Yucheng: health effects of prenatal exposure to polychlorinated biphenyls and dibenzofurans

  • Yueliang L. Guo
  • George H. Lambert
  • Chen-Chin Hsu
  • Mark M. L. Hsu
Review

DOI: 10.1007/s00420-003-0487-9

Cite this article as:
Guo, Y.L., Lambert, G.H., Hsu, CC. et al. Int Arch Occup Environ Health (2004) 77: 153. doi:10.1007/s00420-003-0487-9

Abstract

Yucheng (“oil-disease”) victims were Taiwanese people exposed to polychlorinated biphenyls (PCBs) and their heat-degradation products, mainly polychlorinated dibenzofurans (PCDFs), from the ingestion of contaminated rice oil in 1978–1979. Serial studies in Yucheng offspring born between 1978 and 1992 are summarized. Children of the exposed women were born with retarded growth, with dysmorphic physical findings, and, during development, with delayed cognitive development, increased otitis media, and more behavioral problems than unexposed children. Recently, examination of the reproductive system has suggested that prenatal exposure exerts late effects on semen parameters in young men after puberty. Results of the investigation in Yucheng children will provide important information about the human health effects and toxicology of PCB/PCDF exposure. Prenatal exposure to these environmental chemicals causes the fetus to be sensitive to the toxic effects of persistent organic pollutants.

Keywords

Polychlorinated biphenyls In utero exposure Food contamination Teratogens Dioxin-like chemicals Cognitive development Growth Endocrine disruption 

Introduction

Among the most environmentally ubiquitous persistent organic pollutants (POPs) are polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), and polychlorinated dibenzodioxins (PCDDs). PCDFs and PCDDs are produced and released into the environment during many industrial processes, such as incineration, chlorine bleaching, and manufacture or disposal of chlorine-containing products. PCBs were manufactured for many purposes, including insulators, fire retardants, lubricants for heavy machinery and dielectric fluid in transformers. With long environmental half-lives (Kimbrough 1985), these POPs will remain in the environment for decades to come.

The primary route of human exposure to PCBs, PCDFs, and PCDDs is through contaminated food, such as meat and fish (Schwartz et al. 1983; Chen et al. 2003). These chemicals have long half-lives in humans (Steele et al., 1986), cross the placenta (Kodama and Ota 1980; Masuda et al. 1978) and are excreted in breast milk. They can cause significant exposure to offspring through the placenta and breast milk. In laboratory animals, prenatal exposure to PCBs and tetrachloro-dibenzodioxin (TCDD) has caused significant teratogenic and developmental toxicity (Tilson et al. 1990). In humans, transplacental and lactational exposure caused severe adverse effects (Fein et al. 1984). Fetus, infant, and child are probably more susceptible than the adult to toxic effects caused by these POPs. We review the human health effects in offspring of the Yucheng cohort of Taiwan who were probably the cohort most highly exposed to these chemicals.

In 1979, approximately 2,000 Taiwanese people ingested rice oil contaminated with PCBs and PCDFs. They developed chloracne, hyperpigmentation, peripheral neuropathy, and other signs and symptoms, which were later called Yucheng (Yu, oil; and Cheng, syndrome, in Chinese) in Taiwan, and the incident was very similar to Yusho disease which occurred in Japan in 1968. The acneform eruptions were predominantly open comedones, papules, and pustules, different from acne vulgaris in that they had dark heads and were found not only on the classical sites for acne, but also on extremities, axillae, and external genital areas (Wong et al. 1982; Lü and Wong 1984). The contamination came from a rice-oil company in central Taiwan. At the factory, PCBs were piped into tanks for indirect heating of rice-bran oil, and leakage of the pipe caused contamination of rice oil by the PCBs (Hsu et al. 1985). Repeated heating partially degraded the PCBs into PCDFs and polychlorinated terphenyls and polychlorinated quarterphenyls (PCTs and PCQs) (Masuda et al. 1986). Some PCDF congeners, e.g., 2,3,4,7,8-pentachloro-dibenzofurans (PnCDF), are highly toxic to animals, with potencies approaching that of the most toxic PCDD, 2,3,7,8-TCDD in animal and in vitro studies (Safe 1987). The episode and health effects associated with direct exposure to these chemicals have recently been reviewed elsewhere (Guo et al. 2003). Here, we focus on the effects on people who had been prenatally exposed to these chemicals.

Exposed Yucheng women reported a higher rate of ever having a stillborn baby than their controls (Yu et al. 2000). Among the 39 earliest born Yucheng babies, in utero during the time the mothers ingested the contaminated oil, eight died in the first few years of life (Hsu et al. 1985). Starting in 1985, 128 children born to Yucheng women were recruited, and physical examination of these children was performed and compared with 117 controls (Rogan et al. 1988). Among the Yucheng children examined, follow-up was done yearly, together with another cohort of unexposed children, matched for neighborhood (same township), age (within 15 days for those under 1 year and within 1 month for those older), gender, mother’s age (within 3 years), parents’ combined educational level (within approximately 3 years for the total), and occupation (within one of five classes, from unskilled laborer to professional). Children born to Yucheng mothers or Yucheng fathers between July 1985 and December 1991 were identified in 1992 for follow-up, and two controls were identified for each Yucheng child, by use of criteria similar to those for the early born Yucheng children (Guo et al. 1994a).

Between 1985 and 2002, mental and cognitive development was studied at least yearly in these two groups of children. During 1991–1995, the Yucheng children and their controls were invited to come to the National Cheng Kung University Hospital for examination. Again, during 1998–2000, the young men born to Yucheng children were examined for reproductive development, and their semen samples were analyzed.

Gender ratio

Although gender ratio was not different between offspring born to Yucheng and control women (Rogan et al. 1999), exposed Yucheng men were later found to have fathered a lower percent of male offspring than unexposed controls (del Rio-Gomez et al. 2002). This effect occurred mainly in men exposed before age of 19 and was seen only between 1980 and 1989, the 10 years following the exposure.

Biological levels of exposure

During an average of 9 months of exposure, the Yucheng adults were estimated to have consumed an average of 1,000 mg of PCBs and 3.8 mg of PCDFs in total (Lan et al. 1981). Serum PCB concentrations were measured in the mothers, near the end of pregnancy. The serum PCB levels were distributed log-normally in the exposed mothers, with an arithmetic mean of 49.3 ng/ml, and a median of 26.8 ng/ml. Serum levels of PCDFs were not measured initially. From a group of exposed blind children used as a comparison, in whom blood levels of PCBs and PCDFs were measured between 1979 and 1981 (Kashimoto et al. 1985), Yuchang children’s mothers’ serum 2,3,4,7,8-pentaCDF level can be estimated as 6,940 pg/g lipid and their 1,2,3,4,7,8-hexaCDF level as 20,800 pg/g lipid around the time of delivery of the children (Guo et al. 1995a). The average serum level in 56 Yucheng mothers in February 1992, i.e., approximately 14 years after exposure, was 1,090 pg/g lipid of pentaCDF, 2,560 pg/g lipid of hexaCDF, and 2,820 ng/g lipid of total PCBs (Guo et al. 1997); these are around 40, 130, and 7 times higher than those of the unexposed women in central Taiwan.

The median serum level in 45 serum samples of Yucheng children in February 1991 was 89 pg/g lipid of PnCDF and 180 pg/g lipid of hexaCDF (HxCDF) and was 1.0 ng/ml total PCBs on a whole-weight basis (Ryan et al. 1994). The serum concentrations of PCBs and PCDFs were still much higher than those of a pooled serum sample of matched control children (0.5 ng/ml of PCBs, whole basis; 19 pg PnCDF/g lipid and 23 pg HxCDF/g lipid).

Growth and development

The gestational age-adjusted birth weight in 49 newborn infants delivered to Yucheng women between 1979 and 1985 was 500 g lower than that of the controls (Lan et al. 1987). The deficits were seen in both female and male exposed babies, and the children born early after the outbreak were more affected than those born later. Delay in growth continued to be observed in Yucheng children in 1985 (age range 6 months to 7 years) and 1991 (age range 6 years to 13 years). The Yucheng children were 7% lighter (P<0.01) and 3% shorter (P<0.05) than controls (Rogan et al. 1988). In February 1991, the Yucheng children were still shorter than their controls by 3.1 cm (2.3%, P<0.01), but the weight was not different in these two groups (Guo et al. 1994b). These findings were compatible with those in the offspring of the Michigan fish eaters; those with cord serum PCB levels of 5.0 ng/ml or more had a decreased birth weight of approximately 160–190 g compared to that of the lower exposed children (Fein et al. 1984). There was no difference in joint laxity, total bone mineral density, or total and percent body fat, between Yucheng and control groups. The total lean mass and soft tissue mass were significantly lower in Yucheng children (Guo et al. 1994b).

Cognitive and behavior

When asked about the times that their children achieved 33 developmental milestones, the Yucheng parents reported that 32 milestones had been achieved later in their children than controls, with many of these differences being statistical significant (Yu et al. 1991). The Bayley Scale of Infant Development was used for the children 6 to 30 months of age. The 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 (101 vs 108, P<0.05) indices than did their controls. The delay persisted over the examination periods, i.e., 12, 18, 24, and 30 months of age (Yu et al. 1991).

In the assessment of cognitive development between 1985 and 1990 (Chen et al. 1992), the Yucheng children scored approximately 5 points (0.3 standard deviation) lower than their matched controls on the Stanford–Binet test at the ages of 4 and 5 years and approximately 5 points (0.4 standard deviation) lower on the Wechsler Intelligence Scale for Children, Revised, (WISC-R) at the ages of 6 and 7 years. The children born up to 6 years after their mothers’ intoxication were affected similarly to those children born immediately after the episode. The primary spatial ability of Yucheng children was compared with their controls, from Raven’s progressive matrices, at 6, 7, and 8 years of age (Guo et al. 1995b). The Yucheng children scored lower than the controls. Exposed boys showed a deficit in spatial ability. This finding is compatible with laboratory animal study in which gender-specific learning deficit was found in rats exposed to PCBs during the early stage of development (Widholm et al. 2001).

Rutter’s Child Behavior Scale A (Rutter et al. 1970) was used for assessment of the behavior of Yucheng and control children aged 3 years or above. Rutter’s scale is a screening instrument, filled out by primary 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 the ages of 3 and 9 years (Chen et al. 1994). A Chinese version of the modified Werry–Weiss-Peters Activity Scale (Werry 1968) was used in children aged 3–12 years for evaluation of the children’s activity level. Yucheng children scored 8–53% higher than their controls at each age, and the differences were significant in six age groups. From 1992 through 1995, the behavioral problems of Yucheng children and their controls were measured with the Achenbach Child Behavior Checklist and the Rutter Child Behavior Scale A (Lai et al. 2002). The exposed children scored 3 points (P=0.05) lower than control subjects for IQ; 3 points (P=0.002) higher on the child behavior checklist (an effect size similar to the gender difference); and 6 points (P<0.001) higher on the Rutter scale (3 times the gender difference). Overall, these findings indicate that prenatal exposure to POPs produces long-lasting cognitive and behavioral damage.

Neurological findings

In February 1991, 27 pairs of Yucheng and control children underwent extensive neurological evaluation with auditory event-related potentials (P300), pattern visual evoked potentials (P-VEPs) and short-latency somatosensory evoked potentials (SSEPs) (Chen and Hsu 1994). The P300 is useful for evaluation of the function of information processing, in which latency was related to the speed of cognitive task solving (Brandeis and Lehmann 1986), and amplitude to the frequency of occurrence of target stimulus, reflecting the ability of concentration (Sutton et al. 1965). In children, low amplitude in P300 has been associated with attention deficits and reading disabilities (Holcomb et al. 1986; Robaey et al. 1992), and greater latencies with cognitive impairment (Finley et al. 1985). No difference in neurological abnormality or soft neurological signs was found in the neurological examination of Yucheng and control children. Yucheng children had prolonged latencies (356 vs 329 ms, P<0.01; and 356 vs 331 ms, P<0.05, at two scalp recording positions) indicating slowed cognitive processing, 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), indicating attention deficit. In both Yucheng and control groups, latencies were inversely correlated with WISC-R full-scale intelligent quotient (IQ). No conduction abnormality was shown with P-VEPs and SSEPs. These findings suggested that in Yucheng children, sensory afferent pathways were not affected and the reduced IQ scores might be due to slowed cognitive processing and/or attention deficit.

Dermatological findings

By parents’ history, the Yucheng children had increased rates of hyperpigmentation, eyelid swelling and discharge, deformed nails, and acne scars, compared with controls (Gladen et al. 1990). Examination in 1985 showed that the exposed children had more pigmented or dystrophic nails, acne scars, and hyperpigmentation. In 1991 and 1992, Yucheng children were found to have significantly higher percentage of nail deformities than the controls (Hsu et al. 1995). There were no residual findings of acne or hyperpigmentation. The main nail findings were transverse coarse grooves and irregularly concaved depression in approximately 33% of children, with predilection for thumbs, followed by big toes and other fingers. Those children born earlier after 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, in that the coarse grooving had changed into irregular depressions (Hsu et al. 1995). The typical nail changes found in prenatally exposed children, but not in the directly exposed population, suggested prenatal damage of the nail matrix.

Immunology/infectious diseases

The Yucheng children had a history of more-frequent bronchitis, upper respiratory tract infection, and ear infections, as reported by the parents in 1985 and 1992 (Rogan et al. 1988; Ju et al. 1992). Otolaryngological examination in 1992 showed increased otitis media and its chronic complications in Yucheng children compared with their controls (Chao et al. 1997). The middle ear findings were found to be associated with children’s serum levels of PCDFs, but not PCBs, suggesting stronger immunological effects of PCDFs than of PCBs.

Tooth development

At the initial evaluation of Yucheng children and their controls, exposed mother reported a significantly higher percentage of natal teeth and swollen gums at childbirth (Rogan et al. 1988). Complete dental examination was carried out on 73 Yucheng children and 75 matched controls, aged 7 to 11 years, in 1992. Ten among 73 (14%) exposed children were reported to bear teeth at the neonatal period, with none in the controls (Wang et al. 2003). The exposed group also had a significantly higher percentage of congenitally missing teeth (29% vs 2.7%) or rotation in teeth (19% vs 2.7%) than did the controls. The percentages of developmental defects increased significantly with increasing maternal serum PCB levels, children’s PCB and PCDF levels, and duration of breast feeding. Maternal PCB level clearly played a more important role in increasing the risk of neonatal teeth and developmental defects. The defects were apparent at the start of the lowest tertile of total PCB level of <10 ppb in maternal serum measured nearest to the time of childbirth, in a dose-dependent manner. There tended to be fewer permanent teeth in the exposed group than in the control group, from the age of 11 years and onwards.

Endocrine and sexual development

Because physical examination of the Yucheng children revealed tooth chipping, and their parents had reported prenatal and fragile teeth (Rogan et al. 1988), calcium metabolism in these children was studied in 1992. The children had essentially normal blood levels of parathyroid hormone, vitamin D, serum calcium, alkaline phosphatase, and phosphate, and when compared with controls, no difference in skeletal mineralization was observed when dual-photon absorptiometry was used (Guo et al. 1994b). In a preliminary study on sexual development (Guo et al. 1993), penile length was measured in 55 pairs of Yucheng boys and their control. Boys aged 11 to 14, who were born in the earlier years after the mothers’ intoxication, had reduced penile length compared to that of their controls. In 1998, semen was analyzed in 12 Yucheng young men (sexually mature, aged 16 to 20 years old) and 25 controls (Guo et al. 2000). The sperm in Yucheng men showed significantly increased abnormal morphology (37.6% vs 25.9%), reduced motility (35.1% vs 57.1%), and reduced capacity to penetrate hamster oocytes (65.8% vs 73.5%). The semen volume and sperm count were not different between Yucheng young men and their controls. The effects of PCBs/PCDFs on the reduced body height, length of penis, and semen parameters, might be due to hormonal effects of the toxins, since animals exposed to these chemicals exhibit hormone dysfunction and altered sexual maturation (Platonow et al. 1972; Lione 1988; Safe et al. 1991; Faqi et al. 1998). Further evaluation of reproductive system functions is warranted.

Later-born Yucheng children

Children born to Yucheng mothers or Yucheng fathers between July 1985 and December 1991 and their controls were assessed with the Chinese Child Developmental Inventory (Hsu et al. 1978). The PCB/PCDF toxicities of developmental delays were observed in the offspring with maternal exposure but not in those with paternal exposure (Guo et al. 1994a).

Proposals for future studies

The offspring of Yucheng women after their intoxication represent one of the largest groups of humans prenatally exposed to high levels of PCBs/PCDFs. Although it has been more than 20 years since the Yucheng outbreak, the chemicals might have caused early damage to their bodies, and the Yucheng children continue to demonstrate adverse effects from the exposure. Follow-up and careful selection of controls of the Yucheng children allowed epidemiological studies to provide reliable information on physical, cognitive, and behavioral effects. Assessment of neurobehavioral development, reproductive development and behavior, and even the health of third-generation Yucheng offspring is important to answer many important research questions. Induction of cytochrome P450 IA2 activity in the liver will be tested with the caffeine breath test (Lambert et al. 1986), and the effect of the altered enzyme activity on the metabolism of sexual hormones and sexual development will be reported in the near future. In addition, the Yucheng victims were exposed to PCBs and PCDFs, but except for otitis media which was related to children’s serum PCDFs and not PCBs, which groups of toxicants were more responsible for the observed health effects has not been conclusively determined. More meticulous documentation of exposure levels of both groups of toxicants, and continual follow-up of second and third-generation offspring of intoxicated people, might provide important information on dose–response relationship, developmental toxicities, and endocrine-disrupting mechanisms.

Conclusion

Despite the fact that the manufacture of PCBs has been stopped and that there is more careful monitoring of PCDF/PCDD contamination in the environment, the potential for children’s exposure to these chemicals through the food chain, improper incineration or disposal, or industrial processes, is widespread. The findings from the follow-up of the Yucheng offspring will provide relevant information about the toxicities, health effects, and mechanisms, of PCB/PCDF/PCDD exposure.

Acknowledgement

The investigation of Yucheng cohort was supported by grant nos. NSC91-3112-B-006-006 from the National Science Council and NHRI-EX91-9025PL from National Health Research Institute.

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Yueliang L. Guo
    • 1
  • George H. Lambert
    • 2
  • Chen-Chin Hsu
    • 3
  • Mark M. L. Hsu
    • 4
  1. 1.Department of Occupational and Environmental Health and Department of Internal MedicineNational Cheng Kung University, College of MedicineTainanTaiwan
  2. 2.Center for Child and Reproductive Environmental Health, Department of Pediatrics, Environmental and Occupational Health Service Institute, Robert Wood Johnson Medical SchoolUniversity of Medicine and Dentistry of New JerseyNew BrunswickUSA
  3. 3.Department of PsychiatryEn Chu Kong HospitalTaipeiTaiwan
  4. 4.Department of DermatologyNational Cheng Kung University Medical CollegeTainanTaiwan

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