Environmental Health Perspectives Volume
103, Supplement 6, September 1995
[Citation
in PubMed]
Growth Abnormalities in the Population Exposed in utero and Early
Postnatally to Polychlorinated Biphenyls and Dibenzofurans
Yueliang L. Guo,1 George H. Lambert,2 and Chen-Chin
Hsu3
1Department of Occupational and Environmental Health, National
Cheng Kung University Medical College, Tainan, Taiwan; 2Department
of Pediatrics, UMDNJ-Robert Wood Johnson Medical School, New Brunswick,
New Jersey; and 3Department of Psychiatry, National Cheng Kung
University Medical College, Tainan, Taiwan
Abstract
This article reviews the findings in children exposed to various
levels of polychlorinated biphenyls (PCBs) and related compounds in utero
and early postnatally. Yucheng ("oil-disease") mothers were Taiwanese
women exposed to PCBs and their heat-degradation products from the ingestion
of contaminated rice oil in 1979. Children of these mothers were born growth
retarded, with dysmorphic physical findings, and delayed cognitive
development compared with unexposed children. In this article, findings
in Yucheng children born between 1978 and 1985 are summarized and compared
with two other well-documented cohorts of children prenatally exposed to
different levels of PCBs. Results of the investigation in Yucheng children
will provide important information about the toxicities, health effects,
and mechanisms of PCB/PCDF exposure and demonstrate that the developing
human is more sensitive than the adult to the toxic effects of these chemicals.
-- Environ Health Perspect 103(Suppl 6):117-122 (1995)
Key words: polychlorinated biphenyls, in utero exposure,
food contamination, teratogens, dioxinlike chemicals, cognitive development,
growth, endocrine
This article was presented at the Symposium on Preventing
Child Exposures to Environmental Hazards: Research and Policy Issues held
18-19 March 1994 in Washington, DC.
The investigation in Yucheng cohort was supported by grants
NSC 80-0421-B-006-05Z, NSC 81-0421-B-006-06YZ, NSC 82-0421-B-006-064-YZ,
NSC 82-0421-B-006-065-YZ, NSC 83-0421-B-006-046-YZ, NSC 83-0421-B-006-064-YZ
from the National Science Council, and DOH 83-HR-C13 from Department of
Health of Republic of China.
Address correspondence to Dr. George H. Lambert, Department
of Pediatrics, UMDNJ-Robert Wood Johnson Medical School, New Brunswick,
NJ 08903. Telephone (908) 235-6890. Fax (908) 235-7077.
Background
Polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs),
and polychlorinated dibenzodioxins (PCDDs) are ubiquitous environmental
pollutants found throughout the world and in all human populations. The
PCDFs and PCDDs are produced and released into the environment during many
industrial processes such as chlorine bleaching, incineration, and manufacture
or disposal of chlorine-containing products. PCBs were manufactured for
many purposes, including lubricants for heavy machinery, dielectric fluid
in transformers, and even for use as emersion oil for microscope slides.
PCBs were recognized as potentially harmful environmental contaminants in
the 1970s (1), and their use and manufacture were prohibited in many
countries. Despite the ban on PCBs, PCBs, PCDFs, and PCDDs will be found
in the environment for decades to come because of their long half-life in
the environment (2).
The primary route of human exposure to these chemicals is through contaminated
food such as meat and fresh-water fish (3). PCBs and their heat
degradation products have long half-lives in humans (4), cross the
placenta (5,6), and are excreted in breast milk. Prenatal exposure
to PCBs and PCDDs have caused significant teratogenic and developmental
toxicities in animals (7). In the human, transplacental and possibly
transmammillary exposure has caused severe adverse effects (8). The
developing human is more susceptible to PCB-induced toxic effects than the
adult. The toxic effects seen in children are more severe and affect more
organ systems than those seen in adults. These effects may persist throughout
the child's entire life-span, while in the adult only part of the subject's
life-span may be affected. The objective of this article will be to review
the developmental toxicology data of the children most severely affected
by these chemicals, the Yucheng (Yucheng means "oil disease" in
Chinese) cohort of Taiwan, and compare these effects to those in their matched
control subjects and two other PCB-exposed cohorts of U.S. children not
so severely affected.
These three cohorts of children prenatally exposed to different levels
of PCBs and related compounds all have been carefully followed. They are
a) North Carolina children exposed to background PCB levels, b)
children born to women who reported moderate consumption of Lake Michigan
sport fish during pregnancy, and c) Taiwanese Yucheng children.
This article focuses on the Yucheng children, with reference and comparison
to findings of the other two groups.
Populations
Yucheng Cohort
In 1979, over 2000 Taiwanese people ingested rice oil contaminated with
PCBs and PCDFs. They developed chloracne, hyperpigmentation, peripheral
neuropathy, and other signs and symptoms that later were called Yucheng
in Taiwan and were very similar to Yusho disease described in the 1970s
in Japan. The outbreak and the discovery of the etiology of Yucheng have
been reviewed elsewhere (9). Repeated heating of the contaminated
rice oil partially degraded the PCBs into PCDFs and polychlorinated terphenyls
and quarterphenyls (PCTs and PCQs) (10). Some congeners of these
PCDFs, e.g., 2,3,4,7,8-pentachloro-dibenzofurans (PnCDF), are highly toxic
in animals, with potencies approaching those of the most toxic PCDDs, 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD) in animal and in vitro studies (11).
Of 39 Yucheng babies in utero during the time the mothers ingested
the contaminated oil, eight died in the first few years of life (9).
In September 1985, a field survey was conducted of 128 living children
who were in utero during or after the period of oil contamination.
History and physical examination of these children's development were performed
and compared with those of 117 controls (12). The parents of 118
Yucheng children gave permission for their children to be followed yearly.
For the followup study, an unexposed child was selected as a control for
each Yucheng child, matched for neighborhood (same township), age (within
15 days for those under one year, and within one month for those older),
sex, mother's age (within 3 years), parents' combined educational level
(within about 3 years for the total), and occupation (within 1 class of
5 classes from unskilled laborer to professional).
Between the years 1985 and 1990, mental and cognitive development were
studied regularly in these two groups of children. In February 1991, the
Yucheng children and their controls were invited to come to National Cheng
Kung University Hospital for examination. Seventy-three of the 118 Yucheng
children and 69 of the control children (55 pairs) appeared and examinations
were made of their growth profiles and structures of the joints. Again
in 1992, these children were examined in the local health offices or
in their homes by our investigators.
North Carolina/Michigan Cohorts
In North Carolina, 930 children born to mothers who had no unusual PCB
exposure were followed from birth (13). In Michigan, 242 children
whose mothers consumed moderate quantities of contaminated Lake Michigan
fish and 71 children whose mothers did not eat such fish were
followed from their birth (8). Levels of PCB exposure, growth, and
development have been assessed in both cohorts.
Exposure Levels
In the Yucheng cohort, the adults were estimated to have consumed an
average of 1 g of PCBs and 3.8 mg of PCDFs during an average of 9 months
of exposure to the contaminated oil (14). Serum PCB concentrations
were measured in the mothers close to the end of pregnancy. The serum PCB
values were log normally distributed in the exposed mothers; the arithmetic
mean was 49.3 parts per billion (ppb), and the median was 26.8 ppb. Serum
levels of PCDFs were not measured. However, Kashimoto et al. (15)
measured blood levels of PCBs and PCDFs between 1979 and 1981 in a group
of 113 Yucheng patients in a school for the blind children in Taichung county,
who had been exposed to the same contaminated rice oil as our subjects'
mothers. They had average blood levels of 39 ppb PCBs and 76 part per trillion
(ppt) PCDFs on a whole blood basis. Assuming an average hematocrit of 45
and lipid content of 0.35%, their values for total PCBs of 39 ppb in whole
blood would be converted to 71 ppb in serum, approximately 40% higher than
the average level of PCBs in our subjects' mothers around delivery. If we
assume a 1:3 ratio in contents of PnCDF:1,2,3,4,7,8-hexachloro-dibenzofurans
(HxCDF) in the serum, Kashimoto's PCDF value of 76 ppt would be converted
to approximately 10,000 ppt of PnCDF and 30,000 ppt of HxCDF on a serum
lipid basis. If our subjects' mothers had similar PCDF and PCB serum ratios,
their serum PnCDF level can be estimated as 6940 ppt, and HxCDF 20800 ppt
on a serum lipid basis around the time of delivery of Yucheng children.
The average serum level in 20 subjects' mothers in February of 1992, i.e.,
about 10 years after previous measurements, was 1507 ppt of PnCDF and 3583
ppt of HxCDF on a serum lipid basis, and 9.6 ppb of total PCBs on a whole
weight basis (Guo L, Ryan J, Hsu CC, unpublished data).
The average serum level in 14 serum samples of Yucheng children in February
1991 was 167 ppt of PnCDF and 362 ppt of HxCDF on a serum lipid basis, and
1.5 ppb of total PCBs on a whole weight basis (16). The serum concentrations
of PCBs and PCDFs were still much higher than those in a pooled serum sample
of matched control children (0.5 ppb of PCBs, whole basis; 19 ppt PnCDF
and 23 ppt HxCDF, lipid basis).
Maternal serum concentrations of PCBs averaged 4.7 to 5.9 ng/ml in the
Michigan group, and infants' cord blood serum levels averaged 2.0 to 2.5
ng/ml (17). The relationship between maternal and cord serum level
allows us a very rough estimate of a 1:2 ratio between cord and maternal
serum levels.
The median maternal serum PCB level was 9.06 ppb, corresponding to the
median milk PCB level of 1.77 ppm (fat basis) in the North Carolina cohort;
median cord serum level was less than half the median maternal serum level
(18). PCDFs were not measured in either U.S. study, but they tend
not to be found at any substantial level in the U.S. exposures.
Cohorts History and Physical Findings
A summary of the history and physical findings that will be discussed
is in Table 1.
Forty-nine newborns delivered to Yu-cheng women between 1979 and 1985
had 500 g lower gestational age-adjusted birth weights than those of the
controls (19). The deficits were present in both female and
male exposed babies, and the first and second children born after the
outbreak were more affected than the third child. A persistent delay in
growth in Yucheng children was observed by examination in 1985 (age range,
6 months-7 years) and again in 1991 (age range, 6-13 years). The Yucheng
children were 7% lighter (p<0.01) and 3% shorter (p<0.05)
than controls (12). In February 1991, the Yucheng children were still
shorter than their controls by 3.1 cm (2.3%, p<0.01), but weights
did not differ between these two groups (16). There was no difference
in the weight, joint laxity, total bone mineral density, and total and percent
body fat between Yucheng and control groups. Total lean mass and soft tissue
mass were significantly lower in Yucheng children.
Offspring of the Michigan group that had consumed fish with cord
serum PCB levels of 5.0 ng/ml or more had decreased birth weights of approximately
160 to 190 g compared to the lower exposed children (8). At 4 years
of age the PCB-induced growth-retarded children weighed 1.8 kg less than
the children who were exposed the least (20). The effect on weight
was significant for girls but not for boys. This reduction in weight
correlated with their cord blood serum PCB level at birth but not with PCB
levels at 4 years of age. These children also had reduced head circumferences
of 0.6 to 0.7 cm at birth compared with those of their controls. Head circumferences
were similar at time of re-examination at 4 years of age. In the North Carolina
children, lower birth weights were not associated with high background PCB
exposures.
Dermatological Findings
According to parents' histories, the Yucheng children had increased rates
of hyperpigmentation, eyelid swelling and discharge, deformed nails, acne,
natal teeth, and swollen gums compared to controls (21). Examination
in 1985 showed that the exposed children had more pigmented or dystrophic
nails, acne, and hyperpigmentation. In the examination during 1991 and 1992,
Yucheng children had significantly higher risks of nail deformities
than controls. However, there were no residual findings of acne or
hyperpigmentation. The main nail findings were transverse coarse grooves
and irregularly concaved depression in 25% of children (22), with
predilection for thumbs, followed by big toes and other fingers. Those
children born closer to the mothers' intoxication had more nail deformities
than those born later. In some Yucheng children, improvement of the nail
changes was observed between 1991 and 1992 examination in that the coarse
grooving had become irregular depressions (22). The typical nail
changes found in prenatally exposed children but not in the directly exposed
population suggested prenatal damage of the nail matrix. No abnormal dermatological
findings were reported in the children from the Michigan or North Carolina
cohorts.
Cognitive Developments
Of the 33 developmental milestones recorded, the Yucheng parents reported
32 that were achieved later in their children than in controls, with many
of these differences being statistically significant (23). A
similar delay was observed by neurologist's examination.
A widely used instrument for evaluating high-risk children, the Bayley
Scale of Infant Development, was administered to children 6 months to 2.5
years of age. The Bayley scale consists of two subscales, a mental development
index and a psychomotor development index. Yucheng children scored lower
in both mental (100 vs 106, p<0.05) and psychomotor indexes (101
vs 108, p<0.05) compared to their controls (23).
In the assessment of cognitive development between 1985 and 1990 (24),
the Yucheng children scored approximately 5 points (0.30 SD) lower than
their matched controls on the Stanford-Binet test at 4 and 5 years of age
and approximately 5 points (0.40 SD) lower on the Wechsler Intelligence
Scale for Children, Revised, at 6 and 7 years of age. The children born
up to 6 years after their mothers' intoxication were affected in ways similar
to those children born immediately after the episode.
Both U.S. studies used Brazelton Neonatal Behavioral Assessment Scales
to evaluate psychoneurologic functioning in infants. Both studies detected
primarily motor effects within the Brazelton Assessment in infants with
the highest cord serum PCB levels. In the Michigan cohort assessed at 7
months (20), impaired cognitive functioning was seen on Fagan's test
of visual recognition memory in children with cord serum PCB levels in the
upper 25% of the cohort, i.e., 3.6 to 7.9 ng/ml. This level corresponds
to maternal serum levels of approximately 7 to 17 ng/ml at birth. In the
North Carolina cohort, children in the upper 5 to 10% of transplacental
exposure to PCBs (greater than 3.5 ppm in maternal milk fat) were associated
with lower psychomotor development indices, as determined by Bayley's test
at 6, 12, 18, and 24 months of age (25). No association was detected
between prenatal PCB exposure and Bayley's Mental Development Index. When
the Michigan cohort was assessed at 4 years, a higher cord serum PCB level
predicted poorer performance on verbal and memory subtests of McCarthy Scales
of Children's Abilities. The highest exposed group, with cord serum PCB
levels of 5.0 to 12.3 ng/ml (corresponding to maternal serum levels of 11-25
ng/ml), had most apparent deficits in both verbal and memory scale
scores (26). However, no association was found between prenatal PCB
exposure and McCarthy scores in the North Carolina cohort (27).
In the two U.S. studies, postnatal exposure to background levels of PCBs
through breast milk did not affect developmental test scores (25,26,28).
Table 2 summarizes the cognitive and behavioral development at different
age levels in Yucheng children compared with those of their matched controls.
Neurological Findings
In February 1991, 27 pairs of Yucheng and control children were randomly
selected to have an extensive neurological evaluation with auditory event-related
potentials (P300), pattern visual evoked potentials
(P-VEPs), and short-latency somatosensory evoked potentials (SSEPs) (29).
The P300 have proved to be useful in evaluating the function of information
processing, in which latency relates to the speed of solving cognitive tasks
(30), and amplitude relates to the frequency of the occurrence of
target stimulus, reflecting the concentration ability (31). In children,
low amplitude in P300 has been associated with attention deficits and
reading disabilities (32,33) and greater latencies with cognitive
impairments (34). P-VEPs and SSEPs are noninvasive techniques for
evaluating visual and somatosensory afferent pathways from the peripheral
to the central nervous system (35,36). No abnormalities were found
in the neurological examinations of Yucheng and control children. Soft neurological
signs were present in both groups: 10 of 27 Yucheng children and 6 of 27
control children. Prolonged latencies (356 vs 329 msec, p<0.01;
and 356 vs 331 msec, p<0.05, at two scalp recording positions)
and reduced amplitude (13.9 vs 17.3 mV, p<0.05; and 14.0 vs 17.1
mV, p<0.05, at two positions) were shown with P300, indicating
slowed cognitive processing and attention deficits in Yucheng children
than in controls. Latencies were inversely correlated with WISC-R full-scale
intelligent quotient (IQ). No conduction abnormalities were shown with P-VEPs
and SSEPs. These findings suggested that sensory afferent pathways
were not affected in Yucheng children, and the reduced IQ scores might be
due to slowed cognitive processing and/or attention deficits. Neither
of the U.S. cohorts were assessed using these tools.
Behavior and Activity
Rutter's Child Behavior Scale A (37) was used to assess the behavior
of Yucheng and control children aged 3 or older. Rutter's Scale is a screening
instrument, completed by main caretakers of the child, to identify children
likely to show problems in health, habits, and behaviors. Higher scores
on this scale represent more problems. Yucheng children consistently scored
higher than their controls between age 3 and 9 years (38). At present
there are too few subjects tested at age 10 or older to determine whether
the behavioral problems continued.
A Chinese version of the modified Werry-Weiss-Peters Activity Scale
(39) was used for children aged 3 to 12 to evaluate the children's
activity level. Yucheng children scored 8 to 53% higher than their controls
at each age, and the differences were significant in six age groups
(38).
Both U.S. cohorts presented a different picture from Yucheng children
in the activity assessments. In the North Carolina cohort, using the information
abstracted from report cards, no association was found between exposure
and hyperactivity reported by parents (40). In Michigan, composite
activity ratings were obtained based on examiners' ratings from two home
visits and mothers' ratings on the Activity Scale of Buss and Plomin Emotionality
Activity Sociability Temperament Survey for Children (26,41). The
composite activity rating was negatively related to the 4-year serum PCB
level in a dose-dependent fashion, and the children with serum PCB levels
of 9 ng/ml or greater had the lowest activity ratings. Because the children's
4-year serum PCB levels were related to breast feeding, it is possible that
postnatal exposure to PCBs had a different effect on activity than prenatal
exposure. Another possibility is the nature of exposure to different mixtures;
the Yucheng children were exposed to much higher levels of PCDFs than the
U.S. cohorts.
Immunology/Infectious Diseases
The Yucheng children had histories of more frequent bronchitis, upper
respiratory infections, and ear infections, as reported by the parents in
1985 and 1992 (12,42). On physical examination the Yucheng children
had more frequent chronic ear infections and abnormal auscultory findings
of the chest. Neither of the U.S. cohorts reported similar findings.
Metabolic
Excessive or abnormal porphyrin production occurs as a result of altered
enzyme activity in the heme biosynthesis pathway. Because 15% of heme is
produced in the liver, damage to the hepatocyte membrane causes abnormal
urinary porphyrin excretion, a condition known as hepatic porphyria (43).
PCB exposure in animals caused type B hepatic porphyria, which is characterized
by a urinary uroporphyrins/ coprophyrins ratio of greater than one (44).
Spot urine porphyrins were measured in 1985 for 75 Yucheng children and
74 controls. Average total porphyrin excretion was higher in the Yucheng
children (95 vs 81 mg/l), and more Yucheng children had total urinary porphyrin
concentrations greater than 200 mg/l (11 vs 3%) (45).
Endocrine and Sexual Development
Calcium metabolism in the Yucheng children was studied in 1985, since
their physical examinations revealed tooth chipping and their parents had
reported observing prenatal and fragile teeth (12). The children
had essentially normal blood levels of parathyroid hormone, vitamin D, serum
calcium, alkaline phosphatase, and phosphate, and no difference in skeletal
mineralization was observed using Dual-photon absorptiometry compared to
controls (16). In a preliminary study on sexual development (46),
penile length was measured in 55 pairs of Yucheng boys and their controls.
Boys aged 11 to 14, who were born in the earlier years after their mothers'
intoxications, had reduced penile length compared to those of their controls.
The effects of PCBs/PCDFs on the reduced body height and length of penis
might be due to hormonal effects of the toxins, since animals exposed to
these chemicals have hormone dysfunction and altered sexual maturation (47-50).
Further evaluation on sexual development is needed to confirm the above
findings.
Later-born Yucheng Children Cohort
Children born to Yucheng mothers or Yucheng fathers between July 1985
and December 1991 recently have been identified (51). The effects
of PCB/PCDF exposure on later-born children were examined with the Chinese
Child Developmental Inventory (52). The PCB/PCDF toxicities of developmental
delays were observed in the offspring with maternal exposure but not in
those with paternal exposure.
Conclusion
The Yucheng cohort represents one of the largest groups of children prenatally
exposed to environmental PCBs/PCDFs. Although it has been 15 years since
the Yucheng outbreak, the chemicals still persist in mothers' bodies and
the Yucheng children continue to demonstrate adverse effects from their
mothers' exposures. Careful followup and proper selection of controls of
the Yucheng children allowed epidemiologic studies to provide reliable information
of physical, cognitive, and behavioral effects. Many research protocols
presently are being carried out in the Yucheng cohort and their control
subjects. Assessment of neurobehavioral development, sexual development,
and maturation will continue to be followed in Yucheng children, as the
earlier-born children will go through puberty in the next few years. Induction
of cytochrome P450IA2 activity in the liver will be tested with the caffeine
breath test (53), and the effect of altered enzyme activity on the
metabolism of sexual hormones and sexual development will be examined. PCB
and PCDF congener blood levels will be measured, and the relationship of
blood chemical levels to physical findings will be evaluated. A better
assessment of mothers' levels of exposure and continual followup examinations
of children born to intoxicated mothers may provide important information
on the dose-response relationships of PCBs and related chemicals to developmental
toxicities.
There are several possible reasons why Yucheng children were more severely
affected than U.S. cohorts. The most likely reason is that the Yucheng exposure
involved PCBs with PCDFs and terphenyls and quaterphenyls; also the total
exposure to PCBs and related chemicals were higher than those of the U.S.
cohorts.
Despite widespread concern and a more careful attitude about PCB/PCDF/PCDD
contamination in the environment, the potential for children's exposure
to these chemicals is widespread through the food chain, improper incineration
or disposal, or industrial accidents. Findings from studying the Yucheng
children will provide important information about the toxicities, health
effects, and mechanisms of PCB/PCDF/PCDD exposure.
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