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Monkey
Infants - PCB Laboratory Studies
| Normal monkey behavior includes advanced problem-solving
capabilities, complex social relationships, and sensory acuity equal or
superior to humans. These factors have caused researchers to use monkeys
for studies of neurotoxicants like PCBs (regardless of the moral implications.)
Biologically, our bodies respond to chemicals in similar ways, and monkeys,
like humans, have relatively long periods of gestation, infancy, and adolescence.
(Burbacher et al, 2000) This means we can make close comparisons between
study results in monkeys and humans. |
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The following studies are different from the human baby
studies, because the researchers could precisely measure and control the
doses of PCBs. These were also "pure" PCB exposures, without the usual
mix of other chemicals which most of us humans carry in our bodies. In
particular, the fish in the Fox River and Green Bay contain hundreds of
other chemicals in addition to PCBs, so the effects we face in real life
are PCBs plus whatever the health effects may be of the other chemicals.
Animal studies like these show that PCBs are likely one of the major "active
ingredients" causing the learning problems in the human baby studies.
The following are abstracts of scientific journal articles,
with a summary of findings highlighted above. (Several more studies
have been done with monkeys, showing similar results. We’ll add to the
list as we get copies of the articles.)
Summary of Effects from Eleven Studies
Some of these studies were small and looked at only a
few health factors, while others were larger and more detailed. Some studies
used high PCB doses, while some used low or background levels of PCBs.
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Neurological Damage (6 studies)
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Long-term effects (3 studies)
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Reproductive changes (1 study)
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Immune system changes (1 study)
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90% of PCBs fed were retained in the body (1 study)
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Finger-nail changes (1 study)
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Blood changes (1 study)
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Decreased chloesterol and total bilirubin (1 study)
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The more-toxic congeners of PCBs accumulate selectively in
the offspring (2 studies)
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Decreased conception rates (1 study)
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Increased fetus mortality (1 study)
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Infant PCB levels declined after weaning (1 study)
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Breast-feeding exposures caused negative effects, not just
exposure in the womb (1 study)
Study #1
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Neurological Damage --- Deficits in spatial learning and
memory
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Neurological Damage --- Cognitive deficit
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Long-term effects
Monkeys exposed to low, chronic levels of polychlorinated
biphenyls (PCBs) in utero and during nursing until 4 months after birth
were tested at 4-6 years of age on delayed spatial alternation (DSA), a
spatial learning and memory task. Deficits in performance accuracy were
detected in two cohorts of monkeys whose mothers had been fed 2.5 ppm of
the PCB mixture, Aroclor 1248, in their diet for an 18-month period ending
at least 12 months prior to pregnancy. The deficit was most apparent at
the shorter delays, suggesting that it was not due to memory impairment,
but may have been due to impairments in associational or attentional processes.
There may also have been a deficit in a group of monkeys whose mothers
were fed 1.0 ppm of the PCB mixture, Aroclor 1016. However, the deficit
in this group was less pronounced than in the other groups. The appearance
of a PCB-induced cognitive deficit more than 3 years after the end of exposure
indicated the existence of very long-term adverse consequences of low-level
perinatal PCB exposure. (Levin, et al 1988)
Study #2
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Neurological Damage --- Impaired spatial discrimination
Monkeys exposed to PCB mixtures during gestation and lactation
were tested on two-choice discrimination-reversal learning (DR). In Experiment
1, offspring of mothers fed 1.0 ppm Aroclor 1248, and offspring born 1.5
years after maternal exposure to 2.5 ppm Aroclor 1248 ended did not differ
from controls on spatial, color or shape DR problems. In Experiment 2,
offspring of mothers fed 0.25 or 1.0 ppm Aroclor 1016 and offspring born
3 years after maternal exposure to 2.5 ppm Aroclor 1248 ended were tested
on the same spatial, color and shape problems, but a spatial problem with
color and shape as irrelevant cues was inserted after the initial spatial
problem. Performance of the high dose Aroclor 1016 offspring was impaired
on the initial spatial problem, and facilitated on the shape problem. Performance
of the Aroclor 1248 postexposure offspring was facilitated on the shape
problem. This apparently facilitatory effect may represent a failure of
PCB-exposed monkeys to learn the irrelevancy of the shape cue when it was
initially presented. (Schantz et al, 1989)
Study #3
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Reproductive changes
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Immune system changes
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90% of PCBs fed were retained in the body
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Finger-nail changes --- nail loss, inflammation and dilation
of tarsal glands
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Blood changes --- decreased reticulocytes, platelet volume,
hemoglobin and red blood cells
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Decreased cholesterol and total bilirubin
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Little effect on growth and development
Groups of 16 female Macaca mulatta monkeys, whose average
estimated age at study initiation was 11.1+/-4.1 years, self ingested capsules
containing daily doses of 0, 5, 20, 40 or 80 ug of Aroclor 1254/kg bw for
2 years at which time 93% of the treated monkeys had attained a qualitative
pharmacokinetic steady state. They were mated to untreated males while
continuing to receive a daily dose of Aroclor 1254 during mating, gestation
and the first 6 weeks of nursing. All infants were nursed for 22 weeks
and then separated. The infants received no further PCB. Monitored parameters
included daily health status; feed and water consumption; menstrual status
(daily); body weight (weekly); hematology; serum chemistry; detailed clinical
evaluation; PCB analysis of blood, adipose tissue and feces; T3/T4 levels
(monthly); evaluation of estrogen and progesterone levels during one menstrual
cycle just prior to breeding and immunological testing prior to and post
breeding. Major treatment findings included: Reproduction - a dose dependent
effect upon reproductive parameters; Immunology - several treatment related
effects; PCB analysis - fecal analyses indicated greater than a 90% retention
of the administered dose; Clinicals - changes to nail beds with subsequent
nail loss, inflammation and dilatation of tarsal glands; Hematology - decreases
in reticulocytes, mean platelet volume, hemoglobin, red blood cells; Serum
biochemistry--- decreases in cholesterol and total bilirubin; Infants -
little effect on growth and development. (Arnold et al, 1991)
Study #4
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Neurological Damage --- deficits in two-choice discrimination-reversal
learning
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Neurological Damage --- deficits in spacial learning and
memory
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Long-term effects
In a series of studies at the Harlow Primate Laboratory,
offspring of rhesus monkeys (Macaca mulatta) exposed to commercial PCB
mixtures (Aroclor 1016 or Aroclor 1248) were tested on two-choice discrimination-reversal
learning at 1.5 years of age and on delayed spatial alternation, a spatial
learning and memory task, at four to six years of age. Deficits in performance
were observed on both tasks. The deficit observed on delayed spatial alternation
in Aroclor 1248-exposed monkeys was quite dramatic. The monkeys were tested
for 80 test sessions, but were never able to achieve control levels of
performance. This effect was observed when the monkeys were four to six
years of age (young adulthood), even though they had not been exposed to
PCBs since they were weaned at four months of age. The pattern of effects
on both discrimination-reversal learning and delayed spatial alternation
was suggestive of damage to the prefrontal cortex. (Schantz et al, 1991)
Study #5
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The more-toxic congeners of PCBs accumulate in the offspring
Polychlorinated biphenyl (PCBs) analyses were made on prenecropsy
blood samples and postmortem adipose, liver, kidney, and brain tissues
from female rhesus monkeys fed a daily dose of 0, 5, 20, 40, or 80 ug Aroclor
1254/kg body weight for approximately 6 years. During this time, the females
were bred with non-dosed males. All resulting offspring were nursed for
22 weeks and fed no additional PCBs until they were necropsied at approximately
120 weeks after birth. PCBs were also measured in necropsied infant tissues
to determine PCB levels due to intake of PCB-contaminated milk from the
dosed dams, in addition to in utero exposure. Polychlorinated biphenyl
levels in all tissues of the adult monkeys increased with their dosage.
The highest PCB levels were found in adipose tissue and the lowest levels
were found in the brain. Polychlorinated biphenyl residues in the cortex
of the kidney were lower than in the medulla, while in the brain no appreciable
differences were observed between the occipital and frontal lobes. Necropsy
tissues of infants from dosed dams contained more PCBs than those nursed
by controls, but less than tissues from stillborn infants. Although no
differences were observed between PCB tissue levels from monkeys having
offspring and those having no offspring, those having a stillborn infant
had higher PCB levels in their tissues than those with a viable infant.
Similarly, monkeys that were euthanized because of poor health had higher
PCB levels in their tissues than those necropsied at the conclusion of
the study and showed a dramatic shift from tetra- and hexachlorobiphenyls
to penta-and heptachlorobiphenyls in their tissues. The PCB distribution
pattern in tissues from a dosed mother/infant pair differed considerably.
A larger percentage of heptachlorobiphenyls was found in the infant than
in its dam. The adipose/blood PCB ratio increased with dosage, while the
brain/blood PCB ratio in the adult monkeys remained remarkably constant.
(Mes et al, 1995)
Study #6
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Decreased conception rates
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Increased fetus mortality
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, 1998)
Study #7
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Lower-chlorinated PCBs decrease in infants
Specific polychlorinated biphenyl (PCB) congeners were measured
before, during, and after gestation in the blood of rhesus monkeys, as
well as in their milk and in the blood of their infants during lactation,
as part of a long-term feeding study to evaluate the toxicology of Aroclor
1254 on pre- and postnatal development of infant monkeys. During gestation
a considerable shift from the higher to lower chlorinated biphenyls in
the blood was observed in both dosed and nondosed
animals. The contribution of penta- and hexachlorobiphenyls
in the milk slightly increased with higher dosage. In addition, the percentages
of 2,2'3,4,5'-,2,2',4,5,5'-, and 2,3,3',4',6-pentachlorobiphenyls were
remarkably lower in the milk of dosed dams than in the originally ingested
Aroclor 1254. PCB congener levels in infant blood increased during the
lactation period but immediately decreased upon weaning. The lower chlorinated
biphenyls virtually disappeared from infant blood after 16 weeks of nursing.
Some correlations were observed between PCB congener levels in mother and
infant and the congener ratios calculated. (Mes et al, 1995)
Study #8
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Infant PCB levels declined after weaning
Analytical and quality control procedures are described for
the determination of polychlorinated biphenyls in blood, adipose tissue,
and milk from dosed female monkeys and their offspring, as part of a study
to measure the toxicological effect of Aroclor 1254 on the pre- and postnatal
development of fetus and infant, respectively. Recoveries of polychlorinated
biphenyls from fortified blood, fat, and milk of monkeys ranged from 81
to 96%, whereas recoveries from fortified corn oil, used to evaluate routine
analysis, ranged from 94 to 108%. The coefficient of variation for triplicate
analyses of lipids and polychlorinated biphenyls in blood or adipose tissue
or both was less than 10%. Polychlorinated biphenyl levels in blood, milk,
and fat rose with increasing dosage. After weaning, when the infants were
no longer exposed to polychlorinated biphenyls, their blood levels declined
rapidly and approached maternal levels within 40-50 weeks. Approximately
100 weeks after weaning, polychlorinated biphenyl levels in adipose tissue
of infants from treated dams reached the background levels of those in
the control group. (Mes et al, 1994)
Study #9
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Different toxins produce different types of neurological
damage
While the effects of exposure to PCBs have not been studied
as extensively as those of lead, available data indicate that developmental
PCB exposure produces impaired performance on a number of tasks, the pattern
of impairment appears to be different in some respects from that produced
by lead. In contrast, the consequences of developmental exposure to methylmercury
on cognitive performance in the monkey is much less clear. While deficits
on a couple of tests of cognitive function were observed during infancy
in one cohort of monkeys, assessment of performance on other tasks in this
and other cohorts tested during infancy and adulthood revealed no deficits.
These results stand in marked contrast to the deficits in sensory system
function observed in these same monkeys exposed developmentally to methylmercury.
It appears that each of these neurotoxic agents produces a unique signature
of neurotoxic impairment. (Rice, 1996)
Study #10
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Neurological Damage --- Impaired spatial learning to certain
types of PCBs
Polychlorinated biphenyls (PCBs) are wide-spread environmental
contaminants that have been associated with intellectual impairments in
children exposed in utero. The most pronounced effects have been reported
in tests involving working memory. We have observed similar deficits in
both primates and rodents exposed to PCBs during development. In our initial
studies, rhesus monkeys were exposed to complex commercial PCB mixtures
during gestation and lactation. After weaning, the offspring were evaluated
on learning and memory tests including discrimination-reversal learning
(RL) and delayed spatial alternation (DSA). PCB-exposed offspring exhibited
impaired spatial learning, particularly on the DSA task. Later, we investigated
the effects of individual ortho-substituted and coplanar PCB congeners
on spatial learning and memory in the rat. Three of four ortho-substituted
PCB congeners impaired DSA acquisition. In contrast, exposure to coplanar
PCBs or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) had no effect on the
DSA task, and appeared
to facilitate spatial learning on the radial arm maze.
These disparate findings suggest that the two major classes of PCBs may
have very different actions in the nervous system. The specific molecular
and cellular events underlying PCB-related alterations in spatial learning
and memory are not yet understood, but we are beginning to elucidate electrophysiological,
neurochemical and molecular changes that may be involved in mediating the
behavioral effects. (Schantz, 1998)
Study #11
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Breast-feeding PCB exposures caused negative effects, not
just exposure in womb
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Neurological Damage --- deficits on spatial delayed alternation,
fixed interval, and differential reinforcement of low rate performance
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Neurological Damage --- retarded learning
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Neurological Damage --- perseverative behavior
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Neurological Damage --- inability to inhibit inappropriate
responding
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Long term effects
The preponderance of evidence in humans suggests that PCB-induced
behavioral deficits result PCB exposure before birth rather than exposure
through breast milk, although a recent study reported lower psychomotor
scores during infancy associated with PCB concentration in breast milk.
In this study, monkeys were dosed from birth to 20 weeks of age with a
PCB congener mixture representative of the PCBs found in human breast milk.
Blood and fat levels of PCB-exposed monkeys at the end of the dosing period
were within the range observed in the general human population, while levels
in control monkeys were below averages observed in humans in industrialized
countries. Behavioral assessment on a series of tasks was performed when
monkeys were between 2.5 and 5.0 years of age. Robust deficits were observed
on spatial delayed alternation, fixed interval, and differential reinforcement
of low rate performance. No group differences were observed for the number
of errors on a series of nonspatial and spatial discrimination reversal
tasks. Behavioral deficits included retarded learning, perseverative behavior,
and inability to inhibit inappropriate responding. These results have implications
for the potential contribution of exposure to PCBs through breast milk
to behavioral impairment. (Rice, 1999)
References
Arnold DL, Bryce F, Karpinski K, Mes J, Tryphonas H, Truelove
J, Zawidzka ZZ. "Toxicity of polychlorinated biphenyls (Aroclor 1254) in
adult monkeys as a consequence of continuous exposure and in infant monkeys
exposed during pregnancy and nursing." Toxicologist 1991 Feb;11(1):220
Arnold DL, Bryce F, McGuire PF, Stapley R, Tanner JR,
Wrenshall E, Mes J, Fernie S, Tryphonas H, Hayward S et al. "Toxicological
consequences of aroclor 1254 ingestion by female rhesus (Macaca mulatta)
monkeys. Part 2. Reproduction and infant findings." Food Chem Toxicol 1995
Jun;33(6):457-74 and Comments: Food Chem Toxicol 1998 May;36(5):451-3
Burbacher TM, Grant KS. "Methods for studying nonhuman
primates in neurobehavioral toxicology and teratology." Neurotoxicol Teratol
2000 Jul-Aug;22(4):475-86
Levin ED, Schantz SL, Bowman RE. "Delayed spatial alternation
deficits resulting from perinatal PCB exposure in monkeys." Arch Toxicol
1988;62(4):267-73
Mes J, Arnold DL, Bryce F. "Determination of polychlorinated
biphenyls in postpartum blood, adipose tissue, and milk from female rhesus
monkeys and their offspring after prolonged dosing with Aroclor 1254."
J Anal Toxicol 1994 Jan-Feb;18(1):29-35
Mes J, Arnold DL, Bryce F. "Postmortem tissue levels of
polychlorinated biphenyls in female rhesus monkeys after more than six
years of daily dosing with Aroclor 1254 and in their non-dosed offspring."
Arch Environ Contam Toxicol 1995;29:69-76
Mes J, Arnold DL, Bryce F. "Female rhesus monkeys dosed
with Aroclor 1254: analysis of polychlorinated biphenyl congeners in dam's
milk and in the blood of dams and their offspring before, during, and after
gestation." J Anal Toxicol 1995 Jul-Aug;19(4):209-17
Rice DC. "Effects of developmental exposure to environmental
chemicals on learning and memory performance in monkeys." Teratology 1996
May;53(5):18A
Rice DC. "Behavioral impairment produced by low-level
postnatal PCB exposure in monkeys." Environ Res Feb 1999;80(2 Pt 2):S113-S121
Schantz SL, Levin ED, Bowman RE, Heironimus MP, Laughlin.
"Effects of perinatal PCB exposure on discrimination-reversal learning
in monkeys." Neurotoxicol Teratol 1989 May-Jun;11(3):243-50
Schantz SL, Levin ED, Bowman RE. "Long-term neurobehavioral
effects of perinatal polychlorinated biphenyl (PCB) exposure in monkeys."
Environ Toxicol Chem 1991;10(6):747-56
Schantz SL. "Developmental exposure to polychlorinated
biphenyls impairs learning and memory in primates and rodents." Neurotoxicol
Teratol 1998 May/Jun;20(3):349
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