Chapter 5: Human Health A variety of human health concerns have been raised in relation to review of the experimental literature, which has grown endocrine disruptors. Attention has focused on health end points exponentially in the last decade. However, it is only by integrated considered to be potentially at risk because either their development consideration of the background endocrinology, the human data, or their later functioning in adult life is known or thought to be and the animal findings that the strength of the endocrine influenced by exposure to chemicals with endocrine activity. disruptor hypothesis can be evaluated. In this chapter, four main areas are reviewed: reproduction, neurobehavior, immune function, and cancer. The order of the 5.1 Reproduction chapter sections reflects the continuum of life from conception 5.1.1 Introduction through adult life. Because sex hormones and thyroid hormones are major determinants of development and function of the The possibility that environmental exposure to chemicals might reproductive, central nervous, and immune systems, much of the affect human reproduction is not new. However, the hypothesis that experimental research to date has focused on the effects of EDCs on environmental chemicals acting as EDCs could be causative agents these key hormone systems and their target tissues, and possible links of changes in population-based, reproductive health trends is to human health effects. Endocrine-mediated mechanisms are well relatively recent. Changes occurring in various human reproductive established for certain human cancers, and these are also addressed. health statistics, particularly changes in temporal and geographical Although a few examples in this chapter clearly demonstrate trends, play a key role in the debate about possible effects of adverse effects in humans after high exposures to environmental exposure to EDCs. Although the main focus to date has been on chemicals (such as poisoning incidents), the data are much less clear male reproductive health (Toppari et al., 1996), this review covers for lower levels of exposure, either to single chemicals or to mixtures both male and female reproductive function. with potentially similar actions. It is these lower levels of exposure Much of the interest in the male reproductive system has that raise the most important public health questions, because even stemmed from an hypothesis proposed by Sharpe and Skakkebaek small shifts in population distributions of adverse health outcomes, (1993) that agents that interfere with normal development of the such as infertility or lowered IQ, could potentially have considerable reproductive system via an endocrine mechanism could plausibly be impact on the overall health of large populations. The inherent related to increases noted in human male reproductive disorders over problems in comparing human, laboratory, and epidemiological a number of years. In particular, a link was made between studies conducted at different times and locations and under developmental events that could result in decreased sperm different conditions continue to affect our ability to draw firm count/quality and increased incidences of testicular cancer, testicular conclusions about the existence of any global disease trends, and the maldescent (cryptorchidism), and male reproductive tract lack of adequate exposure data severely hampers the exploration of malformations, such as hypospadias. These could be expressions of hypotheses regarding possible causes of any identified trends. one underlying entity, the testicular dysgenesis syndrome Similarly, the lack of exposure data during critical periods of (Skakkebaek et al., 2001), which could result from disruption of development that influence later functioning in life make it difficult gonadal development during fetal life. Although the evidence linking to draw causative associations between exposure and effect. such effects to human exposure to chemicals is very weak or Hence, this chapter not only explores the available human nonexistent, treatment of experimental animals with certain health data but also draws on relevant data from experimental chemicals during critical windows of development of the male studies in laboratory animals where they support or cast doubt on reproductive system can result in deficits of the type proposed by the the biological plausibility of an adverse effect on human health hypothesis (Chapter 3, section 3.12). The one major exception is the from EDCs. This chapter is not intended to be a comprehensive production of testicular cancer (section 5.4.4). Seminoma, the major List of Abbreviations 2,4-D 2,4-Dichlorophenoxyacetic acid GR Glucocorticoid receptor PCOS Polycystic ovary syndrome AhR Aryl hydrocarbon receptor HCB Hexachlorobenzene PCDFs Polychlorinated dibenzofurans AR Androgen receptor HPOA Hypothalamic preoptic area PHAHs Polyhalogenated aromatic hydrocarbons CI Confidence interval HRT Hormone replacement therapy PND Postnatal day CIS Carcinoma in situ IARC International Agency for Research on Cancer RACB Reproductive assessment through d day Ig Immunoglobulin continuous breeding DBCP Dibromodichloropropane IPCS International Programme on Chemical Safety T3 Triiodothyronine DDE Dichlorodiphenyl dichloroethylene LA Los Angeles T4 Thyroxine DES Diethylstilbestrol LH Luteinizing hormone TCDD 2,3,7,8-Tetrachlorodibenzyl-p-dioxin DDT Dichlorodiphenyl trichloroethane LOAEL Lowest observed adverse effect level TEQs Toxic equivalent quotients DHT Dihydrotestosterone MRC Medical Research Council TGF Tumor growth factor DTH Delayed-type hypersensitivity NOAEL No observed adverse effect level TPOs Thyroid peroxidase inhibitors E2 17β-Estradiol NYC New York City TSH Thyroid-stimulating hormone EDCs Endocrine-disrupting chemicals OECD Organisation for Economic Co-operation USA United States of America EGCG (–)-Epigallocatechin gallate and Development US EPA United States Environmental EGF Epidermal growth factor OR Odds ratio Protection Agency ER Estrogen receptor (α and β isoforms) PBBs Polybrominated biphenyls US FDA United States Food and Drug FSH Follicle-stimulating hormone PCBs Polychlorinated biphenyls Administration GD Gestational day PCDDs Polychlorinated dibenzodioxins wt weight - 51 - IPCS GLOBAL ASSESSMENT OF EDCS form of human testicular cancer, is extremely rare in laboratory value of this limit. From studies in couples attempting to conceive, animals, and until recently, no experimental model existed for its it has been found that the fertility potential of men decreased when production (section 5.4.4.2). However, some chemicals have been the sperm concentration was under 40 × 106/ml (Bonde et al., shown to produce interstitial (Leydig) cell tumors, particularly in 1998). A similar figure of 48 × 106/ml has also been recently rodents, that have been related to disturbances in normal endocrine reported (Guzick et al., 2001). control of male reproductive function. Other sperm characteristics, such as the percentage of motile Changing trends in female reproductive health have been forms or the incidence and the type of morphological much less studied than those in males. However, female abnormalities, seem to be more directly related to male fertility reproductive development is also susceptible to endocrine potential. Recent data that attempt to define a “normal” semen interference (Chapter 3), and effects on female reproductive tissues evaluation indicate, for example, that sperm morphology is a better and pregnancy outcomes may be of value as indicators of discriminator between fertile and infertile men than is sperm environmental influences. A number of aspects of female concentration (Guzick et al., 2001). Sperm morphology and reproductive health are discussed below, and breast cancer is motility could also be useful markers of toxic damage even in the discussed in section 5.4.2. absence of any effect on fertility. The fertilizing ability of The following sections summarize the available literature on spermatozoa is a complex phenomenon involving many molecular adverse outcomes in human reproductive health that have either and cellular events. Some of them are essential, such as the kinetic been proposed to be due to exposure to endocrine disruptors, or for function allowing the sperm to reach the oocyte, or capacitation which an endocrine mechanism is plausible or has been and the acrosome reaction necessary for the interaction with the demonstrated. A number of examples of chemical influences on zona pellucida and the fusion with the oocyte plasma membrane. human reproduction are cited, but it should be noted that evidence The nuclear composition and DNA integrity are also important that these are clearly linked to endocrine-mediated effects is lacking. factors for normal embryo development. Sophisticated biological Emphasis has been put on the plausibility of the endocrine disruptor tests have been developed in recent years to evaluate various sperm hypothesis in relation to each end point considered and on causality. functions, but no single test can ideally measure the fertility Although the focus is on the human literature, experimental animal potential of a man. data have been included to explore plausibility issues and potential In practice, if the sperm count is used to compare fertility mechanistic pathways involving endocrine disruption. potential of different populations at different times or in different places, it may be more appropriate to analyze the distribution of 5.1.2 Sperm Quality and Testis