 |
Monkey Immune System Damage from PCBs
All 8 studies listed below show that very low levels of
PCB exposure can cause changes in the monkey immune system, which is very
similar to a human's. These studies show that even slight effects
could be important for susceptible people or those with existing health
problems. The fetus and young infants are especially vulnerable to PCB
exposure in the womb or through breastfeeding, but even adults can be sensitive
to PCB immune effects.
For more information, see Introduction.
Summary of Results --- 8 Studies of PCB Effects
(Each entry represents one finding in a study --- unless
otherwise noted. Some studies had multiple findings.)
-
low PCB levels change the immune system
-
adult nonhuman primates are sensitive to the immunotoxic effects of low
levels of PCBs
-
serum hemolytic complement activity in all PCB treated groups was significantly
higher
-
significant dose-related increase in natural killer cell activity
-
significant dose-related increase in thymosin alpha-1 levels
-
significant increased interferon levels
-
sustained low-level PCB exposure could have modest to slight immunosuppressive
effects, which might be important depending on the general health of the
individual.
-
significantly lower anti-SRBC antibody titers
-
consistently lower gamma-globulin levels
-
impaired ability to withstand challenge by pathogens and an increased sensitivity
to endotoxin.
-
changes in a number of hematologic, serum chemistry, and immune function
variables at doses lower than previously reported for nonhuman primates.
-
significant decrease in erythrocyte and reticulocyte counts, hematocrits,
mean platelet volumes, serum cholesterol and total bilirubin concentrations
-
significant decrease in IgG, IgA, and IgM antibody responses
-
significant increase in the T-cytotoxic and T-suppressor ratio
-
significant increases in the alpha1 and alpha2 globulin concentrations
-
infants showed immunological test differences
-
low level chronic PCB exposure causes moderate changes in several parameters
of immune system function in rhesus-monkeys
-
significant dose related decrease in the IgM and IgG response to conA and
PHA
-
monocyte response to PMA was significantly increased in a dose related
manner
-
mean proportion of CD2 cells was significantly decreased
-
PCB Aroclor-1254 has a direct effect on the immune system
-
significant dose dependent decreases in antibody responses
-
increases in CD8 positive T-cells and decreases in CD4 positive T-cells
along with the CD48 ratio
-
serum levels of thymosin-alpha-1 showed a significant dose dependent increase
-
decreased levels of thymidine incorporation by mitogen induced proliferating
lymphocytes and decreased mononuclear cell phagocytic activity
-
significant increases in natural killer cell activity
-
monkeys fed "purified" PCBs suffered immune suppression, as did those fed
"pure" furans, or polychlorinated quaterphenyls (therefore, it isn’t just
the furans causing the problem)
-
decreased antibodies --- immunoglobulin-M (IgM) and immunoglobulin-G (IgG)
-
significant increases in absolute and percent T-suppressor (Ts) cells
-
reduction in the percent T-helper (Th) cells
The Monkey Studies
This is not a complete list of all studies on this topic.
For more studies, visit the TOXNET
database operated by the National Library of Medicine (the source of these
abstracts).
Study #1
-
low PCB levels change the immune system
-
serum hemolytic complement activity in all PCB treated groups
was significantly higher
-
significant dose-related increase in natural killer cell
activity
-
significant dose-related increase was noted for thymosin
alpha-1 levels
-
significant increased interferon levels
The effects of low level, chronic polychlorinated
biphenyl--Aroclor 1254--(PCB) exposure were investigated on non-specific
immune parameters in female rhesus (Macaca mulatta) monkeys. Five groups
of monkeys were orally administered with PCB at concentrations of 0, 5,
20, 40 or 80 micrograms/kg bw/day. Immunotoxicity testing was initiated
after 55 months of exposure. The serum hemolytic complement activity
in all PCB treated groups was significantly higher (P less than 0.05)
than that in the control group. A statistically significant dose-related
increase in natural killer cell activity was evident at the 75:1 effector
to target cell ratio. Similarly, a statistically significant dose-related
increase was noted for thymosin alpha-1 levels but not for thymosin
beta-4 levels. Statistically significant increased interferon levels
were noted in the 20 and 80 micrograms/kg groups compared with the control
group while the levels in the 40 micrograms/kg group were decreased
significantly compared with the con (Tryphonas et al, 1991)
Study #2
-
sustained low-level PCB exposure could have modest to slight
immunosuppressive effects, which might be important depending on the general
health of the individual.
-
significantly lower anti-SRBC antibody titers
-
consistently lower gamma-globulin levels
-
impaired ability to withstand challenge by pathogens and
an increased sensitivity to endotoxin.
Female rhesus monkeys were fed either normal chow or chow
containing 2.5 or 5.0 ppm of Aroclor 1248 (PCB (polychlorinated biphenyl;
environmental pollutant)). After 6 mo., the PCB-fed monkeys developed chloracne,
alopecia and facial edema. After 11 mo., control and treated monkeys were
immunized with sheep red blood cells (SRBC) and tetanus toxoid (TT). Monkeys
fed 5.0 ppm of PCB had significantly lower anti-SRBC antibody titers
than controls at only 2 intervals following primary immunization. Antibody
response to TT was not measurably affected by PCB exposure. Both PCB-fed
groups had consistently lower gamma-globulin levels than controls.
Sustained exposure to low levels of PCB could have modest to
slight immunosuppressive effects, which might be important depending on
the general health of the individual. Mice fed up to 1000 ppm of PCB
for 3-5 wk exhibited no signs of PCB intoxication other than liver hypertrophy.
However, these mice, when challenged with Salmonella typhimurium, showed
higher mortality and significantly greater numbers of viable organisms
in the spleen, liver and blood than did controls. Similarly, exposed mice
showed an increased sensitivity to endotoxin. Mice exposed to subclinical
doses of PCB (i.e., doses insufficient to produce overt clinical signs
of intoxication) appear to have an impaired ability to withstand challenge
by pathogens and an increased sensitivity to endotoxin. (Thomas et
al, 1978)
Study #3
-
changes in a number of hematologic, serum chemistry, and
immune function variables at doses lower than previously reported for nonhuman
primates.
-
significant decrease in erythrocyte and reticulocyte counts,
hematocrits, mean platelet volumes, serum cholesterol and total bilirubin
concentrations
-
significant decrease in IgG, IgA, and IgM antibody responses
-
significant increase in the T-cytotoxic and T-suppressor
ratio
-
significant increases in the alpha1 and alpha2 globulin concentrations.
Hematological, biochemical, and hormonal changes resulting
from ingestion of aroclor-1254 (11097691) (aroclor) during the prebreeding
phase were studied in female rhesus-monkeys (Macaca-mulatta). The study
was part of a 6.5 year investigation of the effects of prenatal and lactational
polychlorinated biphenyl (PCB) exposure in rhesus-monkeys. Eighty menstruating
female monkeys, average age 11.1 years, ingested capsules containing 0,
5, 20, 40, or 80 micrograms per kilogram aroclor daily until steady state
PCB concentrations in their adipose tissue were obtained. Blood samples
were collected at monthly or bimonthly intervals to determine standard
hematologic and serum biochemical parameters, serum hydrocortisone concentrations,
and immunoglobulin-A (IgA), immunoglobulin-G (IgG), and immunoglobulin-M
(IgM) antibody concentrations in response to sheep red blood cell immunization.
Differential serum protein analyses and thyroid evaluations were performed
at these times. Serum estrogen and progesterone concentrations were determined
during one menstrual cycle. Skin biopsies were obtained from the scapular
area 1 month before and 10 and 20 months after the start of dosing to examine
the effects of aroclor on sebaceous gland area. Aroclor significantly
decreased erythrocyte and reticulocyte counts, hematocrits, mean platelet
volumes, serum cholesterol and total bilirubin concentrations, and IgG,
IgA, and IgM antibody responses to sheep red blood cells. The T-cytotoxic
and T-suppressor ratios were significantly increased. Among the serum
protein fractions, aroclor induced significant increases in the alpha1
and alpha2 globulin concentrations. No significant effects on serum
estrogen or progesterone concentrations during menstrual cycling were detected.
Aroclor did not significantly affect any of the variables associated with
thyroid function. Aroclor significantly decreased the number of sebaceous
gland lobules per histological length after 20 months of dosing. The authors
conclude that aroclor produces changes in a number of hematologic, serum
chemistry, and immune function variables in rhesus-monkeys at doses lower
than previously reported for nonhuman primates. (Arnold et al, 1993)
Study #4
-
infants showed immunological test differences
A group of 80 menstruating rhesus (Macaca mulatta) monkeys
were randomly allocated to four similar test rooms (20 monkeys/room) and
then randomly allocated within each room to one of five dose groups (four
females/dose group/room). Each day, the monkeys self-ingested capsules
containing doses of 0, 5, 20, 40 or 80 micrograms Aroclor 1254/kg body
weight. After 25 months of continuous dosing, approximately 90% of the
treated females had attained a qualitative pharmacokinetic steady state
with respect to the concentration of polychlorinated biphenyl (PCB) in
their adipose tissue. Commencing on test month 37, each female was paired
with an untreated male until either an impregnation occurred or the 29-month
breeding phase of the study was completed. The females continued to receive
their daily test dose during mating and gestation. To preclude an infant
ingesting the mother's dosing capsule, dosing of the dam was discontinued
when a nursing infant was approximately 7 wk old. Treatment was restarted
when the infant was weaned at 22 wk of age. At parturition, and every 4
wk until weaning, milk and blood samples were obtained from the dam and
a blood sample was obtained from the infant for PCB analysis. When the
infant was 20 wk old, immunological testing was initiated and an adipose
sample was obtained from the infant and dam for PCB analysis. Subsequently,
further adipose and blood samples were obtained from the infant and blood
specimens were obtained from the dam for PCB analysis. Concurrently, each
infant was subjected to anthropometric measurements and detailed clinical
examinations until it was approximately 122 wk old. At 122 wk some of the
control and all of the treated infants were killed humanely and autopsied.
A statistical analysis of the reproduction data provided evidence for a
significant decreasing dose-related trend in conception rates and a significant
increasing dose-related trend in foetal mortality. Several comparisons
between impregnated and non-impregnated females did not implicate 'age'
as a confounding factor regarding these results. The major findings with
the infants involved some immunological test differences and mild
clinical manifestations of PCB ingestion. (Arnold et al, 1995)
Study #5
-
low level chronic PCB exposure causes moderate changes in
several parameters of immune system function in rhesus-monkeys
-
significant dose related decrease in the IgM and IgG response
to conA and PHA
-
monocyte response to PMA was significantly increased in a
dose related manner
-
mean proportion of CD2 cells was significantly decreased
The immunomodulatory effects of aroclor-1254 (11097691) were
studied in monkeys. Female rhesus-monkeys were administered 0, 5, 20, 40,
or 80 micrograms per kilogram (microg/kg) aroclor-1254 daily. Peripheral
blood samples were collected after 55 months and assayed for aroclor-1254.
The effects on immune function were assessed at this time by determining
the immunoglobulin-M (IgM) and immunoglobulin-G (IgG) responses to sheep
red blood cells (SRBCs), the antibody response to pneumococcal antigen,
the lymphocyte proliferative response to concanavalin-A (conA), phytohemagglutinin
(PHA), and pokeweed-mitogen, the mixed lymphocyte response, the monocytic
response to zymosan or phorbol-myristate-acetate (PMA), and the production
of interleukin-1. A flow cytometric analysis of peripheral blood leukocyte
subpopulations was performed. Serum hydrocortisone concentrations were
measured. Eleven of 80 monkeys were removed from the study because they
developed endometriosis, cervical cancer, and polychlorinated biphenyl
(PCB) toxicity. Blood aroclor-1254 concentrations ranged from 21.276 parts
per million (ppm) in the 5microg/kg group to 285.919 ppm in the 80 microg/kg
dose group. Aroclor-1254 caused a significant dose related decrease
in the IgM and IgG response to conA and PHA. The monocyte response
to zymosan stimulation was nonsignificantly increased. The monocyte
response to PMA was significantly increased in a dose related manner.
The mean proportion of CD2 cells was significantly decreased by
aroclor-1254; however, the absolute number of CD2 cells was unaffected.
None of the other parameters of immune system function was significantly
affected by aroclor-1254. The authors conclude that low level chronic
PCB exposure causes moderate changes in several parameters of immune
system function in rhesus-monkeys. These changes may reflect alterations
in T-cell or macrophage function. (Tryphonas et al, 1991)
Study #6
-
adult nonhuman primates are sensitive to the immunotoxic
effects of low levels of PCBs
-
PCB Aroclor-1254 has a direct effect on the immune system
-
significant dose dependent decreases in antibody responses
-
increases in CD8 positive T-cells and decreases in CD4 positive
T-cells along with the CD48 ratio
-
serum levels of thymosin-alpha-1 showed a significant dose
dependent increase
-
decreased levels of thymidine incorporation by mitogen induced
proliferating lymphocytes and decreased mononuclear cell phagocytic activity
-
significant increases in natural killer cell activity
The use of nonhuman primates as an appropriate animal model
to study the metabolism and accumulation of polychlorinated biphenyls (PCBs)
was examined. The metabolism and toxic effects of low doses of PCBs
were studied in female Rhesus-monkeys orally administered up to 80 micrograms
per kilogram Aroclor-1254 (27323188) per day. Immunological effects were
noted with the establishment of a blood PCB pharmacokinetic equilibrium
at 23 months of exposure and 55 months into the study. The blood PCB concentration
noted at 23 months of the study remained at similar levels 55 months into
the study. Significant dose dependent decreases in antibody responses
to sheep erythrocytes were observed. Changes in T-cell subsets included
increases in CD8 positive T-cells and decreases in CD4 positive T-cells
along with the CD48 ratio. Lymphocyte proliferation to alloantigens,
repeated measurements of total serum immunoglobulin levels, and serum protein
fractions did not prove to be sensitive indicators for the possible effects
of Aroclor-1254 on T-cell function. Serum levels of thymosin-alpha-1
showed a significant dose dependent increase. A trend toward decreased
levels of thymidine incorporation by mitogen induced proliferating lymphocytes
and decreased mononuclear cell phagocytic activity was noted. Significant
increases in natural killer cell activity were observed only in the
high dose animals and only at a specific effector/target cell ratio.
Significant dose dependent increases in serum complement activity were
recognized after 55 months of exposure. PCB treatment did not affect serum
levels of corticosteroids in the monkeys, suggesting a direct effect
of Aroclor-1254 on the immune system. The author concludes that
nonhuman primates are sensitive to the immunotoxic effects of low levels
of PCBs. (Tryphonas et al, 1995)
Study #7
-
monkeys fed "purified" PCBs suffered immune suppression,
as did those fed "pure" furans, or polychlorinated quaterphenyls
(therefore, it isn’t just the furans causing the problem)
Effects on humans: In Japan, in 1968, mass consumption of
a cooking oil (Kameni Rice Oil) contaminated with PCB (~2500 ug.L-1 of
Kanechlor 400 (KC 400) previously used as a heat transfer agent) caused
an outbreak of a disease known as "Yusho" which affected over 1000 people
(Hayabuchi et al. 1979; Kuratsune et al. 1972). Later this disease was
attributed at least in part to the 40 tri to hexa PCDFs (including 2,3,7,8-T4CDF,
2,3,4,7,8-P5CDF and 2,3,4,6,7-P5CDF as major components) which also contaminated
the oil at levels up to 5 ug.L-1 (Nagayama et al. 1976; Rappe et al. 1977;
Buser et al. 1978c; Masuda et al. 1982). It has been estimated that Yusho
patients consumed an average of 3.4 mg PCDF (48 ug.kg-BW-1 for a 70 kg
man) (Hayabuchi et al. 1979); 2,3,4,7,8-P5CDF was the major component.
PCDFs have been found in tissue from Yusho patients at ng.kg-1 levels (Chapter
6). The initial toxic clinical symptoms included swelling of the eyelids
and eye discharge, acne, swelling of limbs, digestive disruptions, numbness
and other neurological signs, and skin pigmentation (Kuratsune et al. 1972).
In 1979, a similar episode also involving PCB contaminated rice oil was
reported from Taiwan; about 200 people were involved (Wong et al 1982).
The levels of PCBs (Kanechlor 400 and 500) and PCDFs were somewhat lower
in the Taiwan oil, about 100 and 0.1 ug.L-1 respectively (Masuda et al.
1982), but the isomer spectrum was similar. The occurrence and severity
of the toxic response in Japan correlated with the estimated amount of
oil consumed (Kuratsune et al. 1972; Hayabuchi et al. 1979) but not at
all with the amount of oil consumed per kg-BW per day (Hayabuchi et al.
1979). This may reflect the ability of the highly-chlorinated PCBs and
PCDFs to accumulate in the body. It is interesting to note that the latent
period before the onset of toxic symptoms showed a negative correlation
with the amount of oil consumed per kg per day, in accord with general
principles of toxicology but in contrast to other aspects of PCDF toxicology,
such as the latent period before death following administration of toxic
doses to laboratory mammals (see Section 7.2.5). The signs and symptoms
observed in these human patients resemble those described for laboratory
primates (Section 7.2.1), including mucocutaneous pigmentation, acne, deformed
nails and dry skin (Wong et al. 1982). Fischbein et al. (1982) reported
that in 326 capacitor manufacturing workers a high prevalence (37%) of
dermatological abnormalities was found. The symptoms included erythema,
dryness and thickening of the skin, hyperpigmentation, rash, swelling and
acne. When a subgroup of the most affected workers with skin abnormalities
(thought to related to PCB exposure in particular) were compared with non-affected
workers, a significant difference was found between the mean concentrations
of the higher PCB homologues. PCDF concentrations were not investigated
in this study but capacitor workers could be subject to high PCDF exposure
(Section 5.2.2). It is not possible to draw firm conclusions about the
effect of PCDFs on humans from incidents involving PCBs because in such
cases the people are also exposed to the PCBs per se and other contaminants
such as polychlorinated quaterphenyls (PCQs) in the case of Japanese Yusho.
Although the PCDFs are generally much more toxic than the other chemicals,
they are usually present in relatively small amounts. In Yusho oil the
ratio of PCDF:PCQ:PCB was 1:160:500 (Kashimoto et al. 1981). Hori et al.
(1982) attempted to clarify the effects of PCBs, PCQs and PCDFs by administering
purified PCBs ("free" of PCDF), PCB contaminated with PCDFs, and PCQs,
orally to monkeys (Macaca fascicularis) at 5 mg.d-1 for 20 weeks. In the
groups fed purified PCB, immunosuppression and histopathological
changes of the liver were observed. In the group receiving contaminated
PCBs, there were more marked decreases in body weight, as well as immunosuppression
and fatty liver and histopathological changes; in addition, hair loss,
acne eruptions, edema of the eyelid, congestion of the Meibomian gland
and other characteristic dermatological findings of Yusho disease were
noted. In the group fed PCQs, there was immunosuppression as well
as enlarged liver but no decrease in body weight or skin abnormalities.
These results suggest that the PCDFs were probably largely responsible
for the symptoms observed in Yusho disease. Toxicity to aquatic organisms:
There are very few data on the toxicity of the PCDFs to aquatic organisms.
Juvenile Atlantic salmon, fed a PCDF mixture in the diet (2.7 D2CDF, 5.7
T3CDF, 2.8 T4CDF, 9.1 O8CDF ug.g-diet-l), had a median mortality of 120
+/- 30 d (Zitko and Choi 1973). No mortality was observed when immature
brook trout were given a single dose of 2,8-D2CDF at levels as high as
122 mg.kg-BW-1 (Zitko et al. 1973). Zitko et al. (1973) indicated that
after dietary dosing, tri and tetra PCDFs were retained preferentially
to 2,8-D2CDF in fish liver and muscle, with greatest retention in the liver.
Fingerman and Fingerman (1977) reported that C8CDF at a concentration of
16 x 10E-6 ug.L-1 in the aquarium water slightly inhibited the rate of
molting of the fiddler crab Uca pugilator. (McLeod et al, 1984)
Study #8
-
decreased antibodies --- immunoglobulin-M (IgM) and immunoglobulin-G
(IgG)
-
significant increases in absolute and percent T-suppressor
(Ts) cells
-
reduction in the percent T-helper (Th) cells
Preliminary results were reported concerning immunologic
investigations in adult Rhesus-monkeys initiated at 23 months of age with
daily exposure to Aroclor-1254 (11097691) at concentrations of 5.0, 20.0,
40.0, or 80.0 micrograms/kilogram (microg/kg). Studies were intended to
determine the effects of low levels of the chemical on the immune system
of the adults and their offspring who were exposed in-utero or through
nursing. Analysis of antibody production indicated a statistically significant
trend toward decreased antibody titers as the dose of Aroclor-1254
increased for the immunoglobulin-M (IgM) and immunoglobulin-G (IgG)
class of antibodies to sheep red blood cells (SRBC). This effect was noted
at all dose levels, even at 5.0microg/kg, suggesting a high degree of sensitivity
of this assay in detecting subtle effects on the immune system. Significant
increases occurred in the absolute and percent T-suppressor (Ts) cells
with a concurrent reduction in the percent T-helper (Th) cells. B-Lymphocytes
were not affected by the treatment. No significant differences were noted
in the levels of total serum IgG and IgM. The treatment also had no significant
effect on hydrocortisone levels or the total serum protein, albumin, or
the alpha, beta and gamma globulins. Efforts are currently underway to
determine the mechanism by which the chemical exerts its immunotoxic effects.
(Tryphonas et al, 1989)
Other pages in this Immunity section:
|
