PCBs may cause infertility, reproductive organ damage and alter sexual behavior.
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Infertility, Reproductive Damage, and Sexual Behavior		 Human Studies - Reproductive and Sexual Effects of PCBs
 
Introduction

Human Reproductive Studies:

Infertility, Reproductive Damage and Sexual Behavior
Non-Human Reproductive Studies: Links
References


Introduction

It’s clear from all the studies (human and animal) that PCBs are a threat to human reproduction, even at relatively low exposure levels. The most vulnerable time in a person’s life is during early development in the womb, when the embryo or fetus is growing and changing rapidly. A single change in a chemical signal at a critical moment in development could change the rest of a person’s life. 

The following are conclusions from 29 scientific journal articles. This is not a complete list of all such research, only a sample. For additional study results, visit the TOXNET databases.  Please also read the summaries of PCB reproductive damage in monkeys, rats, mice, marine mammals, polar bears, birds, fish, turtles and other wildlife. 


Summary of Effects Shown in Direct Human Studies 
  • reduced penis length
  • testicular size unchanged
  • weight of testes with caput epididymus (sperm source) increased from 1948 until 1980, then slightly declined
  • puberty in boys and girls has accelerated
  • sexual impotence due to dioxin exposure [certain PCBs are dioxin-like]
  • certain PCBs have endocrine disruptive, estrogenic effects in human cells (4 studies)
  • prenatal exposure to sex hormones may affect sexual orientation (2 studies)
  • prenatal exposure to sex hormones may affect sex-linked behaviors
  • see also the section on PCB Effects in Children
Effects Cited in Study Reviews

Behavioral Changes

  • changed sexual differentiation (3 reviews)
  • sex reversal
  • altered reproductive behavior, abnormal sexual behavior
  • feminization
  • demasculinization
  • delays in sexual maturation
  • some chemical effects show only after puberty
  • reduced fertility by affecting breeding performance
General Physical Changes
  • PCBs are associated with several reproductive and hormonal effects
  • growth retardation
  • reduced fertility (3 reviews)
  • changed testosterone levels
  • changed dopamine levels
  • changed estrogen levels
  • skewed sex ratios
  • numerous other effects (many reviews)
Physical Effects in Males
  • increased incidence of reproductive abnormalities in human males may be due to estrogens
  • declines in semen quality and volume (5 reviews)
  • increased cryptorchism (birth defect --- undescended testicles)
  • increased hypospadias (birth defect --- malplacement of the urinary outlet of the penis)
  • increases in testicular cancer
  • increases in male breast cancer
  • abnormal testicular morphology and size 
  • effects on Mullerian ducts
  • altered sex organ development
  • chemicals which cause testicular change may also be responsible for testicular cancer
Physical Effects in Females
  • urogenital malformations in females
  • endometriosis in females (see Endometriosissection)
  • spontaneous abortion (miscarriage) & fetal loss (2 reviews)
  • low birth weight offspring (2 reviews) (see Baby Studies section)
  • premature births
  • medical surveillance in the workplace is important, especially given increased women workers
General Factors
  • endocrine disruptors operate during critical periods during fetal development in the womb or during infancy
  • endocrine disruptors leave irreversible changes
  • endocrine disruptors may have no "safe" dose level (no lower threshold below which no effects occur)
  • endocrine disruptors may work with other chemicals to add to or multiply health damage 
  • animal studies provide valid information for human risks (see animal studies on reproductive and sexual changes)
  • developing animals are sensitive to estrogenic agents
  • some PCBs are estrogenic (many reviews), some are anti-estrogenic (commercial mixtures of PCBs may contain unknown and inconsistent quantities of both types)
  • certain types of PCBs disrupt estrogen function in a manner that is dose, species and tissue specific 
  • the toxicity of PCBs depends on the identity and proportion of types of PCBs present (bioaccumulated mixes of PCBs can be very different from the original proportions found in the commercial mixes)
  • DIOXIN Toxic Equivalency Factors (TEFs) for PCBs are valid for some health effects, but not others (2 reviews)
  • individual effects of the 209 PCB types (congeners) have not been studied adequately (3 reviews)
  • chemicals of concern are still found in human tissue at levels that can have adverse effects on wildlife and humans.
  • PCBs and dioxin are of particular concern because they persist and bioaccumulate in the food chain
  • from a global viewpoint, PCB concentrations in ecosystems will continue to rise in the future
  • at least some PCB exposure is inevitable for human babies [due to elevated background levels of PCBs everywhere]
  • chemical effects in offspring deserve as much or more regulatory attention as cancer risks
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Human Studies

Study #1

  • reduced penis length
  • testicular size unchanged
  • study measured mixed PCBs and furans
Since environmental chemicals have been shown to alter endocrine function, including sexual maturation, in wildlife and laboratory animals; this study examines if the environmental chemicals, polychlorinated biphenyls (PCBs) and dibenzofurans (PCDFs) may alter sexual maturation in humans. A cohort of adolescent children exposed in utero to very high levels of PCBs & PCDFs, were compared to a closely matched-control cohort of adolescents not exposed to high levels of PCBs and PCDFs in utero. On periodic physical exam the children's Tanner stage of sexual maturation was assessed. In the boys, size of testes and length of the penis were measured using standard techniques. There was no statistical difference in timing of the Tanner stages in either gender. However in the 55 pairs of boys between the ages of 11 and 15 years old, the penis length was decreased in the boys exposed in utero to PCBs and PCDFs. Testicular size was similar in both groups. Future studies will determine if these effects will persist when the boys are sexually mature, and the mechanism(s) of the observed changes. (Guo at al, 1996)

Study #2

  • weight of testes with caput epididymus increased from 1948 until 1980, then slightly declined
  • puberty in boys and girls has accelerated
Etiological studies have reported that a possible cause of regional declines in sperm counts, increases in hypospadias in human males, and accelerated puberty in girls is due to exposure to endocrine disrupting chemicals (DCs). Disturbances of hormonal regulation during fetal or postnatal development in humans may induce adverse effects on the male reproductive system. But adverse effects of EDCs on humans are less clear. Therefore, we investigated fetal exposure to EDCs in Japan by analysing umbilical cords, and changes of testis weight and spematogenesis in Japanese men by using analytical data of necropsy. 1. Detection of EDCs in human umbilical cords in Japan: Human umbilical cords, a part of the fetal tissue, were collected from normal newborns. We detected dioxins, PCBs, DDTs, hexachlorocyclohexane (BHC), chlordens and heavy metals (Cd, Pb and Hg) in both human umbilical cords and cord blood. Bisphenol A and nonylphenols were also detected in human umbilical cords. 2. Analysis of testis weight and spermatogenesis in Japanese men: We examined medicolegal data of about 20,000 Japanese men (20-39 years old) who were subjected to necropsy from 1948 to 1998. The weight of testes with caput epididymis increased constantly from 1948 until 1980, but has slightly declined since then. From the analysis of interrelation among birth year, age and testis weight, we also found that puberty in boys has accelerated as well as with girls in Japan. (Mori, 2000)

Study #3

  • sexual impotence due to dioxin exposure [certain PCBs are dioxin-like]
The existence of a peripheral neuropathy after exposure to polychlorinated dioxins (PCDD) is still discussed, as studies concerning dioxin effects on the peripheral nervous system are rare and contradictory. Clinical and neurophysiological examinations (motor conduction velocity of the peroneal nerve, sensory conduction velocities of the sural and ulnar nerves) were made in 156 dioxin exposed workers (42 with, 114 without cloracne) from one pesticide producing plant. Because of known risk factors for peripheral neuropathy, 7 workers with and 28 without cloracne were excluded from further analysis. Workers with chloracne had a significantly higher exposure against PCDD as documented by back calculated lipid levels. They complained significantly more often of sexual impotence (28.6% compared to 5.8% of workers without chloracne, P<0.001), had significantly more frequent clinical signs of a sensory neuropathy (= abnormal sensory findings plus deep tendon refl (incomplete abstract) (Theomke et al, 1999)

Study #4

  • Certain PCBs have endocrine disruptive, pleiotropic effects
  • slightly increased or inhibited cell proliferation in human breast cancer cells
  • study used PCB 138, 153, 180
Polychlorinated biphenyls (PCBs) are ubiquitous environmental persistent contaminants giving rise to potential health hazard. Some PCBs exert dioxin-like activities mediated through the aryl hydrocarbon receptor. Although reports on interaction with other nuclear receptors are sparse, some congeners are hypothesized to possess endocrine disruptive potential. Here we present evidence that the three PCBs most abundant in biological extracts, 2,2',3'4,4',5-hexachlorobiphenyl (PCB#138), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB#153), and 2,2',3,4,4',5,5'-heptachlorobiphenyl (PCB#180) have pleiotropic effects on the estrogen- and androgen-receptor. In MCF-7 cells [a culture of human breast cancer cells] a slightly increased cell proliferation was observed at low concentrations (1-10 nM) in cells co-treated with 0.01 nM 17beta-Estradiol, whereas the compounds inhibited cell growth significantly at 1 and 10 nM. In reporter gene (ERE-tk-CAT) analysis the three congeners exhibited a significantly estrogen receptor-ligand mediated decrease of the chloramphenicol transferase activity in both control and 10 nM 17beta-estradiol induced MCF-7 cells. In addition, PCB#138 elicited a dose-dependent antagonistic effect on androgen receptor activity in transiently co-transfected Chinese Hamster Ovary cells with an IC(50), of 6.2 nM. In summary, this study indicate that the di-ortho, multiple-chloro substituted biphenyls, PCB#138, PCB#153 and PCB#180, can compete with the binding of the natural ligand to two nuclear receptors and thus possess the ability to interfere with sexual hormone regulated processes. (Bonefeld-Jorgensen et al, 2001)

Study #5

  • some PCBs are estrogenic in human cells
Estrogens are defined by their ability to induce the proliferation of cells of the female genital tract. The wide chemical diversity of estrogenic compounds precludes an accurate prediction of estrogenic activity on the basis of chemical structure. Rodent bioassays are not suited for the large-scale screening of chemicals before their release into the environment because of their cost, complexity, and ethical concerns. The E-SCREEN assay was developed to assess the estrogenicity of environmental chemicals using the proliferative effect of estrogens on their target cells as an end point. This quantitative assay compares the cell number achieved by similar inocula of MCF-7 cells [human breast cancer cells] in the absence of estrogens (negative control) and in the presence of 17 beta-estradiol (positive control) and a range of concentrations of chemicals suspected to be estrogenic. Among the compounds tested, several "new" estrogens were found; alkylphenols, phthalates, some PCB congeners and hydroxylated PCBs, and the insecticide (incomplete abstract) (Soto et al, 1995)

Study #6

  • hydroxylated PCB breakdown products are potent estrogen inducers in human cells
Polychlorinated biphenyls (PCBs) are persistent environmental pollutants which exert a variety of toxic effects in animals, including disturbances of sexual development and reproductive function. The estrogenic effects of PCBs may be mediated in part by hydroxylated PCB metabolites (PCB-OHs), but the mechanisms by which they are brought about are not understood. PCBs as well as PCB-Hs show low affinities for both alpha and beta estrogen receptor isoforms. In the present study we demonstrate that various environmentally relevant PCB-OHs are extremely potent inhibitors of human estrogen sulfotransferase, strongly suggesting that they indirectly induce estrogenic activity by increasing estradiol bioavailability in target tissues. (Kester et al, 2000)

Study #7

  • prenatal exposure to sex hormones may affect sexual orientation
Recent findings suggest that sexual orientation has an early neurodevelopmental basis. Handedness, a behavioral marker of early neurodevelopment, has been associated with sexual orientation in some studies but not in others. The authors conducted a meta-analysis of 20 studies that compared the rates of non-right-handedness in 6,987 homosexual (6,182 men and 805 women) and 16,423 heterosexual (14,808 men and 1,615 women) participants. Homosexual participants had 39% greater odds of being non-right-handed. The corresponding values for homosexual men (20 contrasts) and women (9 contrasts) were 34% and 91%, respectively. The results support the notion that sexual orientation in some men and women has an early neurodevelopmental basis, but the factors responsible for the handedness-sexual orientation association require elucidation. The authors discuss 3 possibilities: cerebral laterality and prenatal exposure to sex hormones, maternal immunological reactions to the fetus, and developmental instability. (Lalumiere et al, 2000)

Study #8

  • prenatal exposure to sex hormones may affect sex-linked behaviors
Masculinity and femininity have been studied by self-ratings in independent areas of research: one investigating personality traits considered masculine (M) or feminine (F); the other, behaviours statistically more common in one than in the other sex (sex-linked behaviours). The two approaches were compared for the first time in the present study of 66 male and 51 female medical students. Consistent with previous findings using the second approach, male but not female subjects' opposite sex-linked "sissy" and "tomboyish" behaviours correlated significantly with their reported ratio of homosexual to heterosexual feelings (Ho/Het). Ho/Het did not correlate with either sex's M and F scores, but high M scores in women correlated strongly with several "tomboyish" behaviours. As "tomboyish" behaviours are shown more strongly by women exposed prenatally to increased levels of opposite sex hormones compared to controls, the findings have implications for the biological theory attributing Ho/Het to such prenatal hormonal exposure. (McConaghy et al, 1995)

Study #9

  • prenatal exposure to sex hormones may affect sexual orientation
  • prenatal exposure to sex hormones may affect hearing (see PCBs and Hearing , effects on the cochlea inner ear structure)
Click-evoked otoacoustic emissions (CEOAEs) are echo-like waveforms emitted by normal-hearing cochleas in response to a brief transient. CEOAEs are known to be stronger in females than in males. In this experiment, the CEOAEs of homosexual and bisexual females were found to be intermediate to those of heterosexual females and heterosexual males. A parsimonious explanation is that the auditory systems of homosexual and bisexual females, and the brain structures responsible for their sexual orientation, have been partially masculinized by exposure to high levels of androgens prenatally. No difference in CEOAEs was observed between homosexual and heterosexual males. (McFadden et al, 1998)

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General Review Articles on PCB Reproductive Effects 

Study Review #1

  • endocrine disruptors operate during critical periods during fetal development in the womb or during infancy
  • endocrine disruptors leave irreversible changes
  • endocrine disruptors may have no "safe" dose level (no lower threshold below which no effects occur)
  • endocrine disruptors may work with other chemicals to add to or multiply health damage
  • chemicals which cause testicular change may also be responsible for testicular cancer
Endocrine disrupting chemicals (EDC) seem to be different from classic environmental toxicants in several points: 1) EDC operates during critical period (s) in the early stage of life characterized by rapid cell differentiation and organogenesis, leaving irreversible disruption thereof. 2) EDC may not demonstrate any clear threshold in exerting its "toxicological" effects and 3) EDCs may act synergistically or additively. Except for few cases such as diethylstilbestrol causing cancer in female offspring, a clear cause effect relationship between cancers in humans and EDC is still hard to demonstrate. Thanks to continual epidemiological endeavors, a few reports suggests such relationship between prostate cancer and herbicides. Because of its frequent association in incidence with inborn abnormalities of male reproductive organs such as undescended testis, hypospadias and degenerated quality of sperm, testicular cancer is suspected to have common or related pathogenesis with them. A hypothesis advanced by Carlsen et al was introduced. (Ohi, 1999)

Study Review #2

  • infertility
  • growth retardation
  • fetal loss
  • changed sexual differentiation
  • reduced sperm
  • changed testosterone levels
  • changed dopamine levels
  • different PCBs cause different effects
Studies of perinatal exposures to dioxin-like compounds (DLCs), coplanar polycyclic halogenated aromatics whose prototype is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), have employed a variety of outcome measures to investigate effects on the reproductive/developmental, endocrine, immune, and neurobehavioral systems. The effects include infertility, growth retardation, fetal loss, changed sexual differentiation, reduced cognitive/motor function, dermatologic and other ectodermal effects, and decreased immune response. Significant biomarkers have included sperm count; CD4/CD8 ratio; and levels of testosterone, T4, and dopamine. Using specific dioxin or PCB congeners, these and other markers were used to investigate the mechanisms of the observed effects. The DLCs, which include some PCB congeners, are characterized by high-affinity binding to the Ah receptor; most biological effects are thought to be mediated by the ligand-Ah receptor complex. Other PCB congeners have low affinity for the Ah receptor, and operate by non-Ah receptor mechanisms. The biologic activity of a PCB mixture is the sum of the agonist and antagonist activities of the different constituents in the mixture. Animal studies with specific PCB congeners can help to clarify these activities. With similar approaches, biologic markers of effect can be developed and applied in epidemiologic studies to monitor for, and predict, adverse effects in humans. (Hooper et al, 1995)

Study Review #3

  • at least some PCB exposure is inevitable for human babies [due to elevated background levels of PCBs everywhere]
  • PCBs are associated with several reproductive and hormonal effects
  • more studies are needed
Studies involving endocrine effects in humans and experimental animals resulting from the exposure to dioxin-like (non-ortho-substituted PCBs, PCDDs/PCDFs) and nondioxin-like (PCBs, OC pesticides) compounds (DLCs and NDLCs) were presented. A variety of reproductive and hormonal parameters, including androgen status, sexual differentiation, and thyroid functionality, were discussed. As in utero and lactational exposure of the human fetus/neonate to these environmental contaminants is inevitable, continued research to identify sensitive biomarkers of effect and susceptibility, as well as to define dose-response relationships, is required. (Feeley, 1995)

Study Review #4

  • declines in semen quality and volume
  • increases in testicular cancer
  • cryptorchidism (birth defect --- undescended testicles)
  • hypospadias (birth defect --- malplacement of the urinary outlet of the penis)
  • male breast cancer
  • effects on Mullerian ducts
A comprehensive review of declining male reproductive health was presented. The review was undertaken at the request of the Danish Environmental Protection Agency with its final content and form decided by a panel of international experts. Trends in male reproductive disorders were discussed, including significant declines in semen quality and volume, and increases in testicular cancer, cryptorchidism, hypospadias and male breast cancer from the 1930s to the present day. African American men had lower rates of testicular cancer than white American men, while Finnish men were less likely to develop testicular or breast cancer than Danish men. The effects of estrogenic pollutants on male reproduction in gastropods, reptiles, fish, birds, porpoises, seals and Florida panthers were described. Reproductive disorders in wildlife were associated with interference of normal prenatal sexual development by estrogenic or other endocrine disrupting environmental pollutants. The function of estrogen in the sexual differentiation in humans and resulting genital development disorders and malignancies was described. The effects of estrogen resistance in mice and man were cited and the effects of overexpression of the estrogen receptor in transgenic mice was described. Structural abnormalities, lower semen quality and incidence of testicular cancer in men prenatally exposed to diethylstilbestrol (56531) were reviewed. Neonatal and prenatal effects of synthetic estrogens in animal models, including effects on Mullerian ducts and developing testis were considered to be dependent on the point in fetal development that exposure occurred. The occurrence and effects of estrogenic environmental chemicals, including organochlorine pesticides, polychlorinated biphenyls, alkylphenol polyethoxylates and phytoestrogens, on male reproductive health were discussed. Existing models and assays for evaluating exposure to estrogenic substances were debated. An appendix describing the reproductive toxicology of numerous pesticides and environmental chemicals was provided. (Toppari et al, 1996)

Study Review #5

  • artificial chemical hormones disrupt sexual differentiaton and reproduction
Male sexual differentiation is dependent on normal testicular function, including secretion of testosterone from the Leydig cells, and mullerian-inhibiting substance from the Sertoli cells. External factors, such as anti-androgens and estrogens, that disturb endocrine balance cause demasculinizing and feminizing effects in the developing male fetus. Estrogens also causes adverse effects in female fetuses, whereas anti-androgens have little influence. A growing number of chemicals have been found to possess either weak estrogenic, anti-androgenic or other hormonal activities, and these are often referred to as endocrine disrupters. In animals in the wild, abnormal sexual development has been associated with exposure to mixtures of endocrine disrupters. The emerging adverse trends in human reproductive health, such as increased incidences of cryptorchidism, hypospadias and testicular cancer, and the ubiquitous presence of endocrine disrupters in the environment, support the hypothesis that disturbed sexual differentiation could in some cases be caused by increased exposure to environmental endocrine disrupters. (Toppari et al, 1998)

Study Review #6

  • hypospadias (birth defect --- malplacement of the urinary outlet of the penis)
The multi-factorial etiology of hypospadias is becoming more defined with ongoing investigation. Implicated factors include testosterone biosynthesis defects, 5 alpha-reductase type 2 mutations, androgen receptor mutations (rare), IVF (progesterone administration or endocrine abnormalities associated with infertility), and environmental agents that can disrupt the male sex hormone axis. It also seems that the incidence of hypospadias is on the rise, both in the United States and in Europe. Hypospadias is a physical manifestation that may be a consequence of numerous physiological aberrations, and our ability to understand and to potentially prevent this problem will require a significant amount of additional work. Our challenge for the future remains to identify the various etiologies, provide prenatal counseling for affected families with a history of hypospadias, and minimize or eliminate exposure to environmental agents that may contribute to this problem. It is even possible that some day we may be able to offer prenatal therapy to prevent hypospadias when the risk for this birth defect seems high. Does this sound far-fetched? Consider the modern management of a family with a child born with the adrenogenital syndrome, another endocrine derangement that can cause abnormal genital development. In this situation, dexamethasone can be administered to the mother in subsequent pregnancies to prevent fetal virilization until the sex of the fetus can be determined or adrenal enzyme mutations can be excluded. Perhaps in the future a similar approach will be taken for those families with strong risk factors for hypospadias. (Silver, 2000)

Study Review #7

  • certain PCBs are estrogenic
  • sex reversal
  • numerous other effects
Human health or diseases is a result of a complex interaction between the environment and ones genes factored over time. A gene-environment interaction which may be appropriate to a sexually mature individual can be catastrophic to a fetus. One of many important interfaces for this interaction is at the level of nuclear transcription factors called nuclear receptors. One super gene family of receptors encodes proteins that recognize many vitamins and hormones, including estrogens. The estrogen receptor is activated by natural ovarian steroid hormones as well as many exogenous chemicals including natural product such as those found in plants (phytoestrogens) and made by fungi (mycotoxin estrogens). In addition, synthetic foreign chemicals such as some polychlorinated biphenyls (PCBs), DDT, and p-nonyl phenol exhibit weak estrogen nativity. The widespread occurrence of estrogenic activities in the environment may have adverse effects on sexual development, based on previous experience with the potent synthetic estrogen, diethylstilbestrol (DES). Prenatal exposure to DES is associated with a number of genital tract lesions in both male and female offspring. Male mice or humans exposed to DES in utero express undescended testes, epididymal cysts, reduced sperm number, infertility, and prostatic inflammation. In mice, DES blocks regression of the Mullerian duct (the fetal precursors to the female genital system) resulting in the coexistence of both male and female genital systems (a structural pseudohermaphrodite). Futhermore, it can be shown that the male tissues express female gene products (an example of "molecular teratology"). These results suggest that estrogens may imprint genes early in development with later functional consequences. While it is not clear that environmental estrogens exert similar effects on sexual development it was recently demonstrated that turtle embryos can be sexually reversed (male to female) by estrogenic PCBs. Since there are increasing reports of feminized birds, fish and reptiles in the wild, concern must be given to the ecological impact of environmental estrogens for all species including humans. (McLachlan et al, 1994)

Study Review #8

  • low birth weight
  • spontaneous abortion
  • birth defects
  • altered sex organ development
  • altered reproductive behavior, abnormal sexual behavior
  • abnormal sperm production
  • abnormal testicular morphology and size
  • reduced fertility and endometriosis in females
  • delays in sexual maturation
  • more studies are needed
This summary report focuses on current studies on reproductive effects reported at the workshop on Perinatal Exposure to Dioxin-like Compounds [such as PCB 169] and supporting data noted in the discussion. Recent laboratory studies have suggested that altered development (e.g., low birth weight, spontaneous abortion, congenital malformation) and reproductive health (e.g., fertility, sex organ development, reproductive behavior) may be among the most sensitive end points when examining the effects of dioxinlike compounds. Thus, future research should target the reproductive health of both males and females exposed postnatally and prenatally. Studies in humans are needed and are on-going. In animal models, postnatal exposure to dioxin or dioxinlike compounds has been associated with abnormal spermatogenesis and abnormal testicular morphology and size in males and with reduced fertility and endometriosis in females. In utero exposure may also produce profound reproductive consequences in both males and females including delays in sexual maturation, abnormalities in development of sexual organs, and abnormal sexual behavior. The mechanism by which dioxin-like compounds cause reproductive effects is not well delineated. (Eskenazi et al, 1995)

Study Review #9

  • reduced sperm
  • urogenital malformations in females
Wildlife populations from contaminated ecosystems display a variety of reproductive alterations, including cryptorchidism in the Florida panther, small baculum in young male otters, small penises in alligators, sex reversal in fish, and altered social behavior in birds. The formation of biologically plausible hypotheses regarding disruption of reproduction in wildlife can be facilitated by mechanistic studies on laboratory animals. To this end, we are investigating the in vivo and in vitro effects of endocrine-disrupting toxicants in rodents. In vitro studies have used receptor binding and transfected cell assays to confirm the suspected mechanism of action, whereas in vivo rodent studies examine altered sexual differentiation. Antiandrogenic pesticides compete with the natural ligands for both rat and human androgen receptors, block androgen-induced gene expression in vitro and in vivo, delay puberty, reduce sex accessory gland size, and alter male rat sex differentiation. In contrast, xenoestrogens affect female central nervous system sex differentiation and fecundity without producing malformation or infertility in male offspring. Prenatal administration of 2,3,7,8-tetrachlorodibenzo-p-doxin (TCDD) or the TCDD-like polychlorinated biphenyls (PCBs) produce yet another profile of effects in the offspring, reducing numbers of ejaculated sperm in male progeny and inducing urogenital malformations in females. Although phthalates are reported to be estrogenic in vitro, in vivo exposure causes developmental alterations that more closely resemble antiandrogenic activity. The mammalian data indicate that exposure to endocrine-disrupting chemicals produces effect that are pathognomonic for mechanisms by which they act. Mechanistic information derived from mammalian studies can enhance our ability to predict toxicant effects on reproduction in fish and wildlife. (Gray et al, 1998

Study Review #10

  • some chemical effects show only after puberty
  • animal studies provide valid information for human risks
  • PCBs and dioxin are of particular concern because they persist and bioaccumulate in the food chain
During sexual differentiation there are a number of critical periods when the reproductive system is uniquely susceptible to chemically-induced perturbations. At these times an inappropriate chemical signal can result in irreversible lesions that often result in infertility, whereas similarly exposed young adults are only transiently affected. The serious reproductive abnormalities that resulted from human fetal exposure to DES, synthetic hormones and other drugs provide grim examples of the types of lesions that can be produced by interfering with this process. Furthermore, it is of concern that many of the abnormalities are not expressed during fetal and neonatal life and only become apparent after puberty. The present discussion will selectively review a wide range of chemically-induced abnormalities of sexual differentiation in mammals. The list of known developmental reproductive toxicants includes a broad spectrum of drugs, pesticides and toxic substances. Some of the xenobiotics, like the PCBs and dioxin, are of particular concern because they persist in the environment and bioaccumulate in the food chain. The fact that these toxicants alter sex differentiation through a wide variety of relatively well understood physiological mechanisms that are common to all mammals allows scientists to use rodent models to predict potential adverse outcomes in humans, domestic animals and wildlife. (Gray, 1992)

Study Review #11

  • certain types of PCBs are estrogenic
  • certain types of PCBs disrupt estrogen function in a manner that is dose, species and tissue specific
  • skewed sex ratios
  • feminization
  • demasculinization
  • reduced sperm counts
  • reduced fertility
Environmental pollutants are known to exert endocrine-disrupting effects on several hormonal axes of animals, including reproduction and development. Many of these xenobiotics modulate the estrogen-receptor signaling pathway(s) in agonistic or antagonistic ways. Some of the compounds are themselves estrogenic (so-called xenoestrogens, environmental estrogens, or ecoestrogens), and are classified as synthetic estrogens, phyto- or fungal estrogens, alkylphenol ethoxylates; certain non-coplanar polychlorinated biphenyls (PCBs), etc. Other molecules are antiandrogenic, e.g., p,p'-dichloro-diphenyl-dichloroethylene (DDE); while still others disrupt estrogen function in a manner that is dose, species and tissue specific, e.g., certain co-planar PCBs and dioxin-like molecules (e.g., tetrachlorodibenzo-p-dioxin (TCDD)). Exposure to some compounds has been correlated with skewing of sex ratios in aquatic species, and feminization and demasculinization of male animals; declines in human sperm counts; and overall diminution in fertility of birds, fish, and mammals. This review will cover these various xenobiotics and evaluate them for their estrogen-modulating effects; and then further concentrate on TCDD specifically. Dioxins are produced as by-products of herbicide overuse, from paper bleaching, plastics manufacture, and waste incineration. TCDD has been correlated with altered fecundity and endometriosis in monkeys, and with certain cancers in experimental animals and humans. TCDD is also correlated with reproductive deficits in many laboratory species. In summary, we believe that some of the reproductive deficits from endocrine-disrupting xenobiotics may be attributable to the modulation of the estrogen-signaling pathway, in positive and negative manners, depending on dose, species, and tissue specificity. (Hutz, 1999)

Study Review #12

  • chemical effects on offspring deserve as much or more regulatory attention as cancer risks
While a variety of effects of toxic chemicals are known in animals exposed both in the laboratory and in situ, it has proven more difficult to obtain definitive information relating harm to humans resulting from environmental contamination. Until quite recently it has been generally assumed that cancer was the human disease of greatest importance. In fact, the majority of regulations of exposure to toxic chemicals by most governments are designed on the basis of presumed cancer risk. The evidence that hazardous chemicals can cause cancer is strong, and concern of cancer risks is appropriate. However, recent evidence has triggered a reevaluation of the assumption that cancer is the sole disease of concern. New evidence has emerged suggesting that exposure to hazardous chemicals may lead to a variety of non-cancer endpoints, and that these effects may occur at low concentrations. Of particular concern is evidence for irreversible effects on the embryo and very young children which influence intelligence, attention span, sexual development and immune function. Some of these actions appear to be direct effects on the brain and other organ systems while others are mediated via disruption of endocrine systems. While these effects are subtle and difficult to quantify, the aggregated evidence is sufficiently compelling as to necessitate reevaluation of those health outcomes upon which regulations are based. (Carpenter, 1998)

Study Review #13

  • developing animals are sensitive to estrogenic agents
This review outlines the historical background of environmental endocrine disruptor issues and the particular sensitivity of the developing animals to exposure to estrogenic agents in the induction of longterm changes in reproductive and nonreproductive organs, and research needs of adverse effects of endocrine disruptors in experimental animals, wildlife and humans. Many chemicals released into the environment disrupt the endocrine system in wildlife and humans, and many of which have estrogenic activity by binding to the estrogen receptor. The animal and cell culture models can be utilized as an indicator of possible consequences of exposure to environmental endocrine disruptors. In humans, although the causes are not clear, hypospadia increased twice from 1970' and sperm count decreased and testicular cancer incidence increased. Epidemiological studies are needed to clarify the cause of these abnormalities in humans. More attention should be paid to abnormalities in genital organs exposed to endocrine disruptors during fetal and early postnatal development in wildlife, experimental animals and humans. (Iguchi, 1998)

Study Review #14

  • the increased incidence of reproductive abnormalities in human males may be due to estrogens
The incidence of disorders of development of the male reproductive tract has more than doubled in the past 30-50 years while sperm counts have declined by about half. Similar abnormalities occur in the sons of women exposed to diethylstilbestrol (DES) during pregnancy and can be induced in animals by brief exposure to exogenous oestrogen/DES during pregnancy. We argue that the increasing incidence of reproductive abnormalities in the human male may be related to increased oestrogen exposure in utero, and identify mechanisms by which this exposure could occur. (Sharpe et al, 1993)

Study Review #15

  • dioxin Toxic Equivalency Factors (TEFs) for PCBs are valid for some health effects, but not others
  • some PCBs are like dioxin, some are not
  • some PCBs are estrogenic, some are anti-estrogenic (commercial mixtures of PCBs may contain unknown and inconsistent quantities of both types)
  • the toxicity of PCBs depends on the identity and proportion of types of PCBs present (bioaccumulated mixes of PCBs can be very different from the original proportions found in the commercial mixes)
  • individual effects of the 209 PCB types (congeners) have not been studied adequately
The methods used to evaluate the toxicological effects of PCBs in animals have been reviewed. The data show that Toxic Equivalency Factors (TEFs) could be developed to assess the potential toxicity of PCB mixtures for certain specific target organ effects (such as the liver and immune system) but would be inappropriate for other effects (e.g. thyroid function and neurochemical effects). More data on a wider range of individual PCB congeners and a method for systematically balancing toxicodynamic and toxicokinetic data are required before the TEF approach can be fully evaluated. 3. With the exception of the teratogenic effects seen in mice and the anti-oestrogenic effects reported in in vitro studies, there are insufficient data on individual PCB congeners to evaluate the structure-activity relationships for the effects of PCBs on reproduction. The data also show that individual PCBs may have opposing effects on a particular aspect of reproduction (for example individual PCB congeners may have either oestrogenic or anti-oestrogenic effects). Studies with individual PCB congeners have shown both enhancement and antagonism of the teratogenic effects of 2, 3, 7, 8-tetrachloro dibenzo-p-dioxin (TCDD) in the mouse. It is not possible to use TEFs to evaluate the reproductive effects of PCBs. 4. The mechanism(s) responsible for the effects of PCBs on postnatal neurobehavioural development in rodents and monkeys have not been elucidated. At least two groups of PCBs which might be responsible for the observed effects have been identified in this review, one affecting the dopaminergic system and the other group affecting thyroid hormone levels. Considerably more research would be required before the TEF approach could be applied to the effects of PCBs on postnatal neurobehavioural development. This would include research on an appropriate animal model to determine whether the critical toxicological mechanism is mediated through the Ah receptor. 5. The reproductive toxicity of complex PCB mixtures such as those found in foods will depend on the identifies and relative proportions of individual PCB congeners in the mixture. It is not possible to give an accurate estimate of a NOAEL or LOAEL from the reproduction studies using commercial PCB mixtures which could be readily applied to the safety assessment of PCBs present as contaminants in food. 6. It is concluded that the data presented in this paper support the hypothesis that there is no satisfactory method derived from the available studies in laboratory animals for evaluating the potential risk of adverse effects on reproduction posed by contamination of foods with PCBs. (Battershill, 1994)

Study Review #16

  • altered sex differentiation
  • reduced fertility by affecting breeding performance
This paper compares the statistical precision and biological sensitivity of multiple indices of reproductive function to infertility in the male rodent. The studies discussed include those that examined reproductive function in the male following perinatal exposure to reproductive toxicants and others in which the compounds were administered to young-adult males, often with very diverse results. For example, some chemicals that alter sex differentiation reduce fertility by affecting breeding performance alone (polychlorinated biphenyls (PCBs), fenarimol, or losulazine), without altering sperm and testicular measures. Others also markedly alter sex differentiation of the genitalia, the accessory glands and the testis in addition to their effects on central nervous system (CNS) sex differentiation and mating behavior (testosterone, flutamide, cyproterone acetate, tamoxifen, estradiol and diethylstilbestrol (DES)). In contrast, prenatal exposure to compounds that alter primary germ cell survival (busulphan, congo red) induce partial gonadal/germ cell agenesis without altering sex differentiation. These chemicals dramatically reduce testicular sperm production in the male offspring, and the most severely affected males are infertile. In a series of studies conducted in our laboratory, young male rats were exposed to known reproductive toxicants in a dose related manner from puberty, through young adulthood and breeding. We have found that the profile of effects varies considerably depending upon the chemical's mechanism of toxicity. When a compound produced infertility through direct effects of testicular function (Carbendazim (MBC) and dibutyl phthalate (DBP)), then testis weight, testicular histology, and testicular sperm head counts provided sensitive indicators of toxicity. In general, dramatic reductions in sperm production are required to induce infertility and these changes were accompanied by elevated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and changes in human chorionic gonadotropin (hCG)-stimulated testosterone synthesis. Chemicals that have hormonal activity, alter the internal endocrine environment, or directly effect CNS function induce a completely different profile of effects. For example, estrogen administration alters the function of the seminal vesicle and the endocrine system, and reduces epididymal sperm reserves; while testicular measures are relatively unaffected. Since very different spectrums of effects are produced by different compounds, no single endpoint will consistently be the most sensitive indicator of reproductive toxicity. For this reason, studies should be designed to measure a sufficient number of well validated endpoints to provide a comprehensive assessment of the entire reproductive axis. (Gray et al, 1998)

Study Review #17

  • medical surveillance in the workplace is important, especially given increased women workers
The mechanisms of various industrial toxins in causing disease of the thyroid, testes, ovary and pancreas are reviewed. Toxins include: polyhalogenated biphenyls, polyhalogenated dibenzodioxins and dibenzofurans, organochlorine pesticides, polycyclic aromatic hydrocarbons, hydroxyphenols and hydroxy pyridines, phthalates, lithium, iodine and radiation. The importance of medical surveillance in the workplace is emphasized in the light of the increasing numbers of women in industry and the associated potential reproductive risks. (Barsano et al, 1992)

Study Review #18

  • chemicals of concern are still found in human tissue at levels that can have adverse effects on wildlife and humans.
This review provided evidence that humans are exposed to chemicals which are able to disrupt the endocrine system, demonstrated that each endocrine disrupting chemical appears to have its own mix of mechanisms of action and unique target sites, and provided insight into the difficulty of interpreting what exposure to these chemicals means. Data were provided concerning the levels of organochlorine contaminants found in human reproductive tissue, adipose tissue, and blood from the general worldwide population. Pesticides commonly reported in human tissue included cyclodienes, such as dieldrin (60571) and chlordane (57749). Human breast milk fat concentrations were compared worldwide with the lowest observed endocrine or reproductive effect levels found in animal studies. Dichlorodiphenylethanes observed in humans were discussed, including DDT (50293), DDD (6088513), DDE (72559), dicofol (115322), perthane (72560), and methoxychlor (72435). Also discussed were hexachlorobenzene (118741), hexachlorocyclohexanes, polychlorinated biphenyls, dioxins, and furans. It was revealed that numerous chemicals of concern were and are still found in human tissue at levels that can have adverse effects on wildlife and humans. (Thomas et al, 1992)

Study Review #19

  • the endocrine effect of PCBs, dioxins and furans is the most manifest within toxicological investigations
  • numerous effects listed
  • from a global viewpoint, PCB concentrations in ecosystems will continue to rise in the future
This review discusses the noxious effects on marine organisms of contaminants that disrupt physiological processes controlled by the endocrine system. It outlines the impacts of several groups of contaminants--heavy metals, chlorinated hydrocarbons, and polyaromatic hydrocarbons--on both the endocrine system and early phases in the reproductive cycles of different marine organisms. A series of respective case studies are reviewed ending in an evaluation of the wildlife/human connection. Xenobiotic effects are observed throughout all trophic levels in the marine system, ranging from zooplankton to top predators such as seals. Impacts can occur at the level of steroid biosynthesis, biotransformation, gametogenesis, oogenesis, and spermatogenesis. This chapter reviews the associations between xenobiotics and corresponding mechanisms in light of the limited information available. The complex, multiple role of cytochrome P-450 in controlling toxicity of chemicals and the balance of steroids will be extensively elaborated. A suite of disturbances in the early phase of reproductive cycles has been associated with xenobiotics and postulated to be linked to hormonal imbalance from the lower to the higher trophic levels in the marine ecosystem. Several classes of effects are described, such as: lowered egg production, retarded maturation of oocytes, decreased ovarian growth, lowered vitellogenesis, retarded follicle development, follicle phagocytosis, pseudohermaphroditism, implantation failure and pathological disorders in the genital tract. Epidemiological studies on interference of xenobiotics within the reproductive system of humans are sporadic and scarcely reveal conclusive results. Within the toxicological investigations on this subject the effects attributed to polychlorinated biphenyls (PCBs), polychlorinated dibenzodioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) are the most manifest. Some effects of these contaminants on embryonic development, follicular maturation, and sperm function are described. Considered from a global viewpoint, in particular, PCB concentrations in ecosystems will continue to rise in the future. The increasing concern about the potential hazards for marine systems, as well as other wildlife and humans, is documented. (Reijnders, 1992)

Study Review #20

  • prematurity and low birth weight
Work related reproductive disorders were reviewed and discussed. The effects of occupational exposures to chemical or physical agents on female reproductive function were reviewed. Reproductive disorders in women can involve effects on hormones that regulate the menstrual cycle, fecundity and fertility, pregnancy outcome, and teratogenesis. Some studies have suggested that synthetic hormones, mercury vapor, and organic solvents can cause menstrual dysfunction. Few studies have investigated the effects on fertility. Some case studies have suggested that exposure to noise, dyes, lead, mercury, and cadmium can cause female infertility. Miscarriages have been associated with exposure to ethylene-oxide and antineoplastic agents. No conclusive evidence of an association between anesthetic gas exposures and miscarriage has been found despite the large number of studies conducted. Polychlorinated biphenyls exposures have been associated with prematurity and low birth weights. Male reproductive disorders can involve decreases in sexuality, semen quality, and fertility and effects on progeny including childhood cancer. The spermatotoxicity of dibromochloropropane (DBCP) was discussed. Besides DBCP, ionizing radiation, chlordecone, and carbon-disulfide have been recognized as being spermatotoxic. Ethylene-dibromide and hyperthermia have been implicated as causing male infertility. A large number of studies of possible associations between paternal occupation and childhood cancer have been conducted. The most credible association has been a two fold increase in the risk of brain cancer in children whose fathers were exposed to organic solvents. Preventing and controlling occupational exposures that can impact on human reproduction was discussed. (Hatch et al, 1988)

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Links to More Information

Our Stolen Future --- an excellent source of information on reproductive effects of chemical pollutants

The Why Files on Endocrine Disruptors --- University of Wisconsin, Board of Regents. Supported by the Graduate School / University of Wisconsin-Madison.

Environmental Estrogens and Other Hormones --- Tulane University
Endocrine Disrupting Chemicals
Introduction to Hormone Disrupting Chemicals

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References

Barsano CP, Thomas JA . Endocrine disorders of occupational and environmental origin. Source: Occupational Medicine: State of the Art Reviews July-Sep. 1992, Vol.7, No.3, p.479-502. 258 ref. 

Battershill JM. Review of the safety assessment of polychlorinated biphenyls (PCBs) with particular reference to reproductive toxicity. Hum Exp Toxicol 1994 Sep;13(9):581-97. Author Address: Department of Health, Health Environment and Food Division (M), Skipton House, London, UK.

Bonefeld-Jorgensen EC, Andersen HR, Rasmussen TH, Vinggaard AM, 2001. Effect of highly bioaccumulated polychlorinated biphenyl congeners on estrogen and androgen receptor activity. Toxicology 158(3):141-153

Carpenter DO Human health effects of environmental pollutants: new insights. Environ Monit Assess 1998 Oct;53(1):245-58 Author Address: School of Public Health, University at Albany, SUNY, Rensselaer, NY.

Eskenazi B, Kimmel G Workshop on perinatal exposure to dioxin-like compounds. II. Reproductive effects. Environ Health Perspect 1995 Mar;103 Suppl 2:143-5 Author Address: University of California School of Public Health, Berkeley 94720, USA.

Feeley MM Workshop on perinatal exposure to dioxin-like compounds. III. Endocrine effects. Environ Health Perspect 1995 Mar;103 Suppl 2:147-50 Author Address: Bureau of Chemical Safety, Health and Welfare Canada, Tunney's Pasture, Ottawa,Ontario.

Gray LE Jr, Ostby J, Ferrell J, Sigmon R, Cooper R, Linder R, Rehnberg G, Goldman J, Laskey J. Correlation of sperm and endocrine measures with reproductive success in rodents. Prog Clin Biol Res 1989;302:193-206; discussion 206-9.  Author Address: Developmental and Cellular Toxicology Division, U.S. Environmental ProtectionAgency, Research Triangle Park, NC 27711.

Gray LE Jr Chemical-induced alterations of sexual differentiation: a review of effects in humans and rodents. Chemically-Induced Alterations in Sexual and Functional Development: the Wildlife/Human Connection (Advances in Modern Environmental Toxicology; v.21) 1992;:203-30 Author Address: Reproductive Toxicology Branch, DTD, HERL, US Environmental Protection Agency, Research Triangle Park, NC.

Gray LE Jr, Ostby J, Wolf C, Lambright C, Kelce W The value of mechanistic studies in laboratory animals for the prediction of reproductive effects in wildlife: endocrine effects on mammalian sexual differentiation. Environ Toxicol Chem 1998;17(1):109-18 Author Address: National Health and Ecological Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC.

Guo YL, Hsu CC, Lambert GH. Effects of environmental chemicals (EC) on sexual maturation. Pediatr Res 1996 Apr;39(4 Pt 2):74A Author Address: Dept. of Occupational & Environmental Health, National Cheng Kung University Medical College, Tainan, Taiwan

Hatch MC, Stein ZA. Reproductive Disorders. Source: Occupational Health, Recognizing and Preventing Work-Related Disease, Second Edition, B. S. Levy and D. H. Wegman, Editors; Little, Brown and Company, Boston, pages 415-429, 39 references,1988 

Hooper K, Clark GC Workshop on perinatal exposure to dioxin-like compounds. VI. Role of biomarkers. Environ Health Perspect 1995 Mar;103 Suppl 2:161-7 Author Address: Hazardous Materials Laboratory, Cal/EPA, Berkeley 94707, USA.

Hutz RJ Reproductive endocrine disruption by environmental xenobiotics that modulate the estrogen-signaling pathway, particularly tetrachlorodibenzo-p-dioxin (TCDD). Journal of Reproduction and Development 1999 Feb;45(1):1-12 Author Address: Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI.

Iguchi T, Environmental endocrine disruptors. Nippon Rinsho 1998 Nov;56(11):2953-62 Author Address: Department of Biology/Graduate School of Integrated Science, Yokohama City University.

Kester MH, Bulduk S, Tibboel D, Meinl W, Glatt H, Falany CN, Coughtrie MW, Bergman A, Safe SH, Kuiper GG, Schuur AG, Brouwer A, Visser TJ. Potent inhibition of estrogen sulfotransferase by hydroxylated PCB metabolites: a novel pathway explaining the estrogenic activity of PCBs. Endocrinology; VOL 141, ISS 5, 2000, P1897-900. Author Address: Department of Internal Medicine, Erasmus University Medical School, Rotterdam,The Netherlands.

Lalumiere ML, Blanchard R, Zucker KJ. Sexual orientation and handedness in men and women: a meta-analysis. 

Psychol Bull 2000 Jul;126(4):575-92. Author Address: Law and Mental Health Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. martin_lalumiere@camh.net

McConaghy N, Zamir R. Sissiness, tomboyism, sex-role, sex identity and orientation. Aust N Z J Psychiatry 1995 Jun;29(2):278-83 Author Address: Department of Psychiatry, Prince of Wales Hospital, Randwick, New South Wales.

McFadden D, Pasanen EG. Comparison of the auditory systems of heterosexuals and homosexuals: click-evoked otoacoustic emissions. Proc Natl Acad Sci U S A 1998 Mar 3;95(5):2709-13. Author Address: Department of Psychology and The Institute for Neuroscience, University of Texas, Austin, TX 78712, USA. mcfadden@psy.utexas.edu

McLachlan JA Environmental estrogens and reproduction. Teratology 1994 Nov;50(5):20A Author Address: Lab. Reprod. Dev. Toxicol., NIEHS, Research Triangle Park, NC.

Mori C. Endocrine disrupting chemicals and spermatogenesis. Teratology 2000 Sep;62(3):7A. Author Address: Department of Anatomy and Developmental Biology, Kyoto University, Kyoto, Japan.

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Reijnders PJ, Brasseur SM Xenobiotic induced hormonal and associated developmental disorders in marine organisms and related effects in humans: an overview. Chemically-Induced Alterations in Sexual and Functional Development: the Wildlife/Human Connection (Advances in Modern Environmental Toxicology; v.21) 1992;:159-74 Author Address: Research Institute for Nature Management, Dept. Estuarine Ecology, Den Burg, The Netherlands.

Sharpe RM, Skakkebaek NE, Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet 1993 May 29;341(8857):1392-5 Author Address: MRC Reproductive Biology Unit, Centre for Reproductive Biology, Edinburgh, UK.

Silver RI, What is the etiology of hypospadias? A review of recent research. Del Med J 2000 Aug;72(8):343-7  Author Address: Department of Surgery, A.I. duPont Hospital for Children, Wilmington, Delaware, USA.

Soto AM, Sonnenschein C, Chung KL, Fernandez MF, Olea N, Serrano FO The E-SCREEN assay as a tool to identify estrogens: an update on estrogenic environmental pollutants. Environ Health Perspect; VOL 103 Suppl 7, 1995, P113-22 Author Address: Tufts University School of Medicine, Department of Anatomy and Cellular Biology, Boston, MA 02111, USA. ASOTO@OPAL.TUFTS.EDU 

Thomke F, Jung D, Besser R , Roder R, Konietzko J, Hopf HC. Increased risk of sensory neuropathy in workers with chloracne after exposure to 2,3,7,8-polychlorinated dioxins and furans. Acta Neurol Scand; VOL 100, ISS 1, 1999, P1-5 Author Address: Department of Neurology, University of Mainz, Germany. 

Thomas KB, Colborn T. Organochlorine Endocrine Disruptors in Human Tissue. Source: Chemically-Induced Alterations in Sexual and Functional Development: The Wildlife/Human Connection, T. Colborn and C. Clement, Editors; Advances in Modern Environmental Toxicology, Vol.XXI, Princeton Scientific Pub. Co., Inc., Prince, 1992

Toppari J, Larsen JC, Christiansen P, Giwercman A, Grandjean P, Guillette LJ Jr, Jegou B, Jensen TK, Jouannet P, Keiding N, Leffers H, McLachlan JA, Meyer O, Muller J, Rajpert-De Meyts E. Male Reproductive Health and Environmental Xenoestrogens. Environmental Health Perspectives, Vol. 104, Supplement 4, pages 741-803, 323 references, 1996

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Infertility, Reproductive Damage and Sexual Behavior

Infertility, Reproductive Damage and Sexual Behavior