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Aroclor 1254
CASRN 11097-69-1
Contents
0389
Aroclor 1254; CASRN 11097-69-1
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Aroclor 1254
File On-Line 10/01/1994
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 11/01/1996
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) no data
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Aroclor 1254
CASRN -- 11097-69-1
Primary Synonym -- PCBs, Polychlorinated Biphenyls
Last Revised -- 11/01/1996
The oral Reference Dose (RfD) is based on the assumption that thresholds exist
for certain toxic effects such as cellular necrosis. It is expressed in units
of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning
perhaps an order of magnitude) of a daily exposure to the human population
(including sensitive subgroups) that is likely to be without an appreciable
risk of deleterious effects during a lifetime. Please refer to the Background
Document for an elaboration of these concepts. RfDs can also be derived for
the noncarcinogenic health effects of substances that are also carcinogens.
Therefore, it is essential to refer to other sources of information concerning
the carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that evaluation
will be contained in Section II of this file.
___I.A.1. ORAL RfD SUMMARY
Critical Effect Experimental Doses* UF MF RfD
-------------------- ----------------------- ----- --- ---------
Ocular exudate, in- NOAEL: None 300 1 2E-5
flamed and prominent mg/kg-day
Meibomian glands, LOAEL: 0.005 mg/kg-day
distorted growth of
finger and toe nails;
decreased antibody
(IgG and IgM) response
to sheep erythrocytes
Monkey Clinical and
Immunologic Studies
Arnold et al., 1994a,b;
Tryphonas et al., 1989,
1991a,b
*Conversion Factors and Assumptions -- None
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Arnold, D.L., F. Bryce, R. Stapley et al. 1993a. Toxicological consequences
of Aroclor 1254 ingestion by female Rhesus (Macaca mulatta) monkeys, Part 1A:
Prebreeding phase - clinical health findings. Food Chem. Toxicol. 31: 799-
810.
Arnold, D.L., F. Bryce, K. Karpinski et al. 1993b. Toxicological
consequences of Aroclor 1254 ingestion by female Rhesus (Macaca mulatta)
monkeys, Part 1B: Prebreeding phase -clinical and analytical laboratory
findings. Food Chem. Toxicol. 31: 811-824.
Tryphonas, H., S. Hayward, L. O'Grady et al. 1989. Immunotoxicity studies of
PCB (Aroclor 1254) in the adult rhesus (Macaca mulatta) monkey -- preliminary
report. Int. J. Immunopharmacol. 11: 199-206.
Tryphonas, H., M.I. Luster, G. Schiffman et al. 1991a. Effect of chronic
exposure of PCB (Aroclor 1254) on specific and nonspecific immune parameters
in the rhesus (Macaca mulatta) monkey. Fund. Appl. Toxicol. 16(4): 773-786.
Tryphonas, H., M.I. Luster, K.L. White et al. 1991b. Effects of PCB (Aroclor
1254) on non-specific immune parameters in Rhesus (Macaca mulatta) monkeys.
Int. J. Immunopharmacol. 13: 639-648.
Groups of 16 adult female rhesus monkeys ingested gelatin capsules
containing Aroclor 1254 (Monsanto Lot No. KA634) in 1:1 glycerol: corn oil
vehicle daily at dosages of 0, 5, 20, 40 or 80 ug/kg-day for more than 5
years. The Aroclor mixture contained 5.19 ppm of polychlorinated
dibenzofurans and undetectable levels of polychlorinated dibenzo-p-dioxins
(Truelove et al., 1990). At study initiation the monkeys were 11.1 +/- 4.1
years old (Tryphonas et al., 1991a,b; Arnold et al., 1993a,b). After 25
months of exposure the monkeys had achieved a pharmacokinetic steady-state
based on PCB concentrations in adipose tissue and/or blood (Tryphonas et al.,
1989). Results of general health and clinical pathology evaluations conducted
during the first 37 months of exposure were reported by Arnold et al.
(1993a,b). Results of immunologic assessments after 23 and 55 months of
exposure were reported by Tryphonas et al. (1989, 1991a,b). Results of
reproductive endocrinology evaluations after 24 or 29 months of exposure were
reported by Truelove et al. (1990) and Arnold et al. (1993a). Effects on
hydrocortisone levels during the first 22 months of exposure were reported by
Loo et al. (1989) and Arnold et al. (1993b). All of the aforementioned
evaluations were performed during the prebreeding phase of the study. Results
of reproduction and histopathology evaluations in these monkeys are not fully
available (Arnold, 1992).
General health status was evaluated daily, and body weight measurements,
feed conversion ratio calculations, and detailed clinical evaluations were
performed weekly throughout the study. Analyses of clinical signs of toxicity
were limited to the occurrence of eye exudate, inflammation and/or prominence
of the eyelid Meibomian (tarsal) glands, and particular changes in finger and
toe nails (prominent nail beds, separation from nail beds, elevated nail beds,
and nails folding on themselves). Each endpoint was analyzed for individual
treatment-control group differences and dose-related trends with respect to
incidence rate, total frequency of observed occurrences, and the onset time of
the condition. With respect to effects on the eyes, the treatment-control
group comparisons showed statistically significant (p less than or equal to
0.05) increases in the total frequency of inflamed and/or prominent Meibomian
glands at 0.005, 0.02 and 0.08 mg/kg-day, and decreased onset time for these
effects at 0.08 mg/kg-day. Significant dose-related trends (p less than or
equal to 0.05) were observed for increased total frequencies of inflamed
and/or prominent Meibomian glands, decreased onset time of inflamed and/or
prominent Meibomian glands, and increased incidences of eye exudate. With
respect to effects on finger and/or toe nails, the treatment-control group
comparisons showed significantly (p less than or equal to 0.05) increased
incidence of certain nail changes at 0.005 mg/kg-day (nail folding) and 0.08
mg/kg-day (elevated nails), increased total frequency of certain nail changes
at 0.005 mg/kg-day (nail separation), 0.04 mg/kg-day (nail folding and
separation) and 0.08 mg/kg-day (nail folding and separation, prominent beds,
elevated nails), and decreased onset time of certain nail changes at 0.005
mg/kg-day (elevated nails) and 0.08 mg/kg-day (nail folding, prominent beds,
elevated nails). Significant dose-related trends (p less than or equal to
0.05) were observed for certain nail changes (prominent beds, elevated nails)
when adjusted for onset time, total frequencies of certain nail changes (nail
folding and separation, prominent beds, elevated nails), and decreases in
onset time of certain nail changes (nail folding, prominent beds, elevated
nails).
Immunologic assessment showed significant (p<0.01 or <0.05) reductions in
IgG (at all doses of Aroclor 1254) and IgM (all doses but 0.02 mg/kg-day)
antibody levels in response to injected sheep red blood cells (SRBC) after 23
months of exposure (Tryphonas et al., 1989). A significant (p<0.05) decrease
in the percent of helper T-lymphocytes, a significant (p<0.05) increase in the
percent and absolute level of suppressor T-lymphocytes (TS) and a significant
(p<0.01) reduction in TH/TS ratio was observed at 0.08 mg/kg-day. The
antibody response to SRBC is an antigen-driven response that requires the
interaction of several distinct cell types (i.e., antigen processing and
presentation by macrophages, participation by T-helper cells and finally
proliferation and differentiation of B cells into plasma cells that secrete
the antibody), which result in the production and secretion of antibodies
specific for SRBC from plasma cells. Perturbation in any of the cells or
cell-to-cell interactions by physical, chemical or biological agents can
result in aberrant antibody responses. The necessity for the interaction of
the three principal cells of the immune system (i.e., macrophage, B lymphocyte
and T lymphocyte), in response to SRBC, is the main reason why this response
has been so widely used in immunotoxicity testing as a surrogate for infection
with a pathogenic organism.
In a recent evaluation of the sensitivity and predictability of various
immune function assays used for immunotoxicity testing in the mouse (Luster et
al., 1992), the antibody plaque-forming cell (PFC) response to SRBC was found
to show the highest association with immunotoxic compounds. Essentially this
means that the antibody PFC response to SRBC is a very good predictor of
immunotoxicants. Also, it has recently been demonstrated that measurement of
serum antibody titer to SRBC using the ELISA assay is as sensitive as the PFC
assay for determining the response to SRBC (Butterworth et al., 1993).
There were no exposure-related effects on total B-lymphocytes, total T-
lymphocytes, total serum immunoglobulin levels, total serum protein, serum
protein fractions after 23 months. No exposure-related effects on serum
hydrocortisone levels were observed although the SRBC assay is considered a
good surrogate (Tryphonas et al., 1989; Loo et al., 1989; Arnold et al.,
1993b).
After 55 months of exposure, there was a significant dose-related decrease
(p<0.0005 for pairwise comparisons and trend test) in the IgM antibody
response to injected SRBC at greater than or equal to 0.005 mg/kg-day at all
times of evaluation (1-4 weeks postimmunization) (Tryphonas et al., 1991a).
IgG antibody response to injected SRBC was significantly (p<0.01) decreased
only at 0.04 mg/kg-day, although the overall trend for dose-response was
significant (p=0.033). The antibody response to pneumococcus antigen did not
differ significantly among all test groups (including controls) at any time
tested and showed no dose-related trend. However, the antibody response to
pneumococcus antigen is a T cell-independent response and the fact that there
is no change with this antigen is not inconsistent with the depressed response
to the T cell-dependent SRBC antigen. Other data corroborate the significance
of Aroclor 1254 suppression of the antibody response to SRBC and point to
effects on T lymphocytes including the dose-related suppression of the Con A
and PHA lymphoproliferative responses. The monkeys treated with greater than
or equal to 0.005 mg/kg-day had significantly (p<0.0001) lower mean percentage
levels of total T-lymphocytes and significant trend for dose-response, but
absolute numbers of T-lymphocytes were similar among test groups. Flow
cytometric analysis showed no treatment-related effects on peripheral blood T-
helper, T-suppressor or B-lymphocytes or TH/TS lymphocyte ratio. A
statistically significant, dose-related increase was noted for thymosin alpha-
1-levels but not for thymosin beta-2-levels. Serum complement activity was
significantly (p<0.025) increased at greater than or equal to 0.005 mg/kg-day
but showed no significant (p=0.1) dose-related trend. Natural killer cell
activity at effect or target ratios of 25:1, 50:1 or 75:1 was not
significantly (p>0.05) increased at any dosage, although there was a
significant (p=0.03) dose-related trend. No signs of microbial infection were
noted in any of the preceding reports.
Clinical pathology was evaluated during the first 37 months of the study
(Arnold et al., 1993b). These evaluations included monthly measurements of
hematology and serum biochemistry (including serum protein, RBC indices, semi-
monthly measurements of thyroid function, and daily measurements of urinary
porphyrins during the 33rd month of dosing). Significant (pÛ0.05) decreases
in average dose-group values compared with controls were found for serum
cholesterol at 0.04 mg/kg-day, and reticulocyte count, serum cholesterol,
total bilirubin, and alpha-1 + alpha-2-globulins at 0.08 mg/kg-day.
Significant dose-related decreasing linear trends were also observed for
reticulocyte count (p=0.002), cholesterol (p less than or equal to 0.001), and
total bilirubin (p=0.005). Dose-related decreasing linear trends were also
observed for red blood cell count (p=0.019), mean platelet volume (p=0.034),
hematocrit (p=0.064), hemoglobin concentration (p=0.041). With regard to
thyroid endpoints [serum thyroxine (T4), serum triiodothyronine (T3) uptake
ratio, percent T3 uptake, and free thyroxine index], dose-response analysis
consisted of group mean comparisons and an assessment of parallelism in the
response profiles (an absence of parallelism would indicate time-dose
interactive effects). No statistically significant changes were observed for
any of the thyroid endpoints.
After approximately 2 years of dosing, each dose group was randomly
divided into two test groups for daily analyses of serum progesterone and
estrogen concentrations during one menstrual cycle (Truelove et al., 1990;
Arnold et al., 1993b). There were no statistically significant differences
between treated and control monkeys in menstrual cycle length or menses
duration, and no apparent treatment-related effects on incidence of
anovulatory cycles or temporal relationship between estrogen peak and menses
onset, menses end or progesterone peak (Truelove et al., 1990; Arnold et al.,
1993a,b).
To summarize the above, monkeys that ingested 0.005-0.08 mg/kg-day doses
of Aroclor 1254 showed ocular exudate, prominence and inflammation of the
Meibomian glands and distortion in nail bed formation. These changes were
seen at the lowest dose tested, 0.005 mg/kg-day, and a dose-dependent response
was demonstrated. Similar changes have been documented in humans for
accidental oral ingestion of PCBs. Among the various immunologic function
tests that were performed, the increases in IgM and IgG antibodies to sheep
erythrocytes are most significant. IgG and IgM antibodies in response to SRBC
were reduced after 23 months of exposure but only the IgM antibodies were
clearly decreased after 55 months. Particular importance is attributed to the
immune response to sheep erythrocytes since it involves participation by the
three principal cells of the immune system: the macrophage, B lymphocytes and
T lymphocytes and has been shown to be the most predictive immunotoxicity test
of those currently in use (Luster et al., 1992). On the basis the studies
described, a LOAEL of 0.005 mg/kg-day was established for Aroclor 1254.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF -- A 10-fold factor is applied to account for sensitive individuals. A
factor of 3 is applied to extrapolation from rhesus monkeys to humans. A full
10-fold factor for interspecies extrapolation is not considered necessary
because of similarities in toxic responses and metabolism of PCBs between
monkeys and humans and the general physiologic similarity between these
species. A partial factor is applied for the use of a minimal LOAEL since the
changes in the periocular tissues and nail bed see at the 0.05 mg/kg-day are
not considered to be of marked severity. The duration of the critical study
continued for approximately 25% of the lifespan of rhesus monkeys so that a
reduced factor was used for extrapolation from subchronic exposure to a
chronic RfD. The immunologic and clinical changes that were observed did not
appear to be dependent upon duration which further justifies using a factor of
3 rather than 10 for extrapolation from subchronic to chronic, lifetime
exposure. The total UF is 300.
MF -- None
___I.A.4. ADDITIONAL STUDIES / COMMENTS (ORAL RfD)
Human data available for risk assessment of Aroclor 1254 are useful only
in a qualitative manner. Studies of the general population who were exposed
to PCBs by consumption of contaminated food, particularly neurobehavioral
evaluations of infants exposed in utero and/or through lactation, have been
reported, but the original PCB mixtures, exposure levels and other details of
exposure are not known (Kreiss et al., 1981; Humphrey, 1983; Fein et al.,
1984a,b; Jacobson et al., 1984a, 1985, 1990a,b; Rogan et al., 1986; Gladen et
al., 1988). Most of the information on health effects of PCB mixtures in
humans is available from studies of occupational exposure. Some of these
studies examined workers who had some occupational exposure to Aroclor 1254,
but sequential or concurrent exposure to other Aroclor mixtures nearly always
occurred, exposure involved dermal as well as inhalation routes (relative
contribution by each route not known), and monitoring data are lacking or
inadequate (Alvares et al., 1977; Brown and Jones, 1981; Colombi et al., 1982;
Fischbein et al., 1979, 1982, 1985; Fischbein, 1985; Warshaw et al., 1979;
Smith et al., 1982; Taylor et al., 1984; Lawton et al., 1985). Insufficient
data are available in these studies to determine possible contributions of
Aroclor 1254 alone, extent of direct skin exposure and possible contaminants.
However, it is relevant to note that dermal and ocular effects, including skin
irritation, chloracne, hyperpigmentation and eyelid and conjunctival
irritation, have been observed in humans occupationally exposed to Aroclor
1254 and other Aroclor formulations.
Aroclor 1254 was fed to groups of eight female and four male adult rhesus
monkeys once daily in dosages of 0, 5, 25 or 100 ug/kg for 14 months, followed
by an observation period of 7 months (Levinskas et al., 1984). The Aroclor
1254 was dissolved in corn oil and offered to the animals in apple sauce prior
to each day's feeding, and the control mixture (corn oil in applesauce) was
used during the observation period. Dosages were adjusted biweekly for
changing body weight as necessary. The monkeys were selected on the basis of
a successful reproductive history, estimated to be at least 6 years old, and
had been in captivity for 2-9 years. After 6 months of treatment the monkeys
were bred to untreated males or females from the same colony over an 8-month
period and offspring were observed for 2 months. Breeding was continued until
conception was diagnosed by digital examination of the uterus and alterations
in the menstrual cycle. Evaluations of adult animals included hematology and
clinical chemistry. Urinalysis was also performed every 3 months during the
study. Semen analyses were performed monthly from just prior to the start of
treatment until the end of the treatment period. After 2 months of
observation; sperm concentration, total sperm, sperm motility, percent
abnormal cells and live/dead ratios were evaluated. Based upon these
parameters, no effect was observed upon male reproductive capacity.
Necropsies including histological examinations were performed on all adult
animals that died during the study or were euthanized at the end of the
observation period. Birth weight and somatic measurements were taken for all
offspring of exposed females or males. The infants of the exposed females
were subsequently evaluated monthly for body weight and complete blood cell
counts were performed. Infants that did not show signs of intoxication were
euthanized after 2 months and those showing signs were weaned, observed for
reversal of signs, and euthanized at the end of the study along with the
adults. Necropsies including histological examinations were performed on all
infants that died or were euthanized.
Death or euthanasia in extremis occurred in 1/12, 0/12, 1/12 and 5/12 of
the adult monkeys in the control, low-, mid- and high-dose groups,
respectively. All of the deaths occurred in females except for one male in
the high-dose group, and the only deaths considered to be related to treatment
were in four of the high-dose animals (3 females, 1 male). Characteristic
signs of PCB intoxication developed in the high-dose group after 9 months of
exposure, including effects on the eyelids (redness and/or edema, wrinkling)
in approximately half the animals and swelling of the lips in all animals.
Other characteristic signs included bleeding gums, abnormal fingernail/toenail
growth pattern and increased alopecia (including eyelashes) in several of the
high-dose monkeys. In general, the signs of intoxication appeared to subside
during the post-treatment period. Some of the monkeys in the mid-dose group
showed signs of intoxication (swelling of the lips in one male and one female)
after 15 and 18 months, respectively, and alopecia and abnormal nail growth,
but no signs attributable to exposure occurred in the low-dose group.
Hematologic effects at the high dose were observed including reduced packed
cell volume, erythrocyte count, hemoglobin and platelet counts. In addition,
increased serum iron and reduced serum cholesterol were observed, particularly
in the monkeys that died. Some of the high-dose monkeys also had prolonged
bleeding and improper healing at biopsy sites. Dermal histological changes
characteristic of PCB poisoning were prominent in the high-dose group,
occurring in 11/12 monkeys (8 females, 3 males), and included loss of
secretory epithelium in the Meibomian (eyelid) glands and sebaceous glands,
partial or total atrophy of sebaceous glands, follicular keratosis and/or
squamous cysts. Dermal changes also occurred in four of the mid-dose monkeys,
but not in the low-dose or control groups. Other histological alterations
included squamous metaplasia in glandular ducts of the tongue or lip (3 high-
dose females, 1 high-dose male), subgingival epithelial cysts of the mandible
(1 high-dose male, 1 high-dose female, 1 mid-dose male) and hyperplasia in the
bile and pancreatic ducts and gall bladder (1 high-dose female). Nonspecific
bone marrow alterations (decreased cellularity and/or granulocyte maturation)
occurred in 6/12 high-dose monkeys (5 females, 1 male) and may have been
compound-related because they correlated with the hematologic changes.
There was no apparent effect on male fertility based on conception rate
following matings with the untreated females or the semen analyses (Levinskas
et al., 1984). In the female control, low-, mid- and high-dose groups, the
numbers of known pregnancies were 7, 7, 7 and 5, respectively, the numbers of
live births were 6, 5, 7 and 1, respectively. Analysis of the preceding data
showed that there was a statistically significant reduction in fertility in
the high-dose group; this analysis refers only to the decreased number of live
births. There was a clear exposure-related effect on birth weight and infant
body weight gain. When compared with control group infants (mean birth
weight 495.2 g) the 0.025 mg/kg-day infants (mean birth weight 392.2 g) showed
a statistically significant reduction in birth weight (p<0.005). Most of the
infants in the mid-dose group and all of the infants in the high-dose had
abnormal clinical signs. These changes included being born with or developed
dermal signs that were consistent with those in the adults (e.g., swollen
lips, swollen eyelids and/or scanty eyelashes) and more severe at the high
dose, and also developed pulmonary signs (e.g., respiratory wheezing).
Histological changes in the infants were generally similar to those observed
in the adults. These effects included changes in the Meibomian and sebaceous
glands, pancreatic ducts and bone marrow. Other histological changes included
thymic atrophy in one mid-dose and the high-dose infant, and other effects in
the high-dose infant (e.g., retarded kidney cortical maturation, bile duct
hyperplasia and gastric mucosal gland cysts).
To summarize the above, no treatment-related effects were observed in the
low-dose adults or their infants, indicating that 0.005 mg/kg-day is a NOAEL.
For the mid-dose infants there was a 15% reduction in birth weight of infants
that was statistically significant (p<0.005). When these infants reached 2
months of age the reduced body weight was 22% below controls and this
difference was also found to be statistically significant (p=0.05). Ocular
and dermal signs and/or histological changes characteristic of PCB
intoxication developed in a some adults receiving 25 and 100 ug/kg-day, as
well as in most of the infants in these groups. Based on these effects the
0.025 mg/kg-day dosage is a LOAEL. Other effects at the high dose included
decreased adult survival, female fertility and numbers of live births,
indicating that 0.1 mg/kg-day is a FEL. This FEL is supported by results of
the Truelove study (Truelove et al., 1982).
Aroclor 1254 was fed to 1, 2 or 1 pregnant rhesus monkeys in reported
average daily doses of 0, 0.1 or 0.2 mg/kg-day, respectively, 3 days/week
for up to 267 days starting on gestation day 60 (Truelove et al., 1982). The
exposure period included gestation and lactation. One of the adult monkeys in
the low-dose group and the one adult in the high-dose group lost their
fingernails after 233 and 242 days of PCB treatment, but other overt signs of
intoxication were not observed. There was a significant reduction in antibody
production in response to injected SRBC in the exposed monkeys, but levels of
antibody production to tetanus toxoid were not appreciably different from
control. The two low-dosage monkeys delivered dead infants. The infant of
the high-dosage monkey died at age 139 days; this infant showed impaired
immune function as assessed by antibody production following SRBC injections.
Hematological evaluation performed bimonthly following parturition in adults
and the surviving infant were inconclusive. Although evaluation of the dead
infants and other results of this study is complicated by the small number of
animals, the characteristic dermal sign of PCB toxicity in the exposed monkeys
and lack of effects in controls strongly indicate that the developmental
toxicity is exposure-related. Therefore, based on the stillbirths, 0.1 mg/kg-
day is a FEL in monkeys.
Groups of four young adult female rhesus monkeys were fed 0 or 0.28 mg/kg
doses of Aroclor 1254 for 5 days/week for 114-121 weeks (Tryphonas et al.,
1986a,b; Arnold et al., 1990). Groups of four mature adult female cynomolgus
monkeys that had a poor breeding history were similarly exposed for 55-58
weeks (Tryphonas et al., 1986a; Arnold et al., 1990). The Aroclor mixture
contained no detectable polychlorinated dibenzo-p-dioxin contaminants.
Adjusting for the partial weekly exposure gives an average daily dosage of 0.2
mg/kg-day. Prominent clinical signs appeared in all exposed rhesus monkeys
during the first 2-12 months of exposure, including facial and periorbital
edema, loss of eyelashes, Meibomian gland enlargement and impaction,
conjunctivitis, nail lesions progressing from dryness to detachment and
gingival hyperplasia and necrosis of varying severity. Two of the exposed
rhesus monkeys developed overwhelming infections of the eye or periodontal
tissue after 27 months of exposure prompting sacrifice within 48 hours. The
hematology and serum biochemistry evaluations showed various changes in the
exposed rhesus monkeys, particularly slight or moderate normocytic anemia,
depressed erythropoiesis in bone marrow and increased triglycerides and SGOT.
The immunologic testing was inconclusive due to large interspecies
variability. Pathology findings in the exposed rhesus monkeys included
effects in the liver of three monkeys (30-55% increased relative liver weight,
hepatocellular hypertrophy and necrosis, bile duct epithelial hypertrophy and
hyperplasia, gall bladder epithelial hypertrophy), thyroid of two monkeys
(enlargement, occasional follicular cell desquamation) and stomach of two
monkeys (hypertrophic gastropathy). The cynomolgus monkeys had effects that
were generally consistent with but less extensive and severe than those
observed in the rhesus monkeys. After 38 weeks of exposure the rhesus monkeys
were mated with untreated males; cynomolgus monkeys were not mated. The
control and exposed rhesus monkeys became pregnant within 7 and 8 matings,
respectively. Following extended post-implant bleeding all of the treated
rhesus monkeys aborted within 30-60 days of gestation. Following recovery
from the abortions the monkeys were bred again up to a maximum of seven times
but none appeared to conceive. The menstrual cycle lengths and durations
became erratic and longer during and subsequent to the breeding. Based on the
abortions, reproductive impairment and pronounced overt signs of toxicity, the
0.2 mg/kg-day dosage is an FEL in monkeys.
Aulerich and Ringer (1977) performed a breeding study in which groups of
eight female and two male adult mink were fed diets containing 0 or 2 ppm
Aroclor 1254 for 39 weeks or until the kits were 4 weeks of age. The Aroclor
was dissolved in acetone which was evaporated from the diet prior to feeding.
Using assumed values of 150 g/day for food consumption and 0.8 kg for body
weight for female mink (Bleavins et al., 1980), the estimated dosage of
Aroclor 1254 is 0.4 mg/kg-day. Approximately monthly determinations
reportedly showed no statistically significant (p<0.05) differences between
the control and treated mink in body weight gain, hemoglobin, and hematocrit.
Only two of seven mated females gave birth, producing one infant each. Of the
two infants, one was born dead and the other had low body weight and was dead
by age 4 weeks. Based on the reproductive and/or fetal toxicity resulting in
nearly complete lack of births, 0.4 mg/kg-day is a FEL for Aroclor 1254 in
mink.
Twelve female and four male adult ranch-bred mink (age 8 months, body
weight not reported) were fed a diet containing 1 ppm Aroclor 1254 for 6
months (Wren et al., 1987a,b). Groups of 15 females and five males were used
for unexposed controls. The mink were bred after approximately 12-14 weeks of
exposure and exposure was continued until weaning at age 5 weeks. Using
assumed values for food consumption and for body weight for female mink
(Bleavins et al., 1980), the estimated dosage of Aroclor 1254 is 0.15 mg/kg-
day. Offspring mortality during the first week of life was 75.8% higher in
the exposed group than in the controls. Average body weight was significantly
lower in the exposed offspring at age 3 and 5 weeks, but not at age 1 week,
suggesting that transfer of PCBs by lactation may have contributed to the
effect. There were no exposure-related effects on adult survival or mating
performance, number of offspring per female mated or female that delivered,
adult thyroid plasma T3 or T4 levels during the exposure period, adult scrotal
diameter, offspring survival or relative liver weight at weaning or organ
weights or histology (brain, kidney, adrenal, pituitary, thyroid).
Teratogenicity was not evaluated. The neonatal mortality indicates that 0.15
mg/kg-day is an FEL in mink.
Groups of 10 female Sprague-Dawley rats were fed 0, 1, 5, 10 or 50 ppm
Aroclor 1254 in the diet for approximately 5-6 months (Byrne et al., 1987).
The Aroclor was dissolved in acetone which was evaporated from the diet prior
to feeding. Based on reported body weight and food consumption data the
dosages are estimated to be 0.09, 0.43, 0.61 and 4.3 mg/kg-day. Serum
thyroxine (T4) and triiodothyronine (T3) were evaluated at five different
times during 140 and 175 days of treatment, respectively. Serum T4 levels
were significantly reduced at 0.09 and 0.43 mg/kg-day by day 35 and at greater
than or equal to 0.61 mg/kg-day by day 14. T3 levels were significantly
reduced at 0.09 mg/kg-day by day 40 and at greater than or equal to 0.4 mg/kg-
day by day 20. The suppressions were generally dose-related for T4 throughout
the treatment period and T3 after 75 days. Disappearance rate of injected L-
[125I] T4 was significantly decreased at greater than or equal to 0.09 mg/kg-
day. Rats treated with only 0.43 or 0.61 mg/kg-day for approximately 5 months
and challenged with i.p. injected TSH had diminished response of serum T4 and
T3. Thyroid histology was not evaluated. There were no treatment-related
effects on relative thyroid weight, body weight or food consumption. The
findings of this study indicate that the decreased serum T3 and T4 resulted
primarily from direct damage to the thyroid rather than suppression of the
hypothalamo-pituitary axis or any enhanced peripheral catabolism (e.g.,
liver). Insufficient data are available to determine if the decreases in
circulating thyroid hormones were physiologically significant. However,
because the effects are indicative of impaired organ function, they are at
least potentially adverse and 0.09 mg/kg-day is considered to represent a
LOAEL in rats.
Groups of 10 female Sprague-Dawley rats were fed 0, 1, 5, 10 or 50 ppm
Aroclor 1254 in the diet for 5 months (Byrne et al., 1988). The Aroclor was
dissolved in acetone which was evaporated from the diet prior to feeding.
Using a rat food consumption factor of 0.05 kg food/kg body weight, the
dosages are estimated to be 0.05, 0.25, 0.5 and 2.5 mg/kg-day. Serum levels
of adrenal cortex hormones were evaluated in 8-10 rats 3-5 times during the
treatment period. Serum corticosterone was significantly (p<0.05) decreased
at greater than or equal to 0.25 mg/kg-day after approximately 60 days of
exposure. Serum dehydroepiandrosterone and dehydroepiandrosterone sulfate
were significantly (p<0.05) decreased at 0.25 and 0.5 mg/kg-day (not evaluated
at other dosages) after approximately 100 days and 25 days of exposure,
respectively. Serum corticosterone is the principal glucocorticoid in rats.
Adrenal weight, adrenal histology and non-adrenal endpoints other than food
consumption were not evaluated. Food consumption did not significantly differ
between and among control and treatment groups. The results of this study are
suggestive of toxicity to the adrenal rather than response to stress which
would be expected to increase the release of glucocorticoids. Insufficient
data are available to determine if the decreases in circulating adrenal cortex
hormones were physiologically significant. However, because the effects are
indicative of impaired organ function, they are at least potentially adverse.
The dosages of 0.05 and 0.25 mg/kg-day therefore are considered to represent a
NOEL and LOAEL, respectively, in rats.
Hepatotoxicity is a prominent effect of Aroclor 1254 that is well
characterized in rats (U.S. EPA, 1990). The spectrum of effects includes
hepatic microsomal enzyme induction, increased serum levels of liver-
associated enzymes indicative of possible hepatocellular damage, liver
enlargement, lipid deposition, fibrosis and necrosis. Estimated subchronic
dosages as low as 1.25-2.5 mg/kg-day have been reported to produce increased
liver weight and hepatic biochemical alterations in rats, but the lowest
dosages producing signs of hepatic effects are generally higher than the
lowest dosages that caused thyroid, adrenal and bone changes (Litterset et
al., 1972; Bruckner et al., 1974; Kling and Gamble, 1982; Andrews et al.,
1989). Rats fed 6.8 mg/kg-day for 8 months (Kimbrough et al., 1972) or an
estimated dosage of 50 mg/kg-day for 30 days (Kling et al., 1978) developed
fatty and necrotic degenerative hepatic histologic changes. Chronic dietary
exposure to 1.25-5 mg/kg-day for approximately 2 years produced only
preneoplastic and neoplastic liver lesions in rats (NCI, 1978; Ward, 1985).
A two-generation reproduction study was performed in which groups of 20
female and 10 male Sherman rats (age 3-4 weeks, body weight not reported) were
fed 0, 1, 5, 20 or 100 ppm dietary Aroclor 1254 (Monsanto Lot No. AK-38) in
peanut oil vehicle (Linder et al., 1974). Reported dosages were 0.06, 0.32,
1.5 and 7.6 mg/kg-day, and different controls were used for the less than or
equal to 0.32 and greater than or equal to 1.5 mg/kg-day groups. Exposure
times (before mating or conception-to-mating) ranged from 62-274 days.
Exposure-related effects included increased relative liver weight in F1a
weanlings at greater than or equal to 0.06 mg/kg-day, enlarged and vacuolated
hepatocytes in F2a weanlings at greater than or equal to 1.5 mg/kg-day, and
15-72% reduced litter size at greater than or equal to 1.5 mg/kg-day in the
F1b, F2a and F2b generations and at 7.6 mg/kg-day in the F1a generation.
Relative testes weights were increased in adult F1b males at 7.6 mg/kg-day
(other groups not evaluated). The highest NOAEL is 0.32 mg/kg-day based on
the increased liver weight without altered histology. The decreased litter
size indicates that 1.5 mg/kg-day is a FEL.
A one-generation reproduction study was performed in which groups of 10
male and 10 female Sherman rats were fed 0, 100 or 500 ppm dietary Aroclor
1254 for 67 or 186 days prior to pair-mating for the F1a and F1b generations,
respectively (Linder et al., 1974). The F0 rats received reported dosages of
0, 7.2 and 37.0 mg/kg-day and were sacrificed after a total exposure duration
of 8 months for hematology, organ weight and liver histology evaluation. The
study was terminated after the F1b pups were weaned. Effects in the P1 rats
included increased liver weight in both sexes greater than or equal to 7.2
mg/kg-day, increased relative testis weight (absolute weight unchanged) at
37.0 mg/kg-day, decreased body weight gain in both sexes at 37.0 mg/kg-day,
and changes in hematological values (reduced hematocrit and hemoglobin in both
sexes, increased total leukocytes with normal differential count in females)
at 37.0 mg/kg-day. Specific information on liver pathology was not reported
but degenerative changes similar to those found in the Kimbrough et al. (1972)
subchronic study were indicated for both dosages. Effects on the offspring
included reduced survival to weaning at 7.2 mg/kg-day (85.9 and 68.1% survival
in F1a and F1b pups, respectively, compared with 95.5% in controls), and
reduced litter size and number and 100% pup mortality by day 3 in F1a rats at
37.0 mg/kg-day. The decreases in postnatal survival indicate that both
dosages are FELs.
Groups of six to eleven female Wistar rats were fed 2.5, 26 or 269 ppm
Aroclor 1254 in the diet during gestation and lactation (Overman et al.,
1987). A control group was fed untreated diet that contained 0.02 ppm PCBs
(i.e., no added PCBs). Using a rat food consumption factor of 0.05 kg food/kg
body weight, the dosages are estimated to be 0.001, 0.13, 1.3 and 13.5 mg/kg-
day. The following neurobehavioral endpoints were significantly delayed or
reduced in the pups: appearance of the auditory startle response at 0.13 and
1.3 mg/kg-day at age 6 days (slightly delayed), development of righting
ability at 1.3 mg/kg-day at days of age (slightly delayed) and performance on
a motor coordination test at 1.3 mg/kg-day at age 7 and 8 days (slower
performance). Grip strength and appearance of eye opening were not affected
by exposure. Other effects attributable to exposure included increased
relative liver weight in pups at weaning at greater than or equal to 1.3
mg/kg-day and reduced birth weight, 50% mortality by 2 days of age and
retarded growth in pups at 13.5 mg/kg-day. There were no exposure-related
effects on maternal weight gain, gestation length, litter size, pup sex
ratios, number of live and dead pups or physical appearance, relative spleen
and thymus weight or relative and absolute brain weight of pups. Brain PCB
levels increased from birth to weaning in all groups. Based on the evidence
for impaired motor coordination in developing infants the 0.13 and 1.3 mg/kg-
day dosages are a NOAEL and LOAEL, respectively.
Dietary Aroclor 1254 was administered to groups of 4-10 female ICR mice in
concentrations of 0, 1, 10 or 100 ppm from 90 days before mating through
gestation day 18 (Welsch, 1985). The investigators estimated the dosages to
be 0.125, 1.25 and 12.5 mg/kg-day. No developmental toxicity was observed as
judged by number of litters, number of dead and reabsorbed fetuses, fetal
weight, incidence of gross malformations or skeletal development. Fetuses were
not examined for internal malformations. Maternal effects other than
significantly increased relative liver weight at greater than or equal to
0.125 mg/kg-day were not observed. No developmental effects were observed in
mice treated with the same doses of PCB only on gestation days 6-18. Based on
the increased maternal liver weight the highest NOAEL is 12.5 mg/kg-day.
Groups of seven adult male New Zealand white rabbits were fed dietary
Aroclor 1254 in reported estimated dosages of 0, 0.18, 0.92, 2.10 or 6.54
mg/kg-day for 8 weeks (Street and Sharma, 1975). Immunological testing was
started after 4 weeks of treatment at which time the rabbits were immunized
with injected SRBCs. No treatment-related changes in serum antibody titers to
SRBC (hemolysin and hemagglutination) were observed. SRBC-induced increases
in serum gamma-globulin were consistently but not statistically significantly
decreased by exposure, and the number of globulin-producing cells in popliteal
lymph nodes was significantly decreased at 0.92 and 6.54 mg/kg-day. Skin
sensitivity to tuberculin was generally lower in the treated groups but none
of the decreases were statistically significant. Marked histologic atrophy of
the thymus cortex was observed at 0.18 mg/kg-day and higher dosages except
0.92 mg/kg-day. There were no treatment-related effects on leukocyte count,
histology of the spleen, thymus, liver, kidneys or spleen, relative kidney or
adrenal weight, terminal body weight or food consumption. Relative liver and
spleen weights were significantly increased at greater than or equal to 2.10
mg/kg-day; the increase in liver weight was 74% at the highest dosage. The
0.18 mg/kg-day dosage is a LOAEL based on the thymic cortical atrophy.
Limited specific information is available on the oral absorption of
Aroclor 1254. Pregnant ferrets that ingested a single oral dose of Aroclor
1254 (approximately 0.06 mg/kg) absorbed approximately 85% of the initial
amount (Bleavins et al., 1984). Studies predominately of individual
chlorobiphenyl congeners indicate, in general, that PCBs are readily and
extensively absorbed by animals. These studies have found oral absorption
efficiency on the order of 75 to >90% in rats, mice and monkeys (Albro and
Fishbein, 1972; Allen et al., 1974; Tanabe et al., 1981; Clevenger et al.,
1989). A study of a non-Aroclor 54% chlorine PCB mixture prepared by the
investigators provides direct evidence of absorption of PCBs in humans after
oral exposure (Buhler et al., 1988), and indirect evidence of oral absorption
of PCBs by humans is available from studies of ingestion of contaminated fish
by the general population (Schwartz et al., 1983; Kuwabara et al., 1979).
There are no quantitative data regarding inhalation absorption of PCBs in
humans but studies of workers exposed suggest that PCBs are well absorbed by
the inhalation and dermal routes (Maroni et al., 1981a,b; Smith et al., 1982;
Wolff, 1985). PCBs distribute preferentially to adipose tissue and
concentrate in human breast milk due to its high fat content (Jacobson et al.,
1984b; Ando et al., 1985).
The metabolism of PCBs following oral and parenteral administration in
animals has been extensively studied and reviewed, but studies in animals
following inhalation or dermal exposure are lacking (Sundstrom and Hutzinger,
1976; Safe, 1980; Sipes and Schnellmann, 1987). Information on metabolism of
PCBs in humans is limited to occupationally exposed individuals whose intake
is derived mainly from inhalation and dermal exposure (Jensen and Sundstrom,
1974; Wolff et al., 1982; Schnellmann et al., 1983; Safe et al., 1985; Fait et
al., 1989). In general, metabolism of PCBs depends on the number and position
of the chlorine atoms on the phenyl ring of the constituent congeners (i.e.,
congener profile of the PCB mixture) and animal species. Although only
limited data are available on metabolism of PCBs following inhalation
exposure, there is no reason to suspect that PCBs are metabolized differently
by this route.
Data exist on the in vitro hepatic metabolism and in vivo metabolic
clearance of 2,2',3,3',6,6'-hexachlorobiphenyl and 4,4'-dichlorobiphenyl
congeners in humans, monkeys, dogs and rats (Schnellmann et al., 1985). The
hexachlorobiphenyl congener is a constituent of Aroclor 1254. For each
congener, the Vmax values for metabolism in the monkey, dog and rat are
consistent with the respective metabolic clearance values found in vivo.
Thus, the kinetic constants for PCB metabolism obtained from the dog, monkey
and rat hepatic microsomal preparations were good predictors of in vivo
metabolism and clearance for these congeners. In investigations directed at
determining which species most accurately predicts the metabolism and
disposition of PCBs in humans, the in vitro metabolism of these congeners was
also studied using human liver microsomes (Schnellmann et al., 1983, 1984).
Available data suggest that metabolism of PCBs in humans would most closely
resemble that of the monkey and rat. For example, the in vitro apparent Km and
Vmax are comparable between humans and monkeys. These studies show
consistency between the in vitro and in vivo findings and collectively
indicate that metabolism of the two congeners is similar in monkeys and
humans.
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- Medium
Data Base -- Medium
RfD -- Medium
Confidence in the principal study is medium. Groups of 16 rhesus monkeys
were tested at four dose levels and LOAEL was established on the basis of
clinical signs and immunologic alterations. Data for female and male
reproductive function and developmental data in a nonhuman primate species is
taken from an unpublished study (Levinskas et al., 1984) which established a
NOAEL for reproductive effects at 0.005 mg/kg-day. The Arnold study also
included evaluation of reproductive function but the data have not been
completely analyzed. Preliminary examination of the Arnold et al. data
indicate that the LOAEL for female reproductive function may be 0.005 mg/kg-
day. This inconsistency in effect levels for reproductive toxicity was viewed
as a limitation to the data base. Furthermore, there is a limitation in the
characterization of reproductive toxicology because results of an unpublished
study have been considered. An extensive number of laboratory animal and
human studies were available for review, including two-generation reproductive
studies. The chronic, 2-year bioassays performed in F344 rats showed evidence
of degenerative hepatocellular changes in addition to the neoplastic changs
that were observed. Only limited assessment of nonhepatic changes were made.
Human occupational and environmental data is available for commercial PCB
mixtures in general but not specifically for Aroclor 1254. The data base is
rated medium on the basis of these considerations. Overall confidence in the
RfD is medium.
___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
Source Document -- This assessment is not presented in any existing U.S. EPA
document.
Other EPA Documentation -- U.S. EPA, 1984, 1989, 1990
Agency Work Group Review -- 06/16/1993, 02/16/1994
Verification Date -- 02/16/1994
___I.A.7. EPA CONTACTS (ORAL RfD)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Aroclor 1254
CASRN -- 11097-69-1
Primary Synonym -- PCBs, Polychlorinated Biphenyls
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Aroclor 1254
CASRN -- 11097-69-1
Primary Synonym -- PCBs, Polychlorinated Biphenyls
This substance/agent has not undergone a complete evaluation and determination
under US EPA's IRIS program for evidence of human carcinogenic potential.
_VI. BIBLIOGRAPHY
Substance Name -- Aroclor 1254
CASRN -- 11097-69-1
Primary Synonym -- PCBs, Polychlorinated Biphenyls
Last Revised -- 10/01/1994
__VI.A. ORAL RfD REFERENCES
Albro, P.W. and L. Fishbein. 1972. Intestinal absorption of polychlorinated
biphenyls in rats. Bull. Environ. Contam. Toxicol. 8: 26-31.
Allen, J.R., D.H. Norback and I.C. Hsu. 1974. Tissue modifications in
monkeys as related to absorption, distribution, and excretion of
polychlorinated biphenyls. Arch. Environ. Contam. Toxicol. 2(1): 86-95.
Alvares, A.P., A. Fischbein, K.E. Anderson et al. 1977. Alterations in drug
metabolism in workers exposed to polychlorinated biphenyls. Clin. Pharmacol.
Ther. 22(2): 140-146.
Ando, M., H. Saito and I. Wakisaka. 1985. Transfer of polychlorinated
biphenyls (PCBs) to newborn infants through the placenta and mothers' milk.
Arch. Environ. Contam. Toxicol. 14: 51-57.
Andrews, J.E. 1989. Polychlorinated biphenyl (Aroclor 1254) induced changes
in femur morphometry calcium metabolism and nephrotoxicity. Toxicology. 57:
83-96.
Arnold, D.L. 1992. Telephone communication with J. Cicmanec, U.S. EPA,
Environmental Criteria and Assessment Office, Cincinnati, OH. January 9.
Arnold, D.L., J. Mes, F. Bryce et al. 1990. A pilot study on the effects of
aroclor 1254 ingestion by rhesus and cynomolgus monkeys as a model for human
ingestion of PCBs. Food Chem. Toxicol. 28(12): 847-857.
Arnold, D.L., F. Bryce, R. Stapley et al. 1993a. Toxicological consequences
of Aroclor 1254 ingestion by female rhesus (Macaca mulatta) monkeys, Part 1A:
Prebreeding phase - clinical health findings. Food Chem. Toxicol. 31: 799-
810.
Arnold, D.L., F. Bryce, K. Karpinski et al. 1993b. Toxicological
consequences of Aroclor 1254 ingestion by female rhesus (Macaca mulatta)
monkeys, Part 1B: Prebreeding phase -clinical and analytical laboratory
findings. Food Chem. Toxicol. 31: 811-824.
Aulerich, R.J. and R.K. Ringer. 1977. Current status of PCB toxicity to
mink, and effect on their reproduction. Arch. Environ. Contam. Toxicol. 6:
279-292.
Bleavins, M.R., R.J. Aulerich and R.K. Ringer. 1980. Polychlorinated
biphenyls (Aroclors 1016 and 1242): Effects on survival and reproduction in
mink and ferrets. Arch. Environ. Contam. Toxicol. 9: 627-635.
Bleavins, M.R., W.J. Breslin, R.J. Aulerich et al. 1984. Placental and
mammary transfer of a polychlorinated biphenyl mixture (Aroclor 1254) in the
European ferret (Mustela putorius furo). Environ. Toxicol. Chem. 3: 637-644.
Brown, D.P. and M. Jones. 1981. Mortality and industrial hygiene study of
workers exposed to polychlorinated biphenyls. Arch. Environ. Health. 36(3):
120-129.
Bruckner, J.V., K.L. Khanna and H.H. Cornish. 1974. Effect of prolonged
ingestion of polychlorinated biphenyls on the rat. Food Cosmet. Toxicol. 12:
323-330.
Buhler F., P. Schmid and C.H. Schlatter. 1988. Kinetics of PCB elimination
in man. Chemosphere. 17(9): 1717-1726.
Butterworth, L., L. Temple, T.T. Kawabata and K.L. White. 1993. Spleen
plaque forming cell (PFC) response vs SRBC-serum IgM in evaluation of
immunomodulation. The Toxicologist. 13: 325.
Byrne, J.J., J.P. Carbone and E.A. Hanson. 1987. Hypothyroidism and
abnormalities in the kinetics of thyroid hormone metabolism in rats treated
chronically with polychlorinated biphenyl and polybrominated biphenyl.
Endocrinology. 121(2): 520-527.
Byrne, J.J., J.P. Carbone and M.G. Pepe. 1988. Suppression of serum adrenal
cortex hormones by chronic low-dose polychlorobiphenyl or polybromobiphenyl
treatments. Arch. Environ. Contam. Toxicol. 17: 47-53.
Clevenger, M.A., S.M. Roberts, D.L. Lattin et al. 1989. The pharmacokinetics
of 2,2',5,5'-tetrachlorobiphenyl and 3,3',4,4'-tetrachlorobiphenyl and its
relationship to toxicity. Toxicol. Appl. Pharmacol. 100: 315-327.
Collins, W.T. and C.C. Capen. 1980a. Ultrastructural and functional
alterations of the rat thyroid gland produced by polychlorinated biphenyls
compared with iodide excess and deficiency, and thyrotropin and thyroxine
administration. Virchow. Arch. B. 33(3): 213-231.
Collins, W.T. and C.C. Capen. 1980b. Biliary excretion of 125I-thyroxine and
fine structural alterations in the thyroid glands of Gunn-rats fed
polychlorinated biphenyls (PCB). Lab. Invest. 43(2): 158.
Collins, W.T. and C.C. Capen. 1980c. Fine structural lesions and hormonal
alterations in thyroid glands of perinatal rats exposed in utero and by milk
to polychlorinated biphenyls. Am. J. Pathol. 99(1): 125-142.
Collins, W.T., C.C. Capen, L. Kasza et al. 1977. Effect of polychlorinated
biphenyl (PCB) on the thyroid gland of rats. Ultrastructural and biochemical
investigations. Am. J. Pathol. 89(1): 119.
Colombi, A., M. Maroni, A. Ferioli et al. 1982. Increase in urinary
porphyrin excretion in workers exposed to polychlorinated biphenyls. J. Appl.
Toxicol. 2(3): 117-121.
Fait, A., E. Grossman, S. Self et al. 1989. Polychlorinated biphenyl
congeners in adipose tissue lipid and serum of past and present transformer
repair workers and a comparison group. Fund. Appl. Toxicol. 12: 42-55.
Fein, G.G., J.L. Jacobson, S.W. Jacobson et al. 1984a. Intrauterine exposure
of humans to PCBs: Newborn effects. U.S. EPA, Duluth, MN. EPA 600/53-84-060.
NTIS PB84-188-887XSP.
Fein, G.G., J.L. Jacobson, S.W. Jacobson et al. 1984b. Prenatal exposure to
polychlorinated biphenyls: Effects on birth size and gestation age. J.
Pediatr. 105: 315-320.
Fischbein, A. 1985. Liver function tests in workers with occupational
exposure to polychlorinated biphenyls (PCBs): Comparison with Yusho and Yu-
Cheng. Environ. Health Perspect. 60: 145-150.
Fischbein, A., M.S. Wolff, R. Lilis et al. 1979. Clinical findings among
PCB-exposed capacitor manufacturing workers. Ann. NY Acad. Sci. 320: 703-
715.
Fischbein, A., M.S. Wolff, J. Bernstein et al. 1982. Dermatological findings
in capacitor manufacturing workers exposed to dielectric fluids containing
polychlorinated biphenyls (PCBs). Arch. Environ. Health. 37(2): 69-74.
Fischbein, A., J.N. Rizzo, S.J. Solomon et al. 1985. Oculodermatological
findings in workers with occupational exposure to polychlorinated biphenyls
(PCBs). Br. J. Ind. Med. 42: 426-430.
Gladen, B.C., W.J. Rogan, P. Hardy et al. 1988. Development after exposure
to polychlorinated biphenyls and dichlorodiphenyl dichloroethene
transplacentally and through human milk. J. Pediatr. 113: 991-995.
Humphrey, H.E.B. 1983. Population studies of PCBs in Michigan residents.
In: PCBs: Human and Environmental Hazards, F.M. D'Itri and M. Kamrin, Ed.
Butterworth, Boston, MA. p. 299-310.
Jacobson, J.L., S.W. Jacobson, P.M. Schwartz et al. 1984a. Prenatal exposure
to an environmental toxin: A test of the multiple effects model. Develop.
Psychobiol. 20(4): 523-532.
Jacobson, J.L., G.G. Fein, S.W. Jacobson et al. 1984b. The transfer of
polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs) across
the human placenta and into maternal milk. J. Public Health. 74(4): 378-379.
Jacobson, S.W., G.G. Fein, J.L. Jacobson et al. 1985. The effect of
intrauterine PCB exposure on visual recognition memory. Child Develop. 56:
856-860.
Jacobson, J.L., S.W. Jacobson and H.E.B. Humphrey. 1990a. Effects of in
utero exposure to polychlorinated-biphenyls and related contaminants on
cognitive-functioning in young children. J. Pediatr. 116: 38-45.
Jacobson, J.L., S.W. Jacobson and H.E.B. Humphrey. 1990b. Effects of
exposure to PCBs and related compounds on growth and activity in children.
Neurotoxicol. Teratol. 12: 319-326.
Jensen, S. and G. Sundstrom. 1974. Structures and levels of most
chlorobiphenyls in two technical PCB products and in human adipose tissue.
Ambio. 3: 70-76.
Kasza, L., W.T. Collins, C.C. Capen et al. 1978. Comparative toxicity of
polychlorinated biphenyl and polybrominated biphenyl in the rat thyroid gland:
Light and electron microscopic alterations after subacute dietary exposure.
J. Environ. Pathol. Toxicol. 1(5): 587-599.
Kimbrough, R.D., R.E. Linder and T.B. Gaines. 1972. Morphological changes in
livers of rats fed polychlorinated biphenyls. Arch. Environ. Health. 25:
354-364.
Kling, D. and W. Gamble. 1982. Cholesterol biosynthesis in polychlorinated
biphenyl-treated rats. Environ. Res. 27: 10-15.
Kling, D., J. Kunkle, A.S. Roller et al. 1978. Polychlorinated biphenyls: In
vivo and in vitro modifications of cholesterol and fatty acid biosynthesis.
J. Environ. Pathol. Toxicol. 1: 813-828.
Kreiss, K., M.M. Zack, R.D. Kimbrough et al. 1981. Association of blood
pressure and polychlorinated biphenyl levels. J. Am. Med. Assoc. 245(24):
2505-2509.
Kuwabara, K., T. Yakushiji, I. Watanabe et al. 1979. Increase in the human
blood PCB levels promptly following ingestion of fish containing PCBs. Bull.
Environ. Contam. Toxicol. 21: 273-278.
Lawton, R.W., M.R. Ross, J. Feingold et al. 1985. Effects of PCB exposure on
biochemical and hematological findings in capacitor workers. Environ. Health
Perspect. 60: 165-184.
Levinskas, G.J., D.P. Martin, H.R. Seibold and J.L. Cicmanec. 1984. Aroclor
1254: Reproduction study with Rhesus monkeys (Macaca mulatta). Unpublished
study by Monsanto.
Linder, R.E., T.B. Gaines and R.D. Kimbrough. 1974. The effect of
polychlorinated biphenyls on rat reproduction. Food Cosmet. Toxicol. 12: 63-
77.
Litterst, C.L., T.M. Farber, A.M. Baker et al. 1972. Effect of
polychlorinated biphenyls on hepatic microsomal enzymes in the rat. Toxicol.
Appl. Pharmacol. 23: 112-122.
Loo, J.C.K., H. Tryphonas, N. Jordan, R. Brien, K.F. Karpinski and D.L.
Arnold. 1989. Effects of Aroclor 1254 on hydrocortisone levels in adult
rhesus monkeys (Macaca mulatta). Bull. Environ, Contam. Toxicol. 43: 667-
669.
Luster, M.I., C. Portier, D.G. Pait et al. 1994. Risk assessment in
immunotoxicology. II. Relationships between immune and host resistance
tests. Fund. Appl. Toxicol. 21: 71-82.
Maroni, M., A. Colombi, G. Arbosti et al. 1981a. Occupational exposure to
polychlorinated biphenyls in electrical workers. II. Health effects. Br. J.
Ind. Med. 38: 55-60.
Maroni, M., A. Colombi, G. Arbosti et al. 1981b. Occupational exposure to
polychlorinated biphenyls in electrical workers. I. Environmental and blood
polychlorinated biphenyls concentrations. Br. J. Ind. Med. 38: 49-54.
NCI (National Cancer Institute). 1978. Bioassay of Aroclor 1254 for possible
carcinogenicity. NCI-GC-TR-38. NCI, Bethesda, MD. NTIS PB279624.
Overmann, S.R., J. Kostas, L.R. Wilson et al. 1987. Neurobehavioral and
somatic effects of perinatal PCB exposure in rats. Environ. Res. 44: 56-70.
Rogan, W.J., B.C. Gladen, J.D. McKinney et al. 1986. Neonatal effects of
transplacental exposure to PCBs and DDE. J. Pediatr. 109: 335-341.
Safe, S. 1980. Metabolism, uptake, storage and bioaccumulation of
halogenated aromatic pollutants. In: Halogenated Biphenyls, Terphenyls,
Naphthalenes, Dibenzodioxins and Related Products, R.D. Kimbrough, Ed.
Elsevier Science Publishers, Amsterdam. p. 81-107.
Safe, S., S. Bandiera, T. Sawyer et al. 1985. PCBs: Structure-function
relationships and mechanism of action. Environ. Health Perspect. 60: 47-56.
Schnellmann, R.G., C.W. Putnam and I.G. Sipes. 1983. Metabolism of
2,2',3,3',6,6'-hexachlorobiphenyl and 2,2',4,4',5,5'-hexachlorobiphenyl by
human hepatic microsomes. Biochem. Pharmacol. 32(21): 3233-3239.
Schnellmann, R.G., R.F. Volp, C.W. Putnam and I.G. Sipes. 1984. The
hydroxylation, dechlorination and glucuronidation of 4,4'-dichlorobiphenyl by
human hepatic microsomes. Biochem. Pharmacol. 33(21): 3503-3509.
Schnellmann, R.G., E.M. Vickers and I.G. Sipes. 1985. Metabolism and
disposition of polychlorinated biphenyls. In: Reviews in Biochemical
Toxicology, Vol. 7, E. Hodgson, J.R. Bend and R.M. Philpot, Ed. Elsevier
Press, Amsterdam. p. 247-282.
Schwartz, P.M., S.W. Jacobson, G. Fein et al. 1983. Lake Michigan fish
consumption as a source of polychlorinated biphenyls in human cord serum,
maternal serum, and milk. Am. J. Public Health. 73(3): 293-296.
Sipes, I.J. and R.G. Schnellmann. 1987. Biotransformation of PCBs metabolic
pathways and mechanisms. In: Polychlorinated Biphenyls (PCBs): Mammalian and
Environmental Toxicology, S. Safe, Ed. Environmental Toxic Series, Vol. 1.
Springer Verlag New York, Inc., Secaucus, NJ.
Smith, A.B., J. Schloemer, L.K. Lowry et al. 1982. Metabolic and health
consequences of occupational exposure to polychlorinated biphenyls. Br. J.
Ind. Med. 39: 361-369.
Spencer, F. 1982. An assessment of the reproductive toxic potential of
Aroclor 1254 in female Sprague-Dawley rats. Bull. Environ. Contam. Toxicol.
28(3): 290-297.
Street, J.C. and R.P. Sharma. 1975. Alteration of induced cellular and
humoral immune responses by pesticides and chemicals of environmental concern:
Quantitative studies of immunosuppression by DDT, Aroclor 1254, carbaryl,
carbofuran, and methylparathion. Toxicol. Appl. Pharmacol. 32: 587-602.
Sundstrom, G. and O. Hutzinger. 1976. The metabolism of chlorobiphenyls. A
review. Chemosphere. 5: 267-298.
Tanabe, S., Y. Nakagawa and R. Tatsukawa. 1981. Absorption efficiency and
biological half-life of individual chlorobiphenyls in rats treated with
Kanechlor products. Agric. Biol. Chem. 45(3): 717-726.
Taylor, P.R., C.E. Lawrence, H.L. Hwang et al. 1984. Polychlorinated
biphenyls: Influence on birth weight and gestation. Am. J. Public Health.
74(10): 1153-1154.
Truelove, J., D. Grant, J. Mes et al. 1982. Polychlorinated biphenyl
toxicity in the pregnant cynomolgus monkey: A pilot study. Arch. Environ.
Contam. Toxicol. 11: 583-588.
Truelove, J.F., J.R. Tanner, I.A. Langlois, R.A. Stapley, D.L. Arnold and J.C.
Mes. 1990. Effect of polychlorinated biphenyls on several endocrine
reproductive parameters in the female rhesus monkey. Arch. Environ. Contam.
Toxicol. 19(6): 939-943.
Tryphonas, L., S. Charbonneau, H. Tryphonas et al. 1986a. Comparative
aspects of Aroclor 1254 toxicity in adult cynomolgus and rhesus monkeys: A
pilot study. Arch. Environ. Contam. Toxicol. 15: 159-169.
Tryphonas, L., D.L. Arnold, Z. Zawldzka et al. 1986b. A pilot study in adult
rhesus monkeys (M. mulatta) treated with Aroclor 1254 for two years. Toxicol.
Pathol. 14(1): 1-10.
Tryphonas, H., S. Hayward, L. O'Grady et al. 1989. Immunotoxicity studies of
PCB (Aroclor 1254) in the adult rhesus (Macaca mulatta) monkey - preliminary
report. Int. J. Immunopharmacol. 11(2): 199-206.
Tryphonas, H., M.I. Luster, G. Schiffman et al. 1991a. Effect of chronic
exposure of PCB (Aroclor 1254) on specific and nonspecific immune parameters
in the rhesus (Macaca mulatta) monkey. Fund. Appl. Toxicol. 16(4): 773-786.
Tryphonas, H., M.I. Luster, K.L. White et al. 1991b. Effects of PCB (Aroclor
1254) on non-specific immune parameters in rhesus (Macaca mulatta) monkeys.
Int. J. Immunopharmacol. 13(6): 639-648.
U.S. EPA. 1980. Ambient Water Quality Criteria Document for Polychlorinated
Biphenyls. Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of
Water Regulations and Standards, Washington, DC. EPA-440/5-80/068. NTIS
PB81-117798/AS.
U.S. EPA. 1984. Health Effects Assessment for Polychlorinated Biphenyls.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and
Remedial Response, Washington, DC. EPA-540/1-86/004. NTIS 86-134152/AS.
U.S. EPA. 1989. Ambient Water Quality Criteria Document Addendum for
Polychlorinated Biphenyls. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA. 1990. Drinking Water Criteria Document for Polychlorinated
Biphenyls (PCBs). Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Drinking Water, Washington, DC.
Ward, J.M. 1985. Proliferative lesions of the glandular stomach and liver in
F344 rats fed diets containing Aroclor 1254. Environ. Health Perspect. 60:
89-95.
Warshaw, R., A. Fischbein, J. Thornton et al. 1979. Decrease in vital
capacity in PCB-exposed workers in a capacitor manufacturing facility. Ann.
NY Acad. Sci. 320: 277-283.
Welsch, F. 1985. Effects of acute or chronic polychlorinated biphenyl
ingestion on maternal metabolic homeostasis and on the manifestations of
embryotoxicity caused by cyclophosphamide in mice. Arch. Toxicol. 57(2):
104-113.
Wolff, M.S. 1985. Occupational exposure to polychlorinated biphenyls (PCBs).
Environ. Health Perspect. 60: 133-138.
Wolff, M.S., J. Thornton, A. Fischbein et al. 1982. Disposition of
polychlorinated biphenyl congeners in occupationally exposed persons.
Toxicol. Appl. Pharmacol. 62: 294-306.
Wren, C.D., D.B. Hunter, J.F. Leatherland et al. 1987a. The effects of
polychlorinated biphenyls and methylmercury, singly and in combination, on
mink: I. Uptake and toxic responses. Arch. Environ. Contam. Toxicol. 16:
441-447.
Wren, C.D., D.B. Hunter, J.F. Leatherland, et al. 1987b. The effects of
polychlorinated biphenyls and methylmercury, singly and in combination, on
mink: II. Reproductive and kit development. Arch. Environ. Contam. Toxicol.
16(4): 449-454.
__VI.B. INHALATION RfC REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
None
_VII. REVISION HISTORY
Substance Name -- Aroclor 1254
CASRN -- 11097-69-1
Primary Synonym -- PCBs, Polychlorinated Biphenyls
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
07/01/1993 I.A. Oral RfD now under review
09/01/1993 All Minor edit
03/01/1994 I.A. Work group review date added
10/01/1994 I.A. Oral RfD summary on-line
10/01/1994 VI.A. Oral RfD references on-line
11/01/1996 I.A.7. Primary contact's office changed
VIII. SYNONYMS
Substance Name -- Aroclor 1254
CASRN -- 11097-69-1
Primary Synonym -- PCBs, Polychlorinated Biphenyls
Last Revised -- 07/01/1993
11097-69-1
Aroclor 1254
Arochlor 1254
CHLORIERTE BIPHENYLE, CHLORGEHALT 54% [German]
CLORODIFENILI, CLORO 54% [Italian]
DIPHENYLE CHLORE, 54% DE CHLORE [French]
HSDB 6357
NCI-C02664
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0389.HTM
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