Hexachlorobenzene exposure and the proportion of male births in Turkey 1935–1990☆
Introduction
The human secondary sex ratio (the ratio of males to females at birth) remains a subject of continuing interest due in part to a reported reduction in some countries [1], [2], [3], [4], and a reported increase in others [5], [6], [7]. The nature of the variation of this ratio has been a subject of exploration for many years [8]. Recently there has been a suggestion of natural variations among certain populations [9]. More explicit theoretical considerations of the mechanisms that modify or alter the human sex ratio have explored the hormonal status of the mother and the father at the point of conception, although the mechanism of such action remains unknown [10]. The impact of warfare on the sex ratio has been subjected to intense statistical scrutiny, resulting in support for the concept that there is an increase in the sex ratio during and shortly after warfare [11]. Recently, by merging family data with sex ratios of offspring, Biggar et al. have demonstrated three major variables affecting population trends: the decline in family size, heterogeneity among couples for sex ratio, and child sex preference [12]
Suggestions that human exposure to chemicals may have an influence on the sex ratio have been emerging. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD; dioxin), has been suggested as having reduced male births to the couples most severely exposed in Seveso, Italy in 1976 [13]. This reduction has been reported to be a function of male mediated effects. However, similar observations could not be supported by exposures to dioxin-like chemicals in Taiwan [14], or exposure of fathers of Operation Ranch Hand in which TCDD contact occurred during distributation by soldiers of a defoliant during the Vietnam war [15]. There is substantial information to implicate dibromochloropropane (DBCP) as a causative agent of altered sex ratio in pregnancies fathered by men exposed occupationally [16]. The reported actions of vinclozolin [17], [18], [19] and borate [20], [21], [22], [23] on the sex ratio are controversial and the reported effects of chlorophenates has been clarified to indicate no effect [24], [25], [26], [27]. As the actual determination of sex remains unexplained, it is not suprising that the mechanism of action of toxic agents has not been determined.
Hexachlorobenzene (HCB) is a ubiquitous chemical that is highly resistant to metabolic degradation, intensely lipophilic and has a long, as yet undetermined half-life in humans. The aryl hydrocarbon receptor (AhR) is a ligand-activated nuclear transcription factor that mediates responses to toxic halogenated aromatic toxicants such as TCDD, polynuclear aromatic hydrocarbons, combustion products, and phytochemicals. HCB has been shown to be a ligand for the Ah receptor, albeit with lower affinity than TCDD [28]. It has been suggested that the Toxic Equivalency Factor, a measure of the relative TCDD-like toxicity of HCB, can in certain circumstances be quite high, but this proposal remains controversial [29], [30]. Despite the controversy, HCB remains a priority chemical of human concern.
HCB was developed as a fungicidal agent to combat Tilletia tritici, a wheat based fungus. HCB was initially reported to be a nontoxic benzene derivative and was first noted to be toxic when it was found to be responsible for an outbreak of porphyria cutanea tarda in southeastern Turkey during 1955–1960, while it was being used as a fungicide [31]. Grain had been treated with HCB for use in planting as a seed grain; however, an unknown number of people consumed the grain directly. It is estimated there were 4000 to 5000 cases of porphyria and a large number of neonatal and infant deaths as a consequence of lactational transfer from patients with porphyria to their children [32], [33]. There is no estimate of the subclinical consumption of the chemical. Although the relationship of the disease to the exposure was identified by an astute clinician in 1958, it was three years before the disorder was shown to be inducible in experimental animals [34].
Subsequent studies have shown that HCB has substantial effects on the reproductive system of subhuman primates as high dose oral administration to Rhesus monkeys had a devastating effect on hepatic and ovarian tissues; lower dosage treatment of cynomolgus monkeys produced similar ovarian germ cell destruction but without hepatic destruction or other evidence of induced illness, including porphyria. [35], [36]. In cynomolgus monkeys treated with HCB and subjected to induced ovulation and in vitro fertilization, healthy mature oocytes were recovered that were capable of fertilization and growth to eight cell blastocysts despite substantial primordial cell damage [36]. To evaluate the human impact of HCB ingestion, a long term (45-year) follow-up study of the reproductive effects of those subjects from Turkey who developed porphyria demonstrated a strong relationship of serum HCB levels measured 40 years later and the risk of spontaneous abortion over their reproductive life-span; a similar relationship between serum HCB levels and spontaneous abortion was also seen among women who did not develop porphyria and among women who did not even live in the part of Turkey involved in the tainted grain episode [37].
This current study was undertaken for a more complete analysis of the effect of HCB on the sex of the offspring at birth. The previous study explored the sex ratio (# males/# females) in the study group and did not find a significant association with serum HCB level. In this manuscript we explored the impact of a number of variables on the proportion of male births (# males/[# males + # females]) born to exposed subjects. Such an analysis permits evaluation of individual exposure and avoids analytic problems in subjects with no female births. Additionally, because the actual distribution of HCB in southeastern Turkey is not known and because there may have been subclinical effects of HCB, as well as exposure to borates in which there is growing interest regarding an effect on sex ratio, a review of the secular change in Turkey was undertaken [23], [38].
Section snippets
Methods
The analysis of the proportion of males was evaluated using several techniques due to the opportunity to study an exposure over a forty-year period of follow-up. representing the outcomes of all progeny, and to relate that information to census-based adjusted sex ratios for the same country for a period of time that spanned the exposure.
Data from the previous study of women exposed to hexachlorobenzene as a fungicidal seed grain were reviewed [37]. Women were documented to have been exposed to
Demographic analysis of the sex ratio of turkey by census data
Between 1935 and 1990 there was a significant change in the calculated sex ratio among children 0–4 years of age (F = 11.62, P = 0.007; Fig. 1). This ratio decreased in an almost linear fashion from 1935 (1.103) to 1970 (1.026). Since 1975, the ratio has not changed appreciably. In 1975, the sex ratio was 1.048; in 1980, 1.048; in 1985, 1.050; and in 1990, 1.052
The hexachlorobenzene episode
The results of the analysis of the proportion of males born to those involved in the long-term follow-up study of HCB exposure are
Discussion
The unique aspect of this study is the opportunity to evaluate a group of subjects with significant prepubertal exposure to a priority chemical at the completion of their reproductive life-span.
The early descriptions of the exposure were identified most clearly by Cam and Schmid who have indicated that while some of the exposure occurred in 1954, the greatest burden to southeastern Turkey was in 1955–1960 [32], [42]. Several authors have indicated that most of the episode was completed by 1961
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Supported by The Medical Research Council of Canada.