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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
* II*
rj
O
CD
lw * u>4 Tw 0 j|>
I OUT«ttMlc
IMM 1 till «n4 Iyp« t
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Structure
21 A 0.15 0.13-0.5
22«
23
24
25*
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
.13-0.25
.13-1
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414*
53 0 1.4 0.13-7
54 A 1.4 0.13-3
55 A 2.1 0.13-7
54 0 2.4 0.13-7
0.94
0.04
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1.00
O.M
0.92
O.M
O.M
0.97
0.01
0.97
O.M
O.M
1.00
1.00
0.72
0.73
O.M
0.92
0.93
1.00
0.90
0.91
0.44
0.99
0.95
2.2'
2.
2.
2.
4.
2.
2.
2.
2,
2.
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2.
2.
2.
37 7-45 0.98 2.
2.
2.
25 7UT«S 0.99 2.
3.
2.3'
•
•
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.4'
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•4.5 2.2'. 4. 5
.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
'.4'. 5 2. 4. 4'. 5
-.4'. 5' 2. 3.3'. 4
.4.4'
.3'. 4-
'.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.)
IV*
o
u«
••H T»Pf I Ml
Tm
•Ural IMC
Structure
51
SO
59
510*
Sll
512
41
42
43
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45
44
41
M
49
4I«
411
412
413
73
14
is
II
111
A*
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&£
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mil
04'
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4.4
S.4
2.4
2.S
2.1
1.9
12
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4.3
1 1
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31
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0.3
13
S\
. J
4.4
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. *
.13-3
.13-1
.13-1
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.13-1
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0.13-1
•.13-1
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•.13-1
•.13-1
0. 13-1
an-l
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0.90
0.03
•••3
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w • w*
• .97
• .97
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000
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>90
44
>90
>90
59
23
>90
>90
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44
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>90
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>90
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>*0
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0.13-90
1-90 0.9«
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1-15 1.00
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0.13-90
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0.13-90
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1-90
0.13-90
1-90
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
CD
O*
-------
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
-------
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.
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
»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
-------
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
-------
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
-------
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
-------
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*
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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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
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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
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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
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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
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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
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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
-------
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
-------
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
-------
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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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.
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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
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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
-------
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
-------
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
-------
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
-------
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
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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
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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
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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
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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
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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
-------
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