內分泌干擾物質普遍存在於環境當中，並且會使生物體受到危害。過去的研究中多探討類(抗)雌激素以及類(抗)雄激素物質於環境中的影響，鮮少有研究著重於類(抗)糖皮質激素及類(抗)鹽皮質激素，然而具糖皮質激素受體和鹽皮質激素受體干擾活性的化學物質亦會對生物體造成危害。
為了解環境中此類物質於臺灣河川中的分布情形，本研究利用基因重組酵母菌檢測臺灣西半部九條河川水相及懸浮固體相之類(抗) 糖皮質激素活性和類(抗)鹽皮質激素活性，並搭配液相層析串聯式質譜儀檢測樣本中內分泌干擾物質之濃度。此外，亦探討過去被鑑定為類(抗)雌激素或類(抗)雄激素之物質對糖皮質激素受體及鹽皮質激素受體之影響。
生物試驗法結果顯示，水相與懸浮固體相樣本皆無檢測出類糖皮質激素活性及類鹽皮質激素活性。然而，抗鹽皮質激素活性於所有河川之水相(<66.8~4324.0 SPL-EQ ng/L)及懸浮固體相(<66.8~1151.8 SPL-EQ ng/L)樣本中都有被檢出，且多數河川之水相(<21.8~94.4 TeCBPA-EQ μg/L)及懸浮固體相(<21.8~106.9 TeCBPA-EQ μg/L)樣本亦被檢測出具抗糖皮質激素活性。在內分泌干擾物質之類(抗)糖皮質激素活性及類(抗)鹽皮質激素活性調查中，除過去已被證實具抗鹽皮質激素活性的睪酮、雙氫睪酮及雙酚A外，三氯沙、三氯卡班及雙酚A之氯化衍生物於本研究中被檢出為具抗鹽皮質激素活性之內分泌干擾物質。同時，本研究亦檢出睪酮、雙氫睪酮、三氯沙、雙酚A及其氯化衍生物具抗糖皮質激素活性。
液相層析串聯式質譜儀分析結果顯示水相樣本中存在雙氫睪酮 (ND~1221.5 ng/L)、睪酮 (ND~93.2 ng/L)、孕酮 (ND~34.2 ng/L)、地賽米松 (ND~98.2 ng/L)、6-α-甲基潑尼松龍 (ND~38.5 ng/L)、醋酸氟氫可的松 (ND~44.9 ng/L)、雙酚A (23.2~19288.1 ng/L)、單氯雙酚A (<0.69~214.5 ng/L)、二氯雙酚A (ND~1251.0 ng/L)、三氯雙酚A (ND~153.9 ng/L)、四氯雙酚A (ND~101.9 ng/L)、壬基酚 (<2.78~1123.4 ng/L)、三氯沙 (ND~204.4 ng/L)及三氯卡班 (ND~292.3 ng/L)。比較由生物試驗法及液相層析串聯式質譜儀分析結果換算而得之抗糖皮質激素活性及抗鹽皮質激素活性，可發現生物試驗法測得之活性普遍較高，顯示樣本中可能含有非儀器分析目標物質之抗糖皮質激素或抗鹽皮質激素物質。因此，環境樣本中之內分泌干擾物質之複合效應在未來仍需受到評估。

Endocrine disrupting compounds present in the aquatic environment could cause side effect on aquatic organisms. Previous studies have focused on estrogenic and androgenic compounds in the environment. However, natural and synthetic (anti)glucocorticoids and (anti)mineralocorticoids which are frequently used as pharmaceuticals to treat various symptoms of human diseases can also be released into the aquatic environment.
In this study, recombinant yeast bioassays were used to detect mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) disrupting activities in water and suspended solids (SS) samples collected from 9 Taiwanese rivers. Also, liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to quantify potential MR and GR disrupting chemicals in the aquatic environment in Taiwan.
Bioassays results showed that no MR and GR agonist activities were detected in river samples. In contrast, MR antagonist activity was detected in water and SS samples of all target rivers (<66.8~4324.0 and <66.8~1151.8 SPL-EQ ng/L, respectively), and most of the water and SS samples showed GR antagonist activity as well (<21.8~94.4 and <21.8~106.9 TeCBPA-EQ μg/L, respectively). Several endocrine disrupting chemicals, including testosterone (T), dihydrotestosterone (DHT), nonylphenol (NP), triclosan (TCS), triclocarban (TCC), bisphenol A (BPA) and its chlorinated derivatives, were tested for MR and GR agonist/antagonist activities using bioassays. TCS, TCC and chlorinated BPA derivatives were identified as new MR antagonists in addition to the known MR antagonists BPA, DHT, T and NP. Also, T, DHT, TCS and chlorinated BPA derivatives were reported as new GR antagonists in this study.
LC-MS/MS results showed that DHT (ND~1221.5 ng/L), T (ND~93.2 ng/L), progesterone (ND~34.2 ng/L), dexamethasone (ND~98.2 ng/L), 6-α-prednisolone (ND~38.5 ng/L), fludrocortisone acetate (ND~44.9 ng/L), BPA (23.2~19288.1 ng/L), CBPA (<0.69~364.7 ng/L), DCBPA (ND~1251.0 ng/L), TrCBPA (ND~153.9 ng/L), TeCBPA (ND~101.9 ng/L), NP (<2.78~1123.4 ng/L),TCS (ND~204.4) and TCC (ND~292.3 ng/L) were often detected in the water samples from target rivers. However, bioassay-derived MR/GR antagonist activities were several times higher than the activities estimated by LC-MS/MS results, which might be due to the unknown MR and GR antagonists in samples.
In summary, this study revealed the occurrence of MR and GR antagonist activities in Taiwanese rivers and identified several new MR and GR antagonists. The combined effects of MR and GR antagonists and the unknown MR and GR disrupting chemicals in the aquatic environment should be taken for concern in future study.

Ahel, M., Giger, W., 1993. Aqueous solubility of alkylphenols and alkylphenol polyethoxylates. Chemosphere 26, 1461–1470.
Ahel, M., Giger, W., Koch, M., 1994. Behaviour of alkylphenol polyethoxylate surfactants in the aquatic environment—I. occurrence and transformation in sewage treatment. Water Res. 28, 1131–1142.
Akner, G., Wikström, A.C., Mossberg, K., Sundqvist, K.G., Gustafsson, J.A., 1994. Morphometric studies of the localization of the glucocorticoid receptor in mammalian cells and of glucocorticoid hormone-induced effects. J. Histochem. Cytochem. Off. J. Histochem. Soc. 42, 645–657.
Auchus, R.J., Rainey, W.E., 2004. Adrenarche - physiology, biochemistry and human disease. Clin. Endocrinol. (Oxf.) 60, 288–296.
Bain, P.A., Williams, M., Kumar, A., 2014. Assessment of multiple hormonal activities in wastewater at different stages of treatment. Environ. Toxicol. Chem. SETAC 33, 2297–2307.
Bellet, V., Hernandez-Raquet, G., Dagnino, S., Seree, L., Pardon, P., Bancon-Montiny, C., Fenet, H., Creusot, N., Aït-Aïssa, S., Cavailles, V., Budzinski, H., Antignac, J.-P., Balaguer, P., 2012. Occurrence of androgens in sewage treatment plants influents is associated with antagonist activities on other steroid receptors. Water Res. 46, 1912–1922.
Bester, K., Theobald, N., Schröder, H.F., 2001. Nonylphenols, nonylphenol-ethoxylates, linear alkylbenzenesulfonates (LAS) and bis (4-chlorophenyl)-sulfone in the German Bight of the North Sea. Chemosphere 45, 817–826.
Birnbaum, L.S., 2013. State of the science of endocrine disruptors. Environ. Health Perspect. 121, a107.
Bovee, T.F.H., Helsdingen, J.R., Hamers, A.R.M., Brouwer, B.A., Nielen, M.W.F., 2011. Recombinant cell bioassays for the detection of (gluco) corticosteroids and endocrine-disrupting potencies of several enviromental PCB contaminants. Anal. Bioanal. Chem. 401, 873–882.
Boyanov, M.A., Boneva, Z., Christov, V.G., 2003. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male Off. J. Int. Soc. Study Aging Male 6, 1–7.
Buckingham, J.C., 2006. Glucocorticoids: exemplars of multi-tasking. Br. J. Pharmacol. 147 Suppl 1, S258–268.
Byford, J.R., Shaw, L.E., Drew, M.G.B., Pope, G.S., Sauer, M.J., Darbre, P.D., 2002. Oestrogenic activity of parabens in MCF7 human breast cancer cells. J. Steroid Biochem. Mol. Biol. 80, 49–60.
Calafat, A.M., Ye, X., Wong, L.-Y., Reidy, J.A., Needham, L.L., 2008. Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003-2004. Environ. Health Perspect. 116, 39–44.
Cashman, A.L., Warshaw, E.M., 2005. Parabens: a review of epidemiology, structure, allergenicity, and hormonal properties. Dermat. Contact Atopic Occup. Drug 16, 57–66; quiz 55–56.
Chang, H., Hu, J., Shao, B., 2007. Occurrence of natural and synthetic glucocorticoids in sewage treatment plants and receiving river waters. Environ. Sci. Technol. 41, 3462–3468.
Chen, J., Ahn, K.C., Gee, N.A., Ahmed, M.I., Duleba, A.J., Zhao, L., Gee, S.J., Hammock, B.D., Lasley, B.L., 2008. Triclocarban enhances testosterone action: a new type of endocrine disruptor Endocrinology 149, 1173–1179.
Chen, J., Ahn, K.C., Gee, N.A., Gee, S.J., Hammock, B.D., Lasley, B.L., 2007. Antiandrogenic properties of parabens and other phenolic containing small molecules in personal care products. Toxicol. Appl. Pharmacol. 221, 278–284.
Chen, K.Y., 2014. Occurrence and combined effects of endocrine disrupting chemicals in Taiwanese rivers.
Chyun, Y.S., Kream, B.E., Raisz, L.G., 1984. Cortisol decreases bone formation by inhibiting periosteal cell proliferation. Endocrinology 114, 477–480.
Clark, R.D., 2008. Glucocorticoid receptor antagonists. Curr. Top. Med. Chem. 8, 813–838.
Creusot, N., Aït-Aïssa, S., Tapie, N., Pardon, P., Brion, F., Sanchez, W., Thybaud, E., Porcher, J.-M., Budzinski, H., 2014. Identification of synthetic steroids in river water downstream from pharmaceutical manufacture discharges based on a bioanalytical approach and passive sampling. Environ. Sci. Technol. 48, 3649–3657.
Cuzzola, A., Mazzini, F., Petri, A., 2014. A comprehensive study for the validation of a LC-MS/MS method for the determination of free and total forms of urinary cortisol and its metabolites. J. Pharm. Biomed. Anal. 94, 203–209.
Davı̀, M.L., Gnudi, F., 1999. Phenolic compounds in surface water. Water Res. 33, 3213–3219.
De Hoffmann, E., 2000. Mass spectrometry, in: Kirk-Othmer Encyclopedia of Chemical Technology. John Wiley & Sons, Inc.
Delyani, J.A., 2000. Mineralocorticoid receptor antagonists: the evolution of utility and pharmacology. Kidney Int. 57, 1408–1411.
DeRijk, R.H., Schaaf, M., de Kloet, E.R., 2002. Glucocorticoid receptor variants: clinical implications. J. Steroid Biochem. Mol. Biol. 81, 103–122.
Duong, C.N., Ra, J.S., Cho, J., Kim, S.D., Choi, H.K., Park, J.-H., Kim, K.W., Inam, E., Kim, S.D., 2010. Estrogenic chemicals and estrogenicity in river waters of South Korea and seven Asian countries. Chemosphere 78, 286–293.
Emmanuelle Vulliet, L.W., 2008. Multi-residue analysis of steroids at sub-ng/L levels in surface and ground-waters using liquid chromatography coupled to tandem mass spectrometry. J. Chromatogr. A 1210, 84–91.
Engvall, E., Perlmann, P., 1971. Enzyme-linked immunosorbent assay (ELISA) quantitative assay of immunoglobulin G. Immunochemistry 8, 871–874.
Erickson, M.D., 1997. Analytical chemistry of PCBs, second edition. CRC Press.
Esteban, S., Gorga, M., Petrovic, M., González-Alonso, S., Barceló, D., Valcárcel, Y., 2014. Analysis and occurrence of endocrine-disrupting compounds and estrogenic activity in the surface waters of Central Spain. Sci. Total Environ. 466-467, 939–951.
Filby, A.L., Shears, J.A., Drage, B.E., Churchley, J.H., Tyler, C.R., 2010. Effects of advanced treatments of wastewater effluents on estrogenic and reproductive health impacts in fish. Environ. Sci. Technol. 44, 4348–4354.
Frey, F.J., Odermatt, A., Frey, B.M., 2004. Glucocorticoid-mediated mineralocorticoid receptor activation and hypertension. Curr. Opin. Nephrol. Hypertens. 13, 451–458.
Friedel, A., Geyer, H., Kamber, M., Laudenbach-Leschowsky, U., Schänzer, W., Thevis, M., Vollmer, G., Zierau, O., Diel, P., 2006. 17beta-hydroxy-5alpha-androst-1-en-3-one (1-testosterone) is a potent androgen with anabolic properties. Toxicol. Lett. 165, 149–155.
Fuller, P.J., Yao, Y., Yang, J., Young, M.J., 2012. Mechanisms of ligand specificity of the mineralocorticoid receptor. J. Endocrinol. 213, 15–24.
Fuller, P.J., Young, M.J., 2005. Mechanisms of mineralocorticoid action. Hypertension 46, 1227–1235.
Guo, J., Yuan, X., Qiu, L., Zhu, W., Wang, C., Hu, G., Chu, Y., Ye, L., Xu, Y., Ge, R.-S., 2012. Inhibition of human and rat 11β-hydroxysteroid dehydrogenases activities by bisphenol A. Toxicol. Lett. 215, 126–130.
Hasan, E.A., Jessop, D.S., Power, L.L., Monk, P.T., Kirwan, J.R., 2009. Use of the dexamethasone-corticotrophin releasing hormone test to assess hypothalamic-pituitary-adrenal axis function in rheumatoid arthritis. Int. J. Endocrinol. 2009.
Hennig, B., Meerarani, P., Slim, R., Toborek, M., Daugherty, A., Silverstone, A.E., Robertson, L.W., 2002. Proinflammatory properties of coplanar PCBs: in vitro and in vivo evidence. Toxicol. Appl. Pharmacol. 181, 174–183.
Hornbeck, P., 2001. Enzyme-linked immunosorbent assays, in: current protocols in immunology. John Wiley & Sons, Inc.
Igarreta, P., Calvo, J.C., Damasco, M.C., 1999. Activity of renal 11βhydroxysteroid dehydrogenase 2 (11βHSD2) in stressed animals. Life Sci. 64, 2285–2290.
Ito-Harashima, S., Shiizaki, K., Kawanishi, M., Kakiuchi, K., Onishi, K., Yamaji, R., Yagi, T., 2015. Construction of sensitive reporter assay yeasts for comprehensive detection of ligand activities of human corticosteroid receptors through inactivation of CWP and PDR genes. J. Pharmacol. Toxicol. Methods.
Itoh, E., Iida, K., Kim, D.-S., del Rincon, J.P., Coschigano, K.T., Kopchick, J.J., Thorner, M.O., 2004. Lack of contribution of 11βHSD1 and glucocorticoid action to reduced muscle mass associated with reduced growth hormone action. Growth Horm. IGF Res. 14, 462–466.
Jin, S., Yang, F., Liao, T., Hui, Y., Xu, Y., 2008. Seasonal variations of estrogenic compounds and their estrogenicities in influent and effluent from a municipal sewage treatment plant in China. Environ. Toxicol. Chem. SETAC 27, 146–153.
Kapoor, A., Dunn, E., Kostaki, A., Andrews, M.H., Matthews, S.G., 2006. Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids. J. Physiol. 572, 31–44.
Kelce, W.R., Monosson, E., Gamcsik, M.P., Laws, S.C., Gray, L.E., 1994. Environmental hormone disruptors: evidence that vinclozolin developmental toxicity is mediated by antiandrogenic metabolites. Toxicol. Appl. Pharmacol. 126, 276–285.
Knox, J.H., Done, J.N., Fell, A.F., Gilbert, M.T., Pryde, A., Wall, R.A., 1978. High-performance liquid chromatography. viii + 205pp.
Kolšek, K., Mavri, J., Sollner Dolenc, M., Gobec, S., Turk, S., 2014. Endocrine disruptome—an open source prediction tool for assessing endocrine disruption potential through nuclear receptor binding. J. Chem. Inf. Model. 54, 1254–1267.
Krishnan, A.V., Stathis, P., Permuth, S.F., Tokes, L., Feldman, D., 1993. Bisphenol-A: an estrogenic substance is released from polycarbonate flasks during autoclaving. Endocrinology 132, 2279–2286.
Kugathas, S., Runnalls, T.J., Sumpter, J.P., 2013. Metabolic and reproductive effects of relatively low concentrations of beclomethasone dipropionate, a synthetic glucocorticoid, on fathead minnows. Environ. Sci. Technol. 47, 9487–9495.
Lange, I.G., Daxenberger, A., Schiffer, B., Witters, H., Ibarreta, D., Meyer, H.H.D., 2002. Sex hormones originating from different livestock production systems: fate and potential disrupting activity in the environment. Anal. Chim. Acta, Papers presented at the 4th International Symposium on Hormone and Veterinary Drug Residue Analysis Antwerp,Belgium,4-7 June 2002. Part I 473, 27–37.
Lee, C.-C., Jiang, L.-Y., Kuo, Y.-L., Hsieh, C.-Y., Chen, C.S., Tien, C.-J., 2013. The potential role of water quality parameters on occurrence of nonylphenol and bisphenol A and identification of their discharge sources in the river ecosystems. Chemosphere 91, 904–911.
Macikova, P., Groh, K.J., Ammann, A.A., Schirmer, K., Suter, M.J.-F., 2014. Endocrine disrupting compounds affecting corticosteroid signaling pathways in czech and swiss waters: potential impact on fish. Environ. Sci. Technol. 48, 12902–12911.
Molina-Molina, J.-M., Hillenweck, A., Jouanin, I., Zalko, D., Cravedi, J.-P., Fernández, M.-F., Pillon, A., Nicolas, J.-C., Olea, N., Balaguer, P., 2006a. Steroid receptor profiling of vinclozolin and its primary metabolites. Toxicol. Appl. Pharmacol. 216, 44–54.
Molina-Molina, J.-M., Hillenweck, A., Jouanin, I., Zalko, D., Cravedi, J.-P., Fernández, M.-F., Pillon, A., Nicolas, J.-C., Olea, N., Balaguer, P., 2006b. Steroid receptor profiling of vinclozolin and its primary metabolites. Toxicol. Appl. Pharmacol. 216, 44–54.
Mo, Q., Lu, S., Simon, N.G., 2006. Dehydroepiandrosterone and its metabolites: differential effects on androgen receptor trafficking and transcriptional activity. J. Steroid Biochem. Mol. Biol. 99, 50–58.
Nanjappa, M.K., Simon, L., Akingbemi, B.T., 2012. The industrial chemical bisphenol A (BPA) interferes with proliferative activity and development of steroidogenic capacity in rat Leydig cells. Biol. Reprod. 86, 135, 1–12.
Odermatt, A., Gumy, C., 2008. Disruption of glucocorticoid and mineralocorticoid receptor-mediated responses by environmental chemicals. Chim. Int. J. Chem. 62, 335–339.
Odermatt, A., Gumy, C., Atanasov, A.G., Dzyakanchuk, A.A., 2006. Disruption of glucocorticoid action by environmental chemicals: potential mechanisms and relevance. J. Steroid Biochem. Mol. Biol. 102, 222–231.
Pariante, C.M., Pearce, B.D., Pisell, T.L., Su, C., Miller, A.H., 2001. The steroid receptor antagonists RU40555 and RU486 activate glucocorticoid receptor translocation and are not excreted by the steroid hormones transporter in L929 cells. J. Endocrinol. 169, 309–320.
Peeters, B.W.M.M., Ruigt, G.S.F., Craighead, M., Kitchener, P., 2008. Differential effects of the new glucocorticoid receptor antagonist ORG 34517 and RU486 (mifepristone) on glucocorticoid receptor nuclear translocation in the AtT20 cell line. Ann. N. Y. Acad. Sci. 1148, 536–541.
Penning, T.M., Lee, S.-H., Jin, Y., Gutierrez, A., Blair, I.A., 2010. Liquid chromatography-mass spectrometry (LC-MS) of steroid hormone metabolites and its applications. J. Steroid Biochem. Mol. Biol. 121, 546–555.
Pitt, B., Bakris, G., Ruilope, L.M., DiCarlo, L., Mukherjee, R., EPHESUS Investigators, 2008. Serum potassium and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Circulation 118, 1643–1650.
Pitt, B., Zannad, F., Remme, W.J., Cody, R., Castaigne, A., Perez, A., Palensky, J., Wittes, J., 1999. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N. Engl. J. Med. 341, 709–717.
Rajasärkkä, J., Virta, M., 2013. High-throughput yeast-based assays to study receptor-mediated toxicity, in: Steinberg, P. (Ed.), High-Throughput Screening Methods in Toxicity Testing. John Wiley & Sons, Inc., pp. 479–499.
Rhen, T., Cidlowski, J.A., 2005. Antiinflammatory action of glucocorticoids — new mechanisms for old drugs. N. Engl. J. Med. 353, 1711–1723.
Rocha, M.J., Ribeiro, M., Ribeiro, C., Couto, C., Cruzeiro, C., Rocha, E., 2012. Endocrine disruptors in the Leça River and nearby Porto Coast (NW Portugal): presence of estrogenic compounds and hypoxic conditions. Toxicol. Environ. Chem. 94, 262–274.
Rocha, R., Funder, J.W., 2002. The pathophysiology of aldosterone in the cardiovascular system. Ann. N. Y. Acad. Sci. 970, 89–100.
Saccò, M., Valenti, G., Corvi Mora, P., Wu, F.C.W., Ray, D.W., 2002. DHEA, a selective glucocorticoid receptor antagonist: its role in immune system regulation and metabolism. J. Endocrinol. Invest. 25, 81–82.
Schmidt, M., Weidler, C., Naumann, H., Anders, S., Schölmerich, J., Straub, R.H., 2005. Reduced capacity for the reactivation of glucocorticoids in rheumatoid arthritis synovial cells: possible role of the sympathetic nervous system. Arthritis Rheum. 52, 1711–1720.
Schrier, R.W., 2010. Aldosterone “escape” vs “breakthrough.” Nat. Rev. Nephrol. 6, 61–61.
Schrier, R.W., Masoumi, A., Elhassan, E., 2010. Aldosterone: role in edematous disorders, hypertension, chronic renal failure, and metabolic syndrome. Clin. J. Am. Soc. Nephrol. CJASN 5, 1132–1140.
Soares, A., Guieysse, B., Jefferson, B., Cartmell, E., Lester, J.N., 2008. Nonylphenol in the environment: a critical review on occurrence, fate, toxicity and treatment in wastewaters. Environ. Int. 34, 1033–1049.
Tanaka, M., Nakaya, S., Katayama, M., Leffers, H., Nozawa, S., Nakazawa, R., Iwamoto, T., Kobayashi, S., 2006. Effect of prenatal exposure to bisphenol A on the serum testosterone concentration of rats at birth. Hum. Exp. Toxicol. 25, 369–373.
Tsai, T.Y., 2013. Evaluation of (anti-)estrogenic and (anti-)androgenic activities in Taiwanese rivers using yeast bioassays and liquid chromatography-tandem mass spectrometry.
Van der Linden, S.C., Heringa, M.B., Man, H.-Y., Sonneveld, E., Puijker, L.M., Brouwer, A., van der Burg, B., 2008. Detection of multiple hormonal activities in wastewater effluents and surface water, using a panel of steroid receptor CALUX bioassays. Environ. Sci. Technol. 42, 5814–5820.
Ye, L., Zhao, B., Hu, G., Chu, Y., Ge, R.-S., 2011. Inhibition of human and rat testicular steroidogenic enzyme activities by bisphenol A. Toxicol. Lett. 207, 137–142.
Zani, C., Toninelli, G., Filisetti, B., Donato, F., 2013. Polychlorinated biphenyls and cancer: an epidemiological assessment. J. Environ. Sci. Health Part C Environ. Carcinog. Ecotoxicol. Rev. 31, 99–144.