Review
Epidemiological evidence on reproductive effects of persistent organochlorines in humans

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Abstract

Organochlorines are widespread pollutants in humans. Concern about adverse reproductive effects of these compounds arises from accidental exposure of humans and experimental studies. Recently, this issue has been addressed by a number of studies of exposed populations and hospital-based case-referent studies. These studies indicate that high concentrations of persistent organochlorines may adversely affect semen quality and cause testicular cancer in males, induce menstrual cycle abnormalities and spontaneous abortions in females, and cause prolonged waiting time pregnancy, reduced birth weight, skewed sex ratio, and altered age of sexual development. However, most effects have been demonstrated at exposure levels above the present day exposure level in European and North American populations. Due to inherent methodological problems in several of the available studies, additional research is needed to fully elucidate the possible adverse effects of organochlorines on human reproductive health.

Introduction

Organochlorines include a number of anthropogenic compounds manufactured in large scale since 1930s. The most widespread organochlorines in the environment and in human tissues are polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane (DDT), especially the DDT degradation product dichlorodiphenyldichloroethylene (DDE) (Fig. 1) [1]. The concentration of these compounds and several other organochlorines is highly correlated in serum samples from the general human population, and exposure to the most common PCB congener (CB-153) has therefore been suggested as an indicator of overall exposure to persistent organochlorines [2]. The co-occurrence of these compounds in human samples makes it difficult to establish which compounds cause the observed effects. Moreover, one group of organochlorines, the dioxins, is more toxic than most PCB congeners, and has the same mechanisms of action as the coplanar PCB congeners [3]. This review intends to describe not the detailed, specific mechanisms of action of individual PCB congeners or DDT and metabolite toxicity, but the epidemiological findings of exposures to mixtures of these compounds. Throughout this paper, we focus on PCBs and DDTs, but will report on the observed effects of dioxins and other persistent organochlorines on reproductive outcomes in the studies where they have been measured together with PCBs or DDTs.

The production of PCBs and DDTs has been limited or completely banned since 1970s in most developed countries. The last PCB production facility, located in Russia, was shut down in 1993 [4]. However, organochlorine compounds including PCBs are still being released into the environment by (1) use, disposal or accidental release from previously produced material, (2) volatilization of previously released material, and (3) creation of PCBs and dioxins during combustion processes [4], [5]. Furthermore, some developing countries are still using DDT as vector control. The compounds are highly lipophilic (log Kow = 4.7–6.9, [3], [6]), and resistant to both biotic and abiotic degradation, which results in long half-lives in both biota and, e.g., sediments. This, in turn, results in considerable bioaccumulation and biomagnification in the food chain. The highest concentrations are found in organisms with a long life (including humans) at the top of the food chain.

The concentration of PCBs and DDTs in human tissues has decreased since the ban of these compounds in most countries some 30 years ago, but during the last 10 years the decrease has leveled off [3], [7]. The compounds continue to be detected in blood and milk samples from humans all over the world. Furthermore, in areas with present DDT use, high concentrations are still found [8]. These xenobiotics may, therefore, still pose a threat to human reproduction. Moreover, since several PCB congeners and some DDTs and their metabolites have weak hormone- or anti-hormone-like action in in vitro and in vivo assays, evidence on the human reproductive toxicity of these compounds may contribute to our understanding of the environmental hormone hypothesis [9].

The reproductive toxicology of persistent organochlorines has been reviewed previously [1], [10], [11], [12], [13], but recent advances within the field – especially new epidemiological data – have added information about the potential adverse effects on human reproduction both in highly exposed areas and in the general population. The most recent review [13] is mainly a descriptive study of the effects of PCBs on development and reproduction in human and animal studies. In this review, we critically evaluate recent advances in epidemiological studies of human reproductive disorders related to persistent organochlorines with particular reference to PCBs and DDTs. We also include key studies dating back to 1980 for reference.

Section snippets

The literature database

To compile relevant papers for the review, an initial search in Medline (PubMed) for human studies published in English with an abstract and using the search string: (PCB or DDE or DDT) and (fertility or reproduction) produced 408 hits on July 14, 2003. Using the abstracts, we identified original epidemiological studies on reproductive outcomes (time to pregnancy, semen quality, congenital malformations of sexual organs, cancers in reproductive organs, birth weight, gestational age, spontaneous

Method for comparison of exposure level among studies

The organochlorine exposure assessments are not complete for all studies, and when measured, different methodologies have been used and the compounds have been measured in different human tissues and secretions. Caution should therefore be taken in direct comparisons among these studies. However, from studies where organochlorine concentration are reported in more than one tissue or secretion, some crude estimates of conversion factors can be made. Hence, the total PCB concentration is about

Male fecundity

A decreasing trend in human sperm counts may have occurred in several European regions during the last 50 years (Paris [19], Scotland [20], Belgium [21], Denmark [22]). A recent study of Danish military conscripts reported a median sperm count close to the value of 40 × 106 ml−1 seminal fluid [23], below which increased waiting time to pregnancy may occur [24]. The decrease in sperm count is paralleled by a rise in the trend of testicular cancer and malformations of the male reproductive organs

Testicular cancer

A new Swedish study found the levels of the organochlorines PCBs, HCB, trans- and cis-nonachlordane, but not p,p′-DDE to be increased in the mothers of 44 testicular cancer cases compared with age-matched controls, but only cis-nonachlordane was significantly increased in the cases themselves [57], suggesting that exposure during the fetal or neonatal stage (lactational) to organochlorines increased the testicular cancer risk. However, the organochlorine level in the mothers was measured at the

Spontaneous abortion

About 15% of all clinically recognized pregnancies end up as spontaneous abortions. Inclusion of the very early, unrecognized pregnancies yields a proportion of spontaneous abortions close to 50% of all conceptions [61]. No increase in the frequency of spontaneous abortions was observed in the population from Taiwan that was highly exposed after consumption of contaminated cooking oil (median serum PCB level of 46 ng/g right after the exposure). However, this study included a limited number of

Perinatal mortality

An elevated perinatal mortality was observed in the highly exposed Yucheng population in Taiwan [41], but none of the studies with lower exposure levels have reported an increased fetal or infant mortality (Appendix A).

Birth weight and preterm delivery

The issue of whether contamination with PCBs or DDTs causes preterm delivery and small for gestational age babies has been investigated in a number of studies. Exposure to high concentrations of PCBs and PCDFs after the Taiwanese oil poisoning caused the proportion of children

Growth – age and size at puberty

Estrogens, androgens, and thyroid hormones are all involved in the regulation of growth and sexual maturation and the action of these hormones can be affected by several organochlorines. In humans exposed to high levels of PCBs and PCDFs (Yucheng accident), the first child born of exposed mothers had a smaller total lean mass and soft tissue mass [95], but the sexual maturation was not delayed [3]. On the other hand, a recent Dutch study indicates a negative effect of PCB on sexual maturation

Discussion

The epidemiological studies reviewed in this paper suggest reproductive abnormalities in human populations exposed to high concentrations of PCB or DDE, including reduced semen quality and testicular cancer in males, menstrual cycle abnormalities and spontaneous abortions in females, prolonged waiting time to pregnancy, reduced birth weight of the offspring, skewed sex ratio, and altered age of sexual development. At lower levels of exposure, such as the present level of contamination with

Acknowledgements

We thank Marcello Spano and Henning Sloth Pedersen for helpful comments. This paper was prepared in the context of the EU shared cost action: INUENDO (www.inuendo.dk) Grant No. QLK4-CT-2001-00202 (contact officer Dr. Achim Boenke).

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