a Department of Public Health, National Cheng Kung University Medical College, Tainan, Taiwan.
b Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan.
c Department of Psychiatry, Tainan City Hospital, Tainan, Taiwan.
d Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Reprint requests to: Dr Yueliang Leon Guo, Department of Environmental and Occupational Health, National Cheng Kung University Medical College, 138 Sheng-Li Road, Tainan 70428, Taiwan. E-mail: leonguo{at}mail.ncku.edu.tw
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Abstract |
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Methods In 19931994, we identified the living Yucheng women and neighbourhood controls and interviewed them about their reproductive experience. Of the 596 living Yucheng women aged 3059 years, we found 368, and interviewed 356. We identified 329 controls, and interviewed 312.
Results Of the Yucheng women, 16% reported abnormal menstrual bleeding compared to 8% (P < 0.05) of control women; 4.2% versus 1.7% reported a stillbirth since 1979 (P = 0.068). Other characteristics of the menses, fertility, frequency of intercourse, and age at menopause appeared unaffected. More of the Yucheng women reported that one of their offspring had died during childhood (10.2% versus 6.1%, P < 0.05), and that they had decided to limit childbearing because of health problems (7% versus 2%, P = 0.01).
Conclusions These findings suggest that high level PCB/polychlorinated dibenzofuran (PCDF) exposure has some effect on female endocrine and reproductive function.
Keywords Polychlorinated dibenzofurans, polychlorobiphenyl compounds, rice oil, infant mortality
Accepted 24 January 2000
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Introduction |
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Children born to Yucheng women up to 6 years after the exposure have ectodermal defects, developmental delay, and disordered behaviour7 and the whole cohort has excess mortality from non-malignant liver disease after 13 years of follow-up.8 Following the study on mortality, which produced current addresses for the Yucheng victims, the Taiwan National Science Council funded a morbidity survey confined to surviving members of the cohort and controls who were 30 years in 1993. Because there is both laboratory evidence9,10 and evidence from the Japanese poisoning11 that female reproductive function might be affected, the women's interviews included questions about menstrual function and reproductive performance.
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Materials and Methods |
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Taiwan has local household registration offices in every village, town, and city precinct. The registration offices, among other functions, keep records of deaths, record changes of residence, and maintain forwarding addresses. Using the address listed in the Yucheng registry, we began in 1992 to locate each subject's record at their registration office, and traced them to 31 December 1991. Among the 2061 subjects included in the Yucheng registry, 70 were actually offspring of the exposed subjects who were born during or after the incident, and so were excluded. Of the remaining 1991 Yucheng subjects, 154 (8%) had the wrong or no address and could not be traced further, leaving 1837 subjects who were located through their neighbourhood household registration offices' records. Of the cohort, 986 (54%) of those located were female, of whom 36 had died by 31 December 1991.8 The overall morbidity survey12 of which the women's reproductive study was a part was limited to those 30 years of age in 1993, in whom the majority of health impairment was expected to occur. In addition, the women's reproductive study was limited to women who were
59 in 1993, and thus
45 when the exposure occurred in 1979 and therefore likely to have been pre-menopausal then. There were 600 such women alive on 31 December 1991. We attempted to find and interview all of them.
Ideally, a control group would have been identified at the time of the poisoning from the areas where the poisoning occurred and then followed in the same way as the exposed group. No such control group was established at the time. There were no telephone books, city registries, or other archival material that listed the residents in the towns where Yucheng had occurred in 1979 and from which we could draw a contemporaneous control sample. Therefore, we used the 1979 addresses of the registry members as index addresses and attempted to identify the people who lived nearby in 1979 from the archives of the registration offices. We did this systematically beginning with the higher or lower numbered dwelling at random; we located the record of the current household, and, if that family had not been there in 1979, we worked through the archived records until we found the record of the family who had lived there. We then enumerated the family members and attempted to identify a control subject within the family. Control subjects were required to be of the same sex, within 3 years of age of the index registry member, and could not themselves be in the registry; if a household contained no eligible control subject, the next closest household was tried. We identified three controls for each registry member, and we attempted to contact the control subject living nearest to the index address in 1979. We only used one of any triplet set. We found 594 control women in the eligible age range.
The interviews took place between July 1993 and June 1994. About 95% of the women were interviewed by telephone by either a trained college student or research assistant, in Taiwanese or Mandarin as the woman preferred. The others, mostly women with no home phone, were interviewed in their homes. The interviewers described the study as a health survey conducted by Cheng Kung University Medical College, and did not mention Yucheng or PCBs specifically. The interviewers were not told the exposure status of the subject; however, some women volunteered that they had been Yucheng victims. The interviewers were not, however, specifically aware of hypotheses concerning reproductive or menstrual dysfunction. The questions about menstrual cycles referred to usual or typical cycles. We did not attempt to have only female interviewers interview female subjects.
Although the selection of controls was a matched procedure, some of the exposed subjects had no match among the successfully interviewed controls, and some of the exposed subjects for which there were interviewed controls were not successfully interviewed. Thus, when we compared frequencies or means, we used unpaired 2 and T tests. Analyses were carried out using the Statistical Analysis System for the personal computer (PC SAS) from the SAS Institute, Cary, NC. Although we had hypotheses derived from the experience of the Japanese Yusho women, animal studies, and our previous studies of the children of these women, this study was also descriptive, and we made no adjustment for multiple statistical comparisons. Not all women answered all questions, and the frequencies are based on the number of responses other than don't know or equivalent.
Between 1979 and 1981, the Health Department measured serum PCB levels of many members of the Yucheng cohort.3 These results were used to stratify participating Yucheng women into high and low exposed groups. Of the 600 exposed women, four had died between the end of the mortality follow-up in 1991 and interview in 19931994. We were able to contact 368 of the remaining women. The others either had wrong or incomplete addresses, no telephone listing, or could not be contacted at the listed number after three attempts. Of the 594 controls, three had died between 1991 and 1993, and we were able to contact 329 of them. Twelve of the exposed women and 17 of the controls refused to be interviewed, and so we had usable interviews from 356 exposed and 312 controls.
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Results |
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Among the Yucheng women, 342 (of the 356) had ever married, and among the controls 302 (of 312) had ever married. Only four of these Yucheng women and three controls had no living children. The average number of living children was the same in both groups, 3.1 (Table 4). The Yucheng women reported stillbirths since 1979 2.5 times more frequently than the controls (P = 0.068), but spontaneous abortion frequency was similar in both groups. Among the Yucheng women, 33 (10%) reported 35 deaths among their offspring during childhood, and 18 (6%) control women reported 18 deaths. Among the deaths reported by the Yucheng women, eight had no dates reported, nine (33%) occurred before 1979 (unexposed children), three (11%) occurred during or after 1979 to children born before 1979 (directly exposed children), and 15 (55%) occurred in children born during or after 1979 (transplacentally exposed children). Among the deaths reported by the control women, four had no dates recorded, five (36%) occurred before 1979, three (21%) occurred during or after 1979 in children born before 1979, and six (43%) occurred in children born during or after 1979. The numbers of women who reported needing longer than a year to get pregnant or getting treated for infertility were small and we did not divide them into time periods, but there appears to be no differences. There is no strong evidence that those with higher PCB levels had greater effects.
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Discussion |
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In 1970, 2 years after the Yusho incident, irregular menstrual cycles were reported by 58% of 81 female Yusho patients, and urinary excretion of oestrogens, pregnanediol, and pregnanetriol of these patients tended to be low.11 We did not measure hormone levels, and the women in our study did not report so high a rate of irregular cycles. This may be because our interviews took place much longer after the exposure than did the interviews in the Japanese study.
There are a number of limitations to our study. The women were interviewed years after the exposure, and not all were studied. The 356 Yucheng women who participated in the survey represent only 59% of the 600 women who were eligible. While women who were harder to find and interview may have had different health outcomes from those easier to locate, we know of no obvious reason for this to be so. Participating women were older; however, based on serum PCB levels drawn around the time of the incident, there was little difference in exposure between the participating and non-participating women.
The women were recalling events that were years in the past at the time of the interview, and the Yucheng women may have recalled events differently from controls. The interviewers did not present the study as a Yucheng study, but rather as a general health survey. In addition, the Yucheng women reported only one characteristic of the menses, abnormal flow, more frequently than controls. Thus, there does not appear to be a general recall or reporting bias in the data.
Monkeys exposed to PCBs had increased rates of spontaneous abortion, stillbirth, and failure to conceive.9 Rats exposed to PCBs via their mother's milk had long-term reproductive impairment.13 The PCDFs have not been studied for female reproductive toxicity, but they generally have intermediate toxicity between PCBs and the chemically similar polychlorinated dibenzodioxins (PCDDs).14 The most potent PCDD, 2,3,7,8-tetrachloro-dibenzodioxin (TCDD), is one of the most carcinogenic and fetotoxic synthetic compounds known. TCDD and similar compounds can interact with the oestrogen receptor, acting as both agonists and antagonists, and can also affect hormone status by inducing the activity of the enzymes responsible for steroid hormone metabolism. Monkeys exposed to TCDD had decreased fertility, an inability to maintain pregnancy, reduced plasma concentrations of oestrogen and progesterone, and signs of ovarian dysfunction such as anovulation and suppression of the oestrous cycle.15 Monkeys exposed to very low doses of TCDD (5 and 25 ppt for 4 years) and then examined 10 years after exposure ceased, had dose-related increases in endometriosis prevalence (3/7and 5/7 animals, respectively) with historical control rates of about 3033%.10 This study, while small, was a major consideration in the World Health Organization's 1998 lowering of the tolerable daily intake for TCDD,16 because it was one of the studies showing toxicity at the lowest dose. Such effects, called critical effects in regulatory toxicology, can determine advisory and regulatory outcomes for a chemical. In this case, because the PCBs, PCDFs, and PCDDs are qualitatively similar, data on reproductive function of PCB/ PCDF exposed women becomes very desirable. Experimental studies in animals often have small numbers, high doses, and the studied physiology may not reflect that seen in human beings. In this particular case, there is no completely adequate animal model of the human menstrual cycle.
Our findings suggest that Yucheng women exposed to high doses of PCBs/PCDFs have relatively mild interference with menstrual function, and no change in fertility as measured by family size, requirement for infertility treatment, or libido as measured by frequency of intercourse. They do report more frequent stillbirths and higher mortality among their children, and from other studies it is known that their surviving children have excess ectodermal defects, developmental delay, and disordered behaviours.7 They were not asked specifically about endometriosis, the outcome of most current concern for advisory purposes, but the women did not complain of dysmenorrhoea or decreased fertility, the most common endometriosis-related symptoms. It is possible that the abnormal flow they report is related to endometriosis, but that symptom is non-specific and could be due to the oestrogenic, anti-oestrogenic, or enzyme-inducing properties of the compounds. These women had exposures high enough to make them clinically ill. Their experience should represent the upper bound of expected toxicity from background exposures. Given the extensive experimental literature on the reproductive toxicity of the PCBs and similar compounds, we think it very likely that there is menstrual dysfunction in these women, and that further study to determine the extent of dysfunction and its mechanism, especially among the younger women, is warranted.
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Acknowledgments |
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References |
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