Document 15091

0000017
ana Teraiotog\. \'o\. II, pp. I^?-I-£ Pcrcamon Press pic. I9°0 Pnntea m ihe U S.A
92-0361'90 S3 00 *
00
Polychlorinated Biphenyls and
the Developing Nervous System;
Cross-Species Comparisons
HUGH A. TILSON1
Laboratory of Molecular and Integrative Neuro sciences
National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
JOSEPH L. JACOBSON
Department of Psychology, \Vayne State University, Detroit. \ll 4S202
AND
WALTER J. ROGAN2
Epidemiology Branch, National Institute of Environmental Health Sciences
Research Triangle Park, NC 27709
TTLSON, H. A.. J, L. JACOBSON AND W. J. ROGAN. Polychlorinaied biphenyis and the developing nervous system:
Cross-species comparisons. NEUROTOXICOL TERATOL 12(3) 239-248. 1990. — Polychlonnaied biphenyis are stable, lipophilic
indusmaJ compounds that are present in residue levels in human tissue, wildlife, and freshwater sediment. They are toxic, and are
known to cross the placenta and intoxicate the letus. Two large outbreaks of PCS poisoning have occurred in Asia; v.omen pregnant
at or alter the exposures had children who were developmentaily impaired. Laboratory experiments in rhesus monkeys and rodencs.
designed to assess neural or developmental effects, show altered activity levels, impaired learning, and delayed ontogeny of reflexes.
Children exposed transplacemaily to levels constdered to be background m the U.S. have hypotoma and byporeilexia at birth, delay
in psychomoior development at 6 and 12 months, and poorer visual recognition memory at 7 months. Allowing for differences in
testing, effects art roughly similar across species, but current methods used to calculate allowable or reference doses give results up
to 4 orders of magnitude apart, with the lowest level based on the neurotoxicology level coming from the human data.
Polychlorobiphenyi compounds
Polychlorinated dibenzofurans
Nervous svstem diseases, chemically induced
IN many species including humans, exposure of the fetus or
neonate to PCBs (polychlorinated biphenyis) produces neural and
developmental changes in the offspring. PCBs are one of the few
agents for which there are adequate data to attempt qualitative and.
to a degree, quantitative cross-species comparisons. Here, we will
review the data from human and experimental studies in which
exposure occurred to ihe mother and the offspring were evaluated.
PCBs are a family of industrial compounds that had widespread
use from their introduction in the 1930's until manufacture ceased
in the rrud-1970's (13). They were soid as mixtures of the
congeners under trade names such as Aroclor. Kanechior. etc.
Child development
Their major use was as a dielectric in transformers and capacitors,
but their insulating, optical, and thermal properties led to their use
in cable, carbonless copy paper, small electric pans, and microscope immersion oil. Goods containing PCBs were discarded
without thought to environmental impact: by 1969 (14), they had
become a worldwide pollution problem, since they resisted physical or biological degradation, and accumulated in the food chain.
PCBs are still routinely delectable in human tissue (30). There are
a few known sources of PCBs, such as Great Lakes fish, and
occupational exposures can produce very high body burdens, but
the route by which most general population exposure occurs is not'
'Current address: Division of Neurotoxicology. Environmental Protection Agency. Research Trianeie Pork. NC 27711.
•Requests forrcpnnts should be aadressea to Walter J. Roean. Mail Drop A3-05. Epidemioioey Branch. NIEHS. POB 121:3, Researcn Trianeie Park.
NC 17709.
239
TILSON. JACOBSON AND ROGAN
TABLE 1
Sl'MMARY OF EFFECTS OF PRENATAL EXPOSURE TO PC3s ON FETOTOXICPTY AND REPRODUCTION
Compound
Species
.Arocior 1248
Rhesus
monkeys
Cohort
Dose
E.^p.1
mg/kg;dayi
Feiotoxic or
Regimen
Reproductive Effect
Reference
1 il)
0.084
(2.5 ppmi
perinatal
(to 3 montns
nursing)
; binhwetght (2\?c loueri
chloracne
(3)
I 'Tla)
0.084
pen natal
(posiexposure i
chloracne
hyperpigmentanon at
hairline
(4)
(2.5 ppm>
no binhweight effect
(8)
3a (Eh)
0.014x3
(0.5 p p m x 3 )
Kanechlor 500
SpragueDaw lev rats
20-100
prenatal
at 100 mg/kg:
I weight female fetuses
100% perinatal mortality
(44)
Arocior 1254
'.Vistar rats
0.2-269 ppm
perinatal
at 269 ppm:
i b.wt.; high perinatal mort
(38)
LOAEL
O.OS4
100
NOAEL
0.014
:o
I number or" litters
Fencior 42
ICR mice
1 1 or 82 ppm
perinatal
no consistent findings
(45)
11
Fischer-344
rats
5-10 x 5 days
IP (before mating)
prenatal
no postnatal body weight effect
no difference in liner size
(39)
10
2-tx 10 days
prenatal
no postnatal bodyweight effect
no difference in litter size
(39)
4
1-2x20 days
(lactation)
postnatal
no postnatal bodyweight effect
(39)
i
3?
prenatal
t number stillborn
(10)
(gestation)
Tetrachloro-
biphenyl
CD-1 mice
(gestation)
32
~~
1 birth weight
40% monaliry from
birth thru weaning
known.
PCBs. as well as the chlorinated naphthalenes and dioxins. had
been known to produce an acneform rash at the site of dermal
contaa (12), but the first evidence of systemic toxiciry came from
a mass poisoning that occurred in Japan in 1968 (34). Cooking oil
had been contaminated by thermally degraded PCBs used in
decolorization during the processing of the oil. About 1000 adults
were affected. Women who were pregnant at or after the time of
exposure had children with a variety of physical and developmental problems. This incident, together with epizootics in chickens
(21) and monkey colonies (22). spurred laboratory research on the
transplacental toxiciry of PCBs. High levels of PCBs in Great
Lakes fish led to a prospective, longitudinal study of the offspring
of fish-eating women in Michigan, and data showing that many
women throughout the U.S. had PCBs in breast milk above the PDA
action levels led to studies of breast-fed children in North
Carolina. Finally, there was an unfortunate replication of the
female rhesus monkeys (M. muianal for 86-89 weeks: dosing was
terminated at the end of 3 months of nursing for those monkeys
with surviving offspring. Oul of the 8 conceptions, there were 5
live births, 3 of which were tested. The mothers received an
average total intake of 293 mg during the course of the study or
0.084 mg PCB/kg/day (Table 1). Four control infants were
selected for subsequent testing from a group of 12 normal infants
bom to control monkeys.
Birth weights of the 3 PCB-treated monkeys were 21 % lower
rhan the controls and by two months of age the PCB-treated
monkeys had developed characteristic PCS toxiciry (3) (Table 1).
These monkeys were tested on a sequence of 11 tasks, beginning
with motor activity, at 6 and 12 months of age (Table 2). The
animals with the highest peak levels were more hyperactive, [n a
subsequent paper. Bowman ei ai. (8) reported that PCB-treated
monkeys displayed a lack of between-session habituation of
activity. In a study on the same monkeys conducted at 44 months
Japanese episode on Taiwan in 1979. in which over 2000 persons
were poisoned. Srudy of children whose only exposure was
cransplacental showed persistent dysmorphism up to six years after
the outbreak.
of age. Bowman and Heironimus (6) reported that PCB-exposed
monkeys hyperactive at 6 and 12 months of age were hypoactive
at 44 months of age (7.8).
The monkeys exposed to PCB in the original cohort (7) were
also tested for PCB-induced alterations in learning and memory, as
RESULTS OF LABORATORY STUDIES
weii as changes in performance, using the Wisconsin General Test
RHESUS MONKEYS
witn the first given at 7 months of age and the last given at 24
Apparatus (WGTA) (Table 3). These tests were given in sequence
Bowman er at. <7) fed 2.5 ppm Arocior 1248 to nine adult
months of aee. PCB-treated monxevs showed deficits on the first
?CBs AND THE DEVELOPING CNS
TABLE :
SUMMARY OF EFFECTS OF PERINATAL EXPOSURE TO PCBs ON SEUROMOTOR FUNCTION IN 0,'IMALS
Compound
Aroclor 12-18
Kanechlor
-^00
Species
Rhesus
monkeys
Rats
Cohort
E.XD. i
Dose
i me.< J; a/day i
Reeimen
Effect
Reference
pen natal
(to 3 months
nursine)
6 months
il months
•U months
* activity
(S)
* activity
. activity
(81
161
2 (Hai
0.084
'2.5 ppmi
pennaul
(postexposurc)
1 2 months
* activity
(8)
3a (Hal
0.014x3
(0.5 ppmx3)
pennaul
12 months
* activity
(8)
3b(Uai
0.030x3
(1.0 ppmx 3»
pennaul
12 months
* activity
(8)
100
postnatal
days 23-55
, activiry
>3U
100
postnatal
LOAEL
0.014
NOAEL
-
not specified
Rats
Fenclor 42
Neuro motor
0.084
'2.5 ppmj
1 HI
cays 21-28
aay 35
(not specified)
Aroclor 1254
Time of
Test
, activiry
impaired, inclined
screen
»32)
Wistar rats
0.2-26 ppm
perinatal
pit weaning
impaired neurological development
(38)
ICR mice
11 or 82 ppm
perinatal
27 days
T activiry
(30 min test)
(45)
11
—
Fischer-3-J-l
rats
5-10x5
days IP
(before mating)
prenatal
days U and 21
day 6
i activity
impaired swimming
(39)
10
2
2-tx 10 days
prenatal
(gestauon)
2.5
0.02
days 14 and 21
no activity effect
days 6, 8. 10
impaired swimming
4
2
i activity
impaired swimming
1
—
52
—
and 12
Tetrachloro-
CD-1 mice
1-2x20
days
i lactation)
postnatal
52 (gestation)
prenatal
biphenyi
day 14
days 6. 8, 10
and 12
>21 days
spinning
(47)
days 35 and 65
spinning.
(10)
| activiry.
neurological signs
two discrimination reversal tasks (spatial and color). PCB-treated
animals were retarded in learning progressive probability shifts
hairiine. Analysis of the milk at the time of weaning revealed PCB
and the object alternation tasks. Extrapolated peak PCB body
burdens (4 months of aeet were correlated significantly with
between 8 and 24 months of age. This cohort of monkeys was
biopsies that included subcutaneous tissues taken from the infants
at binh and 3 month of age indicated PCB levels increasing from
virtually no detectable level to an average of 3.31 ixg per gram of
tissue, respectively (4). Bowman er ai. (8) reponed liitle PCBs in
studied at about 59 months of age for alterations in food-
subcutaneous fat of the offspring at 8 and 12 months of age.
reinforced, schedule-controlled behavior (36). No differences
between treated and control monkeys were observed.
Bowman ei al. (8) took eight surviving breeding monkeys from
the previous experiments (cohort 1) that had been removed from
;he PCB-comaimng diet (2.5 ppmi for periods ranging from 22 to
84 weeks pnor to conception of a second cohort of infants i Table
!). Five infants survived for testing. Seven control infants were
obtained. The average PCB levels in subcutaneous fat for the
mothers was 0.8r0.9 ppm iSDi. which was only slightly higher
Offspring in cohort 2 showed hyperactiviry in 24 daily 90-min
motor activity sessions when they had reached 12 months of age
(8^ (Table 2). The effects were more prominent following repeated
testing, an observation similar to the first cohort.
In a third cohort of animals, two new groups of breeding
mothers (cohort 3) were fed Aroclor 1248 three times per week in
concentrations of 0.5 and 1.0 ppm. respectively, for periods
ranging from 65 to 102 weeks at the time of conception 18) (Tables
1 and 2). Five offspring from each group were used in subsequent
than those of control animals. At birth, analysis of the adipose
•.issue of two stillborn infants reveaied PCB levels of 2-2.5 y.g per
gram 01 tissue. Dunns tne 4 momns of nursing for the surviving 5
monxeys. :he infants developed hyperpigmentation about the
behavioral testing. Motor activity of these monkeys was tested at
! 2 months of age and compared to the activity generated by the
control offspring in cohort 2 (vide supra i. PCB exposure resulted
;n significant do&e-depenaent increases m motor activity. PCB
increased errors in five of the nine learning tasks conducted
levels that averaged 0.05 pig per gram of whole milk. Skin
TILSON. JACOBSON AND ROGAN
TABLE 3
SL'MMARY OF EFFECTS OF PERINATAL EXPOSURE TO PCBs ON LEARNING AND PERFORMAN'CE IN ANIMALS
Compound
Cohort
fExp.)
Species
1 (I)
Arocior 1248 Rhesus
monkeys
Dose
(mg/kg/day)
Regimen
0.084
(2.5 ppm)
perinatal
fio 3 months
0.084
(2.5 ppra)
perinatal
Time of
Test
Learning
Effect
Reference
8-24 months WGTA"— impaired
59 months
SCBt — no effect
(7)
(37)
36 months
(37)
LOAEL
NOAEL
0.014
-
aiming)
2 (Ha)
SCB- 1 ICt
higher SR§
(postexposure)
omission rates
3a (Ho) 0.014x3
(0.5 ppm)
Arocior 1254
Quail
200 ppm
perinatal
42 months
SCB-i 1C
(37)
posthatch
14 days
unconditioned
(33)
avoidance impaired
KanechJor
500
Fenclor 42
Tetrachloro-
ICR mice
11 or 82 ppm
perinatal
23 days
active avoidance —
t latency
(45)
11
-
Spngue-Oawley
rats
20-100
prenatal
91 days
at 20 mg/kg:
water mazeacquisition impaired
(44)
20
-
Fischer-344
5-10 x 5
prenatal
30 days
no active
(39)
10
5
rats
days IP
(before mating)
CD-1 mice
biphenyl
avoidance effect
2-4 x 10 days
(gestation)
prenatal
30 days
impaired active
avoidance
(39)
4
2
1-2x20 days
(lactation)
postnatal
30 days
impaired active
(39)
2
I
32
prenatal
(47)
32
~"
avoidance
35 days
active avoidance—
t latency
(gestation)
•WGTA - Wisconsin General Test Apparatus.
^SCB * Schedule-Controlled Behavior.
;IC - Index of Curvature.
§5R - Scheduled Reinforcement.
body burdens in subcutaneous fat measured at 8 months of age for
the 0.5 and 1.0 ppm groups were 5.2±2.8 (SD) and 8.6 = 2.8
ppm. respectively.
that exposure to PCB altered the degree to which secondary
reinforcing stimuli control responding during omission of food
reinforcement.
The controls aad treated animals derived from mothers from
which 2.5 ppm PCB had been removed from the diet (cohort 2)
QUAIL
and the offspring from mothers receiving 0.5 ppm both before and
during gestation and nursing (cohort 3) were saved for subsequent
testing using schedule-controlled operant responding (37) (Table
Kreitzer and Heinz (33) exposed Japanese quail (Commix
coturnix japomca) chicks to Arocior 1254 (200 ppm) in their feed
3). Testing started at 36 and 42 months of age, respectively. The
estimated peak fat concentration of PCB for the offspring from
cohon 3 was 15 ppm, while the peak fat concentration for treated
monkeys from cohort 2 was 5 ppm. T.-.z monkeys were tested
under a series of fixed-interval schedules of food reinforcement.
Unlike the results from monkeys from the fust cohort (vide supra)
which were tested at about 59 months of age. there was a slight,
but statistically significant lowering of the index of curvature in
these PCB-treated monkeys.
Mele et ai. (37) tested their monkeys on a reinforcementomission procedure under which 25% of the scheduled reinforcers
were randomly omitted. For fixed intervals following reinforcement-omission, the 0.5 ppm postexposure group (cohort 3) had
a significantly higher response rate and greater interanimaJ variability in response rate than controls. Such effects may indicate
beginning at seven days of age. The birds were exposed for eight
days, which was followed by 6 days of no exposure. Twenty-four
hours after initiation of dosing, the chicks were tested for an
unconditioned avoidance response to a moving silhouette. Avoidance response was suppressed in exposed animals (Table 3), even
after untreated feed was restored.
RODENTS
Rats
Shiota (44) gave gravid Sprague-Dawley rats 20 or 100 mg/kg
of KanechJor 500 on days 8 through 14 of gestation or on days 15
through 21 of gestation (Table 1). About one-half of the animals
were sacrificed at day 21 in order to observe the fetuses at term.
while the remaining gravid animals were allowed to litter. Behav-
PCBs AND THE DEVELOPING CNS
TABLE 4
REFERENCE DOSE COMPARISONS
Dose
(mg/kg/day)
LOAEL
Range
Type of Effect
Rodents:
Fetotoxicity
Humans:
3.2x 10"J
I.OxlO"1
3.2X10"2
0.014
0.084
0.014
0.084
0.014
0.014
0.014
I . 4 X 10"*
1.4X 10"*
I . 4 X 10~ 3
—
Reproduction
Motor Activity
Learning/Memory
Fetotoxicity and CWoracne
Postnatal Body Weights
Motor Activity
Learning/Memory
Performance
Hypotomcity on the Brazeiton Scale
Psychomotor Scale Decrement on 12-Month BayJey
Impaired Visual Recognition Memory
Carcinogenicity, Risk* I x 10~*
(EPA quantitative estimate, lifetime exposure) [(1), p. 95]
Reference
Dose*
20-26
2-10
4-26
32-269
1-320.2-2
2-32 1-5
32-269
Postnatal Body Weights
Rhesus Monkeys:
Aroclor 1248
NOAEL
Range
:.oxio—
I.Ox 10"1
I . 4 X 10"J
I . 4 X 10"3
9.3x I0" s
9.3X J0" s
9.3X 10"6
9.3x 10"*
2.7xiO"s
Z.7X10"6
1.3X10' 7
Current EPA Reference Dose
(based on low birthweight in Rhesus monkeys) {(1), p. 94]
1.0X10" 4
•For animal experiments, intra- and interspecies variability were considered. For human data, only intraspectes variability was
considered.
ioral testing started at about 12 weeks of age. Animals were given
five trials in which they were allowed to explore an open field for
a period of 5 mm. Starting at 13 weeks of age, the rats were tested
in a multiple T-raaze using escape from water as the endpoint.
Gestational exposure to KanecbJor 500 had no significant effect
on the total number of implants, number of resorpbons, average
litter size or number of externally malformed fetuses. One of the
females receiving 20 me/kg on days 15-21 died on day 18 of
gestation. No pups from the 100 tngrtcg group survived for testing
The body weights were reduced and ontogeny of negative geotaxis, auditory startle and air righting reflexes of pups from
mothers exposed to 26 ppm were altered prior to weaning (Table
2). Smaller decreases in body weight and delayed development of
auditory startle were seen in pups from mothers exposed to 2.5
ppm PCBs.
Pantaleoni et ai. (39) exposed female rats to Fenclor 42 for 5
days during the 2 weeks prior to mating, during gestation (days
6-15 of gestation), or during lactation (days 1-21 postpartum)
(Table 1).
(Table 1). PCB exposure did not affect maternal weight or weight
There was no significant difference between remaining groups
in weaning rate or survival to the time of behavioral testing. Males
exposed to 20 mg/kg on days 15-21 of gestation had increased
number of errors in the water maze (Tables 2 and 3).
Koja tt ai. (31) administered Kanechlor 400 (100 mg/kg,
orally) for six successive days to rats that were either 3 or 20 days
of age. There was decreased spontaneous motor activity during a
rive minute test period in both groups (Table 2). Performance on
a rotating rod was reported to be "slightly impaired" in rats
of the offspring up to 21 days of age. Preconception or in utero
exposure to PCBs had no effect on cliff avoidance, while this
measure was suppressed in the postnatally treated groups. The
development of swimming behavior was also affected in all three
groups of PCB-exposed rats (Table 2). Rats exposed to PCB prior
to conception were less active in an open field at 14 and 21 days
of age, while rats exposed postnatally were suppressed at 14 days
of age. Rats exposed in utero were not affected. Postweaning
learning using an active avoidance task was studied at 30 days of
age and rats exposed in utero and posmatally were impaired in the
acquisition of this task (Table 3). These data indicate that
behavioral effects following exposure to PCBs may occur following either prenatal or postnatal exposure.
exposed to Kanechlor 400 at 3 days of age when tested at 5 weeks
of age.
In a subsequent study, Koja ei ai. (32) dosed three-day-old rats
orally for 12 successive days with 100 mg/kg of Kanechlor 400. At
three and four weeks of age. there was decreased spontaneous
motor acuviry (Table 2) and impaired performance on an inclined
screen.
Overmann et ai. (38) exposed female Wistar rats via the diet to
Mice
0.02, 2.5, 26 or 269 ppm of Aroclor 1254 from the time of mating
until weaning of their pups (Table 1). The highest dose of PCBs
decreased the number of Utters and lowered pup birth weight: most
pups delivered to these mothers died within a week after birth.
Pregnancy success, pup birth weight and dam body weight and
Chou et ai. (10) studied the 3.4.3'4'-tetrachlorobiphenyl (4CB) in mice (Table 1). Gravid CD-1 mice were dosed by gavage/
on days 10 through 16 of gestation with 32 me/kg of 4-CB. Thfs
dose was not maternally toxic, but did increase the number of
stillborn and resulted in a 40% mortality from birth through
weaning (Table 1). About one-half of ihe Utters displayed a
food intake were not affected at lower concentrations of PCBs.
neurological syndrome, consisting of increased iocomotor activiry
TILSON. JACOBSON AND ROGAN
stanmg at about 15 days of ace liable 21. Affected animals
showed jerkine or rotational movement of the head and episodes of
constant circling around the home cage. Although lighter at birth,
affected 4-CB mice gained weight at approximately the same rate
as unaffected treated animais or controls. The animals had
heterotopic motor neurons and astroglia in ventral spinal fibers and
cylindrical CNS peninsulas that projected into the ventral cranial
another control group *ho were matched by age. sex. socioeconomic status and sib order, exposed infants averaged six to seven
points lower on tne Mental and Psvchomotor Indices of the Bayley
Scales: preschoolers, four points lower on the Stanford-Binet IQ
Test; and older children, seven points lower on Performance IQ as
assessed on the Wechsler Intelligence Scales lor Children-Revised.
and spinal nerve roots of ail the affected 4-CB-treated animals.
Tilson et al. (47) also studied 4-CB in mice (Table 21. CD-I
mice whose mothers were exposed to 4-CB during gestation
displayed at 35 and 65 days of age a neurobehavioral syndrome
There are two cohorts of U.S. children who have been followed
consisting of intermittent stereotypic circling and hyperactivity.
developmentally from binh: one in Michigan (MI), the other in
4-CB-affected mice were markedly hyperactive during the dark
phase of the diurnal cycle and had impaired grip strength and
balance. Hyperactive mice, as well as treated mice not showing
hyperactivity. were both impaired in the acquisition of a one-way,
shock-motivated avoidance response (Table 3). Body weights of
North Carolina (NO. The MI cohort included 313 newborns: 242
of the mothers had consumed Lake Michigan fish presumed to be
contaminated by PCBs (17). Higher cord serum PCB levels and
maternal contaminated fish consumption were associated with
smaller birth size and shorter gestation, an effect also seen in
studies of children whose mothers had occupational exposure
(23.46). The size deficit associated with prenatal PCB exposure
persisted beyond the newborn period (26).
The Brazeiton (9) Neonatal Behavioral Assessment Scale was
administered in bo en the MI and NC studies. The Brazeiton Scale
4-CB-treated animals were not different from controls at 35 days
of age. but female mice showing the neurological impairment were
lighter than controls at 65 days of age. In a separate experiment.
gravid rats were administered radiolabelled 4-CB on days 10-16 of
gestation and radioactivity measured in the bodies of offspring.
U.S. STUDIES
There was no radiolabelled 4-CB at any time after 4 weeks of age.
is designed to assess a broad range of newborn behaviors,
A subsequent study (2) found that at 1 year of age. mice exposed
to 4-CB in utero had elevated levels of motor activity that were
associated with decreased levels of dopamine and dopamine
receptor binding sites in the caudate nucleus, indicating a relatively long-lasting change in the development of striatal synapses.
Storm and colleagues (45) maintained female ICR mice on a
diet containing 0. 11 or 82 ppm of Aroclor 1254 beginning 3 days
prior to mating and continuing until litters were weaned at 21 days
of age (Table 1). The offspring were then maintained on the same
diet as their mothers. One-half of the offspring were tested for
acquisition of an avoidance response over a 13-day period beginning at 23 days of age. The other half of the litters was tested for
activity in an open field in a 30-min test at 27 days of age.
Maternal or fetotoxicity was not a consistent finding by Storm
et al. (45) (Table 1). PCB-exposed mice showed an increased
latency to respond early in training (Table 3). Measures of activity
in the open field indicated that PCB-exposed mice habituated more
slowly during test period (Table 2).
including motor coordination, muscle tone, orientation, and state
changes (that is. arousal and self-quieting). In MI. among 287
newborns tested, infants whose mothers had consumed greater
quantities of contaminated fish exhibited more abnormally weak
reflexes, were less responsive to the stimulation of the Brazeiton
examination, and showed more jerky, unbalanced movement and
more startles (27).
Prenatal exposure was estimated in the NC study on the basis
of the concentration of PCBs in the fat of breast milk; this should
be identical to the concentration in body fat (42). Among 866
infants tested, the more highly exposed infants were hvpotonic and
exhibited more abnormally weak reflexes.
In NC. among 802 infants followed up from the previous
study, prenatal PCB exposure was associated with poorer perfor-
HUMAN STUDIES
YUSHO AND YUCHENG
Yusho and yucheng both mean "oil disease." in Japanese and
Chinese, respectively. Both were epidemics of chronic food
poisoning from contaminated cooking oil. The contaminants were
a complex mixture of PCBs, poiychlorinated terphenyls. quaterphenyls. and dibenzofurans. In Japan, infants born to mothers who
had consumed the contaminated oil were small for gestational age.
had dark pigmentation of the skin and nails, early eruption of
teeth, and swollen eyelids and gums. Four children followed up
at 8 to 19 months of age were described as essentially normal mentally and physically (19). In another pan of Japan,
however. 13 exposed children ranging to 7 years of age were
described clinically as dull, apathetic, and hvpotonic. with IQs in
the 70's (24).
Rogan et al. (41) followed up 117 children born to yucheng
women between 1978 and 1985. Although maternal exposure had
ceased by 1979. the exposed children continued to weigh less and
were more likely to exhibit hyperpigmentation of nails and gums,
nail deformities, diffuse dark pigmentation on skin and mucous
membranes, and bronchitis than neiehborhood controls. Using
mance on the Psvchomotor Index from the Bayley Scales of Infant
Development at 6 and 12 months of age (22). This index assesses
both gross and fine motor coordination. In MI. cord serum PCB
level was associated with poorer performance on a cluster of items
focusing primarily on fine motor coordination, but this effect fell
short of the conventional level of statistical significance (Jacobson, unpublished)
The Bayley Scales depend heavily on motor tasks to evaluate
cognitive functioning (5). In MI. therefore, the infants were also
given a test of visual recognition memory (16), which assesses
cognitive proficiency more directly. Cord serum PCB level and
maternal contaminated fish consumption were both associated
with poorer visual recognition memory performance at seven
months among 123 children, a subgroup of the children tested at
birth (28). Preference for the novel stimulus was related to cord
serum PCB level in a dose-dependent fashion.
Postnatal exposure from nursing was not related to any of the
scales used either in MI (28) or in NC (22). Both cohorts continue
under developmental surveillance.
QUALITATIVE COMPARISONS
LABORATORY ANIMALS
''
Developmental exposure to PCB results in persistent neurobehavioral alterations in monkeys and nonpnmates, similar neurological or behavioral effects are observed across species, and
neurological and behavioral effects can be observed in the absence
'
PCBs AND THE DEVELOPING CNS
of reduced body weights or gross signs of PCS intoxication during
development. The behavioral effects observed in rodents and
avians exposed developmemally lo PCBs were qualitatively similar 10 those seen in rhesus monkeys (Tables 1, 2 and 3). Some of
the dosing regimens used in these studies resulted in growth
retardation m the offspring, although at the time of behavioral or
neurological examination, body weights may not have differed
significantly from controls. Several studies specifically examined
macurational end points at an early age during development and all
reported a suppression, delay or impairment in maturation
(33, 38. 39).
The most common finding in the animal studies was that
developmental exposure to PCBs results in behavioral hyperactivity (Table 2); this was particularly true if the testing period allowed
for habituation to occur during the testing session. Hyperactiviry
'vas observed in mice (10, 45. 47), male rats (44), and monkeys
.8); all of these studies involved pre- or perinatal exposure to
In addition. Bowman and Heironimus (6) reported that
PCB-exposed monkeys hyperactive 12 months of age were hypoactive at 44 months of age. suggesting that aging might influence
the expression of this effect. In experiments in which short time
penods were used to assess motor activity (i.e.. five minutes or
less), developmental exposure to PCBs decreased motor activity
(31.32). Koja and colleagues also exposed their animals postnatally, while other investigators finding hyperactiviry (8, 10. 45.
47) exposed their animals pre- or perinaially. In addition, Pantaleoni et at, (39) reported that preconception or postnatal exposure
to PCBs decreased motor activity in an open fieid. However,
testing was done prior to weaning, while others (7, 8, 10. 45. 47)
studied exposure effects at a later time during development.
That developmental exposure to PCS can influence higher
cognitive processes or learning was observed in rats (39,44). mice
(45.47) and Rhesus monkeys (7). Table 3 indicates that effects on
learning were observed using more complex discrimination tasks
(8) and schedule-controlled performance (37) in monkeys, as well
as unconditioned (33) and conditioned avoidance responses in
primates (39. 45, 47). One study (44) found impaired learning
>~ rats using a water maze. Experiments conducted 4-6 years after
birth with PCB-exposed monkeys found subtle changes in schedule-controlled performance and reactivity to reinforcement omission (37). and in short-term memory function in a delayed spatial
alteration paradigm (35).
Any battery of tests that included hyperactivity and learning
tasks, such as the one being proposed by EPA currently, should
detect PCBs as active agents.
HUMANS
Prenatal exposure to the complex mixture of degraded PCBs in
Japan (24) and Taiwan (41) produced clinically apparent developmental delay. It persisted through at least early school age in some
children. Nearly all of the mothers were themselves clinically ill;
most of the children had additional signs or symptoms (41). There
were effects on both motor and mental function: all developmental
scales used showed effects, except for verbal IQ on the WTSC-R;
more of the exposed children had behavior problems, as assessed
by the Rutter scales.
In the two U.S. studies, in which there was presumed to be no
maternal toxicity. lower birthweight in children with greater
exposures was seen in MI but not in NC (17). The only other
toxicity seen in either study was neurodevelopmental. At birth.
both studies detected primarily motor effects within the Brazelton
Assessment (26.42). The Bayley Psychomotor Index was impaired
by prenatal exposure in NC at both 6 and 12 months (221; in MI.
prenatal exposure appeared to affect a subset of fine motor tasks
within the Bayley. Impaired cognitive functioning was seen in MI
on a visual recognition memory test (28) which was not administered in NC. There is thus consistent evidence that prenatal
exposure 10 levels of PCBs commonly encountered in the U.S.
produce detectable effects on motor maturation and some evidence
of impaired infant learning. Both studies attempted to control for
potentially confounding variables, and it is reasonable to assume
that the effects seen are not due to DDE (the most plausible other
chemical agent) or social and demographic characteristics of the
families (29).
The developing nervous systems of the species tested do not
tolerate PCBs; how that lack of tolerance is manifest appears to
depend more on the conventions of testing than it does on biology.
The most commonly observed toxicity in the laboratory experiments was hyperactiviry. This is a standard and relatively easy
measure in the laboratory, but is rarely done in children. The
clinical condition called hyperactivity in children is a complex and
likely socially mediated group of behaviors, usually not diagnosed
until school age. The two U.S. cohorts are just now at that age.
Using criteria developed in Britain, the Taiwanese children had
several behavior problems, but this is difficult to evaluate in the
presence of chrome illness in the family, the complex exposure,
and the lack of an instrument known to be culture fair for
measuring behavior disorders in Chinese speaking children.
For the most pan, tests of higher conical function in animals
are affected, while the observed delays in development on the
children are predominantly motor. It is hard to assess cortical
function in infants. The evidence of poorer performance on visual
recognition memory, a well-validated assessment of infant cortical
function, is consistent with the animal data. As the data from
assessments of the children at older ages become available, they
may also reflect more the effects on cortical processes. The
hypoactiviry seen in the animals may have a motor basis, and thus
be similar to the motor delays in children, but tests directed
specifically at motor function in animals are relatively unaffected.
QUANTITATIVE ASSESSMENT
LABORATORY ANIMALS
The available animal data were subjected to the nsk assessment
model proposed by the U.S. EPA for developmental toxicity (15).
These begin with either a "no-observed-adverse-effect level"
(NOAEL) or a "lowest-observed-adverse-effect level" (LOAEL).
Uncertainty factors, consisting of dividing the LOAEL or NOAEL
by factors of 10. are applied for 1) intraspecies variability. 2)
interspecies variability (i.e., nonhuman data), and 3) data in which
there is a LOAEL without a NOAEL. The result of this procedure
is a Reference Dose (RfD), the dose at or below which no
observable toxicity is expected to occur.
Table 4 summarizes the results of the risk assessment evaluation of the PCB data for six biological categories, including
feioioxicity and postnatal viability, postnatal body weights, reproductive capacity, neuromuscular reflexes and manirational endpoints, motor activity and cognitive behavior. In each case, a
LOAEL or NOAEL has been established and a reference dose
calculated. Examination of Table 4 shows that, under the experimental conditions used, monkeys have been shown to respond to
the lowest doses, and some measures, such as cognitive behaviors.
are more sensitive than fetotoxiciry and postnatal body weights.
Several PCB formulations were used and. with one exception.
they produced similar effects.
For rhesus monkeys, fetotoxiciry. chloracne and decreased
postnatal body weights have reference doses that are an order of
magnitude higher than those for motor activity and cognitive tests.
TTLSON. JACOBSON AND ROGAN
including discrimination learning and schedule-controlled behavior (Table 4). Table 4 also summarizes the data for rodents
exposed pennatally to PCB. This table lists the ranees of LOAELs
and NOAELs for each endpoint. As in the case of rhesus monkeys,
the reference doses for fetotoxicity and postnatal body weights are
higher than those for measures of neurobehavioral function li.e..
motor activity and learning/memory).
dose among the endpoints considered. Note that the assumptions
for the calculation of the reference dose from the human data are
not conservative: using an older mother, or allowing an extra
safety factor for the bioaccumulation of the chemicals would lower
it. For comparison. Table 4 also lists the current EPA reference
dose, and the "de minimus" fl x 10~ 6 1 dose for carcmogemcity.
DISCUSSION
HUMANS
Unlike the laboratory experiments, dose information is not
available for the women who participated in these studies, and we
need to make a number of assumptions to estimate dose (40). The
data from the NC study have as their measure of prenatal exposure
the estimated amount of PCBs in the fat of breast milk at term. If
we assume that this fat is in steady state with the rest of the body's
fat. and we consider a body weight of 60 kg [U.S. median for 165
cm tail (IS)] and a percentage of thai weight which is fat. 25%,
then we can calculate a "body burden." i.e., the mass of PCBs
accumulated by the mother up to that point. If we assume that she
got that body burden from equal daily doses over her lifetime, that
she has as her only means of excretion either pregnancy or
lactation, and that she is primiparous, then the daily dose associated with any given level in breast milk is the body burden at that
level divided by age in days. (Since the levels in various matrices.
e.g.. cord serum, maternal serum, etc.. are strongly correlated and
approximately linear transforms of each other, we could calculate
In order to predict what will for will not) happen to a human
exposed to a given level of a given agent, we need to know what
the biochemical basis of the action is. how it depends on the
concentration of the agent at the site of action, and how exposure
relates to that concentration. These topics are among those at the
heart of the huge advances in brain pharmacology of the last three
decades. For PCBs. there are now data showing effects believed to
have a neuronal basis in humans and in animals, correlated to
some degree with dose or exposure information: there are few data
on concentrations in the brain, some general pharmacokinetic
data, and vimially nothing about how PCBs interfere with brain
function or development.
In the absence of the above information and a mathematical
model that describes it, predicting the effect of a given dose or
estimating an exposure at which no such effect will occur can only
be done crudely. The safety factor, or reference dose, approach
has inherent problems. The NOAEL or LOAEL concept is
inherently imprecise, and to an inestimable degree. It ignores the
a body burden given any level in any matrix. We use breast milk
quantitative relationship between dose and response, depends
fat because, with the methods available at the time the studies were
begun, it was determined with most precision.)
Neither the NC nor the MI data have been modelled using
techniques to estimate "thresholds.1* and the linear models used to
control confounding assume no threshold. For our purposes, we
therefore use the crude data, in which the outcome variable
heavily on the strain or species used, and is biased in how it uses
information. Since an active chemical studied in an experiment
with only a few animals, using insensitive methods and high
doses, will yield a higher reference dose than the same agent
studied with more animals, sensitive methods, and many doses,
(percent abnormal on the Brazelton assessment or means on the
Besides the generic problems of quantitative comparison, there
are problems specific to PCBs. The fust is that PCBs are not a
specific chemical, but rather a family of 209 congeners, differing
Bay leys) is arrayed by level in milk fat (22,42) and estimate a
NOAEL by inspection. For these data, that level appears to be
about 3.4 ppm in breast milk fat. (This level may have been
estimated to have been as low as 1.8 ppm. if chemical analysis had
been done by the methods used in MI). For visual recognition
memory, the equivalent level is 1.0 ppm in fat of breast milk. The
theoretical 25-year-old, primiparous, 60 kg, 25% body fat mother
who had 3.4 ppm in breast milk fat has a body burden of 51 mg of
PCBs, which she got from daily doses of 5.6 u-g/day, or 0.093
H-g/kg/day. Applicable "safety factors" would be 10 for variation
in susceptibility among exposed humans, finis is arguably low;
there was 7-fold variability in Ah receptor protein in the 9
specimens analyzed by Cook et at. (II); occupancy of the AJt
receptor modulates enzyme induction by PCBs, and presence of
the receptor correlates roughly with toxicity.J This would yield a
reference dose of 9.3 x 10~3 u,g/kg/day; for 1.0 ppm in milk fat.
the reference dose would be 2.7 x 10 ~3 u.g/kg/day. Note that the
median concentration in breast milk fat in the MI data is 0.8 ppm.
which would have been achieved under these assumptions by a
daily dose of 2.2 x 10" - p.g/kg/day, an order of magnitude above
the reference dose. By an entirely different method, involving
analysis of foods commonly consumed in the U.S. (the "Market
Basket Survey'*). FDA estimated that dietary intake in the U.S. in
1978was3x 10~ 2 jig/kg/day.buiby I982was3x lO~ 3 M-g^^day
(20), essentially at the estimated reference dose.
For the very specific and limited purpose of setting a reference
dose, the rhesus monkey data yield an estimate of the reference
dose an order of magnitude higher than the estimate calculated
from the human data (Table 4); the rodent data give a reference
dose that is three orders of magnitude higher. These comparisons
are made using chat effect which results in the lowest reference
the less is known about the chemical, the safer it appears.
in the number and positions of chlorine atoms on the two rings.
Although the qualitative toxiciry of the congeners is similar, the
doses at which they are active vary by orders of magnitude. For
those aspects of toxiciry mediated by occupancy of the Ah
receptor, such as the induction of drug metabolizing enzymes.
coplanar congeners are the most active (43). These congeners may
be responsible for the bulk of observed toxiciry, but represent only
a small portion of either an administered dose or the stored
chemical in an organism. The congeners also vary in their
persistence. The pattern of congeners in breast milk, for example,
is not the same as in any of the commercial mixtures. Toxiciry and
persistence are not necessarily correlated. The tetrachiorobiphenyl
studied by Chou er ai. (10), for example, has a short half life, and
was undetectable in the offspring after administration to the
mother, yet its behavioral effect persisted. Few animal studies
have been carried out using specific congeners, and congener
specific analysis techniques are relatively new. In addition, the
congener mix to which persons in one region are exposed to may
differ from those in another, since the sources may differ, if, for
example, the predominant source of PCBs for persons in Michigan
is Lake Michigan fish, the mix of PCBs is likely very different
from a person with occupational exposure or for a person who
accumulates their body burden from multiple, very low back- ,
ground sources. Finally, since the chemicals bioaccumulate it is ^
plausible thai dose-response modelling should use total dose to the
time of test or measured concentration in tissue rather than
administered dose. The impact of this on the assessment of risk
would have 10 be investigated, but it would likely lower the
estimates of the reference aose.
19.
pCBs AND THE DEVELOPLNG CNS
In the Asian outbreaks, besides the high levels of PCBs to
PCBs would now be introduced. Clean-up of the amounts now in
iich these persons were exposed, the PCBs thai had contami-
the environment, to the degree possible, will be an enormous
undertaking. Current human exposure, however, is above any
d the oil were themselves contaminated by polychlorinated triquaterphenyis and dibenzofurans i36). The toxiciry of the
and quadruple ring structures is poorly characterized. The
iibenzofurans include some extremely toxic congeners, with
toxicity broadly similar to the PCBs. and it is likely that much of
the toxicity seen in ine outbreaks is due to their presence. The
Asian outbreaks are thus far unique in the degree of thermal
degradation of the PCBs. but there is some evidence of widespread very low level environmental contamination by the dibenzorurans (30).
It is unlikely that an agent with the persistence and toxicity of
regulatory guideline, and detectable effects are occurring at about
the 95th percentile in the North Carolina data and perhaps below
that in the Michigan data. The magnitude of the problem and the
degree to which it has been studied should at least allow better
handling of such hazards in the future.
ACKNOWLEDGEMENTS
The authors acknowledge the primary collaboration of S. W. Jacobson
and B. C. Gladen, and the technical assistance of N. B. Raaan.
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