Killing Ourselves With Xenobiotics

Toxic chemicals, otherwise known as “xenobiotics” (Gk: foreign to life) which are scattered all over our planet from the North Pole to the South Pole, are being constantly researched, and the conclusion is that they are extremely toxic to humans as well as wildlife. Even though some chemicals have been taken off the market, those that remain are even more noxious than the ones already banned. Bioaccumulation in soils, water supplies and the tissues of animals and humans is a real problem which results in these chemicals lingering for many, many years even after they have being banned. DDT, for example, has been banned for more than 25 years in the Western world, yet it is still being found in the tissues of wildlife in the arctic, as well as humans in many different countries.

A recent study noted that only five organochlorine compounds and mercury were found in marine mammals in the 1960s. Today over 265 organic pollutants and 50 inorganic chemicals have been found in these species.1

Recent research has focused on how chemicals affect the thyroid and pituitary systems. Some chemicals have been identified as endocrine disrupters because they can interfere with the body’s own hormones, which are secreted by the endocrine glands.

It is also emerging that endocrine disrupters can have many physiological effects not directly associated with the primary system. For example, the thyroid system is well known to regulate metabolism, but it is also a crucial component in foetal brain development in mammals, and too much or too little thyroid hormone at crucial points can do permanent damage. The immune system is also vulnerable to hormone-mediated disruption. Chemicals can cause neurological problems, reproductive and developmental abnormalities, and cancers as well. And researchers are only just beginning to disentangle the questions about the effects of chronic low-level exposure (as opposed to brief high doses of chemicals), combinations of chemicals, and interactions between chemicals and other physiological and environmental factors.

Let us take a brief look at some of the more common xenobiotics chemicals that that have detrimental effects on humans as well as wildlife.

Perfluorochemicals (PFCs)
These compounds are chains of fully fluorinated carbon atoms of varying lengths, yielding chemicals that are extremely resistant to heat, chemical stress, and that repel both water and oil. Because of these properties PFCs, or chemicals that degrade into PFCs, have been widely used since the 1950s by industry as surfactants and emulsifiers and in commercial products, including stain or water protectors for carpet, textiles, auto interiors, camping gear and leather; food packaging; folding cartons and other paper containers; floor polishes; photographic film; shampoos; dental cleaners; inert pesticide ingredients; and lubricants for bicycles, garden tools and zippers.

Their persistence is extreme, particularly perfluorooctanoic acid (PFOA) – there is no evidence that they ever fully degrade, and they have been found in animals, humans and ecosystems worldwide.

The first public indication that PFOS and PFOA were problematic came on May 16,
2000 when 3M, the primary global manufacturer of many perfluoroalkanesulfonates and
PFOA, announced plans to phase out by the end of 2001 the production of perfluorooctanyl chemistry that underpinned their extremely successful Scotchgard™ and Scotchban™ product lines.2

A 2002 European study of PFCs has detected these compounds in bottlenose, common and striped dolphins, whales, bluefin tuna, swordfish and cormorants in the Mediterranean, and in ringed and grey seals, sea eagles and Atlantic salmon in the
Baltic.3

Other research shows that this chemical is now contaminating many wildlife species around the world, including polar bears in the Arctic, seals in Antarctica, dolphins in the river Ganges in India, albatrosses from Midway Atoll in the Pacific, turtles in the United States, gulls in Korea, cormorants in Canada,4 and fish in Japan.5

Fluorinated telomers are used to keep grease from soaking through fast food containers such as pizza boxes, French fry holders, and food wrapping paper. The digestive system can break telomers down into PFOA and related chemicals. Newly revealed tests conducted by 3M showed that a metabolite specific to the telomers was found in 85 per cent of the children tested.6

Red Cross blood banks, conducted by a team including scientists from the 3M Company, estimated the average concentrations in humans to be 30-40 parts per billion (ppb), with males having higher levels.7 By comparison, levels in wildlife have been measured at 940 ppb in common dolphin liver; 1100 ppb in ringed seals from the Bay of Bothnia; and 270 ppb in long-finned pilot whale liver from the North Thyrrenian Sea.8

Health Effects of Perfluorochemicals (PFCs)
In 1979, 3M administered four doses of PFOS to monkeys and all the monkeys in all treatment groups died within weeks. Typically, when a study like this is conducted, the researchers predict that the lowest dose will not cause any harmful health effects.9

In 1981 both DuPont and 3M reassigned women of childbearing age working in their production plants after they learned that PFOA caused developmental abnormalities in laboratory animals. Within weeks of this discovery, DuPont found PFOA in the women’s blood.

It was known as early as 1975 that fumes from hot pans coated with polytetrafluoroethylene can kill pet birds,10 and broiler chicks have died after exposure to polytetrafluoroethylene-coated light bulbs.11 Laboratory experiments reported in 2003 showed that in rats, PFOS exposure can lead to loss of appetite, interrupted oestrus cycles, and elevated stress hormone levels. PFOS was found to accumulate in brain tissue, particularly the hypothalamus, suggesting that PFOS crosses the blood-brain barrier and may interfere with reproductive hormones through the pituitary-hypothalamus process that stimulates their production.12

Recent laboratory studies with PFOA involving rats show low birth weight, small pituitary gland, altered maternal care behaviour, high pup mortality, and significant changes in the brain, liver, spleen, thymus, adrenal gland, kidney, prostate, testes and epididymides13

Several studies indicate PFOA increases estrogens and leads to testosterone dysfunction in males. There is even more evidence that PFOA as well as chemicals that metabolize to PFOs and PFOA lead to underactive thyroid; thyroid dysfunction during pregnancy can lead to many developmental problems, including faulty brain development and neurological and behavioural problems that affect not only infants and young animals (or humans) but continue into adulthood. The EPA considers both PFOS and PFOA to be a carcinogen in animals, with testicular, pancreatic, mammary, thyroid and liver tumours most frequent in exposed rats.

All studies to date indicate perfluorinated compounds damage the immune system. In one experiment, a chemical very similar to PFOA called PFDA resulted in such atrophy of the thymus gland, (the source of T cells that attack bacteria, viruses and cancer cells) that the gland was undetectable upon clinical examination.

Phthalates
Phthalates are a group of chemicals used as softeners in a variety of plastic products, including the ubiquitous polyvinyl chloride (PVC). Products containing phthalates include medical devices (intravenous tubing, blood bags, masks for sleep apnea devices), building products (insulation of cables and wires, tubes and profiles, flooring, wallpapers, outdoor wall and roof covering, sealants), car products (car under-coating, car seats etc.) and children’s products (teething rings, squeeze toys, clothing and rainwear). They are also used in some lacquers, paints, adhesives, fillers, inks and cosmetics.

The most common phthalate in the environment is di-(2-ethylhexyl)phthalate (DEHP), which comprises half of all phthalates produced in Western Europe, with 450,000 tonnes used per year. Concern about children’s exposure to phthalates prompted the EU to ban six types of phthalate softeners in PVC toys designed to be mouthed by children under three years of age.

Both humans and wildlife may be exposed to various phthalates. For example, a 2003 study of two groups of pregnant women, one in New York City and one in Krakow, Poland, compared the levels of four phthalates in the women’s personal ambient air and measured the levels of the metabolites of these phthalates in the urine of the New York women.14 All four phthalates were present in all the air samples, but air concentrations of DBP, di–isobutyl phthalate and DEHP were higher in Krakow than in New York. The study found that air was a significant source of exposure, that some women receive doses high enough to cause concern, and that there was a correlation between air and urine levels of some phthalates.

Other studies in the EU have also raised concerns with regard to current exposure levels. A recent study in Germany, for example, has concluded that exposure to DEHP may be far higher than previously thought. It reported that in 12 per cent of the Germans studied, phthalate levels exceeded the tolerable daily intake (TDI) used by the EU Scientific Committee for Toxicity, Ecotoxicity and the Environment. Exposure to DBP and BBP was also ubiquitous.15

Health Effects of Phthalates
Some phthalates appear to exert endocrine disrupting effects, and can act against the male hormone, androgen, through pathways other than binding to androgen or estrogen receptors. While there is little research on the effects of phthalates on wildlife per se, some studies suggest that there may be serious consequences for both wildlife and humans. Of particular concern is phthalate exposure in pregnant females: some researchers have proposed that the antiandrogenic properties of phthalates might be linked to testicular dysgenesis syndrome, the manifestations of which range from birth defects in males, including undescended testes, to low sperm counts and testicular cancer.16

Numerous Laboratory studies underpin the concern. For example, a study has shown that DEHP, BBP, and DINP administered to pregnant rats induced feminized breasts in the male offspring, as well as other reproductive malformations, including small testes in the case of the DEHP and BBP.17

There are also worries that exposure to manmade chemicals with hormone disrupting properties may be affecting the age of puberty. A study of Puerto Rican girls with premature breast development suggested a possible association with exposure to certain phthalates.18 U.S. researchers recently reported the effects of DEHP on Leydig cells (testosterone-producing cells in the testes) in rats.19 They found that prolonged exposure to DEHP caused the number of Leydig cells to increase by 40 per cent-60 per cent while simultaneously reducing testosterone production. At the same time, blood levels of both testosterone and estrogens increased by 50 per cent. It is known that males with high levels of serum testosterone and luteinizing hormone (a hormone that triggers testosterone production) are at higher risk of early puberty and testicular tumours.
With regard to cancer, a recent study supported other research associating DEHP with liver cancer in rodents.20 A 2003 Harvard study suggested another mechanism for carcinogenic effect of phthalates. The researchers measured levels of eight phthalates in subjects and found an association between monoethyl phthalate (MEP) and increased damage to the DNA in the subjects’ sperm.21 This is the first study showing that phthalates can induce such damage at levels presently found in the environment.

Other studies with phthalates show that additive effects can occur when there is exposure to more than one phthalate.22 This underlines the growing concern with real life exposures to multiple pollutants, and the increasing realisation that current regulatory practices, based on testing chemicals in isolation, may not be protective.

Phenols, Bisphenyl A and Nonylphenol
Evidence for endocrine disruption by the widely used phenol compounds bisphenol A (BPA) and nonylphenol is mounting. BPA is mostly used to make polycarbonate plastic, which has a diverse range of application in making bottles, computer and electronics shells, CDs, crash helmets, and many other consumer products.

Certain compounds that can leach BPA are also used in the plastic linings of food cans
and in dental fillings, through which people can ingest small quantities. In December 2003, concerned about BPA in the plastic linings of food cans, the EU reduced the amount of BPA migration permitted by 80 percent to 0.6 milligrams per kilogram of food.23 However, BPA remains widely distributed in consumer products.

Nonylphenolic compounds have been used in degreasing solutions, and in leather and textile processing, as well as in de-icing fluid, paints, plastics, and pesticides. The EU has imposed restrictions on the marketing and use of nonylphenol and nonylphenol ethoxylates to a certain extent in cleaning products, textile and leather processing, agricultural teat dips, metal working, pulp and paper, cosmetics including shampoos, and personal care products except spermicides.24

Health Effects of Phenols, Bisphenyl A and Nonylphenol
Fish have been shown to be susceptible to the endocrine disrupting effects of both nonylphenol25 and BPA.26 Exposure to either of these chemicals can cause male fish to make vitellogenin (an estrogen-regulated protein produced by female egg-laying vertebrates and not normally produced by males or juveniles), and can also affect the formation of sperm. Before improved regulation, male fish in the river Aire in England were found to be feminised downstream of a wastewater treatment plant discharge containing alkylphenol ethoxylates from the textile industry. Many male fish were found with egg producing cells in their testes, and reduced testis growth rate and size.27,28

Aquatic invertebrates seem particularly sensitive to these chemicals. For example, nonylphenol affects the freshwater algae, Scenedesmus subspicatus at levels of 3.3 micrograms per litre.29 Molluscs in particular have shown effects at very low dose levels. For example, in the mollusc Potamopyrgus antipodarum, BPA and octylphenol, as well as a mixture of these and other chemicals in treated sewage effluent, stimulated egg and embryo production at low doses and inhibited such production at high doses.30

This work supported a 2000 study by some of the same researchers showing that extremely low levels of BPA and octylphenol triggered malformed genitals of female ramshorn (freshwater) snail, Marisa cornuarietis, and the (saltwater) dogwhelk Nucella lapillus.31 In some of the freshwater snails, the excessive growth of the female glands and the egg masses ruptured the egg tube, and the snails died. This syndrome was referred to as superfeminisation. A number of other adverse changes were observed in both species. Another important finding was that in the freshwater snails, the medium doses of octylphenol produced more changes than either the highest or lowest doses.

Other researchers have shown that a single 48-hour exposure to 1 microgram per litre of nonylphenol, comparable to environmental levels, altered the sex ratio of oysters, reduced the survival of offspring, and caused some oysters to become hermaphroditic.32

A 2001 study exposing barnacles to concentrations of nonylphenol similar to those in the environment (0.01-10 micrograms per litre) disrupted the timing of larval development.33 In addition to fish, other vertebrates also show effects when exposed to BPA. For example, in 2003, researchers reported that BPA at environmentally comparable doses resulted in sex reversals and altered gonadal structures in the broad-snouted caiman, an alligator relative native to mid-latitude South America.34 In another study, the offspring of pregnant mice exposed to BPA showed changes in ovarian and mammary gland tissues and disrupted fertility cycles as adults.35 BPA was reported for the first time in 2001 to induce reproductive malformations in birds – specifically, in female quail embryos and male chicken embryos. The female embryos’ oviducts developed abnormally, and the males’ testes were feminized.36

The exact mechanism by which BPA and nonylphenol exert their effects is not clear, but a recent in vitro study demonstrated a molecular mechanism by which BPA and nonylphenol interfere with both the activation and function of cellular androgen receptors.37 In a 2002 study, nonylphenol tested on barnacle larvae induced DNA damage, possibly including mutations, and the authors speculate that this effect may be a mechanism by which higher level reproductive abnormalities are caused.38

Despite evidence from these and other studies, the low dose effects of BPA are still in dispute. Regulators in the EU have been reluctant to act, and further studies have been demanded.

Polybrominated Flame Retardants (BFRs)
Brominated flame retardants (BFRs) in furniture, building material, and clothing have become a serious concern, as their levels are showing sharp increases in living organisms. The first BFRs were taken off the market in the early 1970s after a spill led to poisonings of livestock and farm families in Michigan.39 Three BFRs now dominate the market: TBBPA, the most widely used, primarily in printed circuit boards and in some plastics; HBCD, and the deca-BDEs. The other commercial PBDEs (octa-BDE and penta-BDE) have been banned in the EU as of August 2004,40 and the state of California has taken similar action. However, because of their alarming spread and rate of accumulation in humans and animals, Europe’s ban does not provide complete reassurance, particularly regarding the penta-BDE form used as a flame retardant in polyurethane foam elsewhere in the world.

Researchers recently reported levels of PBDEs in U.S. breast milk.41 Forty-seven Texas women had an average level of 73.9 ng/g lipid; such levels are sharply higher than those found in European studies. There are serious concerns about the transfer of BFRs to nursing infants, and some scientists are worried that BFRs might affect foetal development, including disruption of the thyroid system’s role in foetal brain development.42 In 2003 a WWFUK biomonitoring program found deca-BDE in the blood of seven per cent of those tested.43

New research from Sweden has found high levels of several brominated flame retardants in the eggs of peregrine falcons from 1987-1999. The eggs of falcons living in the wild had significantly higher concentrations of the essentially unregulated deca-BDE than eggs of captive falcons. The fact that deca-BDE was found in eggs demonstrates that the chemical can cross cell membranes, contrary to what scientists had previously thought. The peregrine study represents the first time that the deca formulation has been found in wildlife.44

In 2002, one research team predicted that within 10 to 15 years, concentrations of BFRs in Great Lakes herring gull may be higher than those of PCBs.45 BFRs have also been found in sperm whales,46 ringed seals from the Canadian Arctic,47 mussels and several kinds of fish in Norwegian waters, and harbour seals in San Francisco Bay,48 among other wildlife. Essentially, BFRs are being found wherever we look.

Health Effects of BFRs
Laboratory studies show that certain BFRs are highly toxic to aquatic animals (crustaceans),49 and suggest effects on pubertal development, thyroid and liver in rats, as well as developmental neurotoxicity in mice.50 A recent paper reported behavioural effects in mice pups at a relatively low dose.51 In 1999 Swedish researchers reported that PBDEs and HBCD may have health effects similar to those of DDT and PCBs because of their ability to induce genetic recombination.52

While there are no published epidemiological studies on effects of BFRs on humans, the possible thyroid effects, based on tissue culture and animal studies, are a red flag. As with other chemicals, anything that affects foetal development merits particular study because of the profound, long-term, and often irreversible influence that early exposures have on the entire life of an organism.

What Can We Do To Protect Ourselves?
The answer to this question is two-fold; first we can push for legislation to ban a lot of these harmful chemicals that have been researched and are known to be detrimental to animals and humans. Second, we need to be able to detoxify our bodies in order to eliminate many of these chemicals. Given that we are exposed to these literally daily, this process must be an ongoing one. It is not safe to use chemical chelators on an ongoing basis, but natural ones can be used instead, much like a supplement on a daily basis. HMD™ can be used safely over long periods of time with no side effects – it is presently being tested to see its efficacy in eliminating some of the xenobiotics mentioned in this article.

References
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2 3M. (2000) 3M phasing out some of its specialty materials, May 16, 2000 press release.

3 Kannan, K., Corsolini, S., Falandysz, J., Oehme, G., Focardi, S., Giesy, J.P. Perfluorooctanesulfonate and related fluorinated hydrocarbons in marine mammals, fishes and birds from coasts of the Baltic and MediterraneanSeas. Environ Sci Technol 2002 Aug 1;36(15):3210-6.

4 Geisy J.P. and Kannan K. Global Distribution of Perfluorooctane sulfonate in wildlife.
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5 Taniyasu, S., Kannak, K., Horii,Y., Hanari, N.,Yamashita, N. A survey of perfluorooctane sulfonate and related perfluorinated organic compounds in water, fish, birds and humans from Japan. Environ Sci & Technol 2003, 37:2634-2639.

6 Fields, S. Another fast-food fear. Environ Health Perspect 2003: 111:16:A162.

7 Olsen, G. W., Church, T.R., Miller, J.P., Burris, J.M., Hansen, K.J., Lundberg, J.K., Armitage, J.B., Herron, R.M., Medhdizadehkashi, Z., Nobiletti, J.B., O’Neill, E.M., Mandel, J.H., Zobel, L.R. Perfluorooctanesulfonate and other fluorochemicals in the serum of American Red Cross adult blood donors. Environ Health
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8 Kannan, et al., 2002.

9 Organization for Economic Cooperation and Development (OECD). (2002) Hazard Assessment of perfluorooctane sulfonate (PFOS) and its salts (November, 21 2002). ENV/JM/RD(2002)17/FINAL. Available online at: http://www.oecd.org/dataoecd/23/18/2382880.pdf

10 “PFCs: A Family of Chemicals that Contaminate the Planet,” Part 6: PFCs in Animals Worldwide. Environmental Working Group, 2003.
http://www.ewg.org/reports/pfcworld/part8.php Accessed 3 January 2004.

11 Ibid.

12 Austin, M.E., Kasturi, B.S., Barber, M., Kannan, K., MohanKumar, P.S., MohanKumar, S.M.J. Neuroendocrine effects of perfluorooctane sulfonate in rats.
Environ Health Perspect 2003:111:12:1485-1489.

13 Thayer, K., Klein, J. Gray, S., Houlihan, J.,Wiles, R., Greenleaf, T., PFCs: A Family of Chemicals that Contaminate the Planet. Environmental Working Group 2003.
http://www.ewg.org/reports/pfcworld/part4.php Accessed 5 January 2004.

14. Adibi, J.J., Perera, F.P., Jedrychowski,W., Camann, D.E., Barr, D., Jacek, Ryszard, Whyatt, R.M. Prenatal exposures to phthalates among women in New York City and Krakow, Poland. Environ Health Perspect 2003:111:14:1719-1722.

15 Kock et al, 2003. An estimation of the daily intake of di(2-ethyl) phthalate (DEHP) and other phthalates in the general population. International Journal Hygiene and Environmental Health.

16 Sharpe R.M. (2003). The oestrogen hypothesis – where do we stand now? International Journal of Andrology 26:2-15; Skakkebaek, N.E. et al., (2001) Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Human Reproduction 2001:16:5:972-978.

17 Gray, L.E. Jr., Ostby, J., Furr, J., Price, M., Veeramachaneni, D.N., Parks, L. Perinatal exposure to the phthalates DEPH, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicological Sciences 2000:58:350-565.

18 Colón, I., et al., Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development. Environmental Health Perspectives, 2000. 108(9): p. 895-900.

19 Akingbemi, B.T., Ge, R., Klinefelter, G.R., Zirkin, B.R., Hardy, M.P. Phthalate-induced Leydig cell hyperplasia is associated with multiple endocrine disturbances. Proceedings of the NationalAcademy of Sciences 2004 (Early Edition). www.pnas.org/cgi/doi/10.1073/pnas.0305977101 , accessed 31 December 2003.

20 Seo, K.W., Kim, K.B., Kim,Y.J., Choi, J.Y, Lee, K.T., Choi, K.S. Comparison of oxidative stress and changes of xenobiotic metabolizing enzymes induced by phthalates in rats. Food Chem Toxicol. 2004 Jan;42(1):107-14.

21 Duty, S.M., Singh, N.P., Silva, M.J., Barr, D.B., Brock, J.W., Ryan, L., Herrick, R.F., Christiani, D.C., Hauser, R. The relationship between environmental exposures to phthalates and DNA damage in human sperm using the neutral comet assay. Environ Health Perspect 2003 111:9:1164-1169.
http://ehp.niehs.nih.gov/members/2003/5756/5756.html , accessed 6 January 2004.

22 Foster, P M. Turner K J, Barlow N J. Anti-androgenic effects of a phthalate combination on in utero male reproductive development in the Sprague-Dawley rat: additivity of response? Toxicologist 2000 Mar; 66(1-S), 233.

23 Environmental Data Services, Ends Daily 15th Dec 2003.

24 DIRECTIVE 2003/53/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 18 June 2003 amending for the 26th time Council Directive 76/769/EEC relating to restrictions on the marketing and use of certain dangerous substances and preparations (nonylphenol, nonylphenol ethoxylate and cement), Official Journal L 178 17-7-2003

25 Jobling S., Sheahan D., Osborne J., Matthiessen P., Sumpter J. (1996). Inhibition of testicular growth in rainbow Trout (Oncorhynchus mykiss) exposed to oestrogenic alkylphenolic chemicals. Environ. Toxicol. Chem., 15, 194-202.

26 Sohoni et al, Reproductive effects of long term exposure to bisphenol A in the fathead minnow (Pimephales promelas), Environ Sci Technol 2001:35: 2917-2925.

27 Environment Agency of England and Wales 1998; Endocrine Disrupting Substances in the Environment. What Should Be Done? The EA Bristol.

28 Commission of the European Communities. Proposal for a Directive of the European Parliament and of the Council relating to the restrictions on the marketing and use of nonylphenol, nonylphenol ethoxylate and cement. COM (2002) 459, 2002/0206 (COD).

29 Kopf W. Wirkung endokriner stoffe in biotests mit wasserogranismen. In Stoffe mit endokriner wirkung in wasser. Bayerisches landesamt für wasserwirtschaft, Institut für Wasserforschung München (ed) Oldenbourg (1997) (as detailed in the European Union Risk Assessment Report (2002) 4-NONYLPHENOL (BRANCHED) AND NONYLPHENOL, CAS Nos: 84852-15-3 and 25154-52-3 EINECS Nos: 284-325-5 and 246-672-0, Joint Research Centre, European Commission).

30 Jobling, S., Casey, D. Rodgers-Gray, T., Oehlmann, J., Schult-Oehlmann, U., Pawlowski, S., Baunbeck, T., Turner, A.P., Tyler, C.R. comparative responses of molluscs and fish to environmental estrogens and an estrogenic effluent. Aquat Toxicol 2003 Oct 29;65(2):205-20.

31 Oehlmann, J., Schulte-Oehlmann, U., Tillmann, M., Markert, B. Effects of endocrine disruptors on Prosobranch snails (Mollusca: Gastropoda) in the laboratory. Part I: Bisphenol A and octylphenol as xenoestrogens. Ecotoxicology 2000 9:383-397.

32 Nice, H.E., Morritt, D., Crane, M. Thorndyke, Long-term and transgenerational effects of nonylphenol exposure at a key stage in the development of Crassostrea gigas. Possible endocrine disruption? M. Marine Ecology Progress Series, 2003 256:293-300.

33 Billinghurst, Z., Clare, A.S., Depledge M.H. Effects of 4-n-nonylphenol and 17beta-oestradiol on early development of the barnacle Elminius modestus. J. Exper. Mar. Biol. Ecol. 2001: Mar 15;25(2);255-268.

34 Stoker, C., Rey, F. Rodriguez, H., Ramos, J.G., Sirosky, P., Larriera, A., Luque Munoz-de-Toro, M. Sex reversal effects on Caiman latirostris exposed to environmentally relevant doses of the xenoestrogen bisphenol A. Gen Comp Endocrinol 2003 Oct 1;133(3)287-96.
35 Markey, C.M., Coombs, M.A. Sonnenschein, C., Soto, A.M. Mammalian development in a changing environment: exposure to endocrine disruptors reveals the developmental plasticity of steroid hormone target organs. Evol Dev 2003 Jan-Feb;5(1):67-75.

36 Berg, C., Halldin, K., Brunstrom, B. Effects of bisphenol A and tetrabromobisphenol A on sex organ development in quail and chicken embryos. Environ Toxicol Chem 2001 Dec;20(12):2836-40.

37 Lee, H.J., Chattopadhyay, S., Gong, E-Y, Ahn, R.S, Lee, K. Antiandrogenic effects of bisphenol A and nonylphenol on the function of androgen receptor. Toxicological Sciences 2003 75:, 40-46.

38 Atienzar, F.A., Billinghurst, Z., Depledge, M.H. 4-n-Nonylphenol and 17-beta estradiol may induce common DNA effects in developing barnacle larvae. Environ Pollut 2002;120(3):735-8.

39 Dunckel (cited in Birnbaum, L., Staskal, D.F. Polybrominated flame retardants: cause for concern? Environ Health Perspect 2004:112:9-17. doi10.1289/ehp.6559. available via dx.doi.org. Accessed 5 January 2004.

40 Official Journal of The European Union, L 42/45 Feb. 15, 2003.

41 Schecter, A. Pavuk, M. Papke, O., Ryan, J.J., Birnbaum, L., Rosen, R. Polybrominated diphenyl ethers (PBDEs) in U.S. mothers’ milk. Environ Health Perspect 2003:111:14:1723-1724.

42 http://www.ourstolenfuture.org/NewScience/oncompounds/PBDE/2003/2003-0807schecteretal.htm
Accessed 5 January 2004.

43 http://www.panda.org/about_wwf/where_we_work/europe/what_we_do/policy_and_events/epo/news.cfm?uNewsID=9941 Accessed 8 January 2004.

44 Lindberg, P., Sellström, U., Häggberg, L., and de Wit, C.A. Higher brominated diphenyl ethers and hexabromocyclododecane found in eggs of peregrine falcons (Falco peregrinus) breeding in Sweden. Environ Sci Technol 2004:38;(1): 93-96.

45 Norstrom RJ, Simon M, Moisey J,Wakeford B,Weseloh D.V. Geographical distribution (2000) and temporal trends (1981-2000) of brominated diphenyl ethers in Great Lakes herring gull eggs. Environ Sci Technol. 2002 Nov 15;36(22):4783-9.

46 De Boer, J.,Wester, P.G., Klamer, H.J.C., Lewis,W.E., Boon, J.P. Do flame retardants threaten ocean life? Nature 1998:394:28-29; doi:10.1038/27798

47 Ikonomou et al., 2002a (cited in Birnbaum & Staskel, 2004).

48 Birnbaum & Staskal, 2004.

49 Birnbaum & Staskal, 2004.

50 Birnbaum & Staskal, 2004.

51 Darnerud, P.O. Toxic effects of brominated flame retardants in man and in wildlife. Environ Int 2003 Sep;29(6):841.

52 Helleday, T., Tuominen, K.L., Bergman, A., Jenssen, D. Brominated flame retardants induce intragenic recombination in mammalian cells. Mutat Res 1999:Feb 19;439(2):137-47.

Adapted by the article written by the World Wildlife Fund (WWF) entitled “Cause for Concern: Chemicals and Wildlife. http://www.wwf.org.uk

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