In southeastern Turkey during the period of 1955-57, women were accidentally exposed to the fungicide hexachlorobenzene (HCB) after eating contaminated seed grain and developed porphyria cutanea tarda (PCT). While HCB has been shown to be a potent oocyte toxicant in primates and has been identified as an ovarian follicular fluid contaminant in women, its effect on human reproduction is poorly understood. This study was undertaken to evaluate the effects of HCB on women with a known high dose exposure. A retrospective controlled cohort comparison study of three groups was conducted. Group 1, those with confirmed PCT; Group 2, controls for the region and Group 3, controls for the country of Turkey, were followed-up after approximately 40 years (n=42/group). Blood samples were taken for analysis of serum HCB, estradiol, follicle-stimulating hormone (FSH) and inhibin. Frequency of HCB detection was greatest in Group 3, while number of cases with HCB values exceeding 1 ng/mL was significantly greater in Groups 1 and 2. There were no differences in the other biochemical measures. Interviews were completed for each patient regarding reproductive history (number of pregnancies, live births, spontaneous abortions, still births and sex of live babies). Multiple comparisons of the three groups, based on Fisher's test found the groups were inhomogeneous. When serum HCB was analyzed using correlated response logistic regression, there was a strong relationship between serum HCB levels and risk for spontaneous abortion but not sex ratio of children. The following findings were made. HCB is detectable and ubiquitous in serum samples from women in the country of Turkey with identified and unidentified exposure events. Spontaneous abortion risk is not restricted to women with identifiable exposure to HCB but to a surrogate marker of exposure (serum HCB sample). The risk of spontaneous abortion with HCB exposure requires further investigation.
PIP: During 1955-57, women in southeastern Turkey were accidentally exposed to the fungicide hexachlorobenzene (HCB) after eating contaminated seed grain and an estimated 4000 developed porphyria cutanea tarda (PCT). In a follow-up study of 225 of the original PCT patients 25-30 years after exposure, 25% still had elevated levels of urinary porphyrin excretion. These patients reported 15 spontaneous abortions in 188 pregnancies and 31 child deaths. 40 years after exposure, a retrospective controlled cohort comparative study was conducted to assess the effect of HCB on reproductive outcomes. 42 women were enrolled in each of three groups: 1) women from the initial study with confirmed PCT, 2) age-matched controls from the same region, and 3) age-matched controls from Ankara. The frequency of HCB detection in serum was highest in group 3, while the number of cases with HCB levels exceeding 1 ng/ml was significantly greater in groups 1 and 2. Analysis was compromised by the fact that the three groups were inhomogeneous. It appeared, however, that factors such as number of pregnancies, births, and abortions may contribute to determining the body burden of lipophilic chemicals such as HCB. Correlated response logistic regression revealed a significant association between serum HCB levels and risk for spontaneous abortion but not for sex ratio. Since chronic low-level HCB exposure appears ubiquitous in Turkey, the mechanism of HCB induction of spontaneous abortion merits further investigation.