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UNITED NATIONS SC UNEP/POPS/POPRC.11/INF/15 Distr.: General 9 October 2015 Stockholm Convention on Persistent Organic Pollutants English only Persistent Organic Pollutants Review Committee Eleventh meeting Rome, 1923 October 2015 Item 5 (b) (i) of the provisional agenda* Technical work: consideration of draft risk profiles: dicofol Additional information on dicofol Note by the Secretariat The annex to the present note sets out additional information on dicofol submitted to the Secretariat by Mr. Marcus Richards (Saint Vincent and the Grenadines), the Chair of the intersessional working group on dicofol, on 8 October 2015. The present note, including its annex, has not been formally edited. * UNEP/POPS/POPRC.11/1. 121015 UNEP/POPS/POPRC.11/INF/15 Annex Additional information on dicofol Table 1: Endocrine related effects of dicofol Species / Formulation Results Study type/ /Dose In vivo Alligators, field study Pesticide mixture, composed primarily of dicofol Alligators, field study Accidental spill of pesticides Rat, In vivo 30, 40 and 50 mg/kg body weight, administered orally to normal virgin rats for 30 days Dog, in vivo 2.5 mg/kg Mouse, in vivo, uterine weight 20% commercial dicofol Daphnia magna, sex ratio Rotifier test Fish EstradiolUDPGT activity in carp liver microsomes 1 mM dicofol Synthesis of sex hormones in fish microsomes Females: 17ß-estradiol plasma levels were >2 times higher than in the control lake, abnormal ovarian morphology. Males: <3x testosterone levels than in control males, poorly organized testes and abnormally small phalli Decreased egg availability and juvenile recruitment, altered gonadal morphology and serum hormone concentrations Significant decrease in healthy follicles with concomitant increase in atretic follicles at higher doses; dose-dependent effect, significant decrease in number of estrous cycles, duration of proestrus and diestrus, and increase in the duration of the estrus phase. Inhibition of adrenocorticotrophic hormone (ACTH)-stimulated cortisol release in dogs Significantly elevated uterine weight on immature mice Comments Reference Mixture effects have to be taken into account Guillette et al., 1994 Effects couldn’t be contributed to dicofol alone, rather to a mixture of pesticides, e.g. DDT among others Concentration levels lead to significant toxic effects in multiple organs in a number of studies. Finger & Gogal, 2013 Jadarmkunti & Kaliwal, 1999 US EPA, 1998; WHO 1996 Article in Chinese Zhao et al., 2000 (IPEN, 2015) 1 mM dicofol significantly inhibited testosterone glucuronidation by 81% (IC50 value = 293±11 µM) with no significant effect on estradiolUDPGT Dicofol could interfere with the synthesis of sex hormones in fish microsomes Lavado et al., 2004 Dicofol gave rise to a statistically significant inhibition of aromatase activity Vingaard, 2000 Significant promotion of human breast cancer MCF-7 cell proliferation Du & Xu, 2001 Induction of estrogen receptor alpha and beta transcriptional activity and inhibition of androgen receptor transcriptional activity. Dicofol showed the ability to bind to both androgen receptors and Kojima et al., 2004 Thibaut & Porte, 2004 Human cell lines and tissues Aromatase 50 mM. activity in human placental microsomes Human breast 20% commercial cancer MCF-7 dicofol formulation cell proliferation 4x10-11 and 4x10-6 in vitro g/mL Estrogen and androgen receptor In vitro, Chinese hamster ovary cells, estrogen receptor activity Estrogen receptor2 Dicofol also showed estrogenic activity Okubo et al., 2004 UNEP/POPS/POPRC.11/INF/15 Species / Study type/ Formulation /Dose Results Comments dependent MCF-7 cell proliferation assay Reporter assay in yeast cells transfected with human ovarian estrogen receptor alpha Yeast-based steroid hormone receptor gene transcription assay designed with the human estrogen receptor (hER). Estrogen and androgen receptor in vitro reporter gene binding in Chinese hamster ovary cells In vitro utilizing transiently transfected African green monkey kidney (COS-7) cells estrogen receptors in an MCF-7 cell proliferation assay. in MCF-7 cell culture, causing proliferation of the cells. indication that dicofol can bind to ER alpha in vitro Estrogen receptor competitive binding assay for use in multispecies comparisons Competition binding assay if alligator oestrogen and progesterone receptors p,p’-dicofol displaced up to 83% of 17 ß-estradiol from alligator ERa and was an equivocal binder to human ERa, displacing a maximum of 58% 17 ß-estradiol. Dicofol stimulated a positive estrogenic response, indicating that dicofol can bind to ER alpha in vitro Dicofol acts as a weak hER agonist due to the activity of the p,p’-isomer and the (-)-o,p’enantiomer Estrogenic activity of dicofol The dicofol metabolite, p,p’dichlorobenzophenone showed potent antiandrogenic properties At concentrations measured in alligator eggs from Lake Apopka, USA 45.6 μM (inhibitor concentration for 50%) Transactivation system utilising transiently transfected African green monkey kidney (COS-7) Thyroid hormone interference Rana IC50 of 2.2 μM catesbeiana tadpole red Reference Vinggaard et al, 1999 Estrogenic activity of (+)-17-bestradiol (positive control) and dicofol enantiomers was measured via quantification of bgalactosidase Screening of 200 pesticides by in vitro reporter gene assays Hoekstra et al. 2006 This finding was confirmed by further studies in T47D human mammary carcinoma cells by measuring mRNA and protein expression of androgen dependent genes i.e. TRMP-2 (testosteronerepressed prostate message-2) mRNA and PSA (prostatespecific antigen) protein using baculovirus expressed fulllength recombinant oestrogen receptors in a 96-well plate competitive binding assay Thiel et al. 2011 Kojima et al., 2004 Rider et al. 2010 Dicofol was able to compete for binding to tritiated 17β-estradiol of alligator oestrogen receptors; and reduced binding to alligator progesterone receptors by 40%. Vonier et al., 1996 Degradation of dicofol to p,p’dichlorobenzophenone (DCBP) under alkaline conditions as well as induced by UV-light, and potent antiandrogenic properties of DCBP in vitro Thiel et al., 2011 Dicofol was a powerful inhibitor of the 3,5,3’-triiodothyronine (T3)-uptake system on the plasma Shimada & Yamauchi 2004 3 UNEP/POPS/POPRC.11/INF/15 Species / Study type/ blood cells, triiodothyronine T3 -uptake system on the plasma membrane T3 binding to transthyretin and thyroid hormone receptor in chicken and bullfrog Competitive binding assay Formulation /Dose Results Comments Reference membrane inhibiting more than 80% of the saturable initial uptake. Dicofol significantly depressed the T3 response. 10-10-10-7 M Thyroid Induction at 0.8 and hormone (TH) 10 µM. inducible primary screening assay with a Xenopus laevis cell line Computer based modelling molecular dynamic simulations Dicofol exhibited a biphasic, nonmonotonic effect on thyroid hormone binding totransthyretins. Up to 170%, 0 transthyretins. However, at 4x10-5 M it inhibited T3 binding by 83%. Dicofol exhibited relatively strong interference with the T4 binding site of transthyretin, Dicofol (dicofol) had 3,3‘,5-Ltriiodothyronine- T3- antagonist activity Binding affinity of dicofol to human estrogen receptor ERalpha, using Ishihara et al., 2003 Indicating the potential to lower plasma thyroid hormone levels through interference with hormone transport carriers Self-inactivating (SIN) lentivirus vector (LV) containing a luciferase gene. van den Berg et al., 1991 Sugiyama et al., 2005 Zhuang et al., 2012 References Du K, Xu X (2001): Dicofol stimulation of cell proliferation. Bulletin of Environmental Contamination and Toxicology 67(6):0795–99. Finger JW, Gogal RM (2013): Endocrine-disrupting chemical exposure and the American alligator: a review of the potential role of environmental estrogens on the immune system of a top trophic carnivore. Archives of Environmental Contamination and Toxicology 65(4):704-714. Guillette, LJ, Gross TS, Masson GR, Matter JM, Percival HF, Woodward AR (1994): "Developmental Abnormalities of the Reproductive System of Alligators (Alligator mississippiensis) from Contaminated and Control Lakes in Florida." Env. Health Perspectives, 102 (8): 680-688. Hoekstra PF, Burnison BK, Garrison AW, Neheli T, Muir DCG. (2006): Estrogenic activity of dicofol with the human estrogen receptor: Isomer- and enantiomer-specific implications. Chemosphere 64, 174-177 Ishihara A, Sawatsubashi S, Yamauchi K. (2003): Endocrine disrupting chemicals: interference of thyroid hormone binding to transthyretins and to thyroid hormone receptors. Molecular and Cellular Endocrinology 199(1-2):105-17. Jadaramkunti UC, Kaliwal BB (2002): Dicofol formulation induced toxicity on testes and accessory reproductive organs in albino rats. Bulletin of Environmental Contamination and Toxicology 69(5):741-8. Kojima H, Katsura E, Takeuchi S, Niiyama K, Kobayashi K (2004): Screening for estrogen and androgen receptor activities in 200 pesticides by in vitro reporter gene assays using Chinese hamster ovary cells. Environmental Health Perspectives 112:524-531. Lavado R, Thibaut R, Raldu´a D, Martı´n R, Porte C (2004): First evidence of endocrine disruption in feral carp from the Ebro River. Toxicology and Applied Pharmacology 196, 247– 257. Okubo T, Yokoyama Y, Kano K, Soya Y, Kano I. (2004): Estimation of estrogenic and antiestrogenic activities of selected pesticides by MCF-7 cell proliferation assay. Archives of Environmental Contamination and Toxicology 46(4):445-453. 4 UNEP/POPS/POPRC.11/INF/15 Rider CV, Hartig PC, Cardon MC, Lambright CR, Bobseine KL, Guillette Jr LJ, Gray Jr LE, Wilson VS (2010): Differences in Sensitivity but not Selectivity of Xenoestrogen Binding to Alligator Versus Human Estrogen Receptor Alpha. Environmental Toxicology and Chemistry 29:9, 2064-2071 Shimada N, Yamauchi K (2004): Characteristics of 3,5,3’-triiodothyronine (T3)-uptake system of tadpole red blood cells: effect of endocrine-disrupting chemicals on cellular T3 response. Journal of Endocrinology 183:627–637. Sugiyama, S., Shimada, N., Miyoshi, H., Yamauchi, K. (2005): Detection of Thyroid System-Disrupting Chemicals Using in Vitro and in Vivo Screening Assays in Xenopus laevis. Toxicological Sciences 88:2, 367-374. Thibaut R, Porte C (2004): Effects of endocrine disrupters on sex steroid synthesis and metabolism pathways in fish. J. Steroid Biochem Mol Biol. 92(5):485-94. Thiel A, Guth S, Böhm S, Eisenbrand G (2011): Dicifol degradation to p,p‘-dichlorobenzophenone – A potential antiandrogen. Toxicology 282, 88-93 US EPA (1998) RED: Reregistration Eligibility Decision Dicofol http://www.epa.gov/pesticides/reregistration/REDs/0021red.pdf, 2012-04-16 Van den Berg KJ, van Raaij JA, Bragt PC, Notten WR (1991): Interactions of halogenated industrial chemicals with transthyretin and effects on thyroid hormone levels in vivo. Archives of Toxicology 65(1):15-19. Vinggaard AM, Breinholt V, Larsen JC (1999): Screening of selected pesticides for oestrogen receptor activation in vitro.” Food Additives and Contaminants 16(12):533–542. Vonier PM, Crain DA, McLachlan JA, Guillette LJ, Arnold SF (1996): Interaction of environmental chemicals with the estrogen and progesterone receptors from the oviduct of the American alligator. Environmental Health Perspectives 104(12):1318–1322. WHO (1996): International Programme on Chemical Safety, Dicofol, WHO/FAO Data Sheets on Pesticides No. 81 World Health Organization. Geneva, July 1996 [http://www.inchem.org/documents/pds/pds/pest81_e.htm, 2015-0115] Zhao BS, Zou JC, Chu SG, Xu XB, Du KJ (2000): Bioassay of estrogenic effect of dicofol using uterine weight method in mice. Environmental Science. Acta Scientiae Circumstantiae 20:244-248. In Chinese, Cited in Du et al 2001. Zhuang S, Zhang J, Wen Y, Zhang C, Liu W (2012): Distinct mechanisms of endocrine disruption of DDT-related pesticides toward estrogen receptor a and estrogen-related receptor y. Environmental Toxicology and Chemistry 31(11):2597-2605. __________________________ 5