again
pointed out that these findings  are'dlfflcult  to  Interpret* with respect to
exposure to PCBs.
02380                               VI-29                           04/08/88

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    But  Brown  (1986) did offer  some  evidence to support  a  causa',  re-at'o"1-
shlp.   In  an environmental  survey  conducted  1n  1977 by  NIOSH,  and reported
on 1n  the  earlier  paper  by  Brown and  Jones  (1981),  personal TWA exposures to
PCBs  (Aroclor   1016)  ranged  from 24  mg/m3-393  mg/m3  at plant  1  while  at
plant  2  they  were  higher  at   381  mg/m3-1260   mg/rn3.    Four  of  the  five
liver  cancers  occurred  In female employees  at plants 2.   All  occurred after
the  15th year  of  follow-up  from beginning date of employment.   All  began
working  at  a   time  when   levels  of   exposure  were  likely to  be  highest.
Furthermore, this  group  (Female  employees at  plant  2) contributed  41% of the
total  person-years  to   the  analysis,  the   largest  contribution.   However,
since  the  two  plants may differ In alcohol consumption,  dietary  habits and
ethnic composition as was pointed out by the author. It  would  be  prudent to
continue  following this  cohort  In  order  to confirm that  the excess  risk of
liver  and biliary  passageway cancer  Is  real.    Further  analytical work  on
this  cohort  1s  continuing.  It  would be  prudent  to regard  these findings
cautiously suggestive.

    Bertazzl  et al.  (1987) completed a  retrospective  prospective  mortality
study  of 544 male  and  1556  female employees of  a  capacitor-making facility
1n a   small  Industrial  town  of  Northern  Italy.   Snail capacitors  were made
for  electrical  and  electronic   use while large   capacitors  were  Impregnated
with  PCBs  since 1946.  Aroclor  1254  and  Pyralene 1476  were used until 1964.
After  1964,  they were progressively replaced by  Pyralene 3010 and 3011 until
1970  when the  lower chlorinated Pyralenes  were  excuslvely used.   In 1980,
the  use  of  PCBs  was  completely  abandoned.   Maximum  consumption of  PCBs
occurred In  1967-1968.   Trlchloroethylene  was   used  In  the  final  step  of
manufacturing.   The workers  employed  In  this last  step are described by the


°2380                               VI-30                           04/08/88

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authors  as  being  protected  ylth  efficient  ventilation.   Certain  jr.-que
capacitors  were made  In  which alkylbenzene  and  expoxy resins  were  used but
few Individuals were  Involved  with this.

    Because  of  reports  of  chloracne  among  autoclave  operators   In  1954,
environmental  air  samples were measured.   For  Aroclor  1254  the  values  ranged
from  5200-6800  pg/mj.   Again,  1n   1977  because  of   the  appearance  of   4
cases  of chloracne.  environmental air  samples of Pyralene 3010  ranged  from
48  vg/m»  to  275  mg/m*.   In  addUon,  the  quantity of  PCBs  of workers
hands  and  workplace  surfaces  were measured  first 1n 1977 and  then  again  In
1982  (2 years  after  used  of  PCBs  was abandoned).   These  results will  be
found  1n Table VI-11.  It  1s  noted  by  the authors  that a degree of contami-
nation  continued to persist until  1982.

    The  authors contrasted observed mortality with that expected  from  1946
to 1982 based upon national  and local  Italian mortality  rates.  Compared  to
the  size of the cohort relatively few deaths [30  (5.5X) male  and  34  (2.2%)
female]  were  recorded by 1982 with almost a complete vital status ascertain-
ment  on  the   remaining members  of  the cohort.   Less than  one half  of  1%
remained untraced.

    Overall   mortality  was   not  different   from   expected   In  males   but
significantly  higher  than  expected  In females  when   contrasted with  local
rates  (Table  VI-12).   However,  deaths  from  cancer  were significantly  higher
than  expected  1n  males  whether  national  or   local   rates  were   used  (14
observed versus 1.7  national  and 2.2  local,  p<0.05).  Of  these one was due
to  liver  cancer  and  one was biliary  tract  cancer.   Cancer deaths  (12)  In


02380                                VI-31                            04/08/88

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                                  TABLE IV-11

          Minimum and Maximum Values of PCBs Recovered from Workplace
               Surfaces  and  Workers Hands Before and After PCBs
                    Banning  (1980) and Cleaning Operations*

Workplace Surfaces

Workers Hands

Year
1977
1982
1977
1982
No. of
Samples
18
14
9
12
Values
M1n.
0.2
0.003
0.3
0.09
(uq/cm?)
Max.
159.0
6.3
9.2
1.5
'Source:  Adopted  from Bertazzl  et  al.  (1987)
02380
VI-32
04/08/88

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                                 TABLE IV-12

                      Mortality From Selected Causes of
                   Hale and Female Workers Exposed to PCBs
                           (Bertazzl et al., 1987)
Cause of Death
(ICO 8th Revision)
MALES
All Causes
Malignant Tumors
Observed
Deaths

30
14
Reference Mortality
National Expected Local Expected

27.8 29.8
5.5* 7.6*
    (140-209)

 Gastrointestinal  Tract        6
    (150-159)

 Hematologlc Neoplasms         3
    (200-209)
             1.7*


             0.8
2.2*


1.1
FEMALES
All Causes
Malignant Tumors
(140-209)
Hematologlc Neoplasms
(200-209)

34
12
4

25.8
7.7
1.5

16.5*
5.3*
1.1*
*p<0.05
02380
VI-33
 04/08/88

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females  workers  were  also  elevated  by  comparison  with   local  rates  .5.3
expected,  p<0.05).   However,  this  excess  risk did  not  translate  into  an
Increased  significant  risk  of  cause specific  cancer.   No liver or biliary
cancer  deaths  were noted In females.  Both males and  females  did  experience
an  Increased nonsignificant risk of hematologlc neoplasms  (see  Table  IV-12)
which remains  unexplained at this time.

    There  are  several  problems  with  this  study that  precludes  Its use  at
this  time  1n  upgrading the  classification  of the  we1ght-of-evidence  of
cardnogen1c1ty.   There Is  an  absence  of  significant  site-specific  cancer  In
both males  and females.  However,  this  1s due to the Inadequate power  of the
study to  detect as significant  an  elevated  risk of  site-specific cancer.  In
actuality,  this cohort  needs  further  follow-up to  determine  1f any  trends
are apparent  since so few deaths have  occurred by  the cut-off  period 1n  this
study.   Latent  factors were  not  examined probably  because  of  the  small
number  of deaths observed during the  follow-up period.   Additionally,  other
possible  confounders may  be  present.   Possibly trace  amounts  of  dlbenzo-
furans  (PCOFs) may  be   found  1n the  PCBs.  Other   substances  such as  tr1-
chloroethylene, alkylbenzene and epoxy  resins  have  also  been reported  In the
plant by  the authors.  Furthermore, the  study  does  not  consider the healthy
worker  effect  In  Us  comparison  with national and  local  death  rates nor  does
It analyse  latent  effects except on an Individual case by case  basis.

Human Cancer Studies  (PCBs Poisoning Episodes -  Inqestlon Only)
    Amano  et al.  (1984) recently completed a  16-year  cohort mortality study
of  1086  victims  of  the Yusho  Incident  1n  Japan.   The  581  males and 505
females  sustained  a  total  of  70 deaths (42 males vs. 45.81 expected  and  28


02380                               VI-34                            04/08/88

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females  vs.  31.03 expected through October  2'.  1983.  over age 4G Dase-  -:c-
japanese  national  death  rates).    Expected  deaths  were  derived  from baste
death  rate-data  (sex-,  age-  period-adjusted) for each cause generated by  the
Welfare  Ministry of Japan.   In persons  over  40 years of age overall cancer
mortality  was  greater  than  expected  In men but no different  in women.   In
men  19 cancer  deaths  occurred vs.  11.50 expected,  and in women  7 cancer
deaths occurred  vs.  7.20  expected.  However, by organ site, only  the  risk of
liver  cancer  was consistently high In  both  men and women during the entire
16-year  period  of observation.   Even  after  a 9-year  latent period,  the  risk
of  liver  cancer  In  males   was   significant  (5  observed.  0.75  expected.
p<0.01).   The  risk of  liver  cancer was also significantly elevated  after  9
years  observation time utilizing  just the rates of Fukuoka prefecture  only.
the province where  the Yusho  Incidence occurred  (Table VI-13).

    However.  In  follow-up studies  done  on  the  victims  of  the  rice oil  poi-
soning Incident,  particular  Isomers of  the  Ingested PCBs were found in liver
tissue in  the  proportion 4-1 compared with  PCOFs  several years later.   They
appear  to  persist  In  liver  tissue to a  greater  extent  than do  PCBs.  which
also persist 1n  both liver and adipose tissue (Kuratsune et al.. 1975).

    The  Amano  et al.  (1984)  paper  that  has  been  translated from Japanese  Is
not  without problems.   First,  the Information concerning the  diagnosis  of
liver  cancer 1n  the victims 1s  described  as having been  obtained from the
family of  the victims.   These  diagnoses are not described  In  this paper  as
having been verified.   Second,  the sum  of  the  expected deaths 1n  the tables
do  not add up  to total expected deaths  thus leading  to  speculation that  this
paper  1s  perhaps preliminary or  lacks  scientific  review, although  It was


02380                               VI-35                            04/08/88

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                                  TABLE  VI-13

        Risk of Death From Cancer  of  the Liver  1n Oil  Poisoned Patients
      by Sex and Period of Observation,  Japan  and  In Fukuoka Prefecture*
Region
Japan



Fukuoka Prefecture



Sex and Period
of Observation
Males
1969-1976
1977-1983
Females
1969-1976
1977-1983
Males
1977-1983
Females
1977-1983
Observed
6
1
5
2
1
1

3

1
Expected
1.22
0.44
0.75
0.54
0.19
0.24

0.66

0.17
(P< -01)
(p<0.01)



(p<0.05)


'Source:  Amano et al., 1984
02380
VI-36
04/08/88

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published  in  a Japanese  journal.   TnUd.  no  information ', s q»«en
job  histories  or  the  Influence  of  alcoholism or smoking.  The  Influence  of
type  B  hepatitis  with respect to the risk of  liver  cancer  In  these patients
"can  be  dismissed"  according to the authors because  there appeared to be  no
difference  between  the Australian  antigen positive rate of the  oil poisoned
patients and that of healthy blood donors.

     In  view of the problems that need to be addressed  in this  study a defi-
nite  conclusion that  PCBs  caused  the  significant risk  of  liver  cancer  in
these patients  cannot  be made.  However, the finding of  a  definite elevated
liver cancer  risk  In  the Yusho victims  cannot be dismissed.   Further  con-
firmatory research  needs to be accomplished.   Until  the  questions  above are
answered  It is not possible  to  classify the human  carclnogenlclty evidence
as more  than suggestive with respect to exposure to PCBs.

     In  an  effort  to  determine  whether  the  Increased  risk  of  liver  cancer
reported  by Antano et  al.  (1984) In the  1086  victims of the  Yusho Incident
was  real  or only  artificial, the Cancer  Assessment  Group (CAG) communicated
with  Or.  Hasanorl  Kuratsune of Nakamura Gakuen  College  for  further Informa-
tion.   Or.  Kuratsune  and his  colleagues  In a  preliminary  analysis provided
mortality data  on  a much expanded  cohort  of  some 1821  officially recognized
Yusho patients by  the  Ministry of  Health  and  Welfare  by  the  end of 1983.
From the cohort  the  authors  excluded  nine  deceased  Individuals  who  were
posthumously recognized  as  Yusho and another 51  who could  'not be  confirmed
for  survival  (vital status),"  leaving 1761  (97.5%)  whose vital  status was
determined  through  the  end  of  1983.  One hundred-twenty deaths  (79  males and
41  females) occurred  and were  contrasted with  expected deaths  based upon


02380                                VI-37                            04/08/88

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 National Japanese deatn  rates, age-, sex- and calendar time-spec** :c .   -a e
 expected deaths  equaled  66.13.  while female expected  deaths  equaled  48.9.
 Malignant neoplasms  in males  totaled  34 as  compared with  15.51  expected
 (p<0.01).  This significantly Increased  risk  was  entirely due to  a  signifi-
 cant  excess  risk of  liver cancer  (9  observed  vs.  1.61  expected.,  p<0.01) and
 a  statistically  significant  excess  risk  of  cancer of  the lung  trachea and
 bronchus (8 observed  vs.  2.45 expected., p<0.01).  In  females,  only  liver
 cancer   appeared  excessive  albeit   nonsignificant  (2   observed   vs.   0.66
 expected).   Even  If  death rates  of  Fukuoka  and  Nagasaki  prefectures  were
 used  as  the comparison population,  the  locale  where  the rice oil  poisoning
 took  place,  the  risk of liver cancer  remained  statistically significant.

    Although  the  elevated  risk of  liver cancer  Is  real,  the  authors  are
 reluctant to attribute It to the poisoning because of  the  unusual distribu-
 tion  of deaths.   In Nagasaki  prefecture  where  some 550  patients  live, only
 one  male  liver  cancer patient  was   seen, but  In  Fukuoka prefecture  eight
 liver  cancers  were Identified out of >700 patients residing  there.   Deaths
 from  liver  cancer are  not different from expected In Nagasaki  prefecture.
 The  authors  reported  that they were  examining the medical  records  of the
 decedents to confirm the diagnosis of liver cancer.

    Unfortunately, mortality  for each prefecture  Is not separated; hence. 1t
 1s  difficult  to determine  1f  age,  sex  or socio-economic  factors  or  lack of
 access  to medical care facilities or other  factors could  be  the reason for
 the  differential  liver cancer  mortality  In  patients   of these  two  prefec-
 tures.   Latency  was  also  not examined.    However,  the Incident  occurred in
 1968 and  affected  a  large number  of  persons  with certifiable disease; hence,
all live  patients  had  to  have been observed  at least a minimum of 15 years.

02380                               VI-38                            04/08/88

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But.  <3>  *ds  noted  in  trie  Amano et  al  i'3B*)  review,  -fiese pa:'e^-.-3  .e-e
exposed  to  polychlorlnated  dlbenzofurans  and  polychlorlnated  qulnones  as
well.  Further  efforts  are  under  way  to clarify questions about  this  study.
It would  be  premature to conclude that these results are anything more  than
suggestive at  this time with  respect  to classifying PCBs as  carcinogenic  to
humans.

    Yu-Chenq  Incident.   An  outbreak  of a similar  nature was reported among
some  2000  persons  In the Talchung and Changhwa  provinces of  Taiwan  in March
of 1979.   In  October of 1979  the Illness was found  to  be the result of  the
1ngest1on  of  rice oil  contaminated  with  polychlorlnated  blphenyls  (PCS).
Chen  et al.  (1980)  reported on blood  PCB levels of 66  victims for which  they
had  prepared  gas   chromatograms.   Basically,  blood  concentration  residues
ranged from  11-720 ppb  1n these  patients.   The mean value was 49 ppb;  most
values were  under   100  ppb.   In  only  two  Instances were the concentrations
greater at  120-720 ppb.  The authors  reported  that the higher value of  720
ppb occurred  In a  patient who had  difficulty In  metabolizing and  excreting
PCB components.  They also  maintain  that blood  PCB  levels of these  patients
are "much higher*  than  those of  72  Japanese  Yusho  patients  (Koda  and Nasuda.
1975)  although  Koda and  Masuda reported  the  mean PCB value  In Yusho patients
was 5.9 ppb  with a standard deviation of 4.5 ppb.   Chen et  al.  (1980)  main-
tained that  this difference Is due  to a lengthy time lapse from the exposure
to PCB in  Yusho patients before  measurements were  taken compared  with a much
shorter  time  lapse  1n  Yu-Cheng patients  before  measurements   were  taken.
Furthermore,  the patients of Yu-Cheng consumed  a larger proportion of highly
chlorinated PCBs compared with those  of  Yusho and. as  a result,  they will be
retained longer  in  the body according to the authors.


02380                              VI-39                            04/08/88

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     The  most  important  observation about  tnis  study  is  tnat  ar
-------
    A  retrospective  conort mortality  study  -n  1981  anc  i  puD'vsnea  ,.pcs
-------
    Amano et  al.  (1984) and Kuratsune  (1986)  reported  a statistical'*  5-3-
nlflcant  excess  risk  of liver  cancer  In  Yusho  patients  followed  over  16
years In bo.th male and  female victims.  The authors  regard  these  findings  as
only  tentative because  the  excess was  found  only  In one prefecture and  not
the other.   Furthermore,  the victims consumed polychlorinated  dlbenzofurans
and polychlorlnated qulnones In  much  smaller  quantities at the same time  as
the PCBs.   Hence exposure  to  these  other chemicals cannot  be  ruled out  as
possible contributors  to the excess  risk of  liver  cancer In Yusho  patient.
These authors  are refining  their data  at  this time  and reexamlnlng  their
results.

    Although  these data seem   to  suggest  a possible  carcinogenic  effect
through the  Ingestlon route and  possibly  Inhalation  route In  humans, because
of  the  tentative nature  of  the findings,  and  the  fact  that refinement  and
reevaluatlon  of  the  results are  underway  as  well as  possible  concurrent
exposure to  other  potential  carcinogens,  CA6 regards the human data at this
time as Inadequate but suggestive.

    However.  1t  has  recently  been  learned  (Moolenaar.  1987)  that  the
International Agency  for  Research on Cancer  (IARC)  has  classified  the human
health data  as "limited"  (2A)  based  upon the findings  of the Bertazzl  et al.
(1987)  and   Brown  (1986) studies.   However,  lack   of  site  concordance  and
small power  In  these  studies  precludes  EPA  from classifying  the  weight  of
evidence higher than Inadequate  at this time.
02380                               VI-42                            04/08/88

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Health Effects (Other than Cancer)  -  Summary
    Since  the  start of  their  production,  PCBs  have  become constituents  of
environmental media and they have bloaccumulated In animals and humans.   The
consequences of the presence of PCBs Is not fully understood.   The  following
section summarizes  the studies available for evaluation of  the  environmental
health effects of PCBs.

    Unlike  the  occupational  exposure and  contaminated  rice oil  situations.
environmental exposure  to PCBs has  not  been reported  to cause  overt  toxic
symptoms such as chloracne.  The literature Indicates that  environmental  PCB
exposure may Induce more subtle biochemical alterations.

    It  Is  not  clear whether  PCB mixtures are solely  responsible  for  adverse
health  effects  or   whether contamination  of PCB mixtures with PCOFs  caused
the toxic  response.  In Yusho  and  Yu-Cheng poisoning  Incidents, the presence
of PCOFs In  the contaminated rlsce oil and In  the  liver and other tissues of
the victims  Indicates that PCOFs were the responsible toxic compounds.

    Reproductive  System.   Evidence  for  fetotoxlclty  comes  primarily  from
laboratory  studies  (Chapter  V);  however, a recent  report Indicates  that the
human  perinatal  system may also be  a target for  PCB toxlclty.  A  study of
Individuals  who  consumed moderate  quantities  of PCB-contamlnated  lake fish
Indicated  that PCBs crossed  the  placenta.   PCB  exposure,  as measured by both
contaminated  fish   consumption and  cord  serum  PCB  levels,  predicted lower
birth  weight  and smaller  head  circumference of  Infants  born to these mothers
(Fein  et al., 1984).
 02380                               VI-43                             04/08/88

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    High  PCB  serum levels were found  in  some  *omen  *no  naa  recent ar  •j'-ne*
missed  abortions with mean  PC8  serum levels of 103.04, 82.00 and 20.69 ppb
for  recent, missed abortions,  former  missed  abortions  and control  groups,
respectively  (Bercovlcl  et  al..  1983).   Some  women with  premature delivery
had  mean  PCB  serum levels of  128  ppb In  the premature delivery  group vs.
26.5  ppb   In  the  control  group  (Wasserman  et  al.,  1982).   The  higher  PCB
serum  levels  were associated with  Increased Incomplete  abortions  (BercovUI
et  al.,  1983)  and  premature deliveries   (Hassermann  et al.,  1982),  but  a
definitive  causal  relationship  cannot be  established,  as only small  numbers
of  women  were  examined  (up  to 17  symptomatic;  up  to  10 asymptomatic),  and
some  of these  women  had high serum  levels of some organochloMne Insecti-
cides   (DOT  Isomers  and  their  metabolites,  llndane.  dleldrln.  heptachlor
epoxlde).

    Clinical  Observations.   PCBs  were discovered  In sewage sludge used for
fertilizer  In  Bloomington, Indiana.   The  metabolic consequences  of  PCB  expo-
sure  were  studied  (Baker  et al..  1980).    Serum PCB levels  In  sludge  users
were  not  different from those  of  other  members of  the community  not  using
the  sludge.    In  sludge  users  PCB  levels  were associated  positively  with
degree  of  garden care and negatively with wearing gloves  but  not  correlated
with  amount  of  sludge  used   or  duration  of  exposure.  Plasma  trlglycerlde
levels  Increased significantly with PCB concentrations.

    Krelss et  al.  (1981) examined 4S8  volunteers  from TMana.  Alabama.  >12
years of  age.  and correlated serum  PCB  levels (Aroclor 1260) with elevated
blood pressure.   The mean serum  PCB level  among  this group was  17.2  ppb.
02380                               VI-44                            04/08/88

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Three  classifications  of  blood  pressure  measu'eme-u;  .e^e  alec.   -V^TM'
(systolic of 95 mm Hg).   The  Incidence of borderline  and definite hyper-
tension was Increased 30% more  than  would  be  expected for a general  popula-
tion with the same age,  race and  sex  composition.
 02380                               VI-45                             04/08/88

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                         VII.  MECHANISMS OF TOXICITY
Introduction
    Polychlorlnated  blphenyls  (PCBs),  d1benzo-p-d1ox1ns  (PCOOs).  dibenzo-
furans  (PCOFs)  and naphthalenes  (PCNs) are a  class of  structurally-related
chlorinated aromaUcs  that  are  industrial  products or  by-products  and are
formed  during  the  combustion  of  Industrial and municipal  waste.   The  toxic
and biologic  effects  of  commercial  PCB mixtures and  Individual  Isomers and
congeners  are  dependent  on a  number  of factors  Including the dose  of the
toxin  and  the  sex,  age.  species  and strain  of  animal  used.   The  toxic
responses  observed In several  animal  species  Include  a  wasting syndrome.
thymlc  atrophy  and Immunotoxlclty.  reproductive toxlclty.  endocrine effects,
hepatotoxlclty  and  porphyrla. chloracne and related dermal  lesions, carclno-
geniclty  and   the   Induction  of  diverse  enzymes   Including  several   hepatic
drug-metabolizing  enzymes  (Safe,  1984;  Safe et al., 1982,  1985b;  McConnell,
1980b;  Klmbrough  et al..  1978:  Matthews  et al..  1978; Poland and Knutson.
1982;  Parkinson and  Safe.  1981).   Moreover,  U  has  also  been  noted  that
PCBs.  PCOFs. PCOOs  and PCNs elicit  many similar biologic and toxic responses
In  laboratory  animals  and humans,  and  the  major  differences  within  this
class  of chemical  pollutants are quantitative In nature.

    The proposed mechanism of action of the toxic halogenated aromatlcs has
Initially  been derived  from  studies using the  most  toxic  member  of this
class   of   chemicals.   2.3,7.8-tetrachlorod1benzo-p-d1ox1n   (TCDO).    The
synthesis   of   radlolabeled  [•H]-2.3,7.8-TCDO   with  high   specific  activity
(52.5  d/mwol)  resulted  1n the Identification of  a specific binding protein
In  hepatic cytosol of "responsive" C57B1/6J mice; 1n contrast minimal  bind-
ing activity  was  observed In "non-responsive"  OBA/2J hepatic  cytosol  (Poland


02390                                 VII-1                            11/13/86

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et  al..  19^6).   The  role of  this  Ah receptor  protein  \n the mechanism  o^
action  of  toxic  halogenated  aromatics  has been thoroughly  Investigated  and
satisfies  most of  the specific  criteria  that  support  a receptor  mediated
cellular process  (Poland  et al..  1979,  1983;  Nebert. 1979,  1980;  Nebert  et
al..  1981. 1983;  Nebert  and  Jensen.  1979; Okey,  1983;  Poland and  Glover,
1980;  Safe,  1986).  These criteria Include the  following:   1)  the  existence
of  a  finite  number  of  binding  or  receptor   sites  and   therefore  saturable
binding.  2) high  affinity  Itgand  binding  that  Is  commensurate  with  the
usually  low   levels  of  circulating  hormones.  3) stereoselectlve  binding
capacity  for  the  receptor  and 4) tissue  or organ response  specificity  for
the  receptor  llgand.   The  role of the 2,3.7,8-TCOO (or aryl  hydrocarbon.  Ah)
receptor 1n mediating  the  biologic and  toxic effects  of  PCBs Is supported by
several studies that are summarized In the following sections.

Role of the 2.3.7.8-TCDD Receptor Protein
     Structure-Activity Relationships.
     Induction   of   Cvtochrome   P-4SO-Oependent   Honooxvqenases — It   was
Initially  reported  (Alvares et  al.,  1973;  Alvares  and Kappas, 1975; Utterst
et al.. 1972)  that  Aroclor  12S4 and  some related commercial  PCBs were unique
"mixed"-type  Inducers  of  the hepatic cytochrome P-4SO dependent  monooxygen-
ases.   Aroclor  12S4 Induced mlcrosomal  benzo[a]pyrene hydroxylase  (or  aryl
hydrocarbon hydroxylase,  AHH)  and N-dealkylase enzymes.   The Induced mlcro-
somal  enzyme  activities,  and  the  spectral and  electrophoretlc  character-
istics of  the  proteins were  similar  to  those observed after  coadmlnlstratlon
of  the  classical  monooxygenase  enzyme  Inducers.  phenobarbltal  and  3-HC.
Subsequent  studies  have  shown  that  the activities  Induced   by  Aroclor  1254
are  due to  the  preferential  induction of cytochroraes P-450a. P-450b, P-450c.


02390                                VIU2                           11/13/80

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                                                                      n
P-450d  and   P-450e.    PhenobarbUal   preferentially   induces   cy. jc
P-450b«-e,  3-MC preferentially Induces  cytochromes  P-450c and d and both com-
pounds induce cytochrome P-450a to P-450e  (Ryan et  al.. 1977. 1979; Boteiho
et al.. 1979; Thomas  et  al.,  1983).

    Several   studies  with  selected  PCDO,  PCOF  and PCB  congeners  have shown
that  there was  a rank order correlation between  the  toxlclty of a compound
and Its activity  as  an  Inducer of AHH (Poland et al..  1979).  Thus.  Induc-
tion  of  this enzyme  activity  (which  Is  associated with  cytochrome P-450c)
has served  as a  bloassay  for  Identifying  the most  toxic  PCB  Isomers  and
congeners.

    in  vitro  and in  vivo  structure-activity  relationships  for  PCBs   as
Inducer s of  AHH and cytochrome P-450c showed that  the most  active  compounds.
3,4,4'.5-tetra-CB,      3.3' ,4.4'-tetra-CB.      3.3' .4.4' .5-penta-CB     and
3,3' ,4,4',5,5'-hexa-CB,  required chlorine  substitution at  both  para  and  at
least  two or more meta  positions (Poland and Glover.  1977;  Parkinson  et al.,
1981a).   These four  PCB congeners  contain  no ortho substHuents and  are all
approximate  Isostereomers   of   2,3,7,8-TCOO.   Not  surprisingly  these com-
pounds all bind with  relatively high  affinity  to  the  cytosollc  receptor pro-
tein  and  are also acutely  toxic  (Bandlera  et al.. 1982; Leece et al.,  1985).
However,  analytical  studies  Indicate that  the  four coplanar PCBs  are minor
constituents  of  the  more  active  commercial PCBs,  Aroclor  1254 and  Aroclor
1260  (Slssons and Heltl,  1971; BallschmHer  and  Zell,  1980;  Safe  et  al.,
1985a;  Albro  et  al.,  1981;  Hullln  et  al..  1981) and  this fact  prompted
others  (Safe,  1984; Sawyer  and  Safe,  1982; Parkinson   et  al..  1980a.b,
1981a,b,  1982,  1983b; Greenlee and  Irons,  1981;  Robertson  et  al.,  1984)  to
Identify  the active compounds present in these mixtures.
02390                                VII-3                           05/07/87

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    The Introduction of a  single  ortho-chloro  substltuent  Into the blphenyl
ring results In decreased  coplanarlty between  the  two  phenyl  rings.  It was
Initially assumed  that reduction  In coplanarlty  of  these  compounds  would
reduce their binding  to  the cytosollc receptor and eliminate AHH  induction
activities.   The effects of  ortho substHuents on PCB  activity were evalu-
ated by synthesizing all the mono-ortho  analogs of the most active coplanar
PCBs (that  Is.  3.4.4.5-tetra-CB.  3.3.4.4-tetra-C8. 3.3'.4.4'.5- penta-CB and
S.S'^^'.S.S'-hexa-CB) (Figure  VII-1)   and  determining  the mixed-function
oxldase  enzyme-Inducting  activities  In  rat  hepatoma  H-4-II   E  cells.  ,and
Immature male  Hlstar  and  Long-Evans rats  (Sawyer  and  Safe. 1982;  Parkinson
et al.. 1981a.  1983b).  All of these compounds Induce  hepatic  mlcrosonajl AHH
and OHAP  N-demethylase In  the Ulstar rats  and cytochromes P-450a  to P-450e
In the Long-Evans  rats.  It  was  apparent that the mono-ortho  analogs of the
coplanar PCBs  resembled phenobarbltal plus 3-MC (coadmlnlstered)  and Aroclor
1254  In  their  mode of drug-metabolizing enzyme  Induction.  A  comparison  of
the In vivo and \n  vitro Induction  activities  of  the  coplanar and mono-ortho
coplanar PCBs  clearly  shows  that the orthochloro  substltuent  diminishes but
does  not  eliminate  the  Induction  activity.  These studies clearly  Identify
the  structures of  the active chlorinated  blphenyl components  In the  com-
mercial  PCB.   Several  mono-ortho  coplanar  PCBs.  Including  2.3,3'.4,4'-
penta-CB. 2.3'.4,4',5-penta-CB. 2.3.3'.4.4'.5- hexa-CB and 2.3,3'.4.4'.5.5'-
hepta-CB have  been  Identified  In  a  number  of commercial formulations  Includ-
ing  the  Aroclors,  Phenoclors and Kanechlors (Slssons  and  Weltl.  1971;  Ball-
schmlter  and  Zell, 1980;  Safe et al.,  1985a;  Albro et al..  1981;  Kullln  et
al.. 1981).
 02390                                VII-4                           11/13/86

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ro
o>
«O
o
                                            Cl                   Cl                   Cl


                CI^S^CI       CI^Js^           CI^A^CI
                 2,3,4,<5           2,3;4,4',5           2,3',4.4',6,5I
                                                                               2,3.3',4,<5,5'
oo
o>
              flGURE VI1-1



Coplanar and Mono-ortho Coplanar PCB Analogs

-------
     The  effects  of two ortho-chloro suosHtuents  on  the AHH  and  cytocnrome
P-450c  Induction  activities  of  the  d1-ortho coplanar  analogs were  deter-
mined.   The" results (Parkinson  et  al.,  1981a,b;  Greenlee  and  Irons.  1981)
Indicated  that  In male Ulstar rats  (dose  level  300 ^mole/kg)  at  least five
members  of  this  group,  namely 2,«.' .3.3' ,4.4'-hexa-CB,  2,3,3'.4,4',6-hena-CB.
2,2'.3,4.4',5'-hexa-CB,  2,3.4.4',5,6-hexa-CB  and  2.2' .3.3'.4.4',5-hepta-CB,
exhibited   a   mixed-type   Induction   pattern.   Using   the   more   sensitive
cytochrome  P-450 Isozyme Immunoquantltatlon assay.  It  was  shown  that  these
five  PCBs  and at least  two  additional  compounds. 2.3',4,4',5-penta-CB  and
2,3',4.4',5',6-hexa-CB,   Induced  cytochrones  P-450a   to  P-450e   In   male
Long-Evans  rats   (dose  level  SOO  ^mole/kg)  (Parkinson  et  al..  1981a).
Since  not   all   the  dl-ortho coplanar  PCBs were  evaluated  as Inducers  of
cytochrome P-450c. the  Isozyne associated with AHH Induction. It 1s possible
that  other  members  of  this   group  nay  also   Induce  this  hemoproteln.
2,2l,4,4',5,51-Hexa-CB  was   the  only  dl-ortho  coplanar PCB  that did  not
Induce cytochromes  P-450c and P-450d but.   like phenobarbltal.  Induced  cyto-
chromes  P-450a and P-450b  *  P-450e (Parkinson  et al.,  1981a).   Subsequent
studies have not   Identified  any other PCBs  that Induce AHH activity.

    Receptor Binding  Affinities — The direct binding of  radlolabeled PCBs
to  the  2.3,7.8-TCOO receptor  protein has  not been  Investigated.   However.
competitive  binding  studies  using  [»H]-2.3.7.8-TCDD  as   the  radlollgand
have  been   reported   (Sandiera  et  al..  1982).   The  structure-activity
relationships reported  for  PCBs as  AHH  Inducers  and as  competitive llgands
for  the cytosollc  receptor  protein were comparable;  the coplanar PCB Isomers
and congeners bound with  higher  affinity than the monoortho coplanar analogs
(see Figure VII-1).  Several  compounds  that do not Induce hepatic mlcrosomal


02390                                VII-6                           11/13/86

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AHH  or   cytocnrome  P 450c   exhibit  low  affinity  for  the  receptor  UC^Q
>10~s H)  and  these  values  were  considered nonspecific   llpophillc  Inter-
actions   between   the  llgands  and  the  hydrophoblc  protein  binding  site
(Table VII-I).

    PCB   ToxIcUv  — Several   studies  report  the  toxlcltles  of  diverse  PC8
Isomers  and congeners and the results  clearly demonstrate  that the coplanar
congeners  are  the  most  toxic  group   of  PCB  compounds.   Pretreatment  of
rodents     with    the    3.3'.4.4'-tetra-CB,     3.3'.4.4',5-penta-CB    and
3.3',4.4'.5,5'-hexa-CB  results   In  hepatic  damage,  porphyrla. reproductive
toxldty. thynlc  atrophy, marked Increases  In  liver  llplds.  edema (In mice
and chicks) and hepatomegaly (Parkinson  et al.. 1983b;  Leece et al.. 1985;
Goldstein et al..  1976;  Kohll et al..  1979; Blocca et al..  1981; NcKlnney et
al..  1976;  YosMhara  et  al., 1979; Puhvel  et  al..  1982;  Kawanlshl  et al..
1978; Swain et al..  1983;  Sllkworth and Grabsteln.  1982;  Sllkworth et al..
1984).   In  the rhesus macaques  (Hacaca mulatta).  3.3'.4.4'.5.5'-hexa-CB was
toxic  at   dietary  dose   levels   <1   ppm  whereas  the  2.2'.4.4'.5.5'-.
2.2'.4.4',6.6'- and  2.2'.3.3'.6.6'-hexa-CBs  caused  no  discernible   adverse
effects  at  dose levels  up  to 65 ppm  (NcNulty.  1985); comparable  structure-
activity  relationships were  also noted  In mink (Auerllch  et al..  1985).

    Several studies report that  many of  the mono-ortho coplanar PCB  analogs
are also toxic (Safe, 1984; Parkinson et al.. 1980a.b.  1981a.b.  1982. 1983b;
Sandiera   et  al..  1982;  Leece et  al..  1985;  Slssons  and  Ueltl.  1971;
BallschMlter and  Zell. 1980; Safe  et  al..  1985b;  Albro  et al..  1981; Mullln
et al..  1981; Greenlee and  Irons. 1981;  Robertson  et al..  1984;  Goldstein et
al..  1976;  Kohll  et al., 1979;  Blocca  et  al.,  1981; HcKlnney et  al..  1976;

02390                                VII-7                           11/13/86

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10
o
                                                    1ABLE VII 1
                                 PCBs:  Summary of Structure-function Relationships
Cytochromes P-450 Induction4
(% of control)



1—4
»— 1
00


PCB Structures
(Number)
Coplanar PCBs - le (3)
Coplanar PCBs - 11 f (2)
Nono-ortho Coplanars (8)
01 or t ho Coplanars (12)
2,2'.4.4',5.5'-Hexa-CB
2,3,7.8-TCOO
P-4SOc
P-450d
4100-1800
1500-1100
2400-750
900-250
no
Induction
3500
P 450b
P-450e
no
Induction
1400-600
4700-2600
6300-1000
7300
no
Induction
Relative % Activity
AHH Induction
in vlyob in vltroc
*»» 100-1%
3xlO~»9
o 0.3-2.4x10"*
» Inactive
Inactive Inactive
*tt»» 400
•
Receptor
Binding*
100-35X
0.59
b-1.5
<0.3h
<0.3
PiOO
    aMale Long-Evans rats (dose: 500 aol/kg)
    bMale Utstar rats (dose: 300 nol/kg)
    cRat hepatoma H-4-11-E cells
    Vtermlned by the competitive displacement of (»MJ TCOO bound  to male Hlstar rat hepatic cytosol
S  e3.3'.4.4'-letra-CB, 3,3',4,4'.5 penta-CB and 3,3',4,4',5,5'-hexa-CB
o  f3,4.4'-tr1-CB and 3.4,4',5-tetra-CB
™  Determined only for 3,4,4'.5-tetra Cfl
    ^Represents nonspecific binding

-------
Yoshthara et  al.,  1979;  Yamaraoto et al..  1976;  Ax and  Hansen,  1975).  For
example,   2,3.3',4,4'-penta-CB  administered  to  mice  results  In  a  wasting
syndrome  (weight  loss),  edema,  liver Upld  accumulation,  extensive hepatic
damage,  and  splenic  atrophy.   2.3',4,4',5-penta-CB   causes  100%   embryo
mortality In eggs from pullets receiving the PCS In their diet at  a level  of
20  ppm (Ax  and  Hansen.  1975);  administration  of  2.3',4,4',5-penta-CB and
2,3,3' ,4,4',5-hexa-CB  to  rats  causes   Increased  liver  weights.  Increased
liver llplds and thymlc atrophy;  2.3.3'.4.4',5-hexa-CB,  2.3.4.4',5-penta-CB.
2.3.3'.4,4(.51-hexa-CB.   2.3.3'.4.4',5'-hexa-CB    and    2.3.3'.4.4'-penta-CB
cause  thymlc   atrophy  1n  male   rats.    Quantitative  structure-activity
relationships For several coplanar and  mono-ortho  coplanar  PCBs  has recently
been  reported  (Leece et  al..  1985).  A  comparison of  the EO.Q  values  for
AHH/ethoxyresorufln   0-deethylase   (EROO)   Induction,  body  weight  loss  and
thymlc atrophy  In  the rat  clearly demonstrates the  higher  toxlclty  of  the
formed group of compounds.   Moreover, there  was an excellent  linear correla-
tion  between  the .Irt  vitro  AHH/EROD Induction  potencies of  these compounds
and their in vivo toxlcltles and AHH/EROO Induction potencies.

    The  data Indicate  that  the  mono-ortho analogs  of the coplanar  PCBs
elicit toxic  effects that  resemble  (qualitatively) 2,3.7,8-TCDO;  several  of
these    compounds     (2.3.3*.4.4'-penta-CB.    2.3' ,4,4',5-penta-CB     and
2,3,3'.4,4',5-hexa-CB)  have  been  Identified  In  commercial  PCBs  and  as
residues  In  human tissues   (Slssons  and Ueltl.  1971; Ballschnlter and Zell.
1980; Safe et al., 1985a; Albro et al.. 1981; Nullln et al..  1981).

    The toxlclty of  the dl-ortho  coplanar PCBs has  not been systematically
Investigated;  however,  two  members   of  this   group.  2,2'.3,3'.4,4'- and
02390                                VII-9                           11/13/86

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2.2' .3,*.*' .5' -nexa-C8 are  porphynnogen ic  ^n  rats  after  ",onq-tern  ~<
studies (Stonard  and  Grieg, 1976).  Both  of  these  compounds  are among  the
most active dl-ortho coplanar  PCS Inducers of rat hepatic mlcrosomal  AHH  and
cytochrome "P-450c  (Parkinson et al., 1983b) and warrant  further  studies.

    Pharmicoqenetlc   Studies  and   Response   Specificity.   Pharmacogenetlc
studies with genetically Inbred mice have  been  utilized to probe  the mecha-
nism of action  of 2.3.7.8-TCOO,  PCBs  and  related  compounds (Poland  et al.,
1983;  Nebert et al..  1981.  1983;  Okey.  1983;  Nebert. 1979. 1980;  Nebert  and
Jensen, 1979; Poland  and Glover.  1980).   Responsive mice,  typified by  the
C57B1/6 strain contain relatively  high  cytosollc receptor protein  levels  In
hepatic and  some  extrahepatlc tissues  whereas  nonresponslve mice,  typified
by the OBA/2 strain contain relatively  low (to nondetectable)  levels of  the
cytosollc   receptor.   Studies  with 2.3.7.8-TCDD  In  Inbred mice have  clearly
shown  that many of  the  biologic  and toxic effects elicited by  this compound
segregate  with  the Ah (or 2,3.7,8-TCDD) receptor locus  (Poland  et al.. 1983;
Nebert  et'al..   1981.  1983;  Okey.  1983;  Nebert.  1979.  1980;  Nebert  and
Jensen. 1979; Poland  and Glover,  1980).  Moreover,  H  has  been demonstrated
In genetic  cross  and backcross  experiments  between  C57B1/6  and  OBA/2 mice
that the trait of Ah  or  2,3,7,8-TCOD responsiveness  1s  Inherited  In a simple
autosomal   dominant  mode.   The  differential  activities  of several  coplanar
and mono-ortho  coplanar  PCBs  In  responsive   and  nonresponslve mice also
confirms  the  role of the  receptor 1n  mediating several biologic  and toxic
effects Including AHH/EROD  Induction (Parkinson et  al.. 1982; Robertson et
al.. 1984) thymlc atrophy  (Parkinson  et al.. 1982;  Robertson  et  al.. 1984).
body  weight   loss  (Parkinson  et  al..   1982;  Robertson  et al..  1984)  and
Immunotoxlclty (Sllkworth and Grabsteln.  1982;  Sllkworth et al.,  1984; Clark


02390                                Vll-10                           10/29/86

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et al., 1983).  These experiments  with Inbred mice also demonstrate  that  the
presence of the receptor  In the species also Influences response  specificity
to the biologic and  toxic effects of PCBs.

    Sunmarv.    The   genetic  studies  with   Inbred  mice  and   the extensive
structure-function  relationships  summarized  previously  support the  proposed
receptor-mediated mechanism of  action  for PCBs and related  toxic  halogenated
aryl hydrocarbons.   The precise role of the receptor Ugand complex  has been
determined for  the  Induction  of  cytochrome  P-450c  (Tukey  et  al.,   1981;
Israel and WhUlock.  1984;  Jones  et al..  1985)  and Involves  nuclear  trans-
location of  the Ugand receptor  complex.  Interaction  with nuclear binding
sHe(s) followed by  Induction  of  the mRNA  for  cytochrome  P-450c.   Although
the  Initial  toxin-receptor  Interactions  are probably  Involved In the  ulti-
mate  expression  of  some   of  the  toxic  effects  of PCBs,  2,3,7,8-TCDD  and
related compounds,  the subsequent steps  that  lead  to  the  diverse  toxic
responses  have not  been delineated.

Role of Metabolism  In PCS Toxlclty
    Although  PCBs  produce  a number of diverse  toxic responses  In  a number of
organs., the chemical species responsible  for  the  toxic Hy  are  not known.   It
has  been  suggested  that the parent  compound, reactive  Intermediates  formed
during metabolism  and metabolites of  PCBs all  produce toxic  effects.   For
example.  It  was suggested  that  PCB-lnduced  porphyrla  was  produced by  the
parent  compound  (Strlk et  al..  1979).   Other  Investigators  have suggested
that  the cytotoxlc  and mutagenU  effects of PCBs  result  from reactive arene
oxides that  are  formed during metabolism (Allen and Norback,  1977; Uyndham
et  al.,  1976).  PCBs  that contain  vicinal  unsubstltuted  carbon atoms  are


02390                                VII-11                          04/04/88

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suOstrates  for  oxldat've iwetaooi'sm  by  Mgn'y reac*kve  arene  ox'se  't*.e--
mecMates  that  interact with  cellular macrontolecules  such  as  ONA.  SNA  and
protein (Safe,  1980;  Wyndham and Safe,  1978;  Uyndham et al..  1976;  Morales
and Matthews. 1979; Hesse et al.. 1978;  Hargraves and Allen.  1979;  Hesse and
Wolff, 1977; Wong  et  al.. 1979;  Stadnlckl  et  al..  1979).  For example,  the
nutagenlclty of 4-chloroblphenyl was  expressed only  following Us metabolism
(Uyndham  et  al.,  1976).  In  vitro  studies In a  Chinese hamster ovary  cell
line  demonstrated   that  4-chloroblphenyl  was  metabolized  to  hydroxylated
products  and that 4-chloroblphenyl-equivalents bound  covalently  to  ONA.  SNA,
and  protein  and  produced   ONA  daaage   as  demonstrated  by  Induction  of
unscheduled ONA synthesis (Wong et  al.,  1979).  Other Investigators reported
that  the  arene oxide  Intermediate.  3,4-d1hydro-3.4-epoxy-2,5-tetra-C8,  was
more  potent  than either  4-hydroxy-2.2',5.5'-tetra-CB or  2,2'.5,5'-tetra-C8
as  a  cytotoxlcant  and as an  Initiator  of  single  strand breaks In  ONA  when
Incubated  with  1-929  cells  (Stadnlckl  et  al.. 1979; Stadnlckl and  Allen.
1979).   In vivo  studies 1n  nice  demonstrated that 2.2'.3.3',6.6'-hexa-C8
bound covalently to hepatic RNA and protein at a  level at least one order of
magnitude    greater    than    the    essentially     nonmetabollzed    isomer.
2.2>.4,4'.5,5'-hexa-CB  (Morales  and Matthews.  1979).   These  Investigators
also  observed  that  2,2' ,3,3',6,6'-hexa-C8  bound  covalently  to   ONA  while
2.2',4,4'.5,51-hexa-CB did not.

    Although  most  toxlclty  studies  have  focused  on   the  parent  PCS  or
reactive   Intermediates  formed  during  the  metabolism  of   PCBs.   there  Is
evidence  that  certain  metabolites  may  cause toxlclty.   A monohydroxylated
metabolite  of  3,4,3'.4'-tetra-CB has a   lower  L05Q  In mice  than  the parent
compound  (Yamamoto and  Yoshlmura,   1973).   PCS methyl  sulphones  are stable


02390                                 VII-12                           10/29/86

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llpophlllc metabolites  formed during  blotransformatlon  of PC8  by  tne mer-
captuMc  acid  pathway.   These  metabolites  have  been  found  to  selectively
accumulate >n  the  apical  cytoplasm of nonclllated bronchlolar  (Clara)  cells
of the  rat lung  (Lund  et  al., 1985).  This selective  Ijn vivo uptake  appears
to be  due to the presence of a  protein  with  high affinity and capacity  for
binding PCS methyl sulfones.  This binding protein Is  present In  Clara  cells
and  the  tracheobronchoalveolar  lavage  fluid  from   rats,  mice  and  humans
(Brandt, 1986; Lund et al.. 1986a).  Hethylthlo and methylsulfonyl PCBs have
been  Identified  In  lung  tissue  from Yusho  patients  and  healthy controls
(Haraguchl et  al.,  1984,  1986).   Lund  et   al.  (1986a)  proposed  that  the
binding  protein  was  responsible  for  the  observed  tendency   of  these  PCB
metabolites  to accumulate In  the  lung  tissue of  humans.  While  the  toxlco-
loglcal significance of  these findings  Is not  known.  It has been  suggested
that  these  metabolites   may  be  In  part  responsible  for  the  persistent
respiratory distress seen  In  the victims of  PCB  poisonings  In  Japan  (Yusho)
and the decreased lung vital  capacity  In workers  exposed to PCBs (Shlgematsu
et al.,  1978;  Uarshaw et al..  1979).    In apparently the  only  study on  the
effect  of  PCB metabolites  on  lung  function, Lund  et al. (1986b)  reported
that  A-methylsulphonyl-2.2'.5.51-tetra-CB   Inhibited  a  cytochrome   P-450-
dependent  enzyme activity  1n mouse  lung,  while   Inducing  this activity  In
mouse  liver.   Thus, while  these  results suggest that  PCB metabolites  may
mediate  specific toxic  responses of  PCBs.   further   studies are needed  to
confirm the role of metabolism In the expression of toxlclty.

Other Hechan1s«s
    It  Is  apparent  that many PCB  Isomers and congeners that do  not  bind to
the  2.3,7.8-TCDO receptor protein  elicit a  broad spectrum of biologic  and


02390                                VII-13                          03/02/87

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some toxic  effects.   Several  compounds  Induce  a number  of  mlcrosomal  cyto-
chrome P-4SO  Isozymes and related monooxygenase,  glutathlone  transferases.
epoxlde hydrolase and  glucuronyl  transferases  and  resemble phenobarbUal  in
their mode of  Induction of the  drug-metabolizing enzymes (Parkinson et  al..
1983b; Orberg,  1976;  Genome  et al.,  1983).   Their mechanism of action  Is
unknown.   In addition, other  studies have  demonstrated that diverse commer-
cial PCB  mixtures  and Individual compounds  Inhibit mltochrondrlal function
(Nlshlhara.  1984),  exhibit mild  estrogenlc  properties In female rats (BUman
and Cecil. 1970), act  as  cancer  promoters  In hairless mice and rats (Poland
et al., 1982;  Preston  et  al., 1981) exhibit  antlcarclnogenlc properties  in
other laboratory animal models  for  cardnogenesls   (Kerkvllet  and  Klmeldoof.
1977). are Inactive In the Solt-Farber  model for liver  tumors  (Hayes et al.,
1985) and cause delayed pregnancy In NHRI mice  (Torok.  1978).   Some of  these
activities may  contribute  to the  toxldty of  PCBs.

    It Is also possible that  Interactive effects may also play a  significant
role  In  PCB toxicology.   A recent  study  has  reported  that  2,2',4,4'.5,5'-
hexa-CB  (and  other  related   congeners),  a  compound  that  does  not   Induce
2.3,7,8-TCOO receptor-mediated effects,  elevates  hepatic cytosollc receptor
protein levels (>2-fold)   In the rat and mouse  (Oenomme et  al.. 1986).   More-
over, rats pretreated  with 2,2'.4,4',5,5'-hexa-CB are  more  responsive  to the
Induction  of   hepatic  mlcrosomal  AHH   and  EROD  by  planar  and  mono-ortho
coplanar  PCB  congeners  (Leece  et  al., 1986).   These  results confirm the
Importance of  the  cytosollc  receptor protein  In  the mechanism of action of
PCBs  and  suggest  that  nonaddltlve  Interactive   effects   that  are  due  to
receptor  modulation  (Blrnbaum et al.,  1985) may  Influence the  activity of
PCB mixtures and related  toxic aryl  hydrocarbons.


02390                                VII-14                          11/13/86

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Summary
    Data on purified  PCB  Isomers have established  that  the  toxic,  metabolic
and toxlcoklnetlc  behavior  of  the  different  component molecules  varies  not
only with  the  degree  of chlorlnatlon  (greater  toxic  potency with  greater
degree  of  chlorlnatlon)  but  also  with the  position of  the  chlorine  atoms.
The  relative   toxldty  and  persistence   of  four  pure  hexa-CB  Isomers  was
examined In mice;  3,4,5-sym-hexa-CB was  found  to be the most  toxic  (LD50  »
19 mg/kg bw/day) and  persistent  (levels 1n  liver  and adipose tissue)  Isomer,
followed  by  2,4,6-sym-hexa-CB  >  2,4,5-sym-hexa-CB,  >  2,3,6-sym-hexa-CB.
Although  structure-activity  relationships   are  most  Interesting  for  this
class of compounds,  It Is also Important  to note that highly toxic, coplanar
PCB  Isomers,   such  as 3,4,5-sym-hexa-CB,  have  only been  detected as  very
minor constituents of commercial PCB formulations.
02390                                 VII-15                          03/02/87

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                VIII.  QUANTIFICATION OF TOXICOLOGICAL EFFECTS

Introduction
    The  quantification  of  toxlcologlcal  effects  of  a chemical  consists  of
separate  assessments of  noncarclnogenlc  and  carcinogenic   health  effects.
Chemicals  that  do not  produce carcinogenic  effects  are  believed to  have  a
threshold  dose below which  no  adverse,  noncarclnogenlc health effects  occur,
while carcinogens are assumed to act without a threshold.

    In  the  quantification   of  noncarclnogenlc   effects,  a  Reference  Dose
(RfD).  [formerly  termed  the Acceptable Dally  Intake  (ADI)]  Is  calculated.
The RfD  Is an estimate (with  uncertainty  spanning perhaps  an  order  magni-
tude)   of  a  dally  exposure  to the  human  population (Including  sensitive
subgroups) that  1s  likely  to  be  without an  appreciable  risk of deleterious
health  effects  during a  lifetime.   The RfD Is derived  from a  no-observed-
adverse-effect   level   (NOAEl),   or   lowest-observed-adverse-effect   level
(LOAEL),  Identified  from a  subchronlc  or  chronic study, and divided  by  an
uncertainty factor(s)  times a  modifying factor.   The RfD Is calculated  as
follows:
     RfD	
-------
 the  U.S.  EPA  (1986a)  employs  a modification  to the guidelines  proposed

 the National Academy of Sciences (HAS. 1977, 1980) as follows:


 Standard Uncertainty Factors (UFs)

         Use a  10-fold  factor when  extrapolating  from valid experimental
         results from studies using  prolonged exposure to average healthy
         humans.  This  factor  Is Intended  to  account for  the  variation
         1n sensitivity among the members  of the human population.   [10H]

         Use an additional  10-fold  factor  when extrapolating from valid
         results  of  long-term  studies  on  experimental   animals  when
         results of  studies  of  human  exposure  are not available  or  are
         Inadequate.  This  factor Is  Intended  to account for the  uncer-
         tainty  In  extrapolating animal   data  to  the  case  of  humans.
         [10A]

         Use an additional  10-fold  factor  when  extrapolating from  less
         than chronic  results  on experimental  animals  when there  1s  no
         useful   long-term  human data.   This   factor  1s   Intended  to
         account for  the  uncertainty  In  extrapolating  from  less  than
         chronic NOAEls  to chronic NOAELs.   [10S]

         Use an additional  10-fold  factor  when deriving an  RfD  from  a
         LOAEL  Instead  of  a  NOAEL.   This  factor  Is  Intended to  account
         for  the  uncertainty  In extrapolating  from  LOAELs  to  NOAELs.
         [10L]

Modifying  Factor  (MF)

     •    Use   professional   judgment   to  determine  another   uncertainty
         factor  (MF) that  1s greater than zero and less  than  or  equal  to
         10.   The  magnitude  of  the  MF  depends   upon  the   professional
         assessment  of  scientific  uncertainties  of  the  study  and  data
         base  not explicitly treated  above,  e.g.,  the  completeness  of
         the  overall data  base  and  the number of  species  tested.   The
         default value  for  the MF  1s  1.
    The  uncertainty  factor  used  for  a  specific  risk  assessment  Is based

principally   upon   scientific   Judgment  rather  than  scientific  fact  and

accounts   for   possible  1ntra- and  Interspecles  differences.   Additional

considerations  not Incorporated  In  the NAS/OOW  guidelines  for selection of

an  uncertainty factor  Include the  use of  a  less  than  lifetime  study for

deriving  an  RfO,  the  significance   of  the  adverse  health effects  and the

counterbalancing of beneficial effects.
02400
VIII-2
03/02/87

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c u -
     From  the  RfD,  a  Drinking  Water  Equivalent  Level  (OWED  can  be
 lated.    The  DWEL   represents   a   medium   specific   (I.e.,   drinking  water)
 lifetime exposure  at  which adverse,  noncardnogenlc health  effects  are not
 anticipated  to occur.   The  DWEL assumes 100% exposure  from  drinking water.
 The DWEL provides  the  noncardnogenlc  health  effects basis for establishing
 a   drinking  water  standard.   For  ingestlon  data,  the  OWEL  1s derived  as
 follows:

               nut.     (RfD) x (Body weight  In  kg)
               uwcL « —^~~^	                  — » 	 rag/1
                      Drinking Water Volume  In  i/day

 where:
         Body weight « assumed to be  70  kg for an adult
         Drinking  water volume >  assumed  to  be 2 i/day for an adult

     In  addition  to the  RfD  and  the DWEL,  Health  Advisories  (HAs)  for  expo-
 sures  of shorter  duration {1-day,  10-day  and longer-term)  are determined.
 The  HA  values  are  used  as  Informal   guidance  to municipalities  and  other
 organizations  when  emergency spills or  contamination situations occur.   The
 HAs  are  calculated  using  an  equation  similar  to  the RfD  and DWEL; however,
 the  NOAELs  or  LOAELs are  Identified from  acute or  subchronk  studies.   The
 HAs are derived as follows:
                   u»    (NOAEL or LOAEL1 x  (bwi
                   nn •                     .    • 	 IHQ/l
                           (UF) x (	 t/day)      	

    Using the above equation, the  following drinking water HAs  are  developed
 for noncardnogenlc effects:
    1.  1-day HA for a 10  kg child Ingesting 1  l water per day.
    2.  10-day HA for a  10 kg child  Ingesting 1 l water per day.
    3.  Longer-term HA for a 10 kg child Ingesting 1 l water per day.
    4.  Longer-term HA for a 70 kg adult Ingesting 2 l water per day.

02400                                VIII-3                           03/02/87

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    The  1-day  HA  calculated  for  a  10  Kg  child  assumes  a  single  acute
exposure  to  the chemical and  1s  generally  derived  from  a  study of  <7  days
duration.  -The  10-day  HA assumes  a limited exposure period  of  1-2  weeks  and
Is generally  derived  from a study of <30 days  duration.   The  longer-term HA
1s  derived for  both   the  10  kg  child  and  a  70  kg  adult and assumes  an
exposure  period of  -7  years  (or  10X of  an  Individual's  lifetime).   The
longer-term  HA  1s  generally  derived  from a  study of   subchronlc  duration
(exposure  for 10% of animal's  lifetime).

    The U.S.  EPA categorizes the  carcinogenic  potential  of  a chemical, based
on the overall welght-of-evidence, according to the following scheme:
        Group  A:  Human  Carcinogen.   Sufficient  evidence   exists  from
        epidemiology  studies  to  support a  causal  association between
        exposure to the  chemical and human cancer.
        Group  B:  Probable   Human  Carcinogen.   Sufficient   evidence  of
        carclnogenlclty  In  animals  with  limited  (Group 31)  or Inade-
        quate  (Group 82) evidence  1n humans.
        Group   C:   Possible  Human  Carcinogen.   Limited  evidence  of
        carclnogenlclty  In animals In the absence of human data.
        Group  0:  Not  Classified   as  to  Human  Carclnogenlclty.  Inade-
        quate  human and animal evidence  of  carclnogenlclty or   for which
        no data are available.
        Group   E:   Evidence   of   Noncarc1noqen1c1ty  for  Humans.    No
        evidence  of  carclnogenlclty 1n  at  least   two  adequate animal
        tests  in different  species  or  In both  adequate epldemlologlc
        and animal studies.
    If  tox1colog1cal  evidence  leads  to the classification of  the contaminant
as  a  known,  probable  or possible human carcinogen,  mathematical models  are
used  to  calculate the  estimated  excess  cancer  risk   associated  with  the
Ingestlon of  the  contaminant In drinking  water.  The data  used   in  these
 02400                                    -                            03/02/87

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 estimates  usually  come  from  lifetime exposure  studies  using  an'mais.   In
 order  to predict the risk  for  humans  from animal  data,  animal doses must be
 converted  to equivalent  human doses.   This  conversion  Includes  correction
 for  noncontlnuous exposure,  less  than lifetime studies  and  for differences
 1n  size.  The  factor  that compensates for  the size difference  1s  the  cube
 root  of  the  ratio of the  animal and  human body weights.   It  Is assumed  that
 the  average  adult  human  body  weight  Is  70  kg and  that the  average  water
 consumption  of an adult human  1s 2 l of water per day.

    For  contaminants  with  a   carcinogenic  potential,   chemical  levels  are
 correlated with  a carcinogenic risk  estimate  by employing a  cancer potency
 (unit  risk)  value  together  with  the  assumption  for lifetime  exposure  from
 Ingestlon of water.   The cancer unH  risk  Is  usually derived  from a linear-
 ized multistage  model with a  95%  upper confidence  limit  providing a low dose
 estimate; that  Is,  the  true  risk  to humans, while  not  Identifiable,  Is  not
 likely  to exceed the  upper  limit  estimate  and,  In  fact,  may be  lower.
 Excess cancer risk  estimates  may  also be  calculated  using  other models  such
as  the one-hit,  Helbull,  loglt and  probH.   There  1s  little  basis  In  the
current  understanding  of  the  biological  mechanisms Involved  In cancer  to
 suggest  that any  one of  these  models  1s  able to predict risk more accurately
than any other.   Because each  model  1s based upon differing assumptions,  the
estimates derived for each model can differ by several orders of magnitude.

    The  scientific  data  base  used  to calculate  and support  the  setting of
cancer  risk  rate  levels  has  an  Inherent uncertainty  that   Is due  to  the
systematic and random errors  In scientific measurement.   In most cases,  only
studies  using  experimental  animals  have  been performed.   Thus,  there 1s


02400                               VIII-5                           03/02/87

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uncertainty  when  the  data   are  extrapolated  to  humans.   When  developing
cancer  risk  rate levels,  several  other  areas of  uncertainty  exist,  such  as
the  Incomplete knowledge  concerning  the  health  effects of  contaminants  in
drinking  water,  the  Impact  of   the  experimental  animal's  age,  sex  and
species,  the  nature  of  the   target organ  system(s) examined  and  the  actual
rate of  exposure  of the Internal  targets  1n  experimental  animals  or  humans.
Dose-response  data  usually  are available  only  for  high levels of  exposure
and  not  for  the  lower  levels  of  exposure  closer to where a  standard  may  be
set.   When  there  Is   exposure  to  more  than  one  contaminant,  additional
uncertainty results  from a  lack of  Information about possible synerglstlc  or
antagonistic effects.

    The  evidence  of human exposure  to  PCBs  from  finished  drinking  water  Is
limited.   A  single finished  groundwater   sample  1n  each  of  the  National
Organic  Monitoring  Survey  (NOMS)  II  and III  contained  PCBs  In minimum quan-
tifiable  detectable  limits   that  ranged  from  0.1-0.2 vq/l,  respectively.
PCBs were detected  1n  all   three  phases  of  the  NOMS of  finished  surface
water.    In  this  survey  of  finished   surface   drinking  water,  PCBs  were
detected  In   two  samples  of  NOMS  I at  levels  of  0.13  and  1.4 wg/l;  in
NOMS  II,  two  samples  contained  0.1   u9/l   and  one  sample  had  0.2  vq/i
of PCBs;  and  only  one  sample of  NOMS III contained  PCBs  at a concentration
of  0.2  yg/l.   Schroeder  and  Barnes (1983)  showed that  PCB  removal  from
Hudson River  water  ranged  between 80 and  90% with levels  In finished drink-
Ing  water  seldom exceeding  100 ng/l.   Congeners of Aroclor  1016  were also
detected  In finished  drinking water  with the Hudson River  as  Us source at a
median concentration of 85 ng/l (Brlnkman et  al., 1981).
02400
                                    VIII-6                            03/02/87

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    Groundwater from 32  of  163  wells  In New Jersey had PCBs with  concentra-
tions  ranging  from  0.6-127  wg/l-   Many of  these  wells  sampled  were  from
highly  Industrialized   and   populated   areas  of  the  state.    Congeners  of
Aroclor  1016  have  been  detected  1n  the water  distribution   system  of an
upstate New  York  public  water  supply  system near a heavily polluted  section
of  the  Hudson River at a concentration  level  of  69-100  ng/i (BMnkman et
al., 1980,  1981).   The  Impounded  water  contained a uniform level  of  Aroclor
1016  congeners  (OorHy  Reservoir,  70-130   ng/l;   New   Reservoir,   110-120
ng/l;  Distribution  system,   69-100  ng/i) while  rain  water was much  higher
(1300  ng/l).   Low  levels  of Aroclor  1254 congeners  (up to  36   ng/l)  were
detected  1n  the  New Reservoir only.  The  high  levels of PCBs  1n  the  Hudson
River  (360  ng/l) near  Fort  Edward was thought  to  be  responsible for  high
Impounded water levels.  Finished tap water did  not  show  evidence  of  Aroclor
1254  congeners  (<12  ng/l).   The  median  concentration  of   Aroclor  1016
congeners was  85 ng/l  1n  finished  tap  water.   One sample at  the chlorlna-
tlon site was 30* higher 1n Aroclor  1016 congeners than  at a  household tap.

    The  Aroclor   1016  origin  was  confirmed  by  Identifying   at   least  five
specific surrogate congeners by retention  time  from a possible 19  congeners.
The   19   congeners   were:     4-Cl-CB/2,2'-Cl2-CB    (also   Aroclor   1221);
2,4'-Cl2CB    (also    Aroclor     1221);    2,2'.S'-Cl^CB.    2,2'  ,4' -CyCB;
2,2',3'- and   3,2',6'-Cl3-CB;   4,2' ,6'-Cl3-CB;    two  unidentified  CyCBs;
3,3',5'-Cl3-CB;   3,2' .I'-Clg-CB;   2.4,*' -Cl-j-CB   (also   Aroclor   1221);
2,3',4I-C1,-CB;   2,5,2',5'-Cl4-CB  (also  Aroclor   1254);   2,4,2',5'-C14-CB
(also    Aroclor     1254);     2,3.2',5I-C14-CB     (also    Aroclor    1254);
2,4,2',4'-Cl4-CB   (also  Aroclor   1254);   2,3,2',3'-C14-CB   (also  Aroclor
1254);   and   two  unspecified  Cl4-CBs  (one of which also arose from Aroclor
02400
                                    VIII-7                           04/04/88

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 1254).    Thus.   10  of  the  19   congeners  selected  were  unambiguously  fr:m
 Aroclor  1016, with  6  being resolved  specific  congeners.   In this study,  60
 congeners  were utilized to  Identify  the  possible  presence of Aroclors 1221,
 1016,  1254 and  1260.   Each peak chosen  provided  an Independent estimate of
 the  quantity of  the  Aroclor using the appropriate  response  factor for each
 congener.   The  concentration of the Aroclor  was calculated as the average of
 the  concentrations  by  each of the five chosen peaks.  Representative samples
 were confirmed  by GC/MS.   The  detection  limit  was  50 pg,  equivalent  to a 12
 ng/i (12  ppt)  concentration  In  2 I  of water  subjected  to  the  analysis
 technique.

     It  1s  clear  the  least chlorinated congeners are  the  PCBs that might  be
 expected  to  occur In drinking waters produced from nonchlorlnated processes.
 Chlorlnatlon  may  lead  to the presence of  higher chlorinated PCBs for Aroclor
 1221  and  below but  not  for Aroclor  1242  and above  (Aly  and  Badawy,  1986).
 Most  of  the  residues  In human  tissues are  highly  chlorinated (Holt  et al.,
 1986; Ansarl  et  al.,  1986; Safe,  1984; Bush  et al.,  1985b).  This 1s charac-
 teristic of exposure  through food  sources such as  fish, birds or human milk.
 The  less   chlorinated  congeners  dominate in  inhalation and  drinking  water
 exposures.

     PCBs In the  Hudson  River (from Aroclors  1221,  1242, 1248, 1254 and 1260)
are  still   at levels  causing  concern (Brown  et  al., 1985;  Bush et  al.,
 1985a).   The  more  soluble  less  chlorinated  congeners dominated  In  waters
without sediments, and  the highly  chlorinated congeners were associated with
partlculate matter  (Bush  et  al.,  1985a;  Brown  et  al., 1985; Baker  et al.,
1985).  This  also applied  to wet  deposition  (Mazurek  and  Slmonelt,  1985).


02400                               VIII-8                           03/02/87

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 The  PCS residues  In  sediment,  amolent water  ana  Hsh  in  the  ymtec  S'.d'.e;
 have  been   highest  in  the  Hudson  River,  the  Great  Lakes  apart  from  Lake
 Superior,  the  Ohio River,  the  upper  Mississippi  and  the Cape  Fear  River  in
 North  Carolina.   In the  Great  Lakes  there 1s evidence for  seasonal  cycling
 of PCB  levels  (Baker  et  al.,  1985).   PCBs  In  air,  plants, milk and wild  fowl
 also  confirm  the continuing extensive PCB contamination  in  the  Hudson River
 basin.

    In  the  Hudson River  1n  1983  a specific congener analysis  revealed  that
 half  of  the PCB  transport  (see Table IV-1) Is represented  by  2-,  2,2'- and
 2,6-PCB  (Bush  et  al.,  1985a),  although  these  congeners  are  also volatile and
 biodegradable.   A  specific congener  analysis  revealed   that   fish  1n   the
 Hudson  River  obtained  much  of   their bloaccumulated PCB load from  food chain
 vectors  (Bush et al., 1985a).

    PCBs were  found 1n  the  water  of a  small  upstate New York  public water
 supply   system  near  the  heavily  polluted  section   of   the  Hudson River
 (BMnkman et al., 1981).

Noncardnoqenlc Effects
    Tests of the  acute  lethality of  PCB products  In laboratory animals,  with
 the  possible  exception  of   the guinea  pig,  suggest  that,  m  general,  PCB
commercial   products  nave  similar  acute  toxlclty  regardless   of  route  of
administration,  species  or  age  of   animal.   The   single  dose  oral   L05Q
values  for  commercial  PCB formulations  In  rats,  rabbits,  mice and  mink  range
 from  0.5-11.3 g/kg  bw  (Grant  and  Phillips,  1974;  Bruckner  et  al.,  1973;
Klmbrough et al.,  1978;  Flshbeln,  1974; Gartnoff  et  al., 1981; AuleMch and


02400                               VIII-9                           10/22/87

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 Ringer.  1977).   Route  of  administration also had  little  effect  (300 ppm  (>64 mg/kg
 bw/day),  with  3,3',4,4',5,5'-hexa-CB  being  the  most potent  and persistent
 Isomer  Investigated.  Probably  even  larger  differences  will be  encountered
as  more congeners and   Isomers  are  tested.    It  1s expected  that the lower
chlorinated  congeners  will  be  eliminated  more  quickly  In   humans  than the
highly chlorinated ones.

02400                               VIII-10                           03/02/87

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     Some data are  available  on the nonlethal  acute  toxlcKy  of PCBs
 Istered by  the   oral  route  for  periods  of  30 days  or  less.   The effects
 described  1n these studies were alterations of the liver, thyroid and repro-
 ductive system.    Rosin  and Martin  (1983)  reported  that a dose  of  30 mq/kg
 bw/day   of  Aroclor  1254  for   14  days   to  CD-I mice  decreased phenobarbltal
 sleeping time,  Indicating a  substantial   Induction  of  mlcrosomal  enzymes.
 Exposure of  ICR  mice to diets containing 250 or 62.5 ppm of Aroclor 1254 for
 14  days (Sanders  et  al.,  1974) resulted,   respectively,  In  hepatomegaly  and
 elevated serum cortlcosterone (the  latter   presumably as  a  result of altered
 liver  steroid  metabolism).  These exposures are equivalent  to doses of  32.8
 and 8.1  ppm/day,  assuming  a mouse consumes  13X  of  Us body weight per day.

    Few studies   have  been designed to  define the  minimum  effective  oral
 doses  required  to  Induce hepatic  enzyme activities.   Chu  et al.  (1977)
 reported  Induction  of  hepatic mixed function  oxldase  (MFO)  activity 1n  male
 weanling rats  exposed  to Aroclor 1254  or  1260 In  the diet at  20 ppm for 28
 days.   Similarly,  Garthoff et  al.  (1977) reported  that 5 ppm of Aroclor  1254
 In  the  diet  for  3 weeks  resulted   In  Induction   of   hepatic  amlnopyrlne
 demethylase  activity, while exposure at the same dose for 5 weeks produced a
 significant  Increase In  liver  weight   In  male Holtzman  rats.   Increases  In
 I1ver-to-body  weight  ratio appear  to  be one  of the  sensitive Indicators of
 PCB exposure.  Grant and Phillips (1974)  observed Increased  liver  weight at
 doses  as low  as 5  mg/kg bw/day  In male  and female Hlstar  rats   receiving
 Aroclor  1254 for  7  days.   Carter  (1983) observed significant hepatomegaly 1n
 rats  Ingesting diets containing  as little as  20  ppm Aroclor  1254  (1  mg/kg
 bw/day)  for  4, 8 and 14 days.
02400                               VIII-11                          03/02/87

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     Besides changes In the  liver, other effects  reported  for  exposure  to  low
 levels of PCBs were Increased  thyroid activity  In  Sherman  rats  maintained  on
 diets  containing 250  ppm  of  Aroclor  1254  (12.5 mg/kg  bw)  for  14 days.
 Administration of Aroclor  1254 by  gavage  for 21 days at a dose of 0.05 g/kg
 bw/day resulted  In  weight  loss  and  decreased  body  temperature In  Sprague-
 Dawley rats   (Komlves,  1979;   Komlves  and  Alayoku,  1980).   Ultrastructural
 evidence  suggesting Increased  thyroid gland  activity  has  also been  found  In
 Osborne-Mendel rats maintained on diets  containing  5  ppm of  Aroclor 1254
 (0.25 mg/kg bw/day) for  4 weeks  (Collins  and  Capen,  1980b).   This  exposure
 level  also  resulted 1n Increased  liver enzymes  In  Holtzman rats (Garthoff  et
 al.,  1977).

     The toxlclty  resulting from PCB  exposures  of between 30  and 90  days has
 been  more extensively  studied.   Alterations  In  liver  ultrastructure  occurred
 at  doses  of Aroclor 1254  as  low  as  5 ppm  diet  for 5 weeks In Holtzman rats
 (Kasza  et al., 1978b).   In the mouse (MNRI)  a dose of Clophen A-60 as  low  as
 0.025  mg/mouse (0.8 mg/kg bw/day,  assuming  a  mouse weight 0.03  kg) for   62
 days  Increased  the estrous cycle,  probably   as  a  result   of  PCB-lnduced
 changes In  liver  steroid  metabolism (Orberg and Klhlstrom, 1973).   At higher
 dietary concentrations  of  167  ppm (22 mg/kg bw)  for 6  weeks,  Aroclor 1016
 and  1242  decreased  the  Inrounologic  capability of BALB/CJ mice (Loose et al.,
 1978a).

    Although  other   species  have been  tested  to  a  lesser extent  for this
 duration, the  LOEL  In  these species  were similar to those  described  for rats
 and mice.   Rabbits  exposed to  diets  containing  3.7 ppm of  Aroclor 1254 (0.18
mg/kg bw/day,  assuming  a  rabbit consumes  4.9X  of  Us body weight/day) for 8
weeks   developed  no  significant   hepatomegaly,  although  atrophy  of  the

02400                               VIII-12                           03/02/87

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 cortical  tissues  in the thymus was  noted  (Street  and Sharma.  1975).   In tne
 guinea  pig,  Vos and  van  Genderen (1973)  reported  that  diets  containing 250
 ppm  of  Clophen A-60 (7 mg/kg  bw/day,  assuming a guinea  pig consumes  2.8% of
 Us  body  weight/day)  for  4-7  weeks was lethal; while diets containing 50 ppm
 Clophen  A-60 or Aroclor  1260  (1.4 mg/kg  bw)  for  4-7 weeks produced  Immuno-
 suppresslon.   Allen et al.  (1974a)  and Allen  (1975)  observed  comedones  and
 facial  edema  In  rhesus monkeys  Ingesting diets  containing  25  ppm  Aroclor
 (1.1 mg/kg bw,  assuming a  monkey  consumes  4.2% of Its body weight/day)  for  2
 months.   The LOELs  observed  1n  these  species  were  slightly  higher  than the
 LOELs reported  In rats  and mice.

    Studies  of  chronic  exposure  (>90 days) to PCBs have failed to use suffi-
 ciently low  doses  to  define a NOAEL In rats.  In Sprague-Oawley rats,  Allen
 et  al.   (1976) and Allen  and  Abrahamson  (1979)  reported  that a  52-week
 exposure  to  diets  containing 100 ppm  of Aroclor 1248,  1254 or  1262 (5  mg/kg
 bw/day)  followed  by  a 13-week observation  period  resulted  In  hepatomegaly
 and  liver  necrosis.  At a  lower  exposure  of 75 ppm  In  the diet  (3.75  mg/kg
 bw/day) for  36 weeks.   Sprague-Oawley  rats developed focal  necrosis  (Jonsson
 et al.,  1981).   Porphyrla was  observed by both Klmbrough  et  al.  (1972)  and
 Zlnkl  (1977)  after  exposure of  female Sherman  rats  for  8 months to 20  ppm
Aroclor 1254  (1 mg/kg  bw/day) or  CO rats  for 16 weeks to  10  ppm of  Aroclor
 1254 (0.5 mg/kg bw/day).   In a dietary  study of Aroclor  1254 employing near
 lifetime  exposure  (2   years).  Morgan et al.  (1981)  reported an  Increase In
mortality (17% as  compared with  8%  1n controls)  In  Fischer  344  rats at the
 lowest dose  tested  (25 ppm; 1.25 mg/kg  bw/day).  In summary, the subchronlc
studies  demonstrated   Increasing  liver   pathology  over  the  dose  ranges
studied,  0.5-5 mg/kg  bw/day;  while In the  only  chronic  study,  the  lowest
dose tested (1.25 mg/kg bw/day) resulted 1n early deaths.

02400                               VIII-13                          03/02/87

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     In  mice  dietary  exposure  levels  to  Kanecllor-300.   -400,  or  -500  or
 Aroclor  1254  of  between  100  and 500  ppm  (13-65 mg/kg  bw/day)  for periods
 from 23 weeks  to 11  months  produced hepatomegaly (Ito  et  al.,  1973;  Bell,
 1983;  Klmbrough and  Under,  1974).   The only  study  that  defined a NOAEl in
 mice was  the  study by Koller  (1977).  Groups of  8ALB/CJ mice were maintained
 for  9 months  on  diets containing 0,  3.75,  37.5 or  375  ppm of the Aroclors
 1221,  1242 or  1254   (0.45, 4.57  or  45.7 mg/kg  bw/day).   Aroclor  1221,  with
 the  lowest  chlorine  content  (21X),  produced no liver  lesions, while exposure
 to  Aroclor 1242  (42% chlorine)  resulted  1n  Increased liver  weight  1n  the
 high-dose  group.   In  mice exposed  to Aroclor  1254.  Increased  mortality  was
 observed  In the high-dose group  wUh  mild  hepatopathology being  observed 1n
 the  median-dose group, and no  liver  lesions  detected In  the low-dose group.
 The  NOEL   observed   In  this  study  In mice  of  0.45  mg/kg  bw/day  Is  nearly
 Identical  to  the  LOELs of 0.5  mg/kg bw/day associated wUh  porphyrla In rats
 (Zlnkl, 1977),  or  0.25 mg/kg bw/day associated with  ultrastructural evidence
 suggesting  Increased  thyroid gland activity  (Collins  and Capen, 1980b).

     The only  other species  tested 1n chronic bloassays was  the monkey and It
 proved to  be  highly  sensitive  to the toxic effects of  PCBs.  The most common
 observation In  monkeys exposed  to  Aroclor  1248  1n the  diet for  a  period of
 from 8-39  months  was  skin  lesions,  edema  and  erythema (Barsottl and Allen,
 1975; Allen and Barsottl,  1976; Allen  et  al.,  1980;  Becker  et  al.,  1979).
 These effects were  observed  at  the  lowest doses  tested [2.5-3 ppm  In  the
 diet (0.095-0.126 mg/kg  bw/day)].   In addition, Becker et al.  (1979) report-
 ed that monkeys fed  diets containing 3 ppm of  PCBs had  gastric lesions, body
weight loss and reduced hemoglobin and leukocytes.
02400                               VIII-14                          03/02/87

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     PCBs  have  been  demonstrated   to  be  animal  teratoqens  following  oral
exposure.' and have  been  demonstrated  to adversely  affect  reproduction.   In
an  early  study,  Vllleneuve  et  al.  (1971a)  reported  no  adverse  effects  when
Aroclor 1254  was  administered  to  pregnant WUtar rats at a dose of 100 rag/kg
bw/day  on days  6-15 of gestation.  More recently,  Spencer  (1982)  reported  a
decrease  1n  the  average fetal  weight/ Utter  In Holtzman  rats  that received
Aroclor 1254  at  100 ppm 1n  the diet (5 mg/kg  bw/day)  from  days  6  through  15
of  pregnancy.  A  decrease  In  fetal survival  rate was  observed at exposure
>300 ppm  (15  mg/kg bw/day),  while  dietary exposure to Aroclor 1254 at 50 ppm
(2.5  mg/kg  bw/day)  was  found  to be  the  NOEL  (Spencer,   1982).   Rabbits
exposed  to  Aroclor  1254  had   resorptlons.  abortions  and  dead   fetuses  at
similar  dose  levels  of  12.5  mg/kg  bw/day   administered  on  days 0-28  of
gestation; however,  slightly lower  doses of  10 mg/kg bw/day were reported to
be  the  NOEL   (Vllleneuve et  al.,  1971a).   The Hartley guinea pig,  which has
been  shown  to have greater sensitivity  to  the  toxldty  of PCBs  than  most
other species,  had macerated fetuses after  receiving 2.2 mg/day  (6.5 mg/kg
bw/day) of Clophen A-50 on days 10-60 of gestation (Brunstroem et al., 19B2).

    Toxic  doses of PCBs were lower when exposure occurred  before  and during
gestation.  In a  2-generat1on  reproduction  study, Sherman  rats  maintained on
diets containing   20  ppm  Aroclor  1254  (1 mg/kg bw/day) had reduced  litter
size, and  at  100  ppm  {5  mg/kg bw/day) the  pups that were  born  exhibited  a
significant  Increase In mortality  (Llnder et  al.,  1974).    In  this study,  5
ppm  (0.25 mg/kg   bw/day)  was  the NOEL.   Complete  loss   of fertility  was
observed  In  male  and  female kMstar  rats  caged  together  for 9 weeks while
Ingesting  6.4 mg/kg  bw/day of  Aroclor  1254  emulsified  1n their drinking
02400                               VIII-15                          04/04/88

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water  (Baker  et al..  1977).   Males  regained normal  fertility  after  removal
from  treatment  for  2 weeks.   When  Aroclor  1254  was administered to lactatlng
Holtzman  rats at  32 mg/kg bw/day on  days 3, 5 and 7 of lactation,  the future
mating  behavior  of  nursing male  pups  was  adversely  affected  (Sager,  1983).
A  lower dose of 8 mg/kg bw/day was a NOEL.

    The  mink  and  the monkey  are  the  most  sensitive  species  tested  to  the
reproductive  toxlclty of  the  PCBs.  Bleavlns  et al.  (1980) maintained  mink
on diets  containing 5 ppm Aroclor  1242 or  20 ppm Aroclor 1016 (doses of  0.75
and 3 mg/kg bw/day, assuming  a mink  consumes 15X of Us body weight per  day)
for 8 months  and  observed complete reproductive  failure  In  the Aroclor  1242
group and 25%  mortality  and  Infertility  In the  Aroclor  1016 group.   In  a
limited  study  (8  animals/group),  Barsottl  et  al.  (1976) maintained  rhesus
monkeys  on diets   containing  2.5  or  5 ppm (0.1  or  0.2 mg/kg   bw/day)  of
Aroclor  1248   for   18 months.   In  the low-dose  group,  all  eight  females
conceived, but  only five  delivered viable  Infants.   In  the  high-dose group,
the mothers showed overt signs  of toxlclty.  In  the  5.0 ppm group,  6  of  8
females   conceived,  but only  one  live birth occurred.   After removal  from
exposure  for 1 year,  reproductive  capabilities  appeared to return  to normal;
however,  an Increase 1n  abortion  rate  and  Infant  mortality  was observed for
both PCB  treatment groups (Allen  et  al.,  1980).  It  1s  apparent  that frank
effects  In reproduction  were observed  In  monkeys  at lower doses  than  the
NOEL  In  rats,  rabbits and guinea  pigs following  repeated exposure to PCBs.
Little data are available for  the toxlclty of  specific  congeners.  Dietary
exposure  to  as  little as 1   ppm  of  pure 3,4,5,3' ,4' ,5'-hexa-CB for  28  days
caused liver m1croabsc«sses and  an Increased liver weight In 18-20 g 5-week-
old C57B1/6J mice  (Blocca et  al.,  1981).   In this study, dietary  exposure at

02400                               VIII-16                          04/04/88

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a concentration  of  0.3  ppm resulted In Increased liver weight with no otrer
adverse  effects  (Blocca  et  al.,  1981).   This  dose  could  be  considered a
NOAEL for 3;3',4,4',5.5'-hexa-CB,  which 1s  one of the  most  potent PCBs.

Quantification of Moncardnoqenlc  Effects
    Studies of PCB  toxldty  In experimental animals have demonstrated a pro-
gression of  toxlcologlc  responses correlated with  dose  for  studies of 1-30
days,  vnieneuve et  al.  (1971a)  found Increased Incidences  of fetal death,
resorptlons and  abortions at  12.5  mg/kg  bw/day  of  Aroclor  1254  in  rabbits
when exposed on  days  1  through 28 of  pregnancy.  A dose of  1.0 mg/kg bw/day
appeared to  be  without effect.   Collins and  Capen (1980a,b,c), In a series
of  studies  on  thyroid effects In  rats, determined  that  50 ppm of  diet (2.5
mg/kg  bw/day)   for  4 weeks  was   associated  wHh  clearly  defined  adverse
effects  but  that doses of 5 ppm of diet  (0.25 mg/kg bw/day} produced only
ultrastructural   evidence  suggesting   Increased   thyroid   gland   activity.
Carter  (1983)  demonstrated  liver  hepatomegaly  1n  rats  at  doses  of 20  ppm
Aroclor  1254 of  diet  (1  mg/kg bw/day) for  4,  8 and  14 days; such  an effect
In  the  absence   of  other  signs of  toxldty  (that 1s, fatty  Infiltration  of
the  liver)  might  not  be considered  adverse.   Grant and  Phillips  (1974)
observed Increased  liver  weights  at doses  as low as  5 mg/kg  bw/day  Aroclor
1254 given  In  corn oil  for  7 consecutive  days.   Collectively  these  studies
Indicate that the experimental threshold for  adverse  effects of  Aroclor  1254
In  studies  of  30  days  duration  or less  1s at  or  near  a  dose of  1  mg/kg
bw/day.  Thus,  It  seems  reasonable  to use this  latter  dose as a  basis  for
health  risk  assessments  for  Aroclor   1254-contam1nated soil  for  short  dura-
tion human exposure situations.
02400
                                    VHI-17                          03/02/87

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    Utilizing a  dose of  1  mgAg bw  as  a  no-adverse-effect  dose,  a  10-day
exposure level  to  PCS-contamlnated  soil  may  be  calculated  as follows  (U.S.
EPA, 1986b):

                               i    1  mo/kq/dav x  10  kg    n  ,  __/H.u
           10-day exposure level  * 	a—*  "I         =  0-'  mg/day

where:
    10 kg « assumed body weight of a  child
    100   * uncertainty  (safety)  factors;  this  uncertainty  factor  was
            chosen  1n  the   accordance  with   the  National  Academy  of
            Sciences  guidelines  1n  which a NOAEL  from an animal  study
            Is employed.
    This 10-day  exposure  level  of 0.1 mo/day may be applied  for  a  10-day  HA
for drinking  water  1f  It 1s  assumed that Aroclor 1254 mixtures  are soluble
and detected  In  drinking water.  This  assumption  Is  probably   not  correct
since  the  less  chlorinated  congeners  are much more soluble  than the highly
chlorl-  nated ones and  Aroclor  1254  has not yet  been detected  1n finished
drinking water.

    The  finished water  from the  DorHy  Reservoir  treatment  and  distribution
system  was reported  to  contain Aroclor  1016  congeners  at  a   level  of  86
ng/i   (Brlnkman  et  al., 1981).  The  public  water  supply  system  of  the
village  of Fort Edward,  located near  the  township  of  Moreau  of  Saratoga
County  1n  upstate M«w York, Is  obtained from the DorHy Reservoir  treatment
and distribution system.  The  level  of  Aroclor 1016  In  this finished water
corresponded  well  to  the   median   level  of  99  ng/l 1n  the  Oorlty River
water.   The Brlnkman  et  al.  (1981) study was  discussed earlier In Chapter  IV.
 02400
                                     VHI-18                          04/04/88

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     Silkworm  and Loose  (1978) observed  that  treatment  of male C57B1/6 m'ce
 with 167 ppm  Aroclor  1016 1n  the  diet for 3  weeks  activates  donor lympho-
 cytes  as me'asured by greater  graft  vs. host response.  Loose et al. (1978b)
 observed that  treatment with  the  same  dose (167 ppm) for 6 weeks using male
 BALB/CJ  mice  suppresses the Immune system as measured by  Increased mortality
 to   Salmonella  typhosa  endotoxln  and  Plasmodlum  berghet.  Since  these  are
 single   dose  studies,   no  dose-response  determination  can  be  done.   These
 studies  are  not  adequate  for  deriving   10-day  or  1-day HAs.   No  other
 subchronlc  studies are available  on Aroclor  1016 that can be  utilized  for
 deriving HAs.   Accordingly,   no   10-day  or  1-day  HA  for  Aroclor   1016  Is
 estimated.

     There  are  only  a   few  reports on  the  toxUUy  associated  with  chronic
 exposure to  Aroclor  1016.   Studies  were  conducted  In mink  and  rhesus
monkeys, species  that  exhibit a high degree  of sensitivity to PCBs.  Female
mink  fed a diet  containing 20 ppm Aroclor  1016 for  8  months  exhibited  25%
mortality compared  with 12.5% mortality In  the control  group.   Aroclor 1016
was  less toxic than  Aroclor   1242, which  produced  100X mortality  In female
mink  at  the  same  level   of  exposure  (Bleavlns  et  al.,  1980).   Dietary
exposure to  20 ppm Aroclor 1016  reduced,  but  did not completely eliminate,
reproduction.  Four  of  the nine  mated  females  produced kits  In the Aroclor
1016 group  compared with  16  of 21 1n  the  control group.  Body  weight at 4
weeks  was  significantly  lower for  the kits  nursed by females  fed Aroclor
1016 (20 ppm).   In addition,   higher  kit mortality between birth and 4 weeks
of age was  also  noted.   Bleavlns  et  al.  (1980) also reported that reproduc-
tive parameters,  kit  growth,   and  adult and kit  mortality were not signifi-
cantly  affected   In ferrets   at  a  diet  containing   20  ppm Aroclor  1016.


02400                               VIII-19                          03/02/87

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 In another  study,  Aulerlch and  Ringer  (1977)  exposed  female  minus  tn
 diet  containing 2 ppm Aroclor 1016 for 10 months  (0.3 mg/kg bw/day. assuming
 a  mink consumes  15X of  Us  body weight  per  day).  This  level  of exposure
 produced  no effect  on reproductive parameters,  kit growth, and adult and kit
 mortality.   Thus, chronic  exposure  to 2  ppm  Aroclor 1016  In  the  diet (0.3
 mg/kg  bw/day)  appears  to  be  a NOAEL  In  the mink.   Barsottl and  Van  Miller
 (1984)  exposed 24 adult  rhesus  monkeys  to  diets  containing Aroclor  1016  at
 levels  of  0.025,  0.25 and 1.0 ppm.  No abnormalities were noted In clinical.
 growth  and reproductive parameters of  the adult  monkeys.   The  Infants born
 to  the 1.0 ppm  Aroclor  1016  group (0.042  mg/kg  bw/day, assuming  a  monkey
 consumes  4.2%  of  Its body weight  per  day) were  significantly  smaller than
 the  control  at a confidence  level  of  99V  Thus,  0.25 ppm  (0.0105  mg/kg
 bw/day) appears to be  a  NOAEL for chronic  oral exposure to Aroclor  1016  In
 rhesus monkeys.

    Utilizing  a  dose of  0.01  mg/kg  bw/day (0.25  ppm)  as the NOAEL.  the
 longer-term HA  for Aroclor  1016 may be calculated  as  follows:
                        m 0.01  mq/kq/day  . Q OOQ1    /k /da
                                100
 where TOO  « uncertainty  (safety)  factor.   This uncertainty  factor  was
             chosen  In  accordance with  the National Academy of Sciences
             guidelines  in  which  a  NOAEL  from   an animal  study  1s
             employed.

Longer-term HA  for a  10 kg  child:
                            O.OOQ1 roo/kq/dav x 10  kg
                                    1 l/day
                          » 0.001 mg/i
02400                               VI11-20                          04/24/87

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 for a 70 kg adult:

                             0.0001  ma/kq/dav x 70 kg
                                     2 l/day
                           * 0.0035  mg/i

 However, 0.001  mg/l will  also  be  protective  for a  70  kg adult.

     Because of  their  high  Upophlllc  and  stable  nature,  PCBs  can  rapidly
 bloaccumulate  1n human milk, adipose tissues and serum.  Only 2,4,4'-trl-CB.
 one of the constituents  of Aroclor  1016, has been found as a major component
 with  the  other  seven major and  four minor  components  of PCB  congeners  In
 human  milk  samples.

     On  starvation  and  stress  the  PCB  components   from  the  adipose-rich
 tissues  can  become  free  In   the   bloodstream  and   redistribute  to  other
 compartments.   This can  create  additional  opportunities for  Insult  by free
 PCB  on  different  organ  and  physiologic systems.  This  can  also  result  in
 further  metabolism  of the  free PCBs.   However,  the toxlcologlc  significance
 of  PCB metabolism has not  yet been  delineated.

     It should be noted that during document  review  several  studies Indicat-
 ing  potential alteration  1n postnatal function following exposure during the
 prenatal  or  early   postnatal  period  were  Identified.    These  studies  may
 Impact  on  the   ultimate  quantification  of  noncardnogenlc   effects,  since:
 1) reproductive  and  developmental  effects  have  been  used   1n  establishing
exposure  levels  for noncardnogenlc  effects,  2)  postnatal  deficiencies have
been reported/suspected 1n  cases  of human  exposure (Yusho and Yu Cheng), and

02400                               VIII-21                          04/06/88

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 3)  postnatal  deficiencies could  possibly  occur  at  levels  of  exposure   owe"
 than  those  required  for  effects  on  structural  development  or  viability.
 These  and  other  similar studies  will  be reviewed  for  their  Impact  on  the
 assessment  of developmental  and  reproductive effects and  will be  added  to
 the document  where appropriate.

 Carcinogenic  Effects
    There   are  several  studies  demonstrating  that  PCBs  cause  cancer  In
 laboratory  animals.   Male dd mice fed Kanechlor  500 developed hepatocellular
 carcinomas  and  liver  nodules  (Ito et  al.,   1973).   Male  BALB/CJ  mice  fed
 Arochlor  1254  developed  hepatomas or  liver  adenofIbrosls   (Klmbrough  and
 Under,  1974).   Female  Sherman rats fed Arochlor 1260 developed hepatocellu-
 lar carcinomas  and  neoplastlc  nodules   (Klmbrough  et  al.,  1975).   Male  and
 female  Fischer  344  rats fed  Arochlor  1254  developed hepatocellular  carci-
 nomas  (NCI,  1978).   Although NCI's  results  are  not  statistically  signifi-
 cant,   they  are considered  supportive because  the small sample  sizes  limit
 the study's  power  to show  a significant  response and  because  there  1s  a
 dose-response trend.  Male Hlstar rats  fed Clophen A60 developed hepatocell-
 ular carcinomas  (Schaeffer  et al.,  1984).   Male  and  female Sprague-Oawley
 rats  fed  Arochlor   1260 developed hepatocellular  carcinomas  (Norback  and
Weltman. 1985).

    These studies  provide sufficient evidence regarding the carclnogenldty
of  PCBs.   Liver  cancer  has been  Induced In  several  studies  In  different
animal   strains  fed  several   commercial  PCB  products.   The  contention  that
 these results are due  to  the PCOF  contamination  of PCBs  1s  refuted  by the
02400                               VIII-22                          10/22/87

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 Schaeffer  study,  which tested Us PCS mixtures  and  found  tnem to  De free of
 furans.   This  conclusively  demonstrates   that  PCBs  alone  are  capable  of
 causing canc-er.

    The  combination of  sufficient  evidence  from  animal studies  and  inade-
 quate, but  suggestive,  evidence  from  human  studies  leads to a designation of
 PCBs  as  probable  human carcinogens,  Group  B2  under  EPA's  cancer  guidelines.
 This  designation  Is   not  altered by  the  ancillary  evidence from  several
 mutagenlcHy, promotion, ant1tumor1gen1c1ty, and cocarclnogenlclty studies.

 Quantification of Carcinogenic Effects
    Although  CAG  regards  the  human data  at this time to be  suggestive  of  a
 carcinogenic  risk but  stm  Inadequate overall,  H  has recently been learned
 (Moolenaar,  1987)  that  the  International  Agency  for   Research  on  Cancer
 (IARC)  has  upgraded  their  weight-of-evidence  classification  on  PCBs  to
 "limited" (I.e.. 2A).

    The basis for this  recent decision  by IARC has  not yet been ascertained.
CAG  1s  now attempting  to obtain further  Information from  IARC  representa-
 tives regarding  the rationale for  their  decision.    If  there are  newer  data
available to  IARC  that led  to a  change  in  their position,  It might necessi-
tate  a  reconsideration of  the CAG  position prior  to final  publishing.   CAG
has obtained  a  more recent  study by  Bertazzl et al.  (1986)  not  Included 1n
the current draft.  A  review of  this  study 1s underway at this time and will
be Included In the  final draft.
02400                               VIII-23                           10/22/87

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     Data  Selection^   Human  studies,  altnougn suggestive  of  a  Hnn  oef.*een
 PCBs  and  certain  types  of  cancer, are  not yet  suitable for  quantitative
 cancer risk  estimation.   Consequently,  risk  estimates must  at this  time be
 based on  animal  studies.   The most  sensitive animal  species  tested  appears
 to be the rat.   In  the past the U.S. EPA  has based Us  risk  estimates on a
 study by  Klmbrough et  al.  (1975)  1n which chronic  dietary administration of
 Aroclor  1260 was  shown to  cause  hepatocellular  carcinomas  in  female  Sherman
 rats.   The  following  analysis,  however,  1s  based  on  a  study  by Norback and
 Heltman  (1985)  In which  cnronlc  dietary administration  of  Aroclor  1260 was
 shown  to  cause  hepatocellular  carcinomas  In  male  and female  Sprague-Dawley
 rats.   This   recent study  Is preferred because  the Sprague-Dawley  rat has a
 low  Incidence of  spontaneous hepatocellular  neoplasms,  because the  Norback
 and  Weltman  (1985) study  spanned  the natural  life  of the animal, and because
 concurrent morphologic liver  studies showed  the  sequential  progression  of
 liver  lesions to hepatocellular carcinomas.   Because neoplastlc nodules have
 been   shown   to  precede carcinomas,  animals  with  neoplastlc  nodules  were
 counted  with those developing  carcinomas.   The  tumor  Incidences  for  female
 rats,  which  were more  sensitive  than   the  males, are  presented   In Table
 VIII-1.  The  average  levels  (1n ppm) of  PCOFs In Aroclor 1260  are typically:
 TCDF,  0.2-0.8;  PeCDF,  0.3-0.9;  hexa-COF,  0.3-0.5 (see  Table  II-3).   The
 levels  (1n  ng/g) of  2,3,7,8-substHuted  toxic   Isomers  are:   TCOF,  0.84;
 PeCOF, 2.1;  hexa-COF,  2.4  (see  Table II-5).  The  toxic  PCDFs are  analogues
 of 2,3,7,8-TCDO,  which  Is  a known animal  carcinogen.   The  role of  the PCDFs
 In   PCB  toxldty and  cardnogenesls   Is   still  unknown.   The  following
 dose-response treatment will not consider the  contribution of the PCOFs.
02400                               VIII-24                          10/22/87

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                                 TABLE VIII-1
              Data  Used as  the Basis for the qi* for Aroclor 1260*
 Sex,  strain,  species
 Exposure route, vehicle
 Tumor sUe, type

 Nominal Dose
 Average dally dose
 Equivalent human dose
 Tumor Incidence
 Body weight
 Exposure duration
 Study duration
 Animal llfespan
 Potency (q-|*)
Female Sprague-Dawley rat
Oral, diet
Liver, trabecular carclnoma/adenocardnoma
neoplastlc nodule
   0    100 ppm
   0    3.45 mg/kg/day (5X food rate assumed)
   0    0.59 mg/kg/day (surface-area corrected]
1/49    45/47
3SO g (assumed)
24 months (dose halved during months 17-24)
29 months
29 months (assumed)
7.7 per mg/kg/day
tq-|* derived from Nor back and We It man (1985) study.
02400
      VIII-25
                                                                     10/22/87

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     Dose-Response  Modeling.   Current  available  evidence  on  tne  me'.aoc' • ;.TI
 and kinetics  of  PCBs  Is  Insufficient  to  support the existence  of  nonlinear
 mechanisms  for  the development  of  PCS-lnduced  cancer.    In  the absence  of
 evidence to the  contrary,  the  U.S. EPA uses the  linearized multistage  model
 to estimate Increased  cancer  risks.  The  dose  data are derived  through  the
 following sequence of transformations.  First  the  nominal  dose  level of  100
 ppm In the diet  Is expressed as  5  mg/kg/day, assuming that a  rat  consumes  an
 amount equal  to  5% of  Us body weight each  day.   Then  this  nominal dose  Is
 transformed  Into  a TWA  dally  dose of 3.45 mg/kg/day, which  reflects  the
 dosing schedule of 5 mg/kg/day for  the first 16  months,  half  of  that for  the
 next  8 months, and none  for  the last 5 months.  Finally,  this average  dally
 dose  1s transformed  Into  an  equivalent human  dose  of 0.59 mg/kg/day,  which
 reflects  an  equivalence  between  species  on  the  basis  of   relative  body
 surface  areas.

    The  U.S. EPA  sometimes uses other mathematical  dose-response models  to
 provide  alternate risk estimates  for comparison.  This  cannot  be done with
 the  preferred   data  set  because  the number  of  dosed groups  (one)  does  not
 permit  the  estimation  of  two  or  more parameters  as required by the  other
 models.   In  particular,  with  only  one dosed group  the  multi-hit model with
 one hit  and  the Uelbull model  with shape  parameter  equal  to 1 are  Identical
 to the multistage model used here.

    Potency  Estimation.   Using  the data  described  above and  the  linearized
 multistage model, the human  carcinogenic   potency  of Aroclor  1260 Is  esti-
mated  at 7.7 mg/kg/day.   For  small  exposures  (those for  which  the risk  Is
<10%)  the  Increased cancer risk can  be estimated by multiplying  the potency


02400                                VIII-26                          10/22/87

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 by  the  exposure  rate.   Risks computed  In  this manner  are plauslole  uppe-
 bounds on  the  Increased cancer risk  from  exposure to Aroclor  1260,  meaning
 that the true risk is not likely  to be higher.

     This  potency  estimate  1s  Intended  to  be  representative   of  other PCB
 mixtures  as  well.   At  present  there  1s  no  Information  about  which con-
 stituents  of Aroclor 1260 or  any  other PCB mixture are carcinogenic.   Given
 this  lack  of  Information  about   individual   constituents,  Aroclor  1260  is
 assumed  to  be representative of other  PCB mixtures.  Furthermore, of  all the
 studies  of  any  PCB mixture,  the  Norback  and  Weltman  (1985)  study  using
 Aroclor  1260 has superior characteristics,  and 1s,  therefore, the most  suit-
 able for quantitative risk estimation.

     Drinking Mater  Criteria.   The  concentration  of  Aroclor 1260  In  water
 associated  with a  particular  Increased  lifetime cancer  risk can  be  calcu-
 lated  from  the  following  formula:

                       „     i   i.        Risk  x 70 kg
                       Concentration » - a -
                                       Potency x 2 i/day
 assuming a  typical person weighs  70 kg and consumes 2 t of water  each day.
 For  risks  of  10"*,  10"»  and  10"»  these   concentrations  are  0.5,  0.05
and 0.005 yg/t, respectively.
    Sensitivity  Analysis  — Meoolastlc  Modules.  The  U.S.  EPA's guidelines
for carcinogen  risk assessment call  for  reporting  the relative contribution
of  nonmallgnant  lesions whenever  they are  used In a  risk  estimate.  Table
VIII-2  gives  the  Incidence of  malignant  tumors only.   The  potency  using
02*00                               VIII-27                          10/22/87

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                                 TABLE  VIII-2
                Data Used as the Basis for an Alternate Potency
                        Calculation for Aroclor 1260t
Sex, strain, species
Exposure route, vehicle
Tumor site, type
Nominal Dose
Average dally dose
Equivalent human dose
Tumor Incidence
Body weight
Exposure duration
Study duration
Animal lUespan
Potency (qi*)
Female Spraque-Oawley rat
Oral, diet
Liver, trabecular carclnoma/adenocarclnoma
0       100 ppm
0       3.AS ing/kg/day (5% food rate assumed)
0       0.59 mg/kg/day (surface-area corrected)
0/49    43/47
350 g (assumed)
24 months (dose halved during months 17-24)
29 months
29 months (assumed)
5.7 per mg/kg/day
tqi* derived from Horback and Heltman (1985) study.
02400
                                    VI11-28
                                        10/22/87

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 malignant  tumors  only  1s  5.7  per  mg/kg/day.  26%  less  than  the estimated
 potency Including neoplastlc nodules.  Using  this potency would  Increase  the
 drinking wat.er  criteria  concentration by  35*.

     Sensitivity  Analysis  —  Statistical  Upper  Bounds.   The   linearized
 multistage  model  uses  an explicit  statistical  95% upper  bound  to estimate
 the  Increased  cancer  risk.   It 1s  not always  possible  to know the relative
 contribution  of the  upper  bound  risk estimate  because  the  multistage model
 without an  upper  bound  procedure does  not necessarily  give  estimates that
 are  consistent  with  the  low-dose  linear  model  of carclnogenesls  that   has
 been  adopted by the  U.S.  EPA.   In  this  case,  however,  the  (unllnearlzed)
 multistage  model 1s  consistent  with  the linear model, because  the multistage
 model  with  one  treated  group becomes the  one-stage  model,  which Is  Intrin-
 sically linear  at  small  doses.   The maximum  likelihood  estimate  of   the
 potency Is   5.3  per   mg/kg/day,  31%  less  than the  estimated  upper  bound
 potency.  Using this potency would  Increase  the drinking  water  criteria by
 45%.   Nevertheless,  the  U.S.  EPA  does not  recommend using maximum likelihood
 estimates of risk, because these estimates  are  typically  unstable.

    Sensitivity  Analysis —  Klmbrouqh et  al.  (1975)  Study.   In  the past,
 the  U.S.  EPA has  based   Us  risk  estimates on a study  by  Klmbrough  et  al.
 (1975).  in  which chronic dietary  administration of  Aroclor 1260 was shown to
cause   hepatocellular  carcinomas  In  female   Sherman  rats.   Table   VIII-3
presents the tumor Incidences  from this  study.  The shorter duration of this
study  means that  the  observed liver  lesions  are mostly neoplastlc  nodules
that  had not   yet  progressed  to  hepatocellular  carcinomas.   Although   the
newer Norback and  yeltman (1985)  study Is preferred for  Us longer duration.


02400                               VIII-29                          10/22/87

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                                  TABLE  VI11-3
                Data Used as the Basis for the Previous Potency
                         Calculation for Aroclor 1260+
 Sex,  strain,  species
 Exposure  route,  vehicle
 Tumor  site,  type

 Nominal Dose
 Average dally dose
 Equivalent human dose
 Tumor  Incidence
 Body weight
 Exposure  duration
 Study  duration
 Animal Hfespan
 Potency (q-|*)
Female Sherman rat
Oral, diet
Liver, hepatocellular carclnoma/neoplastlc
nodule
0       100 ppm
0       4.57 mg/kg/day (5X food rate assumed)
0       0.78 mg/kg/day (surface-area corrected)
1/173   170/184
350 g (assumed)
21 months
23 months
23 months (assumed)
3.9 per mg/kg/day
     derived fro* Klmbrough et al. (1975) study.
02400
      VIII-30
10/22/87

-------
 H  Is  useful  to know  how  the new risk  estimate  compares  with me  previous
 one.  Under the  same  assumptions  as  before, the potency using  the  Klmbrough
 et  al.   (19-75)  study  Is  3.9  per mg/kg/day,  49%  less than  the  estimated
 potency  using  the  Norback  and  Heltman   (1985)  study.   Using  this  potency
 would Increase the drinking  water  criteria by  97%.

     Consideration was given to estimating  the  potency from the Schaeffer et
 al.   (1984)  study.  In  which  chronic  dietary  ingestlon  of Clophen  A60 was
 shown to  cause  hepatocellular carcinomas   In  male  Wlstar  rats.   As In the
 Norback  and Weltman (1985)  study, treated rats received doses of  100 ppm for
 the  major  portion  of  their  lifetimes,  over  95% of  treated  rats  developed
 hepatocellular   carcinomas   or  neoplastlc   nodules,   and   the   Incidence  In
 control  rats was <10%.   For these reasons  one would expect similar  potency
 estimates  from the  two  studies.   A precise calculation using the  Schaeffer
 et  al.  (1984)  study   1s  not. however,   possible  at  this time,  because  a
 discrepancy  1n  the published  tables  makes  It Impossible   to  determine the
 number of  animals  at risk.   For now the  Schaeffer et  al. (1984) study can be
 used  to  confirm  the Norback and  Weltman (1985) results,  which  are used to
 estimate  potency.

    Schaeffer  et  al. (1984)  also  studied another  PCB mixture, Clophen A 30,
which  appears  to be less potent  than  Clophen A 60.    It would be  misleading,
however,  to  quantitatively compare the potency that  might  be calculated from
 this  study  with  the potency  that  was  calculated from  the Norback  and Weltman
 study,  because  Schaeffer et   al.  used  male  Wlstar  rats  and  Norback  and
Weltman  showed  that female  (Sprague-Oawley)   rats  are more  sensitive than
males.

02400                               VIII-31                           10/22/87

-------
 Cancer  Potency  Estimates  for  AroclorR  1254 and  other PCB mUtures
     Because  exposure assessments  sometimes  find PCS  mixtures that resemble
 PCB  products other  that  Aroclor*  1260,  1t  Is  often  asked whether separate
 cancer  potency  estimates can  be made for other  PCB mixtures.  Although the
 best  data base  for estimating  the cancer potency  Is on  Aroclor* 1260,  H
 1s  appropriate  to  ask  whether existing  data  on  other  PCB mixtures  are
 adequate  for making  separate  cancer potency estimates.

    A  natural  candidate  for  a  separate  cancer  potency  estimate  Is Aroclor*
 1254.   An estimate can be based on the  1978 National Cancer  Institute (NCI)
 study  of  Aroclor*  1254,  In which statistically  significant,  dose-related
 Increases  In liver  nodules,  benign   tumors,  and malignant  tumors combined
were  seen   1n  Fischer   344  rats  fed  a  diet  containing   Aroclor*  1254.
Preliminary  calculations would  Indicate  a   cancer  potency  of  2.6  per
mg/kg/day  continuous lifetime  exposure  to Aroclor*  1254.   This  estimate  1s
a plausible  upper  bound,  meaning that the  true cancer potency Is not likely
to  exceed this  estimate  and  may  be  lower.    Details  of  the study  and  the
potency calculation  are given In  Table VIII-4.

    Several sources  of uncertainty  deserve mention:

    1. NCI used only 24 rats  per group (50 Is  considered standard today),  so
       the potency estimate 1s rather  Imprecise.
02400                               VIII-32                          04/04/88

-------
                                  TABLE VIII-4

                  Data  Used  for  the Preliminary Cancer Potency
                          Estimate for Aroclor* 1254
     Substance
              Aroclor(R) 1254
Reference
Sex, Strain, Species
Exposure Route. Vehicle
Tumor Site, Type

Nominal Dose

Average Dally Dose
Equivalent Human Dose

Tumor Incidence
Tumor Percentage
Statistical Significance
Trend Significance

Animal Weight
Exposure Period
Study Length
Animal Llfespan

Potency (ql*)
NCI, 1978
Female Fischer 344 rats
Oral diet
Liver nodular hyperplasla and adenomas

0       25    50  100 ppm
0     1.25  2.50  5.00 mg/kg/day (5X food  factor
0     1.16  2.32  4.65 mg/kg/day (105/113  weeks)
0     0.17  0.33  0.64 mg/kg/day (surf-area  adj)

0/24  6/24  10/22 19/24
OX     25X   45X   79%
      IE-02 2E-04 IE-08
<0.001, linearity OK

250    220  200   180 g (at end of  study)
105 week
113 week
113 week (assumed)

2.6 per mg/kg/day
02400
        VIII-33
04/06/88

-------
     2. The  NCI  study lasted  24  months.   Although this  Is  today's  standard,
       Norback  and Heltnwn  demonstrated  that  PCB-fed rats  (but  not  control
       rats) develop  many  tumors  after  24 months.   EPA considers  the  Norback
       and  Weltman study  more  appropriate for estimating  a  lifetime cancer
       potency.

     3. NCI's female  rats  developed only benign liver  tumors  and  nodules,  so
       some  may  argue   that there  was  no cancer.   Norback  and  Weltman,
       however,  demonstrated that nodules  progress  to  benign  tumors,  which
       1n  turn  progress to malignant tumors.   Under  EPA's  cancer guidelines
       U  1s,  therefore,  appropriate to  consider  benign tumors  and nodules.
       Furthermore,  some  male rats  In  the  NCI  study did  develop  malignant
       liver tumors.

    EPA's  cancer  potency  for  Aroclor*  1260,  which  1s  presumed  to apply  to
other  PCB  mixtures  as  well.   Is  7.7   per   mg/kg/day  continuous  lifetime
exposure.   Although   It  appears  that  the  cancer  potency  of Aroclor*  1254
may  be  slightly  less than  that  of  Aroclor*  1260,  this difference  may  not
be real  In light  of  the  uncertainties  dted  above.   Larger  differences  are
commonly  seen  between  different  sexes  and  animal  strains.  For example,  a
comparison  of  the   NCI  and  Norback  and  Weltman   studies  suggests  that
Aroclor*  1254  may  be acre  potent  1n  male Fischer  344 rats  than Aroclor*
1260  is  1n male  Sprague-Oawley rats.   For these reasons,  the  current  data
are   Inadequate   to   differentiate  between  these  PCB   mixtures  with  any
reasonable degree of  confidence.
02400                               VIII-34                          04/04/88

-------
    Further   Investigation,   perhaps   taking   Into   consideration   potency
differences  between  PCB mixtures for  other  toxic effects,  1s  needed  before
there can be  separate  cancer  potency estimates  for  each PCB mixture.   At the
present  time,  though,  the   data  are  Inadequate  for  calculating  separate
cancer potency estimates for each PCB mixture.

Existing Guidelines. Recommendations and Standards
    Manufacture,  sales and distribution  of  PCBs  have  been  restricted  under
Section 6(e)  of  the  Toxic  Substances Control  Act  (TSCA) (P.L.  94-469).   PCBs
were  restricted  to sealed systems  as  of 1977, manufacture  and distribution
were  banned  In 1979.   Rules  for  the disposal  of PCBs  were  proposed  1n 1978
(43 PR  7150).  Hansanto voluntarily suspended  production  of Aroclors  before
the ban.

    The U.S.  EPA (1980a,b) has  set  ambient water  quality  criteria  for PCBs
for the protection of  humans  from Increased risk  of cancer over the lifetime
of  10"f,   10"*   and   10"7,   at   0.79,  0.079   and   0.0079  ng/i,   respec-
tively.   As  a result  of the  large  BCF,  these criteria apply  regardless  of
whether  exposure occurs  through  consumption  of  2 I  of  water and 6.5 g  of
f1sh/d»y or   through  consumption of fish  alone.  Table  IV-6 presents  the
geometric  mean  levels  In freshwater   fish  taken around  the  United  States
between 1976  and  1981  (Schmltt et  al.,  1985).  The  most  contaminated fish
(22 ng/g wet weight)  1n  1980 and 1981 were taken  from the Hudson,  Connect-
icut  and  Delaware  Rivers  1n  New England;  Lakes Michigan. Huron,  Erie and
Ontario; the Mississippi  in  Minnesota;  the Ohio  River;  and  the  Cape Fear
River  in   North  Carolina.   F1sh  bloaccuraulate   the   more  chlorinated  PCB
02400                               VIII-35                          04/04/88

-------
 Uomers  (Ws2olek et al., 1979; Brown et al.. 1985).  Food chain vectors also
 are Important  1n  the  congeners  bloaccumulated  (Bush  et al.,  1985a).   The
 Food  and Drug  Administration  (FDA)  has set  tolerances  for  PCBs  In food and
 food  related  products  as  Indicated  In Table  VIII-5.

    Occupational   exposure  limits  have  been  recommended  by  the  American
 Conference  of Governmental  Industrial  Hyg1en1sts  (ACGIH,  1980).  and a recom-
 mended  criterion set  by  the  National  Institute  for  Occupational  Safety and
 Health  (NIOSH,  1977)  for  PCBs In  the  workroom  air.   The TWA and  STEL for
 Aroclor  1254,  respectively,  are  0.5 and  1.0 mg/m»; and  1  and  2  mg/mj for
 Aroclor  1242  (ACGIH,  1980).   The  NIOSH  (1977) recommended criterion for PCBs
 1s  1.0  vg/m1  for  all  PCBs   for  a  10 hours/day,  40  hours/week  exposure.
 The OSHA  permissible exposure level (PEL) and  Immediately dangerous  to life
 and health  level  (IOLH)  for  Aroclor 1242 are  1  and 10 mg/m»,  respectively,
 and 1 and 5 mg/m«  for  Aroclor  1254 (NIOSH, 1977).

    The  NAS  (1980)  developed a  24-hour  SNARL  for PCBs  of  350  ug/t  based
 on  the  Induction  of  mixed-function oxldase  enzymes  1n  the  liver  of  rats
 administered  Aroclor  1254  at  doses of  1-2 mg/kg.   For this analysis,  an
 uncertainty factor of  100 was  used,  since  only enzyme  Induction was reported
 In this dose  range.
    in
    A  recommendation  was  not made at  this  time  for  1-day or  10-day HAs or a
DUEL  because of  a deficient  data  base on  toxklty  and  exposure  to PCBs
through drinking  water  In the  United States.  A  longer-term HA for Aroclor
1016  for  a  child  has  been  estimated  to  be  0.001  mg/i  and  for  an  adult

02400                               VIII-36                          04/04/88

-------
                                 TABLE  VIII-5
                          FOA Regulations for PCBsa
               Commodity                                Temporary Tolerances
                                                                (ppm)
M1lk (fat basis)                                                  } -*
Manufactured dairy products (fat basis)                           1.5
Poultry (fat basis)                                               3-°
Eggs                                                              °-3
Finished animal feeds                                             °-2
Animal feed components of animal origin                           2.0
Edible portion of fish and shellf1shb                             2
Infant and Junior foods                                           °-2
Paper food packaging material                                    10-°
asource:  21  CFR.  109.30.  51,725;  44(127)  FR 38330-38340; 49(100)  FR  21514-
 21519.
bine  edible portion  of  fish  Includes heads,  scales,  viscera  and  Inedible
 bones.
 02400
                                     VIH-37                           04/04/88

-------
 0.0035  mg/t.   A cancer  based  criterion  for  Aroclor  1260 was  derived and
 calculated   for   excess   lifetime   cancer   risks   of   10"*.  10~*  and   1CTS.
 The  respective  water  concentrations  are  0.5,  0.05  and 0.005  ug/i  (Table
 VIII-6).   If Aroclor  1260 Is  detected  In  the  finished  drinking water  then
 the  cancer  based criterion may be applied.  A decision to utilize the  cancer
 potency  estimate from  Aroclor 1260 to characterize the upper  limit risks and
 or calculate specific  drinking water  criteria for other  PCS mixtures 1s  risk
 assessment  option (policy  choice).
02400                                VIII-38                           04/11/88

-------
o
fO
                                                    TABLE  VI11 -6


                                  SuMury of Calculated Health  Advisories  for  PCBs

£
01
vO

Health NOEL or NOAEL Species/
Advisory Route
1 Day
10-Day 1 ag/kg/day rabbit/diet
Longer -tern 0.01 ng/kg/day Monkey/diet
Lifetime SO-rat/dtet
DUEL
Calculated Level
Effect for Safe Exposure
Child
No data available*
reproductive 100 pg/ft
effect
reproductive 1 pg/t
effect
carcinogenic NA
effect
Adult


3.5 Mg/t
excess cancer
risks at levels
10' « - 0.5 Mg/t
10" s - 0.05 t.g/1
10 * - 0.005 p
-------
                                IX.   REFERENCES

Abe,  S.,  Y.   Inoue  and  M.  Takamatsu.   1975.   PolychloMnated  blphenyl
residues  In  plasma of  Yusho children born  to mothers  who had  consumed  oil
contaminated by PCS.  Kuuoka Acta Hed.  66(10): 605-609.

ACGIH  (American  Conference  of  Governmental   Industrial Hyq1en1sts).   1980.
Documentation  of  the  Threshold  Limit  Values,  4th ed.   (Includes  Supplemental
Documentation.  1981).  Cincinnati. OH.  p. 486.

Acker,  L.  and  £.  Schulte.   1970.   Uber   das  Vorkommen  von  Chlorlerten
Blphenylen und hexachlrobenzol  neben Chlorlerten  Insektlzlden  1n Humanmllch
und Henschllohem Fettqewebe.  Naturwlssenschaften.  57:497-500.   (Ger.)

Ahllnq,  B.  and  S.  Jensen.   1970.   Reversed   liquid-liquid  partition  In
determination  of  polychlorInated blphenyl  (PCB) and chlorinated  pesticides
In water.  Anal. Chem.  42:  1483-1466.

Albers,  P.M.,  L.  Slleo  and  B.N. Hulhern.   1986.  Effects of  environmental
contaminants on snapping turtles  of a tidal  wetland.   Arch.  Environ.  Contam.
Toxlcol.  13: 39-49.

Albro, P.M.  1976.  Quantitative and  qualitative analysis  of  polychlorlnated
blpnenyls  by  gas-liquid chromatography  and   flame  lonlzatlon  detectors.   I.
One to three chlorine atoms.  CA 84:17S675K.
02410                                U-1                            11/14/86

-------
 Albro,  P.W.  and  L.  Flshbeln.   1972.   Intestinal  absorption  of polychloM-
 nated blphenyls \n rats.   Bull.  Environ.  Contam.  Toxlcol.   8:  26-31.

 Albro,  P.W.  and  C.E.  Parker.   1979.   Comparison  of  the  compositions  of
 Aroclor 1242 and Aroclor  1016.   J.  Chromatogr.   169:  161-166.

 Albro, P.M.,  J.T.  Corbett and  J.L.  Schroeder.   1981.   Quantitative charac-
 terization  of  polychlorInated  blphenyl  mixtures  (Aroclors  1248,   1254  and
 1260) by  gas  chromatography  using capillary columns.   J.  Chromatogr.   205:
 103-111.

 Alford-Stevens,  A.L., W.L.  Budde  and  T.A.  Bellar.   1985.   Intel-laboratory
 study  on   determination   of  polychlorlnated  blphenyls  1n  environmentally
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 Alford-Stevens,  A.L., T.A. Bellar,  J.H.  Elchelberger and W.L.  Budde.  1986a.
 Characterization  of  commercial  Aroclors  by automated mass  spectrometrk
 determination  of  polychlorlnated blphenyls  by  level  of chlorlnatlon.   Anal.
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 Alford-Stevens, A.L., T.A. Bellar,  J.W.  Elchelberger and W.L.  Budde.  1986b.
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 chlorlnated  blphenyls with  automated  Interpretation of mass  spectrometrlc
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Allen,  J.R.   1975.   Response of   the  non-human primate  to  polychlorlnated
blphenyls exposure.  Fed.   Proc.  34: 1675-1679.


02410                                IX-2                            03/04/87

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Allen,  J.R.  and  L.J.  Abrahamson.    1973.    Morphological  and  biochemical
changes  1n  the  liver of rats  fed  polychlorInated  blphenyls.   Arch.  Environ.
Contam. Toxlcol.  1: 265-280.

Allen,  J.R.  and L.J. Abrahamson.  1979.  Responses of  rats  exposed  to poly-
chlorinated  blphenyls  for  fifty-two  weeks.   II.  Compositional and  enzymlc
changes In the  liver.  Arch. Environ.  Contam. Toxlcol.  8: 191-200.

Allen,  J.R.  and  O.A.  Barsottl.   1976.   The  effects  of  transplacental  and
mammary  movement of  the  PCBs  on  Infant  rhesus  monkeys.  Toxicology.   6:
331-340.

Allen,  J.R.   and  O.H.   Norback.    1973.    Polychlorlnated  blphenyls- and
trlphenyl-lnduced gastric  mucosal hyperplasla  1n primates.   Science.   179:
498-499.

Allen,  J.R.  and  D.H.  Norback.   1977.   Carcinogenic  potential of the poly-
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In  Humans,   H.H.  Hlatt,   J.O.  Hatson  and   J.A.  Hlnsten,  Ed.   Cold  Spring
Harbor, New York.  p. 173-186.

Allen,  J.R.,  O.H.  Norback and  I.C.  Hsu.   1974a.   Tissue  modifications  In
monkeys as  related  to absorption, distribution and excretion  of polychloM-
nated blphenyls.  Arch. Environ. Contam.  2: 86-95.

Allen,  J.R.,  L.A. Carstens and  D.A.  Barsottl.  1974D.   Residual  effects  of
short-term,   low-level  exposure  of   non-human primates   to  polychlorlnated
blphenyls.  Toxlcol. Appl. Pharmacol.   30: 440-451.

02410                                IX-3                            04/20/87

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 Allen.   J.R..   I.A.  Gartens.   L.J.   Abranamson   and   R.J.   Marian.    I9;5.
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 Allen,  J.R.,  L.A.  Carsten and  L.J.   Abrahamson.   1976.   Responses  of  rats
 exposed  to polychlorlnated blphenyls   for 52  weeks.  I.  Comparison  of tissue
 levels  of  PCS  and  biological  changes.  Arch.  Environ.  Contam.  Toxlcol.   4:
 404-419.

 Allen.  J.R.,  H.A. Margraves.  H.T.S.  Hsla and  F.S.O.  Lin.   1979a.   Compara-
 tive  toxicology of  chlorinated  compounds on  mammalian  species.  Pharmacol.
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 Allen.  J.R.,  O.A.  Barsottl,  L.K.  Lambrecht  and  J.P.  Van Hlller.   1979b.
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 Alvares, A.P.  and A. Kappas.   1975.   Induction of aryl hydrocarbon hydroxyl-
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Alvares, A.P.   and  A.   Kappas.  1979.   Lead  and  polychlorlnated  blphenyls:
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02410                                U-4                            04/20/87

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 Alvares.  A.P., A.  Mshbeln,  K.E.  Anderson  and A. Kappas.   1977.   Alterations
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 Amano.  H.,  K.  Yag1.  H.  Nakajlma, R. Takehara,  H.  Sakat and G.  Umeda.   1984.
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 Ando.  M.   1978.   Transfer of  2,4,5,2',4',5'-hexachloroblphenyl  and  2,2-bls-
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 and suckling rats.  Arch. Toxlcol.  41: 179-186.

 Ando,  M.,   H.  SaUo  and  I.  Waklsaka.   1985.   Transfer  of  polychlorlnated
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Ando,  M.,  H.  Sal to  and  I.  yaklsaka.    1986.   Gas chromatographlc and  mass
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cord blood.   Environ. Res.  41: 14-22.


02410                                IX-5                            11/14/86

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 AnsaM .  G.A.S., G.P. James, L.A. Hu and E.S. Reynolds.  1986.   Organochlorine
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 Arbuckle, W.B.   1986.   Comment on Henry's  law constants  for  the polychloM-
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 Atlas,  E..   A.  Velasco.  K.  Sullivan  and  C.S.  Glam.   1983.   A  radlotracer
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