June, 1999

This information sheet summarizes key findings from studies on alkylphenols (APs) and alkylphenol ethoxylates (APEs) related to this theory. APEs are cleaning agents or surfactants that are widely used in the manufacture of detergents and other products. The most commonly used APEs are nonylphenol ethoxylates (NPEs) and octylphenol ethoxylates (OPEs) with an average of four or more ethoxylate units, e.g., NPE4, NPE9 and OPE5. The APE industry is working closely with government and academic scientists in the U.S., Canada and Europe to further the understanding of the health and environmental profile APs, APEs and their biodegradation intermediates.

Based on the available findings to date, no direct link has been established between exposure to APEs or their biodegradation intermediates in the environment and any harmful effect on humans due to endocrine (hormone) disruption.

In February 1997, the United States Environmental Protection Agency issued an interim report summarizing the scientific literature on this issue. EPA concluded that, "with few exceptions (e.g., the very potent synthetic estrogen DES), a causal relationship between exposure to a specific environmental agent and an adverse effect on human health operating via an endocrine disruption mechanism has not been established" [1].

A similar conclusion was reached at a December 1996 international science workshop in Weybridge, United Kingdom, sponsored by the World Health Organization, the European Environmental Agency and the Organization for Economic Cooperation and Development, among others: "The existing exposure information was considered generally insufficient to definitely associate the health effects seen in humans with chemical exposure" [2].

The German Ministry for the Environment, Nature Conservation and Nuclear Safety states, concerning endocrine disrupters, "Current findings suggest the absence of a human health risk from chemicals due to their inherent estrogenic activity rather than the reverse". (ref. - Basler, A., and J.Lebsanft, Environ. Sci. & Pollution Res., vol.6, no.1, pp 44-48, 1999).

Commercial APEs, such as NPE4, NPE9 and OPE5, have not demonstrated estrogenic activity when tested in the classic live animal (in vivo) test for estrogenic activity (uterotrophic assay) [3, 4]. Estrogenic activity for OPE5, as well as for octylphenol (OP) and other compounds, was claimed in a single study [5] but the results could not be reproduced by the original researchers or by others [6, 7].

Some APE biodegradation intermediates have demonstrated weak estrogenic activity in various test tube (in vitro) tests [8-11]; however, the significance of these results for assessing risk is unknown and regulatory agencies do not consider them suitable for decision-making [12].

The NPE biodegradation intermediate, nonylphenol (NP), in numerous assays did not show estrogenic activity in live animals at oral doses below approximately 40 milligrams NP per kilogram body weight per day. Further, in the uterotrophic assay, even at the highest possible doses, NP produced markedly less of an estrogenic response than estradiol, the natural human estrogen, at the highest possible doses which are approximately 300-600 times higher than estradiol [11, 15, 16].

NP showed no estrogenic activity in a 90-day (subchronic) feeding study in rats [13]. Specifically, no effects at any dose level were observed on estrus cycling, sperm evaluations or endocrine glands in this study.

A study by the U.S. government's National Institute of Environmental Health Sciences showed no effect on reproduction in laboratory animals exposed to nonylphenol and concluded that "NP was not a selective reproductive/developmental toxicant [14]." In this study of three generations of rats, there was some estrogenic activity at the two higher doses (approximately 50 or 150 milligrams per kilogram body weight per day) and no activity at the lower dose (approximately 15 milligrams per kilogram body weight per day). This lower dose is several orders of magnitude higher than estimated, maximal daily human intake. There were no adverse effects on fertility even at the highest dose.

In a study of two generations of rats, octylphenol (OP) showed no effects on reproduction or development. No estrogenic effects were found even though OP tends to show slightly greater activity than NP in in vitro tests. The study was designed to evaluate potential low dose as well as high dose effects with approximate doses ranging from 0.01 to 150 milligrams per kilogram body weight per day [7].

Environmental monitoring studies demonstrate that there is no effect on fish and other aquatic organisms from trace levels of APs and APEs in rivers and lakes when effective sewage treatment is in place. Because levels which may cause toxic effects in the aquatic environment are lower than levels which potentially may cause estrogenic activity, protecting against toxic effects should also protect against potential estrogenic effects. These environmental monitoring studies also demonstrate that effective sewage treatment is key to APE biodegradation and removal.

NP is typically a small portion (approximately 5% or less) of the NPE biodegradation intermediates observed in sewage treatment plant effluent and receiving river water. Other biodegradation intermediates include short chain nonylphenol ethoxylates, such as NPE1 and NPE2, and NP ether carboxylates, such as NPEC1 and NPEC2 [17, 18].

An environmental monitoring study of 30 U.S. rivers was conducted to determine levels of NPEs and key biodegradation intermediates. The highest (and median) concentrations in river water were: 0.64 (<0.11) micrograms/liter for NP, 0.60 (<0.06) micrograms/liter for NPE1, and 1.2 (<0.07) micrograms/liter for NPE2. These concentrations are below the threshold of observable toxic effects in the most sensitive aquatic species. Estrogenic activity from NPE biodegradation intermediates has been reported only at higher concentrations [17].

An additional monitoring study was conducted on the Fox River in Wisconsin which receives discharges from 15 paper mills and 6 municipal sewage treatment plants treating wastewater with high levels of NPEs [18]. This study showed levels of NP, NPE1 and NPE2 in the river within the same range of concentrations as the 30-rivers study [17].

A monitoring study of NPECs showed that the highest (and median) concentrations in 10 U.S. rivers were 13.8 (1.4) micrograms/liter [19]. These concentrations are below the threshold of observable toxic effects in fish [20] and below the threshold of potential estrogenic activity from these compounds [21].

In Canada, an environmental monitoring study was conducted on 35 sites in the Great Lakes basin and the upper St. Lawrence river [22]. The highest (and median) concentrations in lake or river water were: 0.92 (<0.01) micrograms/liter for NP, 0.084 (<0.005) micrograms/liter for OP, 7.8 (0.11) micrograms/liter NPE1, and 10 (<0.02) micrograms/liter for NPE2. These concentrations are comparable to those in the 30-rivers study [17].

Estrogenic activity detected in sewage effluents and receiving waters in the U. K. has been traced to natural hormones from humans [23].

In the U. K., total (dissolved plus extracted from suspended solids) NP concentrations in river water (23 sites on 4 rivers surveyed) ranged from <0.4 to 12 micrograms/liter with a median concentration of 0.6 micrograms/liter. In contrast to these generally low concentrations, total NP concentrations of 82 to 180 micrograms/liter were measured at sites on the River Aire below a sewage treatment plant with inadequate treatment of industrial wastewater [24].

Laboratory tests measured estrogenic activity in male rainbow trout exposed to 20 micrograms NP/liter. Other NPE biodegradation intermediates (NPE2, NPEC1) exhibited estrogenic activity at 30 micrograms/liter [21].

Based on these studies, levels of APEs and APE biodegradation intermediates in rivers and streams in the U. S., in Canada and in the U. K. (except for the River Aire) are generally substantially below levels that may exhibit estrogenic activity. Since levels which may cause a toxic effect are lower than levels which may cause estrogenic activity, protecting against toxic effects should effectively protect against potential estrogenic activity from these compounds.

1. T.M. Crisp, E.D. Clegg, R.L. Cooper, D.G. Anderson, K.P. Baetcke, J.L. Hoffmann, M.S. Morrow, D.J. Rodier, J.E. Schaeffer, L.W. Touart, M.G. Zeeman, Y.M. Patel and W.P. Wood, "Special report on environmental endocrine disruption: an effects assessment and analysis," U.S. Environmental Protection Agency, Washington, D.C., EPA/630/R-96/012, February 1997, page 6.

2. "European Workshop on the Impact of Endocrine Disrupters on Human Health and Wildlife, Report of Proceedings, 2 - 4 December 1996, Weybridge, U.K.," sponsored by European Commission DGXII (Science, Research and Development), the European Environmental Agency, the World Health Organization (WHO) European Center for Environment and Health, the Organization for Economic Cooperation and Development (OECD), the U.K. Department of the Environment, the Environmental Ministry of Germany, the National Chemical Inspectorate of Sweden and the European Chemical Industry Council (CEFIC), Institute for Environment and Health, Leicester, 1997, page 6.

3. D.R. Cerven, "Uterine weight assay of p-nonylphenol (NP) and p-octylphenol ethoxylate-5 (OPE-5) administered orally to ovariectomized Sprague-Dawley rats," Amended Report, MB Research Labs, Spinnerstown, Pennsylvania, May 30, 1997, available from the APE Research Council, Washington, D.C.

4. J. Williams, A.M. Brady, R.W. Lewis and L. Hughes, "Assessment of alkyl phenol derivatives for estrogenic activity in a rat uterotrophic model," Proceedings of the 4th World Surfactants Congress, volume 3, pages 34-41, Barcelona, June 3-7, 1996.

5. R.M. Sharpe, J.S. Fisher, M.M. Millar, S. Jobling and J.P. Sumpter, "Gestational and lactational exposure of rats to xenoestrogens results in reduced testicular size and sperm production," Environmental Health Perspectives, volume 103, pages 1136-1143, 1995.

6. R.M. Sharpe, K.J. Turner and J.P. Sumpter, "Endocrine disruptors and testis development," Environmental Health Perspectives, volume 106, pages A220-A221, 1998.

7. R.W. Tyl, C.B. Myers, M.C. Marr, D.R. Brine, P.A. Fail, J.C. Seely and J.P. Van Miller, "Two-generation reproduction study with p-tert-octylphenol (OP) in rats," Abstract #223, The Toxicologist, volume 48, number 1-S, page 47, 1999; R.W. Tyl, "Two-generation reproductive toxicity evaluation of para-tert-octylphenol administred in the feed to CD® (Sprague-Dawley) rats," RTI Report 65C-6569-200/100, Research Triangle Institute, Research Triangle Park, North Carolina, 1999, available from the APE Research Council, Washington, D.C.

8. A.M. Soto, H. Justicia, J.W. Wray and C. Sonnenschein, "p-Nonyl-phenol: an estrogenic xenobiotic released from 'modified' polystyrene," Environmental Health Perspectives, volume 92, pages 167-173, 1991.

9. S. Jobling and J.P. Sumpter, "Detergent components in sewage effluent are weakly oestrogenic to fish: an in vitro study using rainbow trout (Oncorhynchus mykiss) hepatocytes," Aquatic Toxicology, volume 27, pages 361-372, 1993.

10. R. White, S. Jobling, S.A. Hoare, J.P. Sumpter and M.G. Parker, "Environmentally persistent alkylphenolic compounds are estrogenic," Endocrinology, volume 135, pages 175-182, 1994.

11. J. Odum, P.A. Lefevre, S. Tittensor, D. Paton, E.J. Routledge, N.A. Beresford, J.P. Sumpter and J. Ashby, "The rodent uterotrophic assay: critical protocol features, studies with nonyl phenols, and comparison with a yeast estrogenicity assay," Regulatory Toxicology and Pharmacology, volume 25, pages 176-188, 1997.

12. "Draft detailed review paper: appraisal of test methods for sex-hormone disrupting chemicals," Environmental Directorate, Organization for Economic Co-operation and Development, Environmental Health and Safety Publications, Series on Testing and Assessment, Paris, 1997.

13. H.C. Cunny, B.A. Mayes, K.A. Rosica, J.A. Trutter and J.P. Van Miller, "Subchronic toxicity (90-day) study with para-nonylphenol in rats," Regulatory Toxicology and Pharmacology, volume 26, pages 172-178, 1997.

14. R.E. Chapin, B.J. Davis, J.C. Delaney, L.B. Kaiser, Y. Wang, L.L. Lanning and G.W. Wolfe, "Multigenerational reproductive effects in Sprague-Dawley rats when exposed to nonylphenol in the diet (CAS 84852-15-3)" RACB94021, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, NTIS #PB97-210900, 1997. http://ntp-server.niehs.nih.gov/htdocs/RT-studies/RACB94021.html.

15. J. Odum, I.T.G. Pyrah, J.R. Foster, J.P. Van Miller, R.L. Joiner and J. Ashby, "Comparative activities of p-nonylphenol and diethylstilbestrol in noble rat mammary gland and uterotrophic assays," Regulatory Toxicology and Pharmacology, volume 29, 184-195, 1999.

16. M.D. Shelby, R.R. Newbold, D.B. Tully, K. Chae and V.L. Davis, "Assessing environmental chemicals for estrogenicity using a combination of in vitro and in vivo assays," Environmental Health Perspectives, volume 104, pages 1296-1300, 1996.

17. J.A. Weeks, W.J. Adams, P.D. Guiney, J.F. Hall and C.G. Naylor, "Risk assessment of nonylphenol and its ethoxylates in U.S. river water and sediment," Proceedings of the 4th World Surfactants Congress, volume 3, pages 276-291, Barcelona, June 3-7, 1996.

18. C.G. Naylor, J.B. Williams, P.T. Varineau and D.A. Webb, "Nonylphenol ethoxylates in an industrial river," Proceedings of the 4th World Surfactants Congress, volume 4, pages 378-391, Barcelona, June 3-7, 1996.

19. J.A. Field and R.L. Reed, "Nonylphenol polyethoxy carboxylate metabolites of nonionic surfactants in U.S. paper mill effluents, municipal sewage treatment plant effluents and river water," Environmental Science and Technology, volume 30, pages 3544-3550, 1996.

20. J.B. Williams, R.L. Blessing and P.T. Varineau, "Aquatic fate and effects testing: Data on alkylphenol ether carboxylates," Project Report, Union Carbide Corporation, South Charleston, West Virginia, October 28, 1996, available from the APE Research Council, Washington, D.C.

21. S. Jobling, D. Sheahan, J.A. Osborne, P. Mathiessen and J.P. Sumpter, "Inhibition of testicular growth in rainbow trout (Oncorhynchus mykiss) exposed to estrogenic alkylphenol chemicals," Environmental Toxicology and Chemistry, volume 15, pages 194-202, 1996.

22. D.T. Bennie, C.A. Sullivan, H.B. Lee, T.E. Peart and R.J. Maguire, "Occurrence of alkylphenols and alkylphenol mono- and diethoxylates in natural waters of the Laurentian Great Lakes basin and the upper St. Lawrence River," The Science of the Total Environment, volume 193, pages 263-275, 1997.

23. G. Brighty, "The identification and assessment of oestrogenic substances in sewage treatment works effluents," R&D Technical Summary P38, Environment Agency, Bristol, November 1996.

24. M.A. Blackburn and M.J. Waldock, "Concentrations of alkylphenols in rivers and estuaries in England and Wales," Water Research, volume 29, pages 1623-1629, 1995.                                                                                                                              

     
    

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