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The Endocrine and : Adverse Effects of Hormonally Active Substances?

Helmut A. Greim, MD

ABSTRACT. Chemicals that have the intrinsic property Our Fertility, Intelligence, and Survival? A Scientific to modulate or even disrupt the endocrine system are Detective Story. present in the environment. Because it is the Originally, Carlsen et al2 evaluated a total of 61 potency of such chemicals that determines the toxicologic studies on sperm count and established that there relevance, assessment of the risk to human health must was a decrease from 113 million to 66 million consider both the endocrine disrupting potential and the potency. Usually in vitro assays are applied to detect the sperm/ml of semen between 1938 and 1990. On this 3 potential of a -like effect, and such data are basis, Sharpe and Skakkebaek presented the hy- considered useful to set priorities for additional testing pothesis that the dysfunctions and diseases of the and for mechanistic studies. However, such data allow male sex organs (as testicular , malformations only determination of relative potency of a chemical as of the , or cryptorchidism), which have been compared with other xenobiotics, natural compounds, or described with increasing frequency in the course of endogenous . Relevant information on the en- the past 3 to 5 decades, could be associated with docrine-disrupting potency can be taken only from in chemicals that mimic the action of . In par- vivo assays, eg, the Hershberger (male reproductive or- gans) and uterotrophic (female reproductive organs) as- ticular, medications that mimic the action of estro- says, the updated versions of the 28- and 90-day toxicity gen, , in cow milk, and cer- studies in rodents, and the 2-generation studies in ro- tain industrial chemicals have been considered. This dents. With the use of this information and the concen- assumption is supported by observations in wild tration of these chemicals in , the potency of the . Dichlorodiphenyltrichloroethane (DDT), for effect as compared with endogenous hormone activity example, accumulated in the bodies of birds of prey, can be estimated. So far, the relative potencies of chem- which are at the end of the food chain, and led to icals tested in in vitro systems as compared with reproductive disorders. Colborn et al4 described are several orders of magnitude smaller, whereas potency of the , eg, isoflavones such as genistein or smaller penises in alligators and unfertilized eggs daidzein, can even exceed that of estradiol, especially in that had been laid as the result of an industrial infants who are fed soy-based formula as a sole source of accident in Florida, in which large quantities of the nutrition. Although there are still open questions regard- insecticide dicofol were discharged into a lake. In ing in utero or early postnatal exposure, the low poten- other regions, more female than male offspring were cies and concentrations of manmade chemicals as com- counted in several species of and the gulls that pared with the endogenous hormones in humans make it ate these fish. These observations and hypotheses unlikely that adverse effects occur at common exposure. resulted in a multitude of studies to identify hormon- Pediatrics 2004;113:1070–1075; endocrine disrupters, xe- ally active chemicals and to explain their mechanism noestrogens, phytoestrogens, adverse effects, test systems. of action and their significance for humans and the environment. ABBREVIATIONS. DDT, dichlorodiphenyltrichloroethane; PCB, The different effects have been described and dis- polychlorinated biphenyl; OECD, Organisation for Economic Co- cussed by various authors and committees,5–14 as operation and Development. have the consequences for appropriate testing.15,16 A continuous flow of reports describe an association of eports of decreased sperm counts and in- chemical exposure of children to hormone-related creased incidences of testicular cancer in men disorders. These are birth defects, developmental Rand tumors in women have aroused disorders, declining proportion of male newborns, intense discussions in the general public and the neuromental deficits in families of pesticide work- scientific community. This became common knowl- ers,17,18 testicular dysgenesis syndrome as a result of edge in 1996 with the publication of the book by disruption of embryonal programming and gonadal Colborn et al,1 Our Stolen Future: Are We Threatening development during fetal by adverse environ- mental influences,19 and insufficient action

From the Institute of Toxicology and Environmental Hygiene, Technical in the male fetus with subsequent undervirilization University of Munich, Munich, Germany. and hypospadias in the newborn as a result of intra- Received for publication Oct 7, 2003; accepted Oct 20, 2003. uterine exposure to environmental hormonal disrup- Reprint requests to (H.A.G.) Institute of Toxicology and Environmental tors.20 However, except for high-exposure scenarios ␤ Hygiene, Technical University of Munich, Hohenbachernstra e 15–17, such as Yusho disease after high exposure to poly- D-85354 Freising-Weihenstephan. E-mail: [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- chlorinated biphenyls (PCBs), dibenzodioxins, and emy of Pediatrics. dibenzofurans,21,22 none of these suggested associa-

1070 PEDIATRICS Vol.Downloaded 113 No. 4 from April www.aappublications.org/news 2004 by guest on September 30, 2021 tions demonstrated a sufficiently robust correlation Replacement of a physiologic , eg, an estro- between exposure and effects, so, increasingly, other gen from the by a competitor, eg, a xe- causes for the observed effects are discussed, such as noestrogen, depends on its relative affinity to the sociodemographic characteristics23 or combinations receptor and its concentration. For example, replace- of Ͼ1 problem.19 ment of the physiologic ligand from the receptor by It is impossible to review all information and add a compound of 1000-fold lower affinity requires a to the elaborate reports of the different review pan- 1000-fold higher concentration. Although this over- els. Therefore, possible mechanisms and criteria to simplifies competitive interaction of compounds at a evaluate the plausibility of a correlation between receptor, it demonstrates the need for information on adverse effects in children and exposure to endo- the relative binding affinities of the compounds in crine-disrupting chemicals are described. question and their concentration in the . The Scientific Committee on Toxicology, Ecotoxi- cology and the Environment of the European Com- SUBSTANCES THAT MIMIC THE ACTION OF mission has compared the potency of HORMONES concentrations detected in human blood as a surro- In principle, an “endocrine disrupter” is defined as gate for concentrations at the receptor with the po- an exogenous substance or mixture that alters func- tency of estradiol concentrations in blood.7 It seemed tion(s) of the endocrine system and consequently that the relative potency of o,pЈ-DDT, 4-nonylphenol causes adverse health effects in an intact organism, or bisphenol A are approximately 1 million-fold or its progeny, or (sub)populations.7,24 In the case of lower than that of estradiol. Only the phytoestrogen , it is the stimulation of mitotic activity genistein showed a potency that exceeded that of in the of the female genital tract. Many chem- estradiol. From this it was concluded that an inter- icals that humans ingest with their diet have estro- action of the compounds at the receptor with phys- gen-like effects, which have been identified in a mul- iologic consequences is unlikely. titude of test systems.25 Among them are industrial In addition to the reproductive organs, the , chemicals such as certain herbicides, fungicides, or- , adrenal , central , im- ganochlorine insecticides, nematocides, organophos- mune system, cardiovascular system, and are phates, pyrethroids, , PCBs, and phtha- target tissues of the effect of hormones. The lates. Colborn et al4 compiled 45 chemicals, including corresponding receptors have been identified in the PCBs, dibenzodioxins, dibenzofurans, and DDT, these tissues. Moreover, there are indications of a to which they attribute an influence on the reproduc- concentration-dependent stimulation (low concen- tive system in humans. Also included are the phy- trations) or inhibition (high concentrations) of tumor toestrogens, ie, naturally occurring plant substances. growth by steroid hormones.10,26,27 Interaction with endogenous hormones may occur via different mechanisms. Xenobiotics can influence TEST SYSTEMS FOR IDENTIFICATION OF hormone synthesis—the release, the transport, the ENDOCRINE-DISRUPTING CHEMICALS effect, the , and the of hor- A great variety of test systems are being used with mones. Another group of natural and synthetic sub- different experimental modifications, which makes it stances interferes with the hormones at receptors. difficult to compare the results directly.15,25 In most Phytoestrogens such as coumestrol, daidzein, and cases, standardization is required. The in vitro tests genistein; medications such as diethylstilbestrol, are able to identify the intrinsic hormone-like poten- ethinyl estradiol, and tamoxifen; and industrial tial (hazard identification) of a chemical and its rel- chemicals such as DDT, p-nonylphenol, and bisphe- ative potency. However, they do not include toxico- nol A belong to this group. They bind to the estrogen kinetics of the chemical and its metabolites, so results receptor and interact with the binding of the hor- have to be verified by in vivo testing. Some of the mone. A third group of substances, the DDT metab- tests are described briefly. olite p,pЈ-DDE or vinclozoline metabolites, block the androgen receptors, ie, the receptors for the male In vitro Test Systems hormone . Speculations that xenoestro- The recombinant yeast estrogen assay uses yeast gens may act through unique cellular receptors that cells that are transfected with the human estrogen do not bind endogenous endocrine modulators lack receptor ␣ gene, together with expression plasmids support. (estrogen responsive elements and lac-Z reporter Compounds that interact with a receptor trigger a gene encoding ␤-galactosidase). The cells are incu- cascade of events, which are regulated by the recep- bated with the test compound and a chromogenic tor. Substances that compete with the physiologic compound. Active ligands that bind to the receptor ligand, eg, a hormone at the receptor, and imitate its induce ␤-galactosidase, changing the chromogen to effect are called agonists; those that block the recep- yellow that is quantified by a spectrophotometer.28 tor are antagonists. The kinetics of interactions of In the E-screen test, the human MCF-7 breast can- xenobiotics with an endogenous compound at a re- cer cell line is incubated with the test compound for ceptor are well understood and are the basis for the several days to allow proliferation. Thereafter, the evaluation of drug effects via a receptor (see text- number of cells is quantified, eg, by measuring op- books of ). Interaction of a ligand with tical density.29 a receptor is described by In the estrogen-R(␣) competitor screening test, the Ligand ϩ Receptor ^ Ligand Receptor Complex human is fixed to 96 wells. The test

Downloaded from www.aappublications.org/news by guest on September 30, 2021 SUPPLEMENT 1071 compound and fluorescein-labeled 17␤-estradiol are genic and antiestrogenic potencies of xenoestrogens added. After incubation and washing, the fluores- that may be ingested daily relative to 17␤-estradiol. cence of 17␤-estradiol attached to the receptor is A woman who takes a birth control pill ingests ap- measured.30 proximately 17 000 equivalents per day and during The placental aromatase assay uses aromatase cy- postmenopausal estrogen therapy ingests 3300 tochrome P450–mediated conversion of C19 andro- equivalents, whereas ingestion of estrogenic fla- gens to aromatic C18 estrogens. have vonoids in food is 102 and of environmental organo- been shown to inhibit this reaction.31 chlorine estrogens is 0.0000025. Similar data have The androgen binding or reporter gene assay and been obtained with antiestrogens. the receptor binding assay determine the Bolt et al37 compared the potencies of estimated relative affinity of androgen-like or thyroid hor- daily intake of nonylphenol and bisphenol A (1 mone–like compounds to the specific receptors as ␮g/kg body wt each) with that of 1 mg of the phy- compared with the endogenous hormones. toestrogen daidzein/kg body wt and 0.5 ␮g/kg body wt ethinyl estradiol, ingested daily in a low-dose In vivo Test Systems contraceptive pill. As compared with the daidzein The traditional Hershberger test was originally de- intake, the estrogenic potencies of nonylphenol and signed to differentiate between anabolic and andro- bisphenol A were 125 to 250 and 1000 times lower, genic effects of drugs by determining the weights of respectively, whereas that of ethinyl estradiol was 20 the musc. levator ani and in mice times higher than that of daidzein. Daidzein pene- after treatment for several weeks. Other workers trates the .38 Because soy is the major source have used a wide range of treatment regimens to of phytoestrogens in human food, which can amount determine androgenic potential of chemicals in intact to up to 8 mg/kg body wt in infants who are fed and castrated laboratory animals. The endpoints soy-based infant formula,39 the consequences of used are prostatic weight, seminal vesicle weight, these exposures must be evaluated rather than those and DNA/RNA contents of male reproductive or- of the xenoestrogens. gans.32 Specific low-dose effects postulated by the exper- In the uterotrophic assay, juvenile female rats are iments reported by the group of vom Saal40,41 on treated with the test compound and uterine growth bisphenol A and nonylphenol could not be veri- is monitored after several days of treatment. Several fied.16,42 Attempts to demonstrate potentiation of experimental designs are used, so the test requires low-dose effects by the presence of several com- standardization.33 pounds also failed. McLachlan’s43 research group The Organisation for Economic Co-operation and reported that, in an in vitro system with yeast cells, Development (OECD) Guideline 407 is a 28-day re- the effect of 2 separate weakly active estrogens was peated-exposure test in rats.34 To better detect endo- 1000 times higher in combination. Various other re- crine effects of the test chemicals, it is enhanced by search groups have not been able to repeat these determining weight and histopathology of hormone- results.44 Finally, McLachlan45 officially retracted the regulated organs, analysis of epididymal sperms, es- results and any inferences drawn from them. trous cycle, and battery of hormones. Considering this, a toxicologically relevant effect The OECD Guideline 416 reproductive test in ro- on the prenatal or postnatal phase from synthetic dents permits an in-depth study of the growth, de- chemicals is not plausible and is unlikely. However, velopment, and sexual function of the F1 generation potential beneficial or adverse effects of phytoestro- and includes the monitoring of the subsequent F2 gens and other natural compounds with hormone- generation through weaning.34 The recently revised like effects must be considered in the toxicologic protocol is considered to include parameters such as evaluation. weights and pathologic examinations of the repro- ductive organs, detailed spermatogenesis, and sperm PHYTOESTROGENS IN THE HUMAN DIET investigations of the parental generation and their Phytoestrogens occur naturally in plants. Common offspring. Physical, sexual, and behavioral develop- classes comprise isoflavones, lignins, coumestans, or ment and the learning and memory abilities of the resorcylic acid lactones that are structurally similar offspring are also included. to the mammalian estrogen and have a weak estro- genic potency ranging from 1/500 to 1/1000 that of RELATIVE POTENCY OF XENOESTROGENIC 17␤-estradiol. A major source of human consump- EFFECTS tion of phytoestrogens is soybean derived products, The intensity of the effect of substances, particu- which contain the isoflavones daidzein and larly in comparison with the endogenous hormones genistein. Because of the great differences in the con- or natural hormone-like chemicals, is critical for an sumption of such products, adults in the United evaluation. Sonnenschein et al35 studied the prolifer- Kingdom and the United States ingest approximately ative effect in estrogen-sensitive cells and found that 1 mg of isoflavones per day; Asians ingest 50 to 100 the estrogenic potency of chemicals such as 4-octyl- mg/day.46 Infants who are fed soy-based formula as phenol and bisphenol A was by Ͼ3000-fold and a sole source of nutrition ingest 22 to 45 mg/day.47 30 000-fold, respectively, lower than that of endoge- The biological effects of phytoestrogens in women nous estradiol. In view of the low amounts of these have been investigated in several studies.46,48 These chemicals found in the organism, the resulting inten- indicate that phytoestrogens in the diet have a ben- sity of effect is very low. Safe36 calculated the estro- eficial effect with respect to in women

1072 ENDOCRINE ANDDownloaded REPRODUCTIVE from www.aappublications.org/news SYSTEM by guest on September 30, 2021 by prolonging the menstrual cycle. Mean cycle sions with respect to sperm quality, depending on length in Western countries with high breast cancer the method used. Recent well-designed studies have risk is 28 to 29 days; it is 32 days in Japan, where shown large regional differences in overall sperm breast cancer risk is 4-fold lower. Because breast cell quality and time trends, both within and between division is 4-fold lower during the follicular phase of countries. Even if there has been deterioration in the cycle, the authors hypothesize that longer men- , this would not necessarily be attrib- strual cycles result in longer follicular phases with utable to endocrine disruption. reduced cell division during the premenopausal Temporal increases in the incidence of testicular years. Other beneficial effects may be reduced cancer have been reported in certain countries, but cholesterol levels, low rates of cardiovascular disease rates vary considerably among countries. The under- and cancer, and, especially in postmenopausal lying reason(s) for the increased incidences has not women, promotion of conservation of mass.49 been determined. However, exposure data on endo- In neonates who are fed the recommended soy- crine-disrupting chemicals for critical periods are based formula during the first 3 to 6 months of life, lacking. no clinical effects such as have been Exposure to certain pesticides and organochlorines reported so far. Essex50 assumed that in neonates, the has been linked to increases in the incidence of pros- hypothalamic-pituitary-gonadal axis is more active tate cancer in a few limited studies, but most studies than in older children and adults, which compen- have found no association and the mechanism is sates the estrogenic effects of the high intake of unknown. isoflavones. However, the author concluded that There has been a steady increase in breast cancer breastfeeding obviously is best for infants. If mothers incidence rates in the past decades (in Europe). The do not breastfeed their infants, then a recognized available data associating breast cancer development cow milk formula is preferable. Soy-based formula with exposure to organochlorines do not support a should not be given routinely as prophylaxis to in- causal relationship. Adult women who are currently fants who are at risk for developing allergy or atopy. at risk may have been exposed to endocrine-disrupt- Parents who are vegans may use a soy-based for- ing chemicals in utero or during infancy, childhood, mula because these contain no . and adolescence in the mid-20th century when con- taminant levels of organochlorines were higher. QUESTIONABLE CORRELATION BETWEEN DISEASES AND ABNORMALITIES AND CONCLUSION ENDOCRINE-DISRUPTING CHEMICALS Although in vitro test systems allow estimation of Several well-recognized institutions have evalu- the potentials and the relative potencies of endo- ated the evidence for adverse health effects resulting crine-disrupting chemicals, the results have to be from human exposure to endocrine disruptors.7,51,52 verified by in vivo studies, because toxicokinetics They conclude that analysis of the human data so far and metabolism affect the toxic potency of a sub- has failed to provide firm evidence of direct causal stance. Using test systems such as the improved re- association between low-level exposure to endocrine peated-dose toxicity tests (28 days) in rodents disruptors measured in the general population and (OECD 407) and the 2-generation tox- adverse health effects. The specific conclusions taken icity test (OECD 416), either endocrine disrupters from the Scientific Committee on Toxicology, Eco- showed no effects or effects appeared at very high toxicology and the Environment7 and the Interna- doses. tional Programme on Chemical Safety 52 are that Considering the relatively low exposure of hu- temporal increases in the frequency of developmen- mans to endocrine-disrupting chemicals, there is nei- tal abnormalities of the male reproductive tract, par- ther scientific evidence nor plausibility that low-af- ticularly cryptorchidism and hypospadias, have been finity compounds can displace high-affinity reported, but no causative role for endocrine disrupt- compounds from a receptor unless they reach suffi- ing chemicals has been determined. The reports on ciently high concentrations. Such high exposure in the declining proportion of male newborns during humans has occurred only during high accidental the last decades remain unexplained. Concerns have exposure scenarios. Thus, the assumption that bind- been raised about the influence of endocrine-disrupt- ing of a compound to a receptor per se results in ing chemicals on the timing of , but the pos- biological consequences is not acceptable. sible mechanisms of action and the role of other There is overwhelming experience from the thera- factors such as nutrition need to be clarified. peutic use of very potent synthetic estrogens during High accidental exposure of pregnant women to pregnancy to prevent abortion, for contraception, or certain organochlorines, eg, PCBs, has led to delays to treat menopausal or postmenopausal disorders. In in physical and mental development of the offspring. all of these situations, sufficiently high doses have to Some of these effects seem to result from altered be given to obtain modulation of the endocrine sys- thyroid or function, but in most tem. No one would expect that a dose Ͼ1000-fold or instances, endocrine mechanisms have not been more below the therapeutic dose is effective. demonstrated. Overall, the science-based knowledge on the ro- A number of studies report a decline (since 1939) bustness of the endocrine system, the well-under- in human sperm quality in several countries. Several stood principles of substrate–receptor interactions, reanalyses of these data have indicated possible bias and the generally low exposure of humans to poten- and confounding and have reached different conclu- tially endocrine-disrupting chemicals make it un-

Downloaded from www.aappublications.org/news by guest on September 30, 2021 SUPPLEMENT 1073 likely that the last plays a causative role in diseases 20. Sultan C, Paris F, Terouanne B, et al. Disorders linked to insufficient and abnormalities observed in children or the human androgen action in male children. Hum Reprod Update. 2001;7:314–322 21. Aoki Y. Polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, population in general. and polychlorinated dibenzofurans as endocrine disrupters—what we An array of in vitro test systems to cover relevant have learned from Yusho disease? Environ Res. 2001;86:2–11 endpoints of endocrine disrupters are available. 22. Longnecker MP, Kiebanoff MA, Zhou H, Brock JW. Association be- They are useful for mechanistic studies and may be tween maternal serum concentration of the DDT metabolite DDE and preterm and small-for-gestational-age babies at birth. Lancet. 2001;358: helpful in setting priorities. 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Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/113/Supplement_3/1070 References This article cites 43 articles, 3 of which you can access for free at: http://pediatrics.aappublications.org/content/113/Supplement_3/1070 #BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): http://www.aappublications.org/cgi/collection/endocrinology_sub Gynecology http://www.aappublications.org/cgi/collection/gynecology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

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