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APPENDIXES

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398 HORMONALLY ACTIVE AGENTS IN THE ENVIRONMENT Tang, B.Y., and N.R. Adams. 1980. Effect of equal on oestrogen receptors and on synthesis of DNA and protein in the immature rat uterus. J. Endocrinol. 85(2):291 -297. Tankeyoon, M., N. Dusitsin, S. Chalapati, S. Koetsawang, S. Salbiang, M. Sas, J.J. Gellen, O. Ayeni, R. Gray, A. Pinol, et al. 1984. Effects of hormonal contraceptives on milk volume and infant growth. WHO Special Programme of Research, Development and Research Training in Human Reproduction Task Force on Oral Contraceptives. Contraception. 30(6):505-522. Tao, S.H., and P.M. Bolger. 1998. Dietary Intakes of Arsenic in the United States. Paper presented at the Third International Conference on Arsenic Exposure and Health Effects, July 12-15, San Diego, Calif. Tartan, R., and T. Kemeny. 1969. Multigeneration studies on DOT in mice. Fd. Cosmet. Toxicol. 7:215-222. Taylor, P.R., C.E. Lawrence, H.L. Hwang, and A.S. Paulson. 1984. Polychlorinated biphenyls: Influence on birthweight and gestation. Am. J. Public Health 74(10):1153- 1154. Taylor, P.R., J.M. Stelma, and C.E. Lawrence. 1989. The relation of polychlorinated biphenyls to birth weight and gestational age in the offspring of occupationally exposed mothers. Am. J. Epidemiol. 129(2):395406. Teng, C. 1995. Mouse lactoferrin gene: a marker for estrogen and epidermal growth factor. Environ. Health. Perspect. 103(Suppl. 7):17-20. Terracini, B., M. Testa, J. Cabral, and N. Day. 1973. The effects of long-term feeding of DDT to BALB/c mice. Int. J. Cancer 11 (3):747-764. Terres, G., S.L. Morrison, and G.S. Habicht. 1968. A quantitative difference in the immune response between male and female mice. Proc. Soc. Exp. Biol. Med. 127(3):664-667. Tham, D.M., C.D. Gardner, and W.L. Haskell. 1998. Clinical Review 97. Potential health benefits of dietary phytoestrogens: a review of the clinical, epidemiological, and mechanistic evidence. J. Clin. Endocrinol. Metab. 83(7):2223-2235. Theus, S.A., K.A. Lau, D.R. Tabor, L.S. Soderberg, and J.B. Barnett. 1992. In vivo prenatal chlordane exposure induces development of endogenous inflammatory macrophages. J. Leukoc. Biol. 51(4):366-372. Thigpen, J.E., R.E. Faith, E.E. McConnell, and J.A. Moore. 1975. Increased susceptibility to bacterial infection as a sequela of exposure to 2,3,7,8- tetrachlorodibenzo-p-dioxin. Infect. Immun. 12(6):1319-1324. Thomann, R.V., and J.P. Connolly. 1984. Model of PCB in the Lake Michigan lake trout food chain. Environ. Sci. Tech. 18(2):65-71. Thomas, D. C. , D. B. Petitti, M. Goldhaber, S. H. Swan, E. B. Rappaport, and 1 . Hertz- Picciotto. 1992. Reproductive outcomes in relation to malathion spraying in San Francisco Bay Area, 1981-1982. Epidemiology 3(1):32-39. Thomas, D.J., B. Tracey, H. Marshall, and R.J. Norstrom. 1992. Arctic terrestrial ecosystem contamination. Sci. Total Environ. 122:135-164. Thomas, K.B., and T. Colborn. 1992. Organochlorine endocrine disruptors in human tissue. Pp. 365-394 in Chemically Induced Alterations in Sexual Development: The Wildlife/Human Connection. T. Colborn, and C. Clement, Eds. Princeton, NJ: Princeton Scientific Publishing.

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Page 399 Appendix A— Reproductive Effects Caused by Diethylstilbesterol Much of the conceptual background for the investigation of the actions of hormonally active agents (HAAs) is based on results of studies on the actions of diethylstilbesterol (DES), a potent synthetic estrogen (see Chapter 1). Because this compound is not an environmental toxicant and because to date, no known environmental toxicant has been demonstrated to be more potent than DES, its actions are not discussed extensively in the corpus of this report. Nevertheless, because some workers in the field believe that DES is an important model for the effects of other HAAs, the relevant aspects of the actions of this compound are discussed here. There is extensive literature concerning the long-term effects of in utero exposure of humans to DES (Herbst and Bern 1981; Takasugi and Bern 1988; Mittendorf 1995) and of fetal and neonatal exposure in other animals (Vannier and Raynaud 1980; Bern et al. 1987; Brody and Cunha 1989; Newbold 1995). There is also evidence that developmental exposure to DES can alter the immune-system functioning of laboratory animals (Kalland et al. 1979; Kalland and Forsberg 1980, 1981; Ways et al. 1980; Blair 1981: Holsapple et al. 1983: Luster et al. 1984; Pung et al. 1984, 1985) and humans (Ways et al. 1987; Noller et al. 1988: Blair 1992). Effects on other tissues, such as bone, also have been noted (Migliaccio et al. 1992). However, the major concern has focused on prenatal exposure to DES and its effects on the reproductive system. Table A-1 lists the various female and male reproductive-tract abnormalities in humans and rodents exposed prenatally to DES. Studies show that exposure to DES during the critical period of organogenesis can profoundly disturb differentiation of the reproductive organs. Some of the effects are not observed until adulthood, demonstrating the latent developmental effects of exposure to this potent estrogen.break

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Page 400 TABLE A-1 Reproductive Tract Abnormalities in Humans and Rodents Exposed Prenatally to Diethylstilbestrol (DES) Abnormality Organ Study Details Reference Females         Cancer Vagina and cervix Human Clear cell adenocarcinoma IARC 1979     Rodent Adenocarcinoma McLachlan 1979: Newbold and McLachlan 1982   Ovary Human Germ Cell Cancer Walker et al. 1988     Rodent Not reported     Breast Human No increased risk of breast cancer observed Hatch et al. 1998     Rodent Not reported   Other genital tract changes Uterus Human T-shaped: hypoplasia Haney et al. 1979; Kaufman et al. 1980. 1986: Mittendorf 1995       Rodent Decreased muscle development: hyperplasia followed by hypoplasia Medlock et al. 1988: Brody and Cunha 1989: Wordinger et al. 1991     Cervix Human Adenosis: ectropion; ridging; hooding incompetence Herbst et al. 1972: Scully et al. 1974: Sherman et al. 1974; Sandberg 1976; Poskanzer and Herbst 1977: Kaufman and Adam 1978: Robboy et al. 1979     Rodent NA     Ovary Human Parovarian cysts DeCherney et al. 1981     Rodent Intra and parovarian cysts Newbold et al. 1983   Oviduct Human Withered fimbria DeCherney et al. 1981: Robboy et al. 1982 (table continued on next page)break

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Page 401 (table continued from previous page)break Abnormality Organ Study Details Reference     Rodent Developmental arrest Newbold et al. 1983   Vagina Human Adenosis; ridging, epithelial changes Herbst et al. 1972; Scully et al. 1974; Sherman et         al. 1974; Sandberg 1976; Poskanzer and Herbst         1977; Kaufman and Adam 1978; Johnson et al.         1979: Robboy et al. 1979     Rodent Adenosis Newbold and McLachlan 1982: Bern et al. 1987       Lesions   Pregnancy-   Human Infertility; ectopic pregnancy; premature Barnes et al. 1980; Cousins et al. 1980; Kaufman et related     delivery; spontaneous abortion al. 1980; Herbst and Bern 1981; Mangan et al changes       1982; Stillman 1982; Thorp et al. 1990.     Rodent Infertility, abortion, stillbirths, malformations Halling and Forsberg 1992; Walker 1983 Malesa         Cancer Testis Human Inconsistent results Henderson et al. 1979; Schottenfeld et al. 1980;         Depue et al. 1983; Brown et al. 1986; Gershman         and Stolley 1988     Rodent Adenocarcinoma of the rete testes, Newbold et al. 1985, 1987       interstitial cell carcinoma     Prostate Human No data available       Rodent Squamous cell of dorsolateral prostate Arai et al. 1978 Other genital Penis Human Reduced size; hypospadias Gill et al. 1976, 1979; Henderson et al. 1976; tract changes       Wilcox et al. 1995   Testis Human Cryptorchidism: hypertrophy; capsular Gill et al. 1976, 1979: Rothman and Louik 1978;       induration; epididymal cysts Depue 1984; Newbold 1995; Wilcox et al. 1995         (table continues)

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Page 402 TABLE A-1 Continued       Abnormality Organ Study Details Reference Rodent     Cryptorchidism Bullock et al. 1988: McLachlan et al. 1975       Epididymal cysts       Prostate Human Hyperplasia and metaplasia of the prostatic Driscoll and Taylor 1980; Blacklock 1983       ducts       Rodent Abnormal development: squamous McLachlan et al. 1975: Turner et al. 1989; Prins       metaplasia of prostatic and coagulating 1992: Pylkkanen et al. 1993: vom Saal et al. 1997       gland ductal epithelium   Fertility-   Human Impaired semen quality and sperm Gill et al. 1976. 1979: Andonian and Kessler 1979: related     concentration; impaired fertility Leary et al. 1984: Shy et al. 1984; Newbold 1995; changes     inconsistent Wilcox et al. 1995     Rodent Impaired semen quality and sperm McLachlan 1981       concentration: impaired fertility   a Details of some of these studies are provided in Table A-4.

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Page 403 TABLE A-2 Incidence of Adverse Pregnancy Outcomes in DES-Exposed Daughters and Estimates of their Relative Riska     Incidence in DES Daughters   Estimate of Relative Riskb   Incidence in Abnormal DESc   (95% Confidence Interval) Outcome Controls Vagina-Cervix Uterus All DES Abnormal DESc All DES Ectopic pregnancy 0.01 0.063 0.076 0.044 13.5 (2.1, 84.7) 8.6 (3.4, 21.9) Premature live birth 0.02 0.75 0.38 0.13 9.6 (4.0, 23.4) 4.7 (2.8, 7.9) Spontaneous abortion 0.13 0.19 0.36 0.23 2.6 (1.8, 3.8) 1.8 (1.5, 2.2) Not full-term birthd 0.15   0.67 0.41 4.9 (3.1, 7.7) 2.7 (2.2, 3.0) a Based on controlled studies by Herbst et al. (1980, 1981); Barnes et al. (1980); Kaufman et al. (1980); Cousins (1980); Mangan et al. (1982); Thorp et al. (1990). b Mantel-Haenzel estimate of relative risk; Robins-Greenland estimate of 95% confidence interval. cDES-associated abnormality. d Includes ectopic pregnancy, premature birth, and spontaneous abortion. SOURCES: Adapted from Swan 1992 and Stillman 1982.

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Page 404 Table A-2 provides estimates of adverse pregnancy outcomes in DES-exposed daughters. Because DES was used to treat women with histories of reproductive difficulties, it might be expected that their daughters also would have high-risk pregnancies independent of DES exposure. However, Barnes et al. (1980) has shown that the incidence of these unfavorable outcomes in DES daughters is not related to the obstetric history of the mothers. In fact, as shown in this table, the incidence is related to the presence of genital-tract abnormalities, which are in turn related to the gestational age of first exposure to DES. Table A-3 presents case-control studies of testicular cancer in men in relation to prenatal exposure to DES and other hormones. Exposure assessment for these studies was problematic because none of the study protocols restricted exposure to the critical period of testicular development, and all combined prenatal exposure to all prenatal hormones, rather than to DES alone. Because prenatal DES exposure occurred in about 1% of pregnancies, the power of these studies to isolate a DES effect is limited. Table A-4 shows the effects of exposure to DES on sperm concentration and on abnormalities of the male reproductive system. Table A-5 presents observed effects on the mature reproductive system in workers exposed to DES and DES-like compounds.break TABLE A-3 Case-Control Studies of Testicular Cancer, Relation to Prenatal Exposure to DES and Other Hormones Cases Controls Relative Risk Reference 78 78 5.0a (p = 01) Henderson et al. (1979)     4.3b (p = .01 )   190c 166d 1.8c (p = .20) Schottenfeld et al. (1980)   143e 2.0c (p = .17)   108 108 8.0f (p = .02) Depue et al. (1983)g 225 213 0.8h (not significant) Brown et al. (1986) 79 79 2 DES-exposed cases vs. 0 DES-exposed Gershman and Stolley (1988)     controlsc (not significant)   aHormone treatment not further specified. bHormone treatment for excessive nausea. cDrug use for bleeding, spotting, and/or threatened abortion (DES. other hormones, or unknown). dHospital. eNeighborhood. fExogenous hormones during first trimester of index pregnancy. gContinuation of Henderson et al. 1979. hExogenous hormones during the index pregnancy.

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Page 405 TABLE A-4 Effects of DES on Abnormalities of the Male Reproductive System and Sperm Concentration     Urogenital Abnormalities   Impaired Sperm Sperm count   Exposed Unexposed (Other Than Varicocele) Cryptochidism Concentration (106/mL) Reference 163 168 25% vs. 6.5%''   28% vs. 0%b   Gill et al. (1976)c     p < 0.0005   p < 0.05     225 111 24.4% vs. 15.3%d 3% vs. 1%e     Henderson et al. (1976) 24 24 13% vs. 8% not   17% vs. 20%b   Andonian and Kessler (1979)     significant   not significant     307 308 32% vs. 7.8% 17% vs. 1% 18% vs. 8%b 91 s. 115 Gill et al. (1979)     p < 0.0005 p < .005 p < 0.05 p < 0.05   31 28 p < 0.001f       Driscoll and Taylor (1980)g 265 274 Not significant     12% vs. 15%b Leary et al. (1984)           not significant   51 29 35% vs. 4%. 8% vs. 0% 21% vs. 0%h 74 vs. 77 Shy et al. (1984)     p = 0.0006 p = 0.07 p < 0.02 not significant   253 241 15% vs. 5%             p < 0.01i       Wilcox et al. (1995)c a Epididymal cycts. hypertrophic testis, capsular induration, hypoplastic penis. b Severely pathologic Eliasson score (>10). c Dieckmann cohort. d Problems passing urine (p = .0006) and penile stenosis or hypospadias (p = .034). e Published in Cosgrove et al. 1977 (same population). f For each of hypertrophy and squamous metaplasia of the prostatic utricle; high ratio of Leydig cells to spermatogenic cells in the testis. g Autopsy findings in male perinates. h Poor forward progression. i Significantly higher rate of abnormalities among men exposed before week 11 of gestation (p < .05).

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Page 406 TABLE A-5 Effects of Occupational Exposure to DES or DES-like Compounds on the Mature Reproductive System   Sex of     Compound Workers Observed Effects Reference DES Male Gynecomastia, decreased Shmunes and Burton 1981     libido, decreased genital       size   4,4'-diaminostilbene- Male Decreased total circulating Quinn et al. 1990 2,2'-disulfonic acida   testosterone     Male Decreased total circulating Grajewski et al. 1996     testosterone, decreased       libido, increased impotence     Estrogens Females Increased incidence of Taskinen et al. 1986     spontaneous abortion   aStilbene derivative (DAS: CAS 81-11-8). similar in structure to DES.