EPA-540/1-86-004
Office of Emergency and
Remedial Response
Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfund
vvEPA
HEALTH EFFECTS ASSESSMENT
FOR POLYCHLORINATED BIPHENYLS
-------
EPA/540/1-86-004
September 1984
HEALTH EFFECTS ASSESSMENT
FOR POLYCHLORINATED BIPHENYLS (PCBS)
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
U.S. Envirerrrx-'^ ^ lection Agency
Region '•/, U'- •
-------
DISCLAIMER
This report has been funded wholly or In part by the United States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and H has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
i) r« r
nvironrnent?.! Pr©t©etion Agency
11
-------
PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with
polychlorlnated blphenyls. All estimates of acceptable Intakes and
carcinogenic potency presented 1n this document should be considered as
preliminary and reflect limited resources allocated to this project.
Pertinent toxlcologlc and environmental data were located through on-line
literature searches of the Chemical Abstracts, TOXLINE, CANCERLINE and the
CHEMFATE/DATALOG data bases. The basic literature searched supporting this
document is current up to September, 1984. Secondary sources of Information
have also been relied upon 1n the preparation of this report and represent
large-scale health assessment efforts that entail extensive peer and Agency
review. The following Office of Health and Environmental Assessment (OHEA)
sources have been extensively utilized:
U.S. EPA. 1980b. Ambient Water Quality Criteria for Polychlorl-
nated Blphenyls. Environmental Criteria and Assessment Office,
Cincinnati, OH. EPA 440/5-80-068. NTIS PB 81-117798.
U.S. EPA. 1985. Drinking Water Criteria Document for Polychlorl-
nated Blphenyls. Prepared by the Environmental Criteria and
Assessment Office, Cincinnati, OH, OHEA for the Office of Drinking
Water, Washington, DC. Final Draft.
The Intent in these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited in
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the Interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer is not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time interval (I.e., for an Interval that
does not constitute a significant portion of the lifespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards
exposures from toxicants in ambient air or water where lifetime exposure is
assumed. Animal data used for AIS estimates generally include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
111
-------
The AIC, acceptable Intake chronic, 1s similar In concept to the ADI
(acceptable dally Intake). It 1s an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the llfespan [see U.S. EPA (1980b) for a discussion
of this concept]. The AIC 1s route specific and estimates acceptable
exposure for a given route with the Implicit assumption that exposure by
other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development 1s explained 1n U.S. EPA (1983).
For compounds for which there 1s sufficient evidence of carclnogenlclty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer 1s a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-j*s have been computed based on oral
and Inhalation data 1f available.
1v
-------
ABSTRACT
In order to place the risk assessment 1n proper context, the reader Is
referred to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate Inter-
pretation and use of the quantitative estimates.
Limited human data are available suggesting a relationship between PCB
exposure and cancer. Jji vitro mutagenldty evaluations have been primarily
negative. PCBs have been shown to be carcinogenic 1n rats and mice when
administered orally. Using data for hepatocellular carcinoma and neoplastlc
nodules In female rats, a carcinogenic potency (qi*J of 4.34 (mg/kg/
day)"1 has been estimated for oral exposure of humans to PCBs. Data were
Inadequate to develop a quantitative estimate for the Inhalation route.
-------
ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball was the Project
Officer. The final documents 1n this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
-------
TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE. . . .'
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
3.4. TOXICANT INTERACTIONS
3.5. HUMAN EFFECTS
CARCINOGENICITY
4.1. HUMAN DATA
4.2. BIOASSAYS
4.3. MUTAGENICITY
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.3. CARCINOGENIC POTENCY (q]*)
6.3.1. Oral
6.3.2. Inhalation
Page
1
... 5
... 5
... 7
8
... 8
... 8
... 22
, . . 22
... 22
... 24
... 24
... 28
... 28
... 28
... 31
... 31
... 31
... 36
... 36
, , . 38
... 40
... 40
... 40
... 40
... 40
... 40
7. REFERENCES 42
APPENDIX: Summary Table for Polychorlnated Blphenyls 55
-------
LIST OF TABLES
No.
1-1
1-2
2-1
3-1
3-2
3-3
3-4
4-1
5-1
6-1
Title
Approximate Composition of the Commercially Available
Aroclors
Identification Numbers and Selected Physical and Chemical
Properties of Aroclors
Uptake of PCBs by Rats
Effects of Subchronlc and Chronic Oral Exposure of PCBs
to Rats and Mice
Effects of Subchronlc and Chronic Oral Exposure of PCBs
to Other Species
Effects of Chronic and Subchronlc Exposure of PCBs to
Monkeys
Summary: Teratogenetlc, Fetotoxlc and Reproductive Effects
of Orally Administered PCBs
Summary of Carcinogenic Effects of Orally Administered PCBs. .
FDA Regulations for PCBs
Data Used as the Basis for the CM*
Paqe
2
3
6
g
12
13
25
32
39
41
V111
-------
LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
BCF B1oconcentrat1on factor
bw Body weight
CAS Chemical Abstract Service
CS Composite score
DNA DeoxyMbonuclelc add
PEL Frank-effect level
LOAEL Lowest-observed-adverse-effect level
LOEL Lowest-observed-effect level
mol.wt. Molecular weight
NOEL No-observed-effect level
PCBs Polychlorlnated blphenyls
PCDFs Polychlorlnated dlbenzofurans
ppm Parts per million
RNA R1bonucle1c add
SGOT Serum glutamlc oxalacetlc transamlnase
SGPT Serum glutamlc pyruvlc transamlnase
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
UV Ultraviolet
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
PCBs consist of a mixture of chlorinated blphenyls that contain a
variable number of substituted chlorine atoms on the aromatic rings. The
commercial PCBs manufactured In the United States are known as Aroclors
followed by a 4-d1g1t number. The first two digits Indicate the type of
mixture (e.g., those with "12" as the first two digits are chlorinated
blphenyls; those with "25" are blends of 75% blphenyls and 25% tMphenyls;
and those with "54" are chlorinated trlphenyls), and the last two digits
represent- the approximate weight percent of chlorine 1n the product. The
approximate compositions of the commercially available Aroclors and Kane-
chlors are shown 1n Table 1-1. The relevant physical and chemical proper-
ties and Identification numbers of the Aroclors are presented 1n Table 1-2.
The mobility of different Aroclors 1n soils as 1t pertains to leaching
has been studied by Pal et al. (1980). The two most Important factors that
determine the Teachability of Aroclors In soils are the characteristics of
the soils and the nature of the Aroclors. For example, as the chlorine
content of an Aroclor Increases, 1t may Increase the adsorption
characteristics 1n soils, thereby decreasing Us rate of leaching.
Similarly, soils with more organic matter content may tend to Increase the
adsorption and decrease the leaching rate. Therefore, maximum leaching of
Aroclors Is expected In sandy soils and with Aroclors having lower chlorine
content, such as Aroclor 1221 and Aroclor 1232. Incorporation of 1 ppm
dlchloroblphenyl 1n a sandy loam soil showed that no detectable amounts
(<0.001 ppm) of the compound leached beyond 30 cm soil layer after 1 year of
Incorporation (Pal et al., 1980).
B1oconcentrat1on factors have not been determined for all the Individual
Aroclors. The potential for bloaccumulatlon of Aroclors Is related to the
-1-
-------
TABLE 1-1
Approximate Compositions of the Commercially Available Aroclors*
Aroclor
Nolecular
F omul a
C12H10
C12H,C1
C,2H8C12
C12H7C13
C12H6C14
C12H5C15
C12H4C16
C12H3C17
C12H2C18
C12HC19
Average MO).
No. of
Chlorine
Atoms
0
1
2
3
4
S
6
7
8
9
wt.
No. of
Isomers
1
3
12
24
42
46
42
24
12
3
mol. wt.
154
169
223
258
292
326
361
395
430
464
wt.
XC1
0
18.8
31.8
41.3
48.6
54.3
58.9
62.8
66
68.7
1221
11
51
32
4
2
<0.5
ND
ND
ND
NO
201
1232
<0.1
31
24
28
12
4
<0.1
ND
ND
ND
232
1242
<0.1
1
16
49
25
8
1
<0.1
ND
ND
267
1248
ND
ND
2
18
40
36
4
ND
ND
ND
300
1254
<0.1
<0.1
0.5
1.0
21
48
23
6
ND
ND
328
1260
ND
ND
ND
NO
1
12
38
41
8
ND
376
1016
<0.1
1.0
20
57
21
1
<0.1
ND
ND
ND
258
Kanechlor
300
ND
ND
17
60
23
0.6
ND
ND
ND
ND
NA
400
ND
ND
3
33
44
16
5
ND
ND
ND
NA
500
ND
ND
ND
5
27
55
13
ND
ND
ND
NA
'Source: Callahan et al.. 1979; IARC. 1978
ND . Not detected; NA . not available
-------
TABLE 1-2
Identification Numbers and Selected Physical and Chemical Properties of Aroclors3
Identification Numbers
i
CO
Properties
Vapor pressure
im Hg at 2S'C
Mater solubility
mg/l
Log octanol/water
partition coefficient
CAS Registry
Number
1221 1232
[6.7xl(T»] [4.06xlO~»]
O.S9b at NA
24'C
[2.8] [3.2]
4.09 >4.S4
11104-28-2 11141-16-5
1016
I4xl0~«]
0.42 at
25'C
4.38
>5.58
12674-11-2
1242
4.0bxlO'«
0.24C at
25*C
4.11
>5.58
53469-21-9
1248
4.94x10'*
0.054 at
25*C
[5.75]
>6.11
12672-29-6
1254
7.71xlO"»
0.012e at
25-C
[6.03]
11097-69-1
1260
4.05xlO"»
0.0027C at
25*C
[7.14]
>6.11
11096-82-5
aA11 values are taken from Callahan et al.. 1979, except where noted; the bracketed data are estimated.
bVerschueren. 1983
cMackay and Lelnonen. 1975
NA = Not available
-------
number of chlorines, with the BCF value Increasing with higher chlorine
content (Callahan et al., 1979). The BCF value 1n freshwater species may
vary from 3000 for the muscle of a brook trout, Salvellnus fontlnalls. to
274,000 for the whole body of a fathead minnow, Plmephales promelas. (U.S.
EPA, 1980b).
The half-life of PCBs In air 1s not known. Although photolysis of PCBs
In the atmosphere 1s a likely process, 1t 1s expected to be slow (Pal et
al., 1980). The removal of PCBs from the atmosphere by physical removal
processes, such as wet and dry deposition, may not be significant (CupHt,
1980). The half-life of PCBs as a result of chemical reactions with OH
radicals and O3 1n air has been estimated to be >8 days (CupHt, 1980).
The half-life of a PCB In aqueous media will depend on both the nature
of the PCB and the characteristics of the body of water. PCBs with
Increasing chlorine content, because of their lower volatility and blodegra-
datlon and higher sorptlon characteristics, will have longer half-lives.
Based on published reports, PCBs containing less than three chlorines may be
degraded 1n aquatic media (Callahan et al., 1979; Pal et al., 1980), al-
though no estimation of half-lives 1n natural bodies of water 1s available.
PCBs with four chlorines appear to be somewhat degradable, while those with
five or more appear to be recalcitrant.
The half-life of PCBs In soils Is expected to follow the same pattern as
1n water. Both volatility and blodegradatlon may destroy PCBs containing
one or two chlorine atoms; the half-lives of such PCBs may be a few days.
PCBs containing three or four chlorine atoms will have longer half-lives,
whereas PCBs containing five or more chlorine atoms may be refractory (Pal
et al., 1980).
-4-
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
One of the problems associated with understanding the toxlcoklnetlcs of
PCS products 1s that they are mixtures of many different Isomers, each with
Us own characteristic kinetics of behavior 1n the animal body. In one of
the early studies of oral absorption, Albro and Flshbeln (1972) administered
5, 50 or 100 mg of 19 "pure" PCB Isomers and the totally unchlorlnated
blphenyl by gavage to male CD rats (number not reported). Feces were
collected for 4 days; the total amount excreted 1n the feces and the amount
absorbed or metabolized 1n the gut were determined. The results are
presented 1n Table 2-1. For all compounds tested at all dosage levels,
absorption was >90%. The authors recognized that this study did not Inves-
tigate the possibility of Intestinal metabolism, enterohepatlc redrculatlon
or the effects of dietary status on retention of PCBs, all of which would be
required for full elucidation of the PCB absorption process.
Gavage administration of 1.5 or 3.0 g Aroclor 1248/kg bw to adult rhesus
monkeys resulted 1n uptake of >90% of the total dose {Allen et al., 1974),
confirming the data of Albro and Flshbeln (1972). These Investigators sub-
sequently administered a single 18 mg dose of 2,5,2',5'-tetra PCB/kg bw to
seven adult male rhesus monkeys. Excreta were collected and analyzed for 14
days. Over 12% of the total dose was recovered unmodified 1n the feces
(Allen et al., 1975). Norback et al. (1978) administered one dose of
9H-labeled 2,4,5,2',4',6'-hexa PCB to two young monkeys with bile duct and
duodenal cannulae. The authors reported that 59.3-87% of the total dose
passed unmodified through the Intestinal tract within the first week. It
was unclear why relatively little of this Isomer was absorbed.
-5-
-------
TABLE 2-1
Uptake of PCBs by Rats3
Percentage Retained*3
Compound
Blpheny"!
2-C1
3-C1
4-C1
2,6-Cl2
2,2'-Cl2
2,4-Clp
2,3'-Cl2
2,A'-C12
3,4'-Cl2
4,4'-Cl2
2,5,2'-Cl3
2,3,5'-Cl3
3,4,3'-CL3
2,4,4'-Cl3
2,5,2',5'-Cl4
2,3,4,5-Cl4
3,4,3',4'-Cl4
2,4,5,2',5'-Cl5
2,4,5,2',4',5'-C16
5 mg/kg
99.5
98.9
98.0
97.3
NR
95.0
NR
NR
97.2
95.7
95.4
NR
NR
NR
NR
96.0
97.3
98.8
95.1
95.3
1 S.O.
0.11
0.45
1.01
1.73
NR
2.42
NR
NR
3.38
3.45
3.05
NR
NR
NR
NR
1.75
0.86
0.57
0.57
1.11
50 mg/kg
98.8
98.0
96.6
96.3
95.0
97.4
95.7
96.8
95.5
94.3
95.6
95.1
95.6
93.5
92.6
NR
NR
NR
NR
NR
i S.D.
0.25
0.30
0.10
0.40
0.96
0.20
0.40
0.51
1.20
0.86
1.12
3.00
1.05
2.85
0.86
NR
NR
NR
NR
NR
100 mg/kg
98.2
98.4
97.3
96.4
94.9
98.2
97.1
97.9
96.6
97.1
97.4
94.3
95.0
90.3
94.0
NR
NR
NR
NR
NR
± S.D.
0.30
0.15
0.40
0.42
0.75
2.10
0.35
0.28
0.78
0.63
1.10
3.18
1.12
3.58
1.50
NR
NR
NR
NR
NR
aSource: Albro and F1shbe1n, 1972
bŁach value 1s the average of three determinations on each of two rats:
(amount fed) - (amount excreted)
Percentage Retained
x 100%
amount fed
NR = Not reported; S.D. = standard deviation
-6-
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2.2. INHALATION
One brief report concerning Inhalation absorption of PCBs was located.
Benthe et al. (1972) exposed male Wlstar rats once to Pydranll A200 (number
of rats, concentration of Pydranll A200 and length of exposure time not
specified). Animals were killed and examined at 15 minutes, 2 hours, 24
hours and 2 days post-exposure. At the end of 15 minutes, liver concentra-
tions were >50% of the maximum concentrations attained after 2 hours.
During the first 24 hours, rapid Increase 1n brain and fat levels of PCBs
was noted. At the end of 2 days, liver and brain levels of PCBs had fallen,
and levels 1n adipose tissue had reached a maximum. Indicating very good
absorption; however, absorption factors were not quantHated.
-7-
-------
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Subchronlc oral exposure of experimental animals to PCBs
has been Investigated 1n detail In several species, and PCB toxlclty In rats
appears to have been studied most extensively. The details of protocol and
results of these studies are summarized In Tables 3-1, 3-2 and 3-3. In an
early study, Klmbrough et al. (1972) compared the effects of Aroclor 1254
and Aroclor 1260 on groups of 10 male and 10 female Sherman rats. Aroclor
1254 was Included 1n the diet at 0, 20, 100 or 500 ppm (mg/kg/dlet), and
Aroclor 1260 was Included 1n the diet at 0, 20, 100, 500 or 1000 ppm
(mg/kg/d1et). The duration of exposure was 8 months. Aroclor 1260 appeared
to be more toxic to female than to male rats, since none of the male rats
fed Aroclor 1260-contalnlng diets died, but 1/10, 2/10 and 8/10 females fed
diets containing 100, 500 and 1000 ppm Aroclor 1260, respectively, died.
Aroclor 1254 at dietary levels of 500 ppm resulted 1n the death of two male
rats and one female rat.
Dietary levels >500 ppm Aroclor 1260 or Aroclor 1254 seemed to reduce
rate of weight gain severely 1n treated rats, although statistical analysis
was not performed to substantiate that observation. There was, however, a
statistically significant Increase 1n relative liver weight (liver weight
expressed as percent of body weight) 1n all rats at dietary levels >20 ppm
of either of the Aroclors tested, except for females exposed to 20 ppm
Aroclor 1260 1n the diet. Because the diets with 20 ppm of either Aroclor
1260 or Aroclor 1254 were set up at a different time from the diets
containing other levels, they had their own simultaneous female and male
control groups. These control females had unusually high liver weights (no
-8-
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TABLE 3-1
Effects of Subchrontc and Chronic Oral Exposure of PCBs to Rats and Nice
Species/
Strain Sex/No.
Rat/F344 H.F/191
Rat/ F/400
Sherman
Rat/Wtstar N/290
Rat/ N/6/group
Sprague-
Oawley
Rat/ N/96
Sprague-
Dawley
Source
of PCB Vehicle
Aroclor 1254 diet
Aroclor 1?60 diet
Kanechlor-300. diet
-400 or -500
Aroclor 1242 diet
Ar odors 1248, diet
1254 or 1262
Dosage
Schedule
0. 25. SO. 100
mg/kg diet for 2
years
0 or 100 mg/kg
diet for 21
months
0. 500 or 1000
mg/kg diet for
27-52 weeks
0. 5 or 25 «g/kg
diet for 2. 4 or
6 months
0 or 100 mg/kg
diet for 52 weeks
Duration
of Study
2 years
21 months
1 year
2, 4 or
6 months
65 weeks
Animal Effects
Reduced body weight. Stomach: •Intestinal"
metaplasia, dose-related; adenocarclnoma of
glandular stomach.
No effect on food Intake; reduced body weight.
Elevated tan liver modules (170/164), hepatocellu-
lar carcinoma (26/184). Other areas: hepatic
disruption.
Heavy mortality. Hepatomegaly, oval cell and bile
duct proliferation, fatty liver Infiltration.
Cholangloftbrosls at 1000 mg/kg level of all 3
Kanechlors, nodular hyperplasla. Depressed final
body weight.
Elevated hepatic mlcrosomal enzyme activity, llpld
content. Elevated urinary coproporphyrln levels.
Present after 2 months at 5 mg/kg.
Increased hepatic protein. RNA and llpld; decreased
DMA. Increased Mlcrosomal total protein and cyto-
chrome P-450. Induced N-demethylase nltroreductase.
Inhibited glucose-6-phosphatase.
Reference
Morgan
et a!..
1981
Klmbrough
et al..
1975
Ito et al.,
1974
Bruckner
et al..
1974
Allen and
Abrahamson,
1979
Rat/CD
f/300
Aroclor 1254 diet
Rat/Donryu N/15. F/15
Kanechlor-400 diet
0. 10. 30 or 100
mg/kg diet for up
to 20 weeks
total Intake 450-
1500 mg over 159-
560 days
20 weeks Serum cholesterol, beta globulin Increased; gamma Zlnkl, 1977
globlln decreased (dose-related). >30 mg/kg:
Reduced rate of gain, hepatomegaly, cardtomegaly
(dose-related). >10 mg/kg: Hepatic porphyrlnlc
fluorescence. >10 mg/kg: Erythema, crustiness,
hyperkeratosts,~perlkeratosts on ears, dorsum of
nose and feet, tall.
560 days All treated rats: fatty liver degeneration. Klmura and
Females 1200-1500 mg: multiple adenomatous Saba. 1973
nodules. All rats >700 mg: hepatomegaly. Lung
and Intracranlal abscesses suggested Impaired
resistance to Infection.
-------
TABLE 3-1 (cont.)
Species/
Strain Sex/No.
Source
of PCB
Vehicle
Dosage
Schedule
Duration
of Study
Animal Effects
Reference
Rat/
Sprague-
Dawley
f/6/group
Aroclor 1242
diet
Rat/
Sherman
o
i
N/10. F/10 Aroclor 1254
In each group
N/10. f/10 Aroclor 1260
In each group
diet
diet
Rat/
Sprague-
Dawley
N/96
Aroclors 1248. diet
12S4 or 1262
Hlce/dd
H/114
Kanechlor-300.
-400. or -SOO
diet
0. 75 or 150 mg/kg
diet for 8 or
36 weeks
0. 20, 100. SOO
mg/kg diet for
8 months
0. 20. 100. 500.
1000 mg/kg diet
for 8 months
0 or 100 mg/kg
diet for 52 weeks
0. 100. 250. or
500 mg/kg diet
for 32 weeks
36 weeks Both levels: massive venous engorgement of liver Jonsson
with characteristic darkening; marked focal et al..
necrosis and regeneration, enlarged hepatocytes; 1981
many mitoses and multlnucleate cells, accumulation
of pigment adjacent to veins, heaviest In Kupfer
cells; accumulation of llpld droplets In cytoplasm.
some with areas suggestive of llpld-cholesterol
complexes; marked smooth ER proliferation; deposits
of Iron; granular degeneration of mitochondria; many
hepatocytes contained whorl-like membranous bodies.
8 months Mortality (3/20) and reduced rate of gain at 500 Klmbrough
mg/kg. Hepatomegaly, enlarged hepatocytes with et al.. 1972
foamy cytoplasm-containing Inclusions at >?0 mg/
kg. Adenoflbrosls and pigment accumulation at
>100 mg/kg.
8 months Mortality 1/10, 2/10. 8/10 of females In 100. 500.
1000 mg/kg groups. Decreased rate of gain at >500
mg/kg. Hepatomegaly. MiF at >20 mg/kg. discolored
livers with UV fluorescence, enlarged hepatocytes
with foamy cytoplasm-containing Inclusions.
Increased llpld content at >100 mg/kg. Pigment
accumulations at 500 mg/kg. Adenoflbrosls at >100
mg/kg.
65 weeks Normal appetites, appearance, weight gain. Allen
Hb. PCV. UBC. serum protein. A/G ratios. Elevated et al.. 1976
serum total llplds. cholesterol. Total llpld and
trlglycerld spiked very high peaks on Aroclor 1254
(only) at 52 weeks. Cholesterol levels persisted
at 65 weeks (13 weeks off exposure). Trlglycerlde
levels fell
-------
TABLE 3-1 (cont.)
Species/
Strain Sex/No.
Nice/ H/25/group
BALB/C
Source Dosage
of PCB Vehicle Schedule
Aroclor 1221. diet 0. 3.7S. 37.5. or
1242 or 1254 37S mg/kg diet
for b Months
Duration
of Study Animal Effects
9 months 375 mg/kg Aroclor 1242 and all Aroclor 1254-
exposed groups: significant (p<0.01) Increase
In liver weight after 6 months. Significant
(p<0.01) decrease In liver weight of 375 mg/kg
Aroclor 1242 and 37.5 mg/kg Aroclor 1254-exposed
groups after 3-month recovery period. Aroclor 1254:
375 mg/kg: mortality and severe hepatopathology;
37.5 mg/kg: mild hepatopathology; 3.75 mg/kg:
Aroclor 1242: 375 mg/kg: moderate
hepatopathology.
Aroclor 1221: no liver lesions.
Reference
Roller. 1977
i, Mice/Swiss f/63
-> Albino
i
HIce/BALB/ N/200
CJ
HIce/ddN F/60
Aroclor 1254
Aroclor 1254
•PCB'
diet
diet
olive or
rice bran
oil
200 mg/kg diet
for 23 weeks
0 or 300 mg/kg
diet for 6 or 11
months
0. 0.5% V/V PCB
In olive oil, or
1600 mg/kg PCB In
bran oil for 13,
17. 22 or 26 weeks
23 weeks Thickening and erylhemla of pinna of ear; Bell. 1983
changes In mlcrovasculature.
11 months Both 11* and 6-month exposure: Hepatomegaly, Klmbrough
hepatomas, liver degeneration and elevated and Under,
porphyrln. 1974
26 weeks Both exposed groups: slight weight loss, reduced Nlshliumt,
activity; eczematous and ulccrattve skin 1970
lesions, hepatomegaly and hepatopathology.
A/6 B Albumin/globulin; Eft - endoplasmlc retlculum; Hb » hemoglobin; PCV - packed cell volume
-------
TABLE 3-?
Effects of Subchronlc and Chronic Oral Exposure of PCBs to Other Species
Species/
Strain
Mink/
Pastel
Sex/
Number
H.F/105
Source of PCBs
Aroclor 1242
Aroclor 1016
Vehicle
diet
diet
Dosage Schedule
0, 5, 10. 20 or 40
mg/kg diet
0 or 20 mg/kg diet
Duration
of Study
B nonths
AnlMl Effects
Mortality of all
mg/kg diet.
Death of 3/12 (2!
•Ink on >20
iX) of females.
References
Bleavlns
et al.. 1980
I
~J
ro
Ntnk/
NR
F/7 or
8/group
Aroclor 1016,
1221, 1242 or
1254
diet
0 or 2 mg/kg diet
•10 Months
Necropsy: emaciation, complete
absence of body fat. gastric
ulceratlon. Aroclor 1?4? at 5
or 10 ng/kg diet: complete re-
productive failure. Aroclor
1016 at 20 ng/kg diet: reduced
reproductive performances.
Aroclor 1254: Interference with
reproduction. All Aroclors tested:
no significant differences In body
weight gains, hemoglobin, PCV.
Aulerlch and
Ringer. 1977
NR - Not reported; PCV . packed cell volume
-------
TABLE 3-3
Effects of Chrontc and Subcnrontc Exposure of PCBs to Monkeys
Strain Sex/No.
Rhesus F/24
M/NR
Source
of PCBs Vehicle Dosage
Aroclor 1240 diet 0. 2.5. or S.O
mg/kg diet.
-IB Months
Duration
of Study
-39.6
Months
AnlMal Effects
Hales (S.O Mg/kg level only): moderate erythema
and perlorbltal edema. Females: more severe skin
lesions (alopecia, acne); extreme weight loss.
Irregular menstrual cycle length, depressed serum
progesterone. Considerable Improvement after 1-
year recovery period.
Reference
Barsottl
and Allen,
1975
Rhesus F/30
M/10
Aroclor 1248
Aroclor 1248
diet
diet
0. 2.5 or 5.0
mg/kg diet
0 or 5.0 mg/kg
diet. -16
months
-16 months;
total Intake
90 or 180 mg/
kg by females
In 6 months
CO
I
F/8/group Aroclor 1248 diet
F/24
Rhesus NR/7
Aroclor 1016
Aroclor 124B
Aroclor 1248
diet
trans-
placental
or
mother's
Milk
trans-
placental
or
mother's
milk
0.5 or 1.0 mg/kg
diet 3 times
weekly for
-16.6 months
0.025. 0.25 or
1.0 mg/kg diet
for unreported
length of time
mothers exposed
to PCBs 6 months
before gesta-
tion, through
gestation and 3
to 4 months of
nursing
mothers removed
from exposure to
PCBs for 22-84
weeks before
conception
-16.6 months,
total Intake
~8 or 16 mg
after 7 months
NR
up to Infant
age of 24
months
Skin lesions as above; 15X weight loss In
females. Normal hematograms. After 6 months:
serum total llplds reduced, shift In A/G ratio.
elevated SGPT. Menstrual cycles lengthened.
Serum progesterone and estradlol reduced.
After 12 months, serum cholesterol and trlgly-
cerlde reduced.
No Irregularities In menstrual cycle, or serum
estradlol, progesterone or reproduction success.
Infants smaller, skin hyperplgmented.
No abnormalities of clinical, gross or reproduc-
tive parameters. 1.0 mg/kg: Infants had reduced
birth weight.
Significantly Increased locomotor behavior
(hyperacttvlty). Significantly retarded learn-
ing ability.
Mothers exposed to >2.S mg/kg: hyperactlvtty.
Barsottl.
et al.. 1976
Allen
et al.. 1979a
Barsottl,
1981
Bowman and
Hetrontmus,
1981; Bowman
et al., 1981
-------
TABLE 3-3 (cent.)
Source Duration
Strain Sex/No. of PCBs Vehicle Dosage of Study
Rhesus H/3/group 3,4.3'.4'-TCB diet 3 mg/kg reduced Up to 215
to 1 ng/kg reduced days
to 0.3 mg/kg
2,5.2',5'-TCB elevated to 1 mg/
kg
f
Animal Effects
Mortality of all three by day 21S In 3. 4.3'. 4'-
TCB-exposed groups: emaciation, skin lesions,
nail bed hyperplasla, loss of nails, thymis
atrophy, gastric lesions as described (Allen,
197S). 2.5.2'.5'-TCB: no signs of toxlctty.
no gross or hlstologlc lesions.
Reference
NcNulty
et al., 1980
N/4-S/group 3.4.3',4'-TCB diet
or
2.5.2'.5'-KB
Aroclor 1242
Rhesus H/6
Aroclor 1242 diet
Cynomol- F/4
gus
Cynomol• f/7
gus
Aroclor 1254
P-KC-400*
Y-PCB>>
PY-PCBC
control
corn oil,
gelatin.
apple
juice
olive oil
In banana
1 mg/kg for 38
days or 133 days.
then control diet
1 mg/kg for 133
days 5 mg/kg
additional 2 months
0, 3, 10. 10. 30
or 100 mg/kg diet
-190
days
Up to 245
days
0, 100. 100 or
400 mg/kg bw/day.
3 days/week
5 mg/monkey/day
5 or 10 mg/
monkey/day
5 mg/monkey/day
NA
all above treat-
ments given 6
days/week
Up to 238
days
20 weeks
1 death: necropsy findings as above. Others:
squamous metaplasm of sebaceous glands.
No evidence of toxlctty.
All PCB-exposed monkeys: palpebral swelling,
erythemla; weight loss, rough hair coat, reduced
lib. leukocytosls. Mortality of 4/6 by day 245.
Gastric lesions: hyper trophic gastric mucosa con-
sisting of elongated hyperplastlc glands, destruc-
tion of parietal and zymogenlc cells. Only spe-
cific region along greater curvature affected.
Lost fingernails, fetal toxlctty. Substantially
reduced antibody production to SRBC antigen.
Death of 10 mg V-PCB-dosed monkeys by 8 weeks.
Height loss of P-KC-400 and 5 mg Y-PCB-dosed
monkeys. V-PCB-dosed: alopecia, acne, hyper-
pigmentation, perlorbltal edema. All treatments:
reduced antibody productton to SRBC. Htstopath-
ology Y-PCB: enlarged hepatocytes with enlarged
smooth ER, focal necrosis, bile duct proliferation.
Dilated renal tubules with casts, epithelial
vacuoles. Melbomlan cysts, skin hyperkeratosls.
Hlstopathology P-KC-400 and PY-PCB: lesions In
liver, kidney as above, but more mild. Perlorbl-
tal skin: no lesions.
Becker
et al., 1979
Truelove
et al., 1982
Horl et al..
1982
aP-KC-400 - Kanechlor-400 with PCDfs removed.
t>Y-PCB was prepared from Kanechlor 400. contained =400 ppm PCOfs.
fpY-PCB > Y-PCB with PCDFs removed.
A/G » Albumin/globulin; Hb « Hemoglobin; NR » Not recorded; ER - Endoplasmlc retlculum NA
Not available; SRBC - Sheep red blood cells
-------
explanation was given) which undoubtedly accounted for the apparent lack of
statistical significance 1n relative liver weights of the females exposed to
20 ppm Aroclor 1260.
At levels >20 ppm, exposure to Aroclor 1254 or 1260 resulted In hepato-
cellular enlargement with foamy cytoplasm that contained Inclusions.
Livers, particularly those from rats exposed to Aroclor 1260, were dis-
colored; many fluoresced under UV light, Indicating porphyrla. Accumula-
tions of pigment were noticed In Hvcrs from rats exposed to >100 ppm of
Aroclor 1254 or 1260. L1p1d accumulation and extensive foci of adenofl-
brosls were also noted 1n livers from rats exposed to 100 ppm Aroclor 1260.
Ultrastructurally, an Increase of smooth endoplasmlc retlculum, cyto-
plasmlc Inclusion of I1p1d-conta1n1ng vacuoles and atypical mitochondria
were noted. Structures of concentrically arranged membranous whorls sur-
rounding I1p1d-conta1n1ng vacuoles were also seen. The most striking dif-
ference 1n livers from rats exposed to these two Aroclors was considerably
greater adenof1bros1s (synonyms: cholanglof1bros1s, bile duct prolifera-
tion, flfaroadenoma) In livers from Aroclor 1254-exposed rats. Under the
conditions of this study, 20 ppm of Aroclor 1254 or 1260 appeared to produce
effects such as hepatomegaly and hepatocytlc enlargement because of the
expanded smooth endoplasmlc retlculum, which may be considered adverse
effects. Therefore, 20 ppm Aroclor 1260 or 1254 was considered a PEL for
this study.
Subsequently, Bruckner et al. (1974) exposed groups of six male Sprague-
Dawley rats to 0, 5 or 25 ppm (mg/kg/d1et) Aroclor 1242 for 2, 4 or 6 months
to evaluate the results of prolonged exposure to relatively low levels.
These authors observed no differences 1n either body weight gain or food
consumption resulting from Aroclor 1242 exposure. The high-dose group
-15-
-------
(25 ppm) suffered a slight but significantly reduced hematocrH after 2
months of exposure, and both treatment groups suffered slight but signifi-
cantly reduced hemoglobin levels. These appeared to be temporary phenomena,
since both hematocrH and hemoglobin values recovered quickly for the dur-
ation of the study.
MUrosomal enzyme assays Indicated a significant (p<0.05) Induction of
mixed-function oxldase activity after 2 months of exposure to 25 ppm Aroclor
1242 1n the diet, and after 4 months of exposure to 5 ppm. N-demethylase
activity was significantly (p<0.001) Induced by 25 ppm Aroclor 1242 after 4
months of exposure. Urinary coproporphyrln levels were elevated after 2
months of exposure to 25 ppm Aroclor 1242 In the diet (p<0.001) and after 6
months of exposure to 5 ppm (p<0.05). Liver weight expressed as percent of
body weight was elevated only at the 25 ppm dietary level (p<0.02) and only
after 4 months of exposure. Liver llpld expressed as mg/g wet weight was
elevated (p<0.02) after only 2 months of exposure, but after 6 months, only
livers from rats exposed to 25 ppm showed elevated (p<0.02) I1p1d content.
Upon hlstopathologlcal examination, no hepatic lesions were found 1n any
rat after 2, 4 or 6 months of exposure. Sudan IV staining, however, re-
vealed Increased liver I1p1d 1n all rats exposed to Aroclor 1242 for 2, 4 or
6 months. Hlstopathologlcal examination of the kidney revealed a slight
vacuollzatlon of convoluted tubules only after exposure to 25 ppm Aroclor
1242 1n the diet for 4 or 6 months. In this study, 1t appeared that dietary
exposure of rats to 5 ppm Aroclor 1242 for 2, 4 or 6 months resulted 1n
Induction of mlcrosomal hydroxylase activity, Increase 1n urinary copropor-
phyrln and Increase In liver I1p1d content. These changes are probably
reversible and, over a short term, do not appear to threaten life or health,
since neither body weight gain nor food consumption was affected. In this
study, 5 ppm Aroclor 1242 for 2, 4 or 6 months appeared to be a LOAEL.
-16-
-------
Zinkl (1977) exposed 300 female CD rats to diets containing 0, 10, 30 or
100 ppm (mg/kg/d1et) Aroclor 1254 for 20 weeks, and reported that there was
no change 1n hematocMt throughout the trial. Serum cholesterol was
elevated within 2 weeks 1n rats exposed to >30 ppm dietary Aroclor 1254
(p<0.01). SGOT was elevated (p<0.05) and serum gamma globulin was reduced
(p<0.01) In rats exposed to 100 ppm Aroclor 1254. A dose-related Increase
(p<0.05) 1n beta globulin was also noted. Rats exposed to >30 ppm Aroclor
experienced decreased body weight gain (p<0.01) and Increased relative liver
weights (p<0.01), which appeared to be dose-related (p<0.01).
Liver lesions were similar to those described previously (Klmbrough et
al., 1972; Bruckner et a!., 1974). Upon gross examination, the livers of
100 ppm-exposed rats were noticeably enlarged and dark 1n color, often
exhibiting an accentuated lobular pattern. Porphyrla fluorescence was
eventually seen 1n livers from all groups of Aroclor 1254-exposed rats.
Microscopically, focal necrosis was observed, accompanied by Inflammation.
Kupfer cells were noted to accumulate a brownish, Iron-positive pigment.
Mldzonal and centrllobular degeneration consisting of vacuolated or eoslno-
phlUc hepatocytlc cytoplasm was noted. Lesions 1n Hvers from 30 ppm-
exposed groups were similar to but less dramatic than those observed 1n
livers from 100 ppm-exposed rats.
Most striking were skin lesions on the ears, which eventually Involved
15/60 of the high-dose (100 ppm) group, 4/60 of the mid-dose (30 ppm) group
and 1/60 of the low-dose (10 ppm) group rats. These lesions consisted of
alopecia, hyperkeratosls, perlkeratosls and deep rete pegs. Keratlnous
plugging of follicles was noted. Desslcated serum and other blood elements
-17-
-------
were observed on the surface of the skin. Subcutaneous tissues were
slightly edematous and contained focal areas of polymorphonuclear Infiltra-
tion and accumulation. Similar lesions were seen on the tall and on the
dorsum of the nose. This was the only report found of skin lesions 1n rats
associated with PCBs. Since no mention was made of liver pathology 1n 10
ppm-exposed rats, and they suffered neither reduced body weight gain,
hepatomegaly nor altered blood chemistries, 10 ppm Aroclor 1254 was
considered a LOAEL 1n this study.
Skin lesions on the ears of mice were reported by Bell (1983), who
exposed female Swiss Albino mice to a much higher level, 200 ppm (mg/kg
diet) Aroclor 1254 for 23 weeks, and observed erythema and thickening of the
pinna of the ear. Hyperkeratosls and occluslve cystic degeneration of the
pHosebaceous units were seen. Basal layer cells became elongated and
markedly thickened. Ultrastructurally, the most striking lesions Involved
the mlcrovasculature and Included gross enlargement of the cells of the
basal layer of the capillaries and small venuoles. The resultant lumenar
stenosis caused a failure of the mlcroclrculatlon, which was associated with
the skin lesions.
In a large experiment, Keller (1977) fed diets containing 0, 3.75, 37.5
or 375 ppm {mg/kg diet) Aroclor 1221, 1242 or 1254 to groups of 25 male
BALB/C mice for 6 months. Groups of mice fed 375 ppm Aroclor 1254 exper-
ienced high mortality during the 5th and 6th months. The mice exhibited the
hepatic lesions discussed above that were found In rats. No other groups
experienced mortality. Hepatomegaly (p<0.01) was observed In all Aroclor
1254-exposed groups and 1n the 375 ppm Aroclor 1242-exposed groups. No
lesions other than moderate hepatomegaly were found 1n livers from 3.75 ppm
Aroclor 1254-exposed rats. Liver lesions In Aroclor 1242-exposed rats
-18-
-------
occurred only 1n the 375 ppm group. None of the Aroclor 1221-exposed mice
evidenced hepatic lesions. Exposure to Aroclor-contalnlng diets was termi-
nated after 6 months, and all remaining mice were given a control diet with-
out added PCBs for an additional 3-month observation period. Hepatomegaly
persisted 1n the Aroclor 1254-exposed groups and the 375 ppm Aroclor
1242-exposed group. H1ld liver lesions persisted only In the 37.5 ppm
Aroclor 1254-exposed group.
In this study, Aroclor 1254 was clearly the most toxic substance and
Aroclor 1221, the least toxic substance tested. Since the lowest dose of
Aroclor 1254, 3.75 ppm, resulted only 1n reversible hepatomegaly without
h1stolog1cally demonstrated liver lesions, 3.75 ppm may be considered a
LOAEL 1n this study.
Other studies describing subchronlc exposure of rats and mice to PCBs
are detailed 1n Table 3-1.
M1nk are especially sensitive to the effects of PCBs (see Table 3-2).
Bleavlns et al. (1980) Investigated the toxldty of Aroclor 1242 and Aroclor
1016 to pastel mink. Aroclor 1242 was fed at dietary levels of 0, 5, 10, 20
or 40 ppm (mg/kg diet) and Aroclor 1016 was fed at levels of 0 or 20 ppm.
The duration of exposure was 8 months.
Each treatment group consisted of 12 females and 3 males; the control
group contained 24 females and 6 males. Aroclor 1242 at >20 ppm resulted 1n
mortality of all mink. At 10 ppm diet, Aroclor 1242 resulted 1n mortality
of 8/12 of the females and 2/3 of the males. Only one female fed the 5 ppm
Aroclor 1242 diet died. Among controls, 3/24 females died. No explanation
was given for death of control group mink. Aroclor 1016 resulted 1n death
of 3/12 females exposed to 20 ppm 1n the diet. Necropsy procedures con-
sisted of gross examination only and revealed emaciation characterized by
-19-
-------
almost complete absence of body fat and the presence of gastric ulcers.
Reproduction was not possible 1n mink exposed to >5 ppm Aroclor 1242, while
20 ppm Aroclor 1016 seriously Interfered with reproduction. Clearly,
Aroclor 1242 was more toxic to mink than Aroclor 1016 1n this study. The
finding of gastric ulceratlon and severe cachexla (emaciation) had not been
reported previously 1n experimental animals. It was not clear If the one
female that died 1n the 5 ppm Aroclor 1242 group exhibited the lesions
associated with PCB-lnduced mortality at higher dietary levels. Since more
sensitive criteria of toxldty were not evaluated, It Is not possible to
derive a NOEL or LOAEL from this study.
In an earlier study, AuleMch and Ringer (1977) exposed groups of seven
or eight female mink to 0 or 2 ppm Aroclor 1016, 1221, 1242 or 1254 1n the
diet for -10 months. No overt signs of toxldty Involving any of these
Aroclors occurred. Body weight gain, hemoglobin and hematocrlt remained
normal. Aroclor 1254 at 2 ppm 1n the diet Interfered with reproductive per-
formance. For nonreproductlve parameters, 2 ppm of the Aroclors tested
appeared to be a NOEL In this study.
Monkeys have also been found to be very sensitive to PCBs (see Table
3-3). Barsottl et al. (1976) and Allen et al. (1979a) fed diets containing
Aroclor 1248 for 7 months to rhesus monkeys. The control groups consisted
of 12 females and 6 males. Treatment groups were as follows: nine females
received 200 g/day of a diet containing 2.5 ppm (mg/kg diet) Aroclor 1248
(low-dose group); nine females received 200 g/day of a diet containing 5.0
ppm Aroclor 1248 (high-dose group); and four males received 300 g/day of a
diet containing 5.0 ppm Aroclor 1248.
Within 2 months, Aroclor 1248-treated females exhibited frank weight
loss, which continued through the 6 months of exposure. Females In both
-20-
-------
groups began to show alopecia, acne of the face and neck, and palpebral
edema and erythema. These lesions were present to some degree 1n all
females by the end of 6 months. Hlstologlcally, keratlnlzatlon of hair fol-
licles (biopsy specimens) was the prominent finding. Hemograms remained
normal, but an Increase In SGPT was observed. After 4 months of exposure,
menstrual cycle length and duration of menstrual bleeding were both
Increased, and other disruptions of the menstrual cycle occurred. Concep-
tion rate 1n the high-dose group females was depressed. Animals that con-
ceived In both groups experienced a high level of early fetal mortality
(resorptlons) and abortions. By 6 months, one of the low-dose group females
had died. Major gross findings Included generalized alopecia, acne and sub-
cutaneous edema. Epidermal hyperkeratlnlzatlon, hyperplasla of folUcular
epithelium and localized Inflammation were noted microscopically. Hepatic
focal necrosis, enlarged hepatocytes and Upld accumulation resembled the
lesions discussed 1n other species.
By 6 months, only one of the males (high-dose level) exhibited slight
perlorbltal edema and erythema. Male reproduction was not affected by
Aroclor 1248 at these dosage levels.
It 1s clear from this study that monkeys are more sensitive to PCBs then
rats and mice, and that no LOEL can be derived for monkeys from these data.
Truelove et al. (1982) dosed four cynomolgus monkeys with 0, 100, 100 or
400 pg Aroclor 1254 1n apple juice dally for 238-267 days. Since this
experiment was directed primarily toward studying effects of Aroclor 1254 on
reproduction, treatment began -100 days prepartum. Both of the 100 yg
Aroclor 1254-treated monkeys delivered full-term stillborn male Infants.
The 400 yg Aroclor 1254-treated monkey delivered an apparently normal
female Infant, which died of bronchlo-pneumonla at 139 days of age;
-21-
-------
this was presumed to be evidence of Impaired 1mmunolog1cal competence. The
400 v9 and one of the 100 pg Aroclor 1254-treated monkeys lost their
fingernails (Indicating severe hyperplastlc hyperkeratosls) after -235
days. No other overt signs of maternal toxldty were reported.
Barsottl (1981) exposed 24 adult female rhesus monkeys to diets con-
taining 1.0. 0.25 or 0.025 ppm (mg/kg/d1et) Aroclor 1016, presumably
throughout gestation and lactations. Infants born to the 1 ppm Aroclor 1016
groups were significantly smaller at birth. No other manifestations of
toxldty were reported. For this study, a dietary level of 0.25 ppm Aroclor
1016 appeared to be a NOEL. It 1s possible that Aroclor 1016 1s less toxic
to monkeys than the other Aroclors usually tested, as was demonstrated 1n
mink (Bleavlns et al., 1980).
3.1.2. Inhalation. Pertinent data regarding the effects of subchronlc
Inhalation of PCBs were not located 1n the available literature.
3.2. CHRONIC
3.2.1. Oral. Reports of chronic oral exposure of laboratory species to
PCBs are summarized In Tables 3-1 and 3-2. These studies Involved labora-
tory animals exposed to maximally tolerated doses 1n order to create and
Investigate the frank effects of PCBs on various target organs or tissues.
They do not define LOAELs or NOELs that would be useful 1n risk assessment;
therefore, this discussion will be a brief review of those studies that most
clearly elucidated the toxic effects of PCBs.
As was noted 1n the discussion of subchronlc studies, frank mortality In
rats occurred at dietary levels >500 ppm Aroclor 1254, Aroclor 1260
(Klmbrough et al., 1972) or Kanechlor-300, -400 or -500 (Ito et al., 1974).
Other signs reported 1n rats were reduced appetites, reduced rate of body
-22-
-------
weight gain and reduced final body weight. Dietary levels of 100 ppm of
several Aroclors (Klmbrough et a!., 1975; Allen and Abrahamson, 1979; Allen
et al., 1976) or -200-300 ppm Kanechlor-400 (Klmura and Baba, 1973) resulted
1n severe hepatomegaly 1n rats; often livers were 3- to 4-fold normal size.
Livers frequently exhibited multiple elevated tan or discolored liver
nodules {Klmura and Baba, 1973; Klmbrough et al., 1975), oval cell prolife-
ration, bile duct proliferation (cholanglof1bros1s) {Ito et al., 1974),
fatty Hver degeneration (Ito et al., 1974; Klmura and Baba, 1973) and focal
necrosis and degeneration (Allen et al., 1976). Hepatocellular carcinomas
were also found (Klmbrough et al., 1975) (Chapter 4). Concurrent with these
liver changes 1n rats were elevated serum I1p1ds and cholesterol levels
(Allen et al., 1976); Increased hepatic protein, RNA and llpld and decreased
DNA content; and Increased hepatic mlcrosomal total protein and cytochrome
P-450 content (Allen and Abrahamson, 1979). Many hepatic mlcrosomal enzyme
activities were markedly Induced and remained that way for the duration of
exposure (Allen and Abrahamson, 1979). Morgan et al, (1981) reported
"Intestinal" metaplasia and adenocardnoma In rats exposed to 25 ppm Aroclor
1254 for 2 years.
The only other laboratory species for which chronic PCB exposure data
are available 1s the monkey, which Is considerably more sensitive than the
rat to PCBs. As reported 1n Section 3.1., liver pathology 1n monkeys and
associated serum chemistries (Barsottl et al., 1976) resembled those 1n
other species. No reports of liver neoplasla In monkeys were located 1n the
available literature, but no studies were found where exposure to PCBs ex-
ceeded 1-1/2 years. Skin lesions were the most consistently reported toxic
manifestation of PCBs 1n monkeys. Dietary levels as low as 2.5 ppm Aroclor
-23-
-------
1248 produced erythema and peMorbltal edema, which progressed to alopecia,
acne, facial edema and hyperplgmentatlon (Barsottl and Allen, 1975).
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Several authors have Investigated the teratogenldty and
fetotoxldty associated with various mixtures of PCBs. Little evidence of
teratogenldty was found; most reports concerned fetotoxldty of PCBs. The
more relevant studies are summarized 1n Table 3-4.
Collectively, these studies reveal several aspects of the toxldty of
PCBs. First, manifestations of fetotoxldty 1n mice (Orberg and Klhlstrom,
1973), rats (Under et al., 1974) and monkeys (Barsottl, 1981) were observed
1n the absence of overt signs of maternal toxldty. The ability of PCBs or
their metabolites to cross the placenta and cause abortions or fetal
mortality has been demonstrated 1n rats (Baker et al., 1977; Spencer, 1982),
rabbits (VUleneuve et al., 1971) and mice (Orberg and Klhlstrom, 1973,
Marks et al., 1981). Reduced Utter size was observed In rats from dams
exposed to diets containing 100-500 ppm Aroclor 1254 from 3-4 weeks of age
to termination of a 1-2 generation study (Under et al., 1974).
Infants from monkeys exposed to >2.5 ppm Aroclor 1248 1n the diet from
-6 months before mating were born with hyperplgmentatlon, a mild sign of
PCB-1nduced toxldty 1n monkeys (Allen and Barsottl, 1976; Allen et al.,
1979b). Reduced birth weights were observed 1n Infants from monkeys exposed
to 1.0 ppm Aroclor 1016 1n the diet (Barsottl, 1981). Nursing resulted In
loss of facial hair, edema of the eyelids, gastric hyperplasla and vomiting,
liver degeneration and other general signs of PCB-lnduced toxldty, Indica-
ting the ability of monkeys to excrete substantial quantities of PCBs and
-24-
-------
TABLE 3-4
Sumary: Teratogenetic, Fetotoxic and Reproductive Effects of Orally Administered PCBs
Species/
Strain Source of PCBs
Dosage Level and
Duration of Treatment
Maternal Response
Progeny Response
Reference
Rabbit
Aroclor 1254
Rat/Wlstar Aroclor 1254
Rat/Sherman Aroclor 1254
Rat/
Holtzman
Nice/CD]
Aroclor 1260
Aroclor 1254
Aroclor 1254
3.3'.4.4',5.5'
HCB
0. 1.0. 10.0. 12.5. 25.0,
50 Mg/kg/day on days 1-2B
of pregnancy; 25 mg/kg/day
on days 7-2B of pregnancy
0. 6.25. 12.5. 25.0. 50.
100 mg/kg/day on days 6-15
of gestation
0. 1. 5. 20, 100. 500 mg/kg
diet fro* 3-4 weeks of age
to termination of 1- or 2-
generatlon study
0, 5. 20. 100, 500 mg/kg
diet fro* 3-4 weeks of age
to termination of 1- or 2-
generatlon study
0,10.50.100 mg/kg/day dosed
on days 7-15 of gestation
0.25.50,100,200.300.600.900
mg/kg diet/day on days 6-15
of pregnancy
0,0.1.1.0.2.0.4.0.8.12
mg/kg/day, on days 6-15
of gestation
dose >25 mg/kg: maternal
deathT weight loss >10.0
mg/kg: hepatomegaly 25
mg/kg days 7-2B: reduced
rate of gain.
none reported
none reported
none reported
none reported
>600 mg/kg: partial
anorexia and weight loss
>8 mg/kg/day: reduced
rate of gain, lethargy.
vaginal bleeding
dose >12.5 mg/kg/day: fetal death.
resorptlons, abortions
none reported
F]a 500 mg/kg: reduced litter size;
100 mg/kg: reduced Utter size;
Fit 10° *9/kg: reduced survival at
weaning; 20. 100 mg/kg: reduced
litter size;
F?a 100 mg/kg: reduced Utter size and
reduced survival at weaning;
20 mg/kg: reduced Utter size;
Fjb 20. 100 mg/kg: reduced Utter size.
Fjj 500 mg/kg: reduced Utter size
and reduced survival at weaning.
FII> 500 mg/kg: reduced Utter size.
100 mg/kg/day: reduced Utter size.
>30 mg/kg: fetal death at delivery
>100 mg/kg: reduced Utter weight
fetal mortality.resorp-
Increased Incidence of
>4 mg/kg/day:
lions;
>2 mg/kg/day:
cleft palate;
>4 mg/kg/day: Increased Incidence of
hydronephrosls;
>1 mg/kg/day: Increased Incidence of
cream colored liver;
>1 my/kg/day: Increased Incidence of
undersized renal papillae.
Vllleneuve et
al.. 1971
Llnder et al..
1974
Spencer,
1982
Harks et al.,
1981
-------
TABLE 3-4 (cent.)
Species/
Strain
Rat/Sprague-
Dawley
Rat/Ulstar
HIce/NNRl
MIce/NR
, Rabbit
cr
' Mink
Source of PCBs
Aroclor 1221
1242 or 1260
Aroclor 1254
Clophen A60
2.2»,4.4»,
5.51 hexa-
chloroblphenyl
Aroclor 1221.
Aroclor 1254
Aroclor 1242
Dosage Level and
Duration of Treatment
0 or 30 mg/kg bw, days 14-
20 of pregnancy
0 or 70 mg/t drinking water
(6.4 Mg/kg bw); 9 wks
0 or 0.025 mg/day; 72-76 days
0 or 0.5 mg/day; 7 or 13
days of pregnancy
0,1.0 or 10 mg/kg bw;
first 28 days of pregnancy
0-40 Mg/kg diet; B months
Maternal Response Progeny Response
none none
mortality at 7 wks fetal resorptton
lengthened estrus cycle fetal resorptlon
hepatomegaly none
none none
>10 mg/kg: significantly NA
Increasing mortality
>5 mg/kg: complete re- NA
Reference
Gellert and
Wilson. 1979
Baker et al..
1977
Or berg and
Klhlstrom. 1973
Nattsson
et al.. 1981
Vllleneuve
et al.. 1971
Bleavlns
et al.. 1980
Aroclor 1016 20 mg/kg diet
Nonkey/ Aroclor 1254 0.100 or 400 mg/kg bw/day;
cynomolgus continuous starting at 60
days of pregnancy
Nonkey/ Aroclor 124B 0.2.5 or 5.0 mg/kg diet;
rhesus 18 months starting 6 months
pregestatlonal
Aroclor 1248 0.2.5 or 5.0 mg/kg diet;
off treatment for 1 year
Nonkey/ Aroclor 1016 0.0.025. 0.25 or 1.0 mg/
rhesus kg diet for unspecified
length of time
productive failure
25JC mortality, reduced
fertility
fingernail loss; Immuno-
loglc Incompetence
facial edema, cachexla,
hair loss, hyperplg-
mentatton
persistent hyperplgmen-
tatlon
none
Increased mortality, decreased
body weight by 4 weeks
fetal mortality; Immunologic
Incompetence
fetal death. Infant facial and eye-
lid edema, loss of facial hair.
facial hyperplgmentatlon. gastric
hyperplasla and vomiting, lymphotd
degeneration, hypocellular bone
marrow, fatty liver
fetal death; reduced neonatal weight
hyperplgmentatlon
1.0 mg/kg diet: Infants had reduced
birth weight
Truelove
et al., 1982
Allen and
BarsotM. 1976;
Allen et al..
1979b;
Allen et al..
1980
Barsottl. 1981
NA . Not applicable
-------
their toxic metabolites by .lactation (Allen and Barsottl, 1976; Allen et
a!., 1979b, 1980). This phenomenon had been suggested earlier by Under et
al. (1974), who noticed decreased survival at weaning 1n rats from dams
exposed continuously to dietary concentrations >100 ppm Aroclor 1254.
Only one report associating teratogenldty with oral exposure to PCBs
has been found. Marks et al. (1981) treated 13-63 pregnant CD, mice/group
with 0, 0.1, 1.0, 2.0, 4.0, 8 or 12 mg 3,3',4,4',5.5'-hexa CB/kg bw/day by
gavage for days 6-15 of gestation. Although no deaths occurred 1n exposed
dams, lethargy and vaginal bleeding were observed 1n dams exposed to >8
mg/kg/day. At dosages >4 mg/kg/day, the average number of live fetuses/dam
was reduced. A reduction 1n the number of Implants and an Increase 1n fetal
resorptlons were observed 1n mice treated with >8 mg/kg/day. Possibly
because of the greater care used In examining fetuses 1n this study, terata
were found. Significant (p<0.001) Incidences of cleft palate occurred 1n
groups dosed at >2 mg/kg/day. The occurrence of cleft palate was 2/247,
4/83, 5/63, 20/117, 69/154, 118/176 and 82/108 1n fetuses from dams, respec-
tively, 1n the groups described above. Hydronephrosls also followed a
significantly (p<0.001) dose-related trend In fetuses from dams exposed to
>4 mg/kg/day. Cream-colored liver nodes were significantly (p<0.001) assoc-
iated with dosage levels >1 mg/kg/day. The authors mentioned briefly that
they had also found 3,3',4,4'-tetra CB to be teratogenlc, but that
3,3',4,4',5,5'-hexa CB was the more potent teratogen.
In these studies, as 1n the toxldty studies reviewed In Chapter 3,
monkeys appeared to be the species most sensitive to fetotoxlc effects of
PCBs. Barsottl (1981) reported reduced birth weights 1n Infants from
monkeys treated with 1.0 ppm Aroclor 1016 1n the diet. The observation of
fetotoxlc effects at levels lower than those reported to cause toxldty 1n
-27-
-------
animals after birth reduces considerably the confidence placed In risk
figures derived solely from subchronlc and chronic toxldty studies (Section
6.1.1.). The fact that Aroclor 1016 Is probably the least toxic of the PCB
products 1n the environment further erodes confidence 1n risk figures
derived from studies using Aroclor 1016.
3.3.2. Inhalation. Pertinent data regarding the fetotox1c1ty or terato-
genldty associated with Inhalation exposure to PCBs could be located In the
available literature.
3.4. TOXICANT INTERACTIONS
Many of the Interactive effects between PCBs and other xenoblotlcs can
be predicted from an understanding of the mlcrosomal enzyme-Inducing capa-
bilities of PCBs. For example, PCB pretreatment of rats resulted In
Increased rate of metabolism and excretion of pentobarbltal, and 1n reduced
pentobarb1tal-1nduced sleeping times (Chu et al., 1977; VUleneuve et a!.,
1972). Hepatotox1c1ty Induced by vinylldene fluoride (Conolly et al., 1979)
and halothane anesthesia (S1pes et al., 1978) was Increased 1n rats by pre-
treatment with PCBs. Cadmium, however, appeared to have an antagonistic
effect on the biochemical changes that result from PCB-1nduced hepatic
enzymes (Suzuki, 1980; Horlo et al., 1981). The exact nature of this
protective effect has not been elucidated, but the effect appears to be
additive (Suzuki, 1980).
3.5. HUMAN EFFECTS
Several reports of human effects resulting from occupational or acci-
dental exposure are available. Melgs et al. (1954) reported seven cases of
chloracne among 14 workers Intermittently exposed to Aroclor vapors. The
mean length of exposure was 14.3 months for affected and 11.4 months for
-28-
-------
unaffected workers, but no significant correlation between duration of expo-
sure and effects occurred. Apparently, a one-time measurement revealing an
Aroclor concentration of 0.1 mg/m3 was made 19 months after exposure began.
F1schbe1n et al. (1979) reported a cross sectional clinical field survey
of 326 workers 1n two capacitor-manufacturing plants who were exposed to
Aroclors 1254, 1242, 1016 and 1221. A1r levels (8-hour TWA) of PCBs In
these plants were 0-11.0 mg/m3. Dermatologlc symptoms reported 1n 76/168
(45%) male and 87/168 (55%) female workers were rash, pruritus, acne, hyper-
pigmentation, and thickening and discoloration of the fingernails. Respira-
tory complaints were made by 3.4-13.8% of these workers, and 48.2% com-
plained of eye Irritation (Warshaw et al., 1979). Gastrointestinal symptoms
(18%) and neurological symptoms (39% of males and 56% of females) were also
reported (F1schbe1n et al., 1979). The authors performed extensive bio-
chemical and hematologlcal studies on these workers and concluded that there
was no correlation between any symptoms and duration of employment but that
a positive association between plasma PC8 level and serum SCOT level (Indi-
cating extent of liver damage) existed.
Ouw et al. (1976) compared dermatologlc and hepatic function parameters
of 34 electrical Industry workers exposed to electrical grade ("no" Impuri-
ties) Aroclor 1242 with those of 30 control volunteers. Control volunteers
had no history of occupational exposure to PCBs, and PCBs were not detected
1n their blood. Exposed workers had hepatic function tests that yielded
scattered abnormal values: one worker had chloracne and five had eczematous
rashes on hands and legs. These effects were associated with air levels of
<1 mg Aroclor 1242/m3.
Accidental 1ngest1on of PCBs occurred 1n >1000 persons 1n Japan 1n 1968
as a result of contamination of rice oil with Kanechlor-400, a PCB product
-29-
-------
used as a heat transfer agent. The average total PCB consumption by
affected Individuals was estimated to be -2 g, with 0.5 g being the smallest
total amount consumed by a group of 325 people (Kuratsune et al., 1972).
The contaminated rice oil also contained ~5 ppm PCDFs, presumably formed
from continual reheating of PCBs. PCDFs are thought to be several times
more toxic than PCBs. The dermal and respiratory symptoms reported 1n this
case of "Yusho" poisoning were similar to those reported 1n occupatlonally
exposed workers but were considerably more severe. Additionally, palmar
sweating and muscular weakness were common complaints (Kuratsune et al.,
1969). Yamashlta (1977) reported premature delivery, reduced birth weight
and height, hyperplgmentatlon of skin and mucous membranes, precocious
dental eruption and decreased calcification of the cranium 1n Infants of
Yusho women. In addition to these findings, Kuratsune et al. (1969) also
reported delivery of 3 stillborn and 10 live Infants from 11 Yusho women.
By 1979, 31 Yusho patients had died, 11 (35.4%) of these from malignant
neoplasms (Urabe et al., 1979). These 11 malignancies Included 2 stomach
cancers, 1 stomach and liver cancer (possibility of metastasis not dis-
cussed), 2 liver cancers 1n clrrhotlc livers, 2 lung cancers, 1 lung tumor,
1 breast tumor and 2 malignant lymphomas.
In 1979, -2000 persons 1n central western Taiwan developed symptoms
practically Identical to those observed 1n Yusho patients (Chen et al.,
1981). These persons had also consumed rice oil contaminated by PCBs used
as a heat transfer agent In the manufacturing process. Samples of contami-
nated rice oil were obtained and were found to contain 53-405 ppm PCB; no
estimates of total PCB Intake or duration of exposure were reported.
-30-
-------
4. CARCINOGENICITY
4.1. HUMAN DATA
There are few data regarding the cardnogenlclty of PCBs 1n humans.
Urabe et al. (1979) reported that 11/33 deaths (35.454) among Yusho patients
who had died by 1979 resulted from malignancies. These mallg- nancies
Involved various body sites, and expected Incidences based on unexposed
populations were not available; therefore, the significance of these data 1s
uncertain. Bahn et al. (1976, 1977) reported 2 cases of malignant melanoma
among 31 workers "heavily exposed" and 1 case of malignant melanoma among 41
workers "less heavily exposed" to Aroclor 1254. IARC (1978) estimated that
only 0.04 cases would be expected 1n an unexposed population of this size
and concluded that this was suggestive evidence that PCBs are human
carcinogens. Davldorf and Knupp (1979) examined the Incidence of ocular
melanoma In several counties of Ohio during 1967-1977, attempting to
associate higher Incidences with areas known to have higher concentrations
of PCBs because of Industrial contamination. No significant associations
were found.
4.2. BIOASSAYS
Protocol and results of the major cardnogenlclty bloassays are sum-
marized In Table 4-1. Early cardnogenlclty bloassays Involving dietary
administration of PCBs to rats and mice either Involved too few animals or
had too short a duration to generate statistically or biologically
significant data. Klmura and Baba (1973) fed diets containing levels of
Kanechlor-400 that varied from 38.5-616 ppm to 10 male and 10 female Oonryu
rats for 22-80 weeks. The study was Inconclusive because of early mortality
from a number of unrelated causes. Hyperplastlc liver nodules, which the
authors suggested were precancerous lesions, occurred In all female rats
-31-
-------
TABLE 4-1
Smmary of Carcinogenic Effects of Orally Administered PGBs
Hepatopalhology: No. Affected/No. Necropsled
Species/ PCB
Strain Sex Source
Rats/ H control
Donryu
F control
H Kanechlor-400
Ł, f Kanechlor-400
1 Nice/ N control
dd
Kanechlor-SOO
Kanechlor-SOO
Kanechlor-SOO
Kanechlor-400
Kanechlor-400
Kanechlor-400
Kanechlor-300
Kanechlor-300
Kanechlor-300
Dietary Level
(ppm)
0
0
38.5
38.5
0
500
250
100
500
250
100
500
250
100
Number
Treated
5
5
10
10
6
12
12
12
12
12
12
12
12
12
Exposure
•days)
NA
NA
159-530
244-560
224
224
224
224
224
224
224
224
224
224
Neoplasttc
Nodules
0/10
0/10
0/10
6/10
0/6
0/12
0/12
0/12
0/12
0/12
0/12
0/12
0/12
0/12
Adenof Ibrosts
0/10
0/10
0/10
0/10
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
Hepatoma
NR
NR
NR
NR
NR
NR
NR
HR
NR
NR
NR
NR
NR
NR
Hepatocellular Reference
Carcinoma
0/10 Klmura and
Baba. 1973
0/10
0/10
0/10
0/6 Ito et al.,
1973
5/12
0/12
0/12
0/12
0/12
0/12
0/12
0/12
0/12
-------
TABLE 4-1 (cent.)
co
i
Hepatopathology: No. Affected/No. Necropsled
Species/
Strain
Rats/
Ulstar
Nice/
CJ
Balb
Rats/
Sherman
PCB
Sex Source
N control
Kanechlor-SOO
Kanechlor-SOO
Kanechlor-SOO
Kanechlor-400
Kanechlor-400
Kanechlor-400
Kanechlor-300
Kanechlor-300
Kanechlor-300
N control
Aroclor 1254
Aroclor 1254
F control
Aroclor 1260
Dietary Level Number
(ppn) Treated
0
1000
SOO
100
1000
SOO
100
1000
SOO
100
0
300
300
0
100
IB
290
rats
total
In
1 con-
trol. 9
treatment
groups
100
SO
50
200
200
Exposure
(days)
378
378
378
378
378
0/8
378
378
378
378
330
330
180
630
630
Neoplastlc
Nodules
0/18
5/13
5/16
3/25
3/10
0/8
2/16
0/15
0/19
1/22
NR
NR
NR
0/173
144/184
Adenof Ibrosis
0/18
4/13
0/16
0/25
2/10
NR
0/16
2/15
0/19
0/22
0/58
22/22
0/24
NR
NR
Hepatoma Hepatocellular Reference
Carcinoma
NR
NR
NR
NR
NR
0/8
NR
NR
NR
NR
0/58
9/22
1/24
NR
NR
0/18 Ho et a!.,
1974
0/13
0/16
0/25
0/10
0/16
0/15
0/19
0/22
NR Klmbrough
and Under.
NR 1974
NR
1/173 Klmbrough
et al.. 1975
26/184
-------
TABLE 4-1 (cont.)
i
09
Hepatopathology: No. Affected/No. Necropsled
Species/
Strain
Rats/
Fischer
344
Sex
M
M
N
M
F
F
F
F
PCB
Source
control
Aroclor 12S4
Aroclor 1254
Aroclor 1254
control
Aroclor 1254
Aroclor 1254
Aroclor 1254
Dietary Level Number
(ppn) Treated
0
25
50
100
0
25
50
100
74
24
24
24
24
24
24
24
Exposure
(days)
735
735
735
735
735
728-735
728-735
735
Neoplastlc
Nodules
MR
NR
NR
NR
NR
NR
NR
NR
Adenof Ibrosls
0/24
0/24
0/24
1/24
0/23
0/24
1/22
2/24
Hepatoma
NR
NR
NR
NR
NR
NR
NR
NR
Hepatocellular Reference
Carcinoma
0/24 NCI. 1978
0/24
1/24
2/24
0/23
0/24
0/22
0/24
NA-Not applicable; NR-not reported
-------
that survived long enough to consume >1200 mg Kanechlor-400. Hyperplastlc
nodules were not found 1n male rats.
Ito et al. (1973) produced hepatocellular carcinomas 1n 5/12 male dd
mice exposed to 500 ppm Kanechlor-500 for 32 weeks. Lower dietary levels
(250, 100 ppm) of Kanechlor-500 and all three levels of Kanechlor-400 and
Kanechlor-300 failed to cause hepatocellular carcinoma. These authors sur-
mised that degree of chlorlnatlon was Important 1n determining the carclno-
genlcHy of PCB products. A subsequent study by Ito et al. (1974) produced
considerable mortality but no cancer In Wlstar rats exposed to 100, 500 or
1000 ppm Kanechlor-300, -400 or -500 1n the diet for 378 days.
Exposure of 200 female Sherman rats to 100 ppm Aroclor 1260 (similar to
the PCBs contained 1n Kanechlor-500) 1n the diet for 630 days resulted 1n
144 livers containing neoplastlc nodules from the 184 rats that survived to
termination. Hepatocellular carcinomas were found In 26 of the 184 treated
survivors. No neoplastlc .nodules and only one hepatocellular carcinoma were
found In the 173 control group survivors (Klmbrough et al., 1975).
The NCI (1978) exposed groups of 24 male and 24 female Fischer 344 rats
to dietary levels of 0, 25, 50 or 100 ppm Aroclor 1254 for 728-735 days. No
Hver tumors were found 1n any female rats. Among the male groups, 1/24 and
2/24 rats 1n the 50 ppm and 100 ppm groups, respectively, developed
hepatocellular carcinomas. The Incidence did not seem to follow a
dose-related pattern and was not significant by either the Cochran-ArmHage
or Fisher exact tests. The NCI (1978) concluded that Aroclor 1254 was not
carcinogenic under the conditions of this bloassay.
-35-
-------
4.3. MUTAGENICITY
Schoeny et al. (1979) Investigated the mutagenlclty of Aroclor 1254 to
Salmonella typhlmurlum In the Ames assay. Negative results were obtained 1n
S. typhlmurlum strains TA1535, TA1539, TA98 and TA100 without hepatic S-9
activation, and with S-9 activation from rats pretreated with Aroclor 1254
as a hepatic enzyme Inducer. Schoeny (1982) also obtained negative results
1n these same four strains with one monolsomer, two separate tetralsomers
and one hexalsomer of PCBs. Activation with hepatic S-9 fractions with and
without several kinds of Induction failed to elicit positive results. The
only report of positive response In the Ames assay Involved 4-chlorob1phenyl
and, to a lesser extent, Aroclor 1221, tested 1n S. typhlmurlum strain
TA1538 (Wyndham et al.. 1976). These authors used rabbit liver mlcrosomal
preparation as the metabolic activator; no reason for this choice was
mentioned.
PCB products failed to produce positive results In the dominant lethal
assay 1n rats (Green et al., 1975a) or chromosomal changes 1n D. melano-
gaster (Nllsson and Ramel, 1974) or 1n sperm and bone marrow cells of rats
(Green et al., 1975b; Garthoff et al., 1977).
4.4. WEIGHT OF EVIDENCE
IARC (1978) has developed and used a method of qualitative risk assess-
ment of potential carcinogens, based upon sufficiency of evidence from human
studies and animal bloassays. The degrees of evidence for carc1nogen1c1ty
1n human studies were categorized as sufficient evidence, limited evidence
or Inadequate evidence. Based upon the studies of PCB-lnduced cancers 1n
humans, the evidence for a carcinogenic role of PCBs 1n humans was judged
Inadequate. As discussed In Section 4.2., Kanechlor-500 has been shown to
be carcinogenic 1n mice (Ito et al., 1973) and Aroclor 1260 has been shown
-36-
-------
to be carcinogenic to rats (Klmbrough et al., 1975). There was judged to be
sufficient evidence to conclude that PCBs are carcinogenic 1n laboratory
rodents. Applying the criteria for evaluating the overall weight of evi-
dence for cardnogenlcHy to humans proposed by the Carcinogen Assessment
Group of the U.S. EPA (Federal Register, 1984), PCBs are most appropriately
classlfed as Group B2 - Probable Human Carcinogens.
-37-
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5. REGULATORY STANDARDS AND CRITERIA
Under Section 6{e) of the Toxic Substances Control Act (TSCA) (P.I.
94-469), the manufacture, sale and distribution of PCS products have been
restricted. PCB products were further restricted to sealed systems as of
1977, and manufacture and distribution were banned In 1979.
The U.S. EPA (1980b) has set ambient water quality criteria for PCBs for
the protection of humans from Increased lifetime risk of cancer of 10~5,
10~6 and 10~7 at 0.79, 0.079 and 0.0079 mg/i. Because these compounds
have a large BCF, these criteria apply regardless of whether exposure occurs
through consumption of 2 I of water and 6.5 g of fish/day or through con-
sumption of fish alone. The FDA has set temporary tolerances for PCBs In
food and related products as reported 1n Table 5-1 (Code of Federal Regula-
tions, 1981.)
Occupational exposure limits recommended by the ACGIH (1980) for Aroclor
1254 are a TLV of 0.5 and a STEL of 1.0 mg/m3. For Aroclor 1242, the
recommended TLV Is 1 and the STEL Is 2 mg/m3. The NIOSH (1977) criterion
1s 1.0 vg/m3 for an exposure of 10 hours/day, 40 hours/week.
-38-
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TABLE 5-1
FDA Regulations for PCBs*
Commodity Temporary Tolerances
(ppm)
M1lk (fat basis) 1.5
Manufactured dairy products (fat basis) 1.5
Poultry (fat basis) 3.0
Eggs 0.3
Finished animal feeds 0.2
Animal feed components of animal origin 2.0
Edible portion of fish and shellfish 5.0
Infant and junior foods 0.2
Paper food packaging material 0.0
*Source: Code of Federal Regulations, 1981
-39-
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
PCBs have been shown to be carcinogenic 1n laboratory animals and data
are sufficient for estimation of carcinogenic potency. It Is Inappropriate,
therefore, to derive an AIS for PCBs.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
PCBs have been shown to be carcinogenic 1n laboratory animals and data
are sufficient for estimation of carcinogenic potency. It 1s Inappropriate,
therefore, to derive an AIC for PCBs.
6.3. CARCINOGENIC POTENCY (q *)
6.3.1. Oral. Data from female rats 1n the study by Klmbrough et al.
(1975) were chosen by the U.S. EPA Carcinogen Assessment Group to quantify
the carcinogenic risk from exposure to PCBs (U.S. EPA, 1980b). The TWA
dietary level was determined to be 88.4 ppm, equivalent to 4.42 mg/kg
bw/day, assuming an adult rat eats food equal to 5% of Us body weight/day
and weighs 0.4 kg. For statistical analysis, the Incidences of hepato-
cellular carcinoma (26/184 1n treated rats and 1/173 In controls) and
neoplastlc nodules (144/184 1n treated rats and 0/173 1n controls) were
combined to produce total tumor Incidences of 170/184 1n treated rats and
1/173 1n controls, respectively. Using these data, the data 1n Table 6-1
and the linearized multistage model developed by Crump and adopted by the
U.S. EPA (1980a), a q^ for human exposure to PCBs of 4.3396
(mg/kg/day)"1 was calculated.
6.3.2. Inhalation. No studies of carclnogenlcHy of PCBs related to
Inhalation exposure have been located 1n the available literature, and no
carcinogenic risk data for this route can be calculated.
-40-
-------
TABLE 6-1
Data Used as the Basis for the q-j*
Criteria
Details
Species
Strain
Sex
Body weight (assumed)
Length of exposure
Length of experiment
Tumor site
Tumor type
PCB product tested
Dose
(mg/kg/day)
0
4.42
rat
Sherman
female
0.4 kg
645 days
730 days
liver
combined hepatocellular carcinomas
and neoplastlc nodules
Aroclor 1260
Incidence
(no. responding/no, tested)
1/173
170/184
-41-
-------
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*
*
*» • Z1nkl, J.G. 1977. Skin and Hver lesions 1n rats fed a polychlorlnated
blphenyl mixture. Arch. Environ. Contam. Toxlcol. 5(2): 217-228. (Cited
1n U.S. EPA, 1985)
-54. U.S. Envirorrr ••:' • r, •'. ,;t;on Agency
Region V, Li,.,
230 Soulii E.\- . ' : , ;'32t
Chicago, Illinois
*
V •
-------
APPENDIX
Summary Table for PCBs
en
i
Carcinogenic
Potency
Inhalation
Oral
Species
NA
rat
Experimental
Dose/Exposure
NA
4.42 mg/kg/day
Effect
NA
hepatic
tumors
Unit Risk or
qi*
NO
4.34
(mg/kg/day)-1
Reference
NA
Klmbrough et al., 1975;
U.S. EPA, 1980b
NA = Not applicable; ND = not derivable
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