-------
presented at the National Conference on Polychlorinated Biphenyls
(1976), and a more detailed analysis was presented by the U.S. EPA
t
(1976a). One thousand Charles River rats were divided into ten
treatment groups. Fifty male and 50 female rats served as a common
control group. Each of nine treated groups contained 50 animals of
each sex. Groups were fed 1, 10 and 100 ppm of Aroclors 1242, 1254,
and 1260, respectively,, Treatment was initiated with 4- to 6-week-
old animals and continued for a total of 24 months. Five animals of
each sex were sacrificed at 3, 6, and 12 months, leaving 35 animals
in each group at the beginning of the second year. In addition,
mortality was high, leaving only 6 to 21 animals remaining in each
treatment/sex subgroup by the end of the experiment. As seen in
the previously described studies, the principal effects were ob-
served in the liver. Vacuolar changes and hyperplasia were the
major abnormalities originally noted in the treated animals. In
addition, chromophobe adenomas of the pituitary were found in eight
of nine treated groups but not in the controls. In 1975 the origi-
nal liver slides were re-evaluated with rather different results.
The combined results for animals treated with 100 ppm of all three
Aroclors included 11 hepatomas, 5 cholangiohepatomas> and 28 nodu-
lar hyperplasias. Hepatocellular carcinomas were not observed.
Recently, a bioassay for the possible carcinogenesis of Aro-
clor 1254 has been conducted by the Nationcil Cancer Institute
(1978) . in -this study, 24 Fischer 344 rats of each sex were orally
ji
administered Aroclor 1254 at 25, 50, or 100 ppm for 104 to 105
weeks. Matched controls consisted of 24 untreated rats of each
sex. Mortality among the treated males was s
C-69
ignificantly higher
-------
than among the controls and related to dose (P 0.001) but was not
different among the females (P 0.05). Interstitial-cell tumors of
the testes in males and leukemias of either granulocytic or lympho-
cytic type were observed frequently in both control and treated
animals. Tumors were observed in several other tissues but their
presence did not correlate with treatment. Proliferative lesions
of the liver were common in treated animals but were not found in
controls. The types and frequencies of lesions are detailed in
Table 11. They included nodular hyperplasia in all treated groups
increasing in frequency with dose, adenomas (one male, three fe-
males) and hepatocellular carcinoma (three males, no females). In
addition, adenocarcinomas of the stomach,, jejunum or cecum of two
treated males and two treated females but no controls were ob-
served. Statistical analysis of the frequencies of tumors and pro-
liferative lesions indicated that the combined incidences of leuke-
mia and lymphoma in treated males were significant by one test
(Cochran-Armitage test for positive dose-related trend) but not by
a more stringent test (Fisher exact test). The tumors of the liver
and gastrointestinal tract were not statistically significant; how-
ever, the occurrence of nodular hyperplasia appeared to be related
to treatment. The study concluded that Aroclor 1254 was not carci-
nogenic in Fischer 344 rats. However, the high frequency of hepa-
tocellular proliferative lesions was considered to be a result of
treatment, and the carcinomas of the gastrointestinal tract also
were considered possibly associated with the treatment.
The tumors observed in rodent experiments with PCBs were pre-
dominantly adenofibrosis (cholangiofibrosis), neoplastic nodules,
C-70
-------
and hepatocellular carcinomas. Stewart and Snell (1957) concluded
that adenofibrosis cannot be considered to be a pre-malignant le-
sion, while Reuber (1968) proposed that cholangiofibrosis might be
a precursor to cholangiocarcinoma. Neoplastic nodules have been
observed before the appearance of carcinomas in several studies
with known carcinogens (Kimbrough, et al. 1975). Well-differenti-
ated mouse hepatomas have been shown to be potentially malignant,
with a proportion being transplantable and capable of metastasis
(Andcrvant and Dunn, 1952). :
Several conclusions can be drawn from the results of the ro-
dent studies. A correlation between degree of chlorination and
tumor inducing potential was observed in mice
(Ito, et al. 1973)
and rats (Ito, et al. 1974) with the most highly chlorinated prepa-
rations being most potent. However, Aroclor 1254 was more potent
than Aroclor 1260 in rats. Where examined, female rats were found
to be more sensitive than males (Kimura and Baba, 1973; Kimbrough,
et al. 1972). No comparisons of sex-related effects were made in
mice. ;
'i
It should be noted that none of these studies was a lifetime
study. In all cases, animals were treated for fixed times then
killed and examined. No lifetime studies with PCBs were found in
this survey. Such studies, if available, might indicate more
clearly the significance of the potentially preneoplastic lesions
induced by PCBs in the studies described here. '
Data on the possible carcinogenicity of PCBs in humans are
sketchy at this time. The largest group of exposed individuals
followed longitudinally are the "Yusho" patients. By late 1973,
C-7.1
-------
two of 1,291 patients had died, nine of them with malignant neo-
plasms (two stomach cancer, one stomach and liver cancer, one liver
cancer with cirrhosis, one lung cancer, one lung tumor, one breast
cancer, and one malignant lymphoma) (Urabe, 1974; Kuratsune, et al.
1976). The authors did not have sufficient information to make a
detailed epidemiplogical analysis but concluded that 9/22 deaths
from cancer may represent an excess of deaths.
Two cases of malignant melanoma were reported in a group of 31
industrial workers exposed "heavily" to Aroclor 1254 in the process
of its manufacture. Based on a person-year analysis and the use of
the Third National Cancer Survey incidence rates (NCI, 1978), 0.04
malignant melanomas would have been expected making these data sig-
nificant at the O.OOJ. level. In addition, one of 41 workers ex-
posed to lower levels of Aroclor 1254 developed a malignant mela-
noma (Bahn, et al. 1976).
Although these studies involve small numbers of individuals
and provide little information about exposure or other relevant
factors, they do suggest that human exposure to PCBs may be associ-
ated with increased risk of neoplasia.
In addition to the carcinogenic effects observed with PCBs,
they have been shown to have a significant effect on the carcino-
genic properties of other substances found in the environment. The
co-carcinogenic properties of the PCBs result from their ability to
induce the'mixed function oxidases, particularly in liver, as dis-
cussed in the Acute, Subacute, and Chronic Toxicity section. Ito,
et al. (1973) observed that dietary levels of 250 ppm Kanechlor
500 markedly promoted hepatocellular carcinoma and nodular hyper-
C-72
-------
plasia in mice exposed to benzene hexachloride at levels o€ 100 or
250 ppm in the diet. Kanechlor 400 at 10 or;100 ppm in the diet
failed to promote cervical carcinoma or progression toward it in
mice exposed to 20-methylcholanthrene saturated thread imclanted
in the cervix and uterus (Uchiyama/ et al. 1974) . Ito, et al.
(1978) observed a pronounced increase in the incidence of preneo-
plastic, hyperplastic nodules in N-2-fluorenylacetamide treated
rats. The animals were fed 1,000 ppm PCB (type not specified) for
e .t weeks following two weeks exposure to the carcinogen. This
increase in preneoplastic lesions over a short period was taken to
be a significant indicator of carcinogenic activity. The ability
of Aroclor 1254 to initiate (as opoosed to promote) tumors in the
two-stage mouse skin system was recently examined by DiGiovanni, et
al. (1977). Aroclor 1254 proved to be a weak initiator of papillo-
mas when a 100 ug treatment of skin was followed by 32 weeks o.f
treatment with the promoter 12-0-tetradecanoyl»phorbol-13' acetate.
When used in combination with the potent initiator dimethylbenzan-
thracene Aroclor 1254 slightly increased the incidence of paoillo-
mas. Aroclor 1254 also failed to promote skin tumors initiated bv
dimethylbenzanthracene in the same system (100 ug Aroclor 1254
applied twice weekly for 30 weeks) (Berry, et al. 1978) .
Kanechlor 500 promoted heoatocellular carcinoma initiated by
diethylnitrosamine (DENA) in male Wistar rats (Nishizumi, 1976).
Promotion was observed when PCB treatment was begun one week fol-
lowing the end of DENA treatment. The number of tumors was signif-
icantly higher in rats treated with DENA and PCB than DENA alone or
DENA and phenobarbital, although a promoting effect was observed
with the latter drug as well. . J
,1
C-73 ;
-------
Hepatocarcinogenesis initiated by 3'-methyl-4-dimethylamino-
azobenzene (3'-Me-DAB) in female Donryu strain rats was promoted by
oral administration of PCBs following initiation. Tumor incidences
in animals treated with 3'-Me-DAB + PCS, 3'-Me-DAB alone, or PCB
alone were 64 percent, 13 percent, and 0 percent, respectively.
PCB treatment preceding or simultaneous with 3'-Me-DAB treatment
did not produce tumors (Kimura, et al. 1976).
By contrast to the hepatic co-carcinogenic effects of PCBs
observed by Kimura, et al. (1976), Nishizumi (1976), and Ito, et
al. (1973, 1978), other investigators have observed an inhibition
of tumor formation or growth in the presence of PCBs. Makiura, et
al. (1974) fed male Sprague-Dawley rats 3'-Me-DAB, 2FAA, DEN, or
pair-wise combinations of them for 20 weeks followed by four weeks
on a stock diet. Incidence of hepatocellular carcinoma ranged from
65.2 to 92.3 percent, and nodular hyperplasia reached 100 percent
in animals fed pairs of carcinogens. The addition of 50 ppm Kane-
chlor 500 to the diet resulted in a large decrease in the tumor
incidence and liver weight as compared to carcinogen treatment
without PCBs. PCBs alone induced no tumors or hyperplastic nodules
but did result in an increased liver weight. The principal differ-
ence between this study and those of Ito, et al. (1978), Nishizumi
(1976), and Kimura, et al. (1976) using the same chemicals is that
PCB exposure was delayed until after the initiating treatment in
the latter "studies. This suggests that the induction of mixed
function oxidases by PCB at the time of carcinogen treatment re-
sults primarily in the inactivation of the chemicals and that the
promoting effects observed with sequential exposure result from
C-74
-------
some other mechanism. The co-carcinogenesis of PCBs with simulta-
neous exposure to BHC may reflect a difference iir the liver metabo-
I
lism of this compound. j
In rainbow trout, Salmo gairdnerii, 100 ppm Aroclor 1254 added
to the diet reduced the size and frequencies of liver tumors in-
duced by 6 ppm aflatoxin B^ after a one year exposure (Hendricks,
et al. 1977). '
In addition to the inhibition of tumor induction by some chem-
icals, PCBs were also1shown to inhibit the growth of experimental
tumors in rats. Sprague-Dawley rats were inoculated with Walker
256 Carcinosarcoma cells and the effects of PCBs determined. Both
dietary (Kerkvliet arid Kimeldorf, 1977a) and injected (Kerkvliet
and Kimeldorf, 1977b) Aroclor 1254 reduced the size of solid tumors
and increased animal life span. Total dietary PCB intake of 1,100
to 2,000 mg/kg over a 40-day period reduced tumor weight to 60 to 40
percent of control in both male and female rats. Aroclor 1254 in-
jected intraperitoneally reduced the efficiency of tumor takes when
10 tumor cells were injected from 81.3 in control to 50.0 percent
in animals receiving 200 mg/kg/day. Mean tumor sizes were reduced
and lifespans increased by PCBs in animals;; inoculated with 10
tumor cells. Administration of PCBs for five days preceding tumor
inoculation or the first five days after inoculation was more ef-
fective than administration between days 5 and 10.
C-75
-------
CRITERION FORMULATION
Existing Guidelines and Standards
The Toxic Substances Control Act (TSCA) (P.L. 94-469) was
signed into law October 11, 1976. Provisions in section 6(e) of
the law specifically regulate the manufacture, sale, distribution,
and disposal of PCBs, Manufacture, sale, or distribution of PCBs
was restricted to sealed systems as of October 11, 1977. Manufac-
ture was banned as of -January 1, 1979 and all processing and dis-
tribution in commerce ceased July 1, 1979. Allowance for certain
exemptions is provided in the law. The proposed rules to implement
the terms of section 6(e) of TSCA were released June 7, 1978 (43 FR
24802). Proposed rules on the disposal of PCBs were released Feb-
ruary 17, 1978 (43 FR 7150). The U.S. Environmental Protection
Agency has proposed a water quality criterion for the protection of
freshwater and marine life of 0.001 ug/1 (U.S. EPA, 1976b) . The
Food and Drug Administration established tolerance levels in foods
in 1973 (38 FR 18096) and proposed new tolerance levels further
restricting levels in 1977 (42 FR 17487). Both the current allowed
levels and the proposed levels were presented in Table 3.
The occupational exposure limits adopted in 1968 are based on
the recommendations of the American Conference of Governmental
Industrial Hygienists (ACGIH, 1968). They set the time-weighted
average eight-hour exposure limits to 1.0 mg/m for mixtures con-
taining 42 percent chlorine and 0.5 mg/m for mixtures containing
54 percent chlorine. The newly recommended standard proposed by
NIOSH (1977) is 1.0 ug/m3 air TWA over a 10-hour day and 40-hour
work week.
C-76
-------
Current Levels o£ Exposure
Human exposure to PCBs in the United States has been broad.
Several studies of tissue and plasma levels of PCBs have detected
them in a high percentage of randomly chosen subjects. Yobs (1972)
detected PCBs in 31.1 percent of 637 human ^adipose tissue. The
National Human Monitoring Program for Pesticides in fiscal years
i
1973 and 1974 found PCBs in 35.1 and 40.3 percent of adipose tis-
sues tested (Kutz and Strassman, 1976). Table 12 indicates the
distribution of PCB concentrations in the population. A study of
Canadian human adipose tissue PCB levels found 1 ppm or more in 30
percent of 172 samples (Grant, et al. 1976);. The eastern prov-
inces, particularly Ontario, had the highest incidences. Average
adipose tissue PCB levels were just below 1 mg/kg (ppm) with males
having slightly higher accumulations than females. The same study
found human breast milk to contain about 1 mg/kg on a fat basis.
PCBs were detected ini8 of 40 samples of breast milk in Colorado at
levels between 40 and 100 ppb (whole milk) ,i
described earlier found average levels in 400
30 ppb (Yakushiji, et al. 1977). PCB levels in plasma in U.S. popu-
lations were detected in 43 percent of 723
positive samples ranged from 1.5 to 29 ppb with a mean around 2 to 3
ppb. White populations had higher levels than black populations
(Finklea, et al. 1972).
As discussed in the section on exposure,
The Japanese study
milk samples of about
samples. Levels in
the median water lev-
els of PCBs are around 0.1 to 0.3 ug/1 in positive samples with 0 to
20 percent of samples being positive around the U.S. (Dennis,
1976). Average PCB intake in food was estimated in the mid-1970fs
C-77
-------
TABLE 12
Levels of Polychlorinated Biphenyls
in Human Adipose Tissue*
Data
Source
Yobs,
1972
FY 1973
Survey
FY 1974
Survey
Sample
Size
683
1,277
1,047
Percent
Nondetected
34.2
24.5
9.1
Percent
1 ppm
33.3
40.2
50.6
Percent
1-2 ppm
27.3
29.6
35.4
Percent
2 ppm
5.2
; 5-5
4.9
*Source: Kutz and Strassman, 1976
C-78
-------
to be about 9 ug/day with fish being the major dietary source. Am-
bient air concentrations are around 100 ng/m3 (Kutz and Yang,
1976). :
Special Groups at Risk i
The preceding discussion of human exposure makes clear the
fact that a high percentage of the U.S. population has been and is
exposed to low levels of PCBs in food, water, and air. Those groups
at particular risk for PCB exposure include industrial workers ex-
posed in the workplace, individuals consuming large amounts of con-
taminated fish, such as sport fisherman (42 FR 17487), and nursing
infants who, per kg body weight, may accumulate significant body
burdens from the levels in human breast milk.| With the cessation
of manufacture of PCBs by Monsanto in 1977 and the great decline in
its use which should result from the implementation of section 6(e)
of TSCA, industrial exposure should decline substantially. Since
many PCB-containing sealed systems can be expected to remain in
service for many years, continuing vigilance will be necessary to
minimize accidental pollution of waterways or
air and to prevent
further occupational exposure.
Basis and Derivation of Criterion
In arriving at a criterion for PCB levels in ambient waters
several factors must be taken into account. First, PCBs are highly
persistent in the environment and accumulate to a high degree in
food webs. - As discussed in the section Ingestion from Foods, an
average bioaccumulation factor for PCBs in all
shellfish of 31,200 has been determined. As
leave the environment very slowly once they have entered it. Not
C-79
freshwater fish and
a consequence, PCBs
-------
only do PCBs persist and accumulate in the environment but in man
as well. The current environmental levels are not producing obvi-
ous acute ill health in the general population. However, several
animal studies report that PCBs produce a carcinogenic response and
that they may enhance the carcinogenic activities of other sub-
stances.
Although other adverse effects of PCB exposure could be used
as a basis for formulating a criterion, carcinogenicity will be
used for a variety of reasons. The most extensive chronic studies
!
with PCBs have identified carcinogenicity as the malor end point.
Although no carcinogenicity studies have been extended to more than
one generation and firm data exist only for the female rat, a cred-
ible carcinogenic response to PCBs has been demonstrated and cannot
be ignored. Kimbrough, et al. (1972) observed an incidence of
hepatocellular carcinoma of 26/184 in treated rats compared to
1/173 in controls. The National Cancer Institute (NCI) bioassay
observed a lower percentage of hepatocellular carcinoma at a simi-
lar dose level which was statistically not significant because the
number of animals was low. In addition, a number of nonmalignant
proliferative processes observed in liver at high frequencies in
the PCB-treated animals in these studies were also observed in both
rats and mice in other studies (Ito, et al. 1973, 1974; Kimura and
Baba 1973; Kimbrough, et al. 1972; Kimbrough and Linder, 1974).
PCBs were classified as carcinogenic by the International Agency
for Research on Cancer (IARC, 1974). Evidence from human popula-
tions suggests but does not confirm an increase in cancer frequency
due to PCB exposure (Kuratsune, et al. 1976; Bahn, 1976). Finally,
C-80
-------
a theoretical basis exists for the quantitative extrapolation of
carcinogenic effects in treated animals to human populations. Var-
ious models, such as the one used below, can provide quantitative
risk estimates based on animal data and certain assumptions about
the induction of neoplasia (e.g. one-hit or multi-hit induction).
No basis .exists for extrapolation with mathematical models from
animals to man for many other kinds of biological effects.
Although the criterion established below! is based on animal
carcinogenicity data, it should also be noted that other adverse
effects have been observed in mammals at levels below the dose
which produces tumors in rats. The carcinogenic effect was ob-
served in rats consuming an average of 4.9 mg/kg/day. Dietary lev-
els at 2.5 ppm produced adverse reproductive effects in Rhesus mon-
keys (Allen and Barsotti, 1976). If a food intake of 350 g/day is
assumed, the PCB dose is 146 yg/kg/day in 6 kg animals. At this
time no data are available to indicate the minimal level in the
diet at which PCBs produce toxic effects in Rhesus monkeys.
In mink, ingestion of as little as 61 mg of Aroclor 1254 over
nine months or 90 mg of Aroclor over four months resulted in sharp-
ly reduced reproduction (Aulerich and Ringer,
1977). Assuming a
weight of 1 kg for adult mink and a food intake of 150 g/day, the
PCB dose at 2 ppm was about 300 ug/kg/day, which is similar to the
level producing reproductive toxicity in monkeys.
These data can be used in one approach to developing an ambi-
ent water quality criterion. If 300 yg/kg/day is taken as the
lowest-observable-effect-level (LOEL), then an Acceptable Daily
C-81
-------
Intake (ADI) can be calculated for a 70 kg man using an uncertainty
factor of 100:
7£ = 210 yg/day
Assuming that exposure to PCBs is based on the consumotion of
2 liters of drinking water, 6.5 g (0.0065 kg) of fish and shell-
fish, and a bioconcentration factor of 31,200; then the following
calculation can be made:
X [(2 1) + (0.0065 x 31,200)] = 210 ug ;
X = 1.03 ug/1
As will be seen later, the carcinogenicity criterion is lower
and presumably more cautionary.
An assessment of carcinogenic risk will be, made by extrapola-
tion from animal data using a linearized multistage (non-threshold)
model, The extrapolation used takes into account the bioaccumula-
tion of PCBs in fish and shellfish. It is assumed that an average
of 2 I/day of water are consumed along with 6.5 g of fish taken from
that water source. Exposures from other food sources, air, or oc-
cupational exposure are not included in the criterion level derived
by this model.
Among the studies reviewed in this document, only one appears
suitable for use in the cancer risk assessment. None of the mouse
studies involved feeding for most or all of a lifetime and are
therefore unsuitable. Of the rat studies, the only one involving
long term exoosure and adequate numbers of animals is the study of
Sherman rats by Kimbrough, et al. (1975).
This study has some drawbacks in that it lacks any evidence of
a dose-response (due to the use of only one dose level) ; it tests
C-82
-------
only one sex -of the species, and only one commercial mixture of
PCBs. Yet the experimental design is a good one in many ways: the
treatment was given over a long portion of the life span; there was
an appropriate route (food) and distribution of exposure (uniform
dose over time) ; the authors provided good documentation of the
actual intake dose; a sufficiently large number of experimental and
control animals were used to detect a statistically significant
increase in tumors; and there was a thorough and well documented
description of the pathology (hepatocellular carcinoma). The NCI
study (1978) was the only other study involving a long-term expo-
sure and was suggestive of a carcinogenic effect; however, the lack
of an adequate number of animals renders it unsuitable as a study
upon which to base an estimate of carcinogenic risk.
Under the Consent, Decree in NRDC v. Train, criteria are to
state "recommended maximum permissible concentrations (including
where appropriate, zero) consistent with the protection of aquatic
organisms, human health, and recreational activities." PCBs are
suspected of being human carcinogens. Because there is no recog-
nized safe concentration for a human carcinogen, the recommended
concentration of PCBs in water for maximum protection of human
health is zero.
Because attaining a zero concentration level may be infeasible
in some cases and in order to assist the Agency and States in the
possible future development of water quality regulations, the con-
centration of PCBs corresponding to several incremental lifetime
cancer risk levels have been estimated. A cancer risk level pro-
vides an estimate of the additional incidence of cancer that may be
C-83
-------
expected in an exposed population. A risk of 1
-------
(2) Approximately 99 percent of the PCB exposure results from the
consumption of aquatic organisms which exhibit an average bio-
concentration potential of 31,200-fold. The remaining 1 per-
cent of PCB exposure results from drinking water.
Concentration levels were derived assuming a lifetime exposure
to various amounts of PCBs, (1) occurring from the consumption of
both drinking water and aquatic life grown in Waters containing the
corresponding PCBs concentrations, and (2) occurring solely from
consumption of aquatic life grown in the waters containing the cor-
responding PCB concentrations. Although total exposure information
for PCBs is discussed and an estimate of the contributions from
other sources of exposure can be made, this data will not be fac-
tored into ambient water quality criteria formulation until addi-
tional analysis can be made. The criteria presented, therefore,
assume an incremental risk from ambient water exposure only.
These criteria are exceedingly low. Although sharp restric-
tion of open PCB use in 1970 resulted in notable declines in water
PCB levels in the next several years (Dennis, J1976), the residual
levels remaining are still two to three orders, of magnitude above
the criterion indicated by this extrapolation.
PCBs in water today is probably not new effluents from industrial
or domestic sources, but the PCB-containing sludges underlying
waterways which typically contain 100- to 1,000-fold higher concen-
trations than the water itself (Dennis, 1976). Efforts to reduce
water levels significantly by eliminating current pollution sources
will probably have little effect on average water PCB concentra-
tions.
C-85
The major source of
-------
The very low limits suggested by this risk estimate are due in
large part to the very large bioaccumulation factor in fish
(31,200). This figure is an average for a wide variety of salt-
water and freshwater organisms (see Ingestion from Food section).
As possible strategies to reduce human exposures to PCBs are
considered, the relative contributions of ingested water and fish
should be kept in mind. At the assumed consumption rate of 2 liters
of drinking water and 6.5 g of fish/day, 99 percent of the dietary
PCBs will be obtained from fish. Strategies which focus separately
on the reduction of PCB levels in water and fish for human consump-
tion might be more practical and productive than a single standard
for water which takes bioaccumulation in fish into account.
A final comment about the risk level derived from this study
is that it is based on animal data in which a dose-response rela-
tionship was not demonstrated. The weight of evidence indicates
that PCBs are carcinogenic in rodents. However, the carcinogenic
i
activities of these compounds are not great. An acceptable noncar-
cinogenic level could be established with greater certainty if bet-
ter quantitative data on carcinogenicity were available. Studies
with larger numbers of animals designed to measure relatively small
effects are needed. Also, the rat appears to be much less sensi-
tive to the acute and subacute effects of PCBs than man or non-
human primates. . Further investigation of the effects of PCBs in
Rhesus monkeys, particularly with reference to the gastric lesions
produced, would be useful.
C-86
-------
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t
Albro, P.W. and L. Fishbein. 1972. Intestinal absorption of poly-
chlorinated biphenyls in rats. Bull. Environ. Contam. Toxicol.
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i
Allen, J.R. 1975. Response of the non-human primate to polychlo-
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Allen, J.R. and L.J. Abrahamson. 1973. Morphological and biochem-
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Allen, J.R. and D.A. Barsotti. 1976. The effects of transpla-
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Allen, J.R. and D.H. Norback. 1973. Polychlor
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ence. 179: 498.
inated biphenyl- and
in primates. Sci-
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Allen, J.R. and D.H. Norback. 1976. Pathobiological Responses of
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Allen, J.R. and D.H. Norback. 1977. Carcinogenic Potential of the
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Allen, J.R., et al. 1974a. Tissue modifications in monkeys as
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Allen, J.R., et al. 1974b. Residual effects of short-term, low-
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Allen, J.R., et al. 1975. Responses of rats and non-human pri-
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Alvares, A.P., et al.. 1973. Polychlorinated biphenyls.- A ne* type
of inducer of cytochrome P-448 in the liver.' Proc. Natl. Acad.
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i
Alvares, A.P., et al. 1977. Alterations in1 drug metabolism in
workers exposed to polychlorinated biphenyls.: Clin. Pharmacol.
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i
!
American Conference of Governmental Industrial? Hygienists. 1968.
Threshold limit values for 1968 - recommended and intended values,
i '
adopted at 30th Annu. Meet. St. Louis, May 13. j
i
Anderson, M.W. , et al. 1977. The construction of a pharmacoki-
netic model for the disposition of polychlorinated biphenyls in the
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C-113
:ine pesticides in
6: 28.
Polychlorinated Si-
Conf. Polychlor. Bi-
560/6-75-004. Off.
Washington, D.C.
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APPENDIX *?•
Mi
t
Summary and Conclusions Regarding the Carcinogenicitv of
Polychlorinated Biohenyls*
i
Polychlorinated biphenyls (PCBs) are prepared by the chlorina-
tion of biphenyl and are complex mixtures containing isomers of
chlorobiphenyls with different chlorine content.
Because of the widespread industrial use of PCBs, their long
half-life, and the documented disease-oroducing capability of these
compounds in several species, regulations have been promulgated
banning most of the manufacturing, processing, and distribution of
PCBs in the United States (44 PR 106).
Human studies concerning the possible carclnogenicitv of PCBs
have involved small numbers of individuals and provide little in-
formation about exposure. Although these studies are only marginr-
ally useful in describing the carcinogenic!ty of PCBs, the inci-
dence of malignant neoplasms in "Yusho" patients and in industrial
workers exposed to Aroclor 1254 suggests that human exposure to
PCBs is associated with an increased risk of neoplasia.
In two separate studies, PCBs have been reported to induce
hepatocellular carcinomas in both mice and rats (male mice fed
Kanechlor 500 at 500 ppm and female Sherman rats fed Aroclor 1260
at 100 ppm).
*This summary has been orepared and approved by the Carcinogens
Assessment Group of EPA on June 15, 1979.
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in an NCI bioassay, Aroclor 1254 was not carcinogenic in Fis-
cher 344 rats, but the high frequency of hepatocellular prolifera-
tive lesions was considered to be the result of treatment and car-
cinomas of the gastrointestinal tract possibly associated with
treatment. In one other mouse study and three other rat studies,
various PCBs induced proliferate lesions of the liver which might
be indicative of carcinogenicity. The most commonly seen lesions
were adenofibrosis (cholangiofibrosis) and neoplastic nodules.
A correlation between degree of chlorination and tumor induc-
ing potential was observed in both mouse and rat species. The most
highly chlorinated preparations were also the most potent tumor
inducers with the exception of Aroclor 1254 which was more potent
than Aroclor 1260 in one rat study. where examined, female rats
were found to be more sensitive than males. No comparisons of sex
related effects were made in mice. |
PCBs have been reported to be co-carcinogens, initiators, and
promoters in both mouse and rat species.
The mutagenicity of different PCB preparations has been evalu-
ated in several test systems with conflicting results. in one
study, the single isomer 4-chlorobiphenyl was reported to be highly
mutagenic in Salmonella typhimurium strain TA1538 after liver
microsomal activation, while Aroclor 1221 was Reported to be less
mutagenic and Aroclors 1254, 1268, and 2,5,2-,5'-tetrachlorobi-
phenyl were" inactive. The fact that mutagenic activity decreased
with increasing chlorination is consistent withi the characteristic
insensitivity of the Ames test to chlorinated hydrocarbons. in
other test systems, Kanechlor 300 inhibited bacterial DNA repair
C-115
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deficient cells and induced cytogenetic abnormalities in Yoshida
sarcoma cells. Kanechlor 500 tested positive in a mouse bone mar-
row cytogenetic analysis.
in summary, carcinogenic responses have been induced in mice
and rats. These results, together with positive mutagenic re-
sponses and suggestive epidemiologic evidence, constitute substan-
tial evidence that PCBs are likely to be human carcinogens.
The water quality criterion for PCBs is based on the Kim-
brough, et al. (1975) study on the induction of hepatocellular car-
cinomas and neoplastic nodules in female Sherman strain rats fed
100 ppm Aroclor 1260. It is concluded that the water concentration
of PCBs should be less than 0.79 ng/1 (-0.8 ng/1) in order to keep
the lifetime cancer risk below 10
,-5
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f*
«k.
a
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Suiranary of Pertinent Data
The water quality criterion for PCBs is derived from the hepa-
tocellular carcinoma and neoplastic nodule ^response of Sherman
strain female rats fed Aroclor 1260 at a nominal dietary level of
100 ppm (Kimbrough, et al. 1975). A time-weighted average dose of
88.4 ppm (i.e., the dose varied between 70 and 107 ppm in the Kim-
orough, et al. study) was administered for' approximately 21.5
months and the animals were ooserved for an additional six weeks
before terminal sacrifice. The criterion is calculated from the
following parameters where the adjustment factor of 0.05 represents
the fraction of food consumed in relation to body weight:
Dose
(mg/kg/day)
0
4.42
(i.e., 88.4 ppm x 0.05)
le = 645 days
Le = 730 days
L = 730 days
Incidence
(No. responding/No, tested)
il/173
170/184
w = 0.400 kg
R = 31,200 I/kg
With these parameters the carcinogenic; potency factor for
humans is 4.3396 (mg/kg/day)
-1
The resulting water concentration
of PCBs calculated to keep the individual lifetime cancer risk
below 10~5 is 0.79 ng/1. !
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•*•
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