The emergence of Endocrine Disruption as a Toxicological Problem

For a number of years, concern has been growing over changes in the health and fecundity of both humans and wildlife which may be associated with the disruption of hormonal systems by environmental chemicals.1—5 The issue of environmental endocrine disrupters has become a focus of considerable media attention throughout the world and is now on the agenda of many expert groups, panels and steering committees of governmental organizations, industry and academia in Europe, the USA and Japan. The major findings driving this interest are derived from experimental and epidemiological studies on humans and wildlife, particularly those pertaining to effects on reproductive health which may result from exposure to endocrine disrupters early in life.

It is pertinent to ask why endocrine disruption has become such an active and controversial issue in the last decade, and whether toxicology has neglected effects on the endocrine system in the past. It might reasonably be assumed that the effects of chemicals on the endocrine system, a vital and integral part of the biology of higher organisms, would be detected by long-established tests for

1 T. Colborn and C. Clement, Advances in Modern Environmental Toxicology: Volume XXI. Chemically-Induced Alterations in Sexual and Functional Development: The Wildlife/Human Connection, Princeton Scientific, New Jersey, 1992.

2 J. Toppari, J. C. Larsen, P. Christiansen, A. Giwercman, P. Grandjean, L. J. Guillette Jr., B. Jegou, T. K. Jensen, P. Jouannet, N. Keiding, H. Leffers, J. A. McLachlan, O. Meyer, J. Muller, E. Rajpert-De Meyts, T. Scheike, R. Sharpe, J. Sumpter and N. E. Skakkebaek, Environ. Health Perspect., 1996, 104, 741.

3 Institute for Environment and Health; Assessment A1, Environmental Oestrogens: Consequences to Human Health and Wildlife, IEH, Leicester, 1995.

4 R. J. Kavlock, G. P. Daston, C. DeRosa, P. Fenner-Crisp, L. E. Gray, S. Kaatari, G. Lucier, M. Luster, M. J. Mac, C. Maczka, R. Miller, J. Moore, R. Rolland, G. Scott, D. M. Sheehan, T. Sinks and H. A. Tilson, Environ. Health Perspect., 1995, 104 (suppl. 4), 715.

5 US Environmental Protection Agency, Special Report on Environmental Endocrine Disruption: An Effects Assessment and Analysis, EPA, Washington, 1997, EPA Report No. EPA/630/R-96/012.

Issues in Environmental Science and Technology No. 12 Endocrine Disrupting Chemicals © The Royal Society of Chemistry, 1999

toxicity in experimental animals. For example, one might expect standard regulatory tests for reproductive toxicity in rodents to detect the consequences of disruption of sex hormone action. If a chemical had a biologically significant effect on reproductive capacity, then such tests would be expected to detect it, regardless of the mechanism involved. Indeed, many compounds have been tested for adverse effects on the reproductive system and in some cases these effects can be ascribed to, or at least include, disruption of part of the endocrine system. Ethanol, for example, could be said to be an endocrine disrupter in that it causes a variety of hormonal disturbances in experimental animals and humans.6,7 In female mice, rats, rabbits and monkeys it causes disturbances of the oestrus cycle, ovulatory function and fertility. In male rats, testicular atrophy and a decrease in the plasma levels of testosterone and luteinizing hormone has been observed. A lowering of plasma testosterone levels, leading sometimes to testicular atrophy and impotence, was also found in male alcoholics. When these effects were discovered, they were regarded as interesting and important but were not sufficient to trigger the rapid growth of a distinct new area of toxicology dedicated to endocrine disruption.

With regard specifically to oestrogenic chemicals, the range of toxicological effects that they can produce, and their detectability by rodent toxicity tests, is well illustrated by work on the synthetic oestrogen diethylstilboestrol (DES). Used pharmaceutically from the late 1940s to the early 1970s to prevent abortions and pregnancy complications in women, DES was eventually found to increase abortions, neonatal deaths and premature births and to increase, post-pubertally, the incidence of clear-cell adenocarcinoma of the vagina of girls exposed in utero.8 A study of men exposed in utero showed that 31.5% had abnormalities of the reproductive tract compared with 7.8% of controls.9 The abnormalities included cryptorchidism and hypospadias. Sperm concentration and quality were also lower, although reduced fertility has not been observed in these men.10 Exposure of mice in utero induced very similar effects to those seen in humans.11 In 1979, the International Agency for Research on Cancer (IARC) concluded from the evidence then available that DES was causally associated with the occurrence of cancer in humans. i2 At the same time, there was 'sufficient evidence' for its carcinogenicity in experimental animals; studies as early as the 1940s showed an increase in mammary tumours in mice.

It is not certain that all the effects of DES can be ascribed to its oestrogenic activity (that is to say, directly related to its ability to bind to the oestrogen receptor), but it would appear from experience with this compound that rodent assays are able to detect the relevant toxicological effects. What then was the

6 T.J. Cicero, E.R. Meyer and R.D. Bell, J. Pharmacol. Exp. Ther., 1979, 208, 210.

7 J. S. Gavaler and D. H. Van Thiel, Mutat. Res., 1987, 186, 267.

8 A. L. Herbst, H. Ulfelder and D.C. Poskanzer, N. Engl. J. Med, 1971, 284, 878.

9 W. B. Gill, G. F. B. Schumacher, M. Bibbo, F. H. I. Straus and H. W. Schoenberg, J. Urol, 1979,122,36.

10 A. J. Wilcox, D. D. Baird, C. R. Weinberg, P. P. Hornsby and A. L. Herbst, N. Engl. J. Med, 1995, 332, 1411.

11 J. A. McLachlan, in Developmental Effects of Diethylstilboestrol (DES) in Pregnancy, ed. A. L. Herbst and H. A. Bern, Thieme-Stratton, New York, 1981, p. 148.

12 IARC, Evaluation of the Carcinogenic Risk of Chemicals to Humans; Volume 21: Sex Hormones (II), IARC, Lyon, 1979.

stimulus to the rapid growth of the endocrine disruption issue in the 1990s? As is usually the case, the convergence of several lines of enquiry was crucial. A number of worrying trends had been reported relating to male human reproductive health: declining sperm counts and increases in the incidence of testicular cancer, hypospadias and cryptorchidism. One suggested explanation for these trends was increasing exposure to certain environmental chemicals. By this time, a variety of adverse trends in the reproductive health of wildlife had also been noted and ascribed to pollution. In some cases, specific chemicals were implicated and endocrine disruption already suspected as a common mechanism. At the same time, evidence was emerging from a variety of experimental studies that many extensively used chemicals, often widely distributed in the environment, had the ability to bind to, and activate, oestrogen receptors. In general, their affinity for the receptor was very weak compared with the natural ligand or with synthetic oestrogens such as DES. However, their activity was seen as sufficient to support a working hypothesis that environmental chemicals might be damaging the reproductive health of human and wildlife populations by disrupting sex hormone action. A crucial factor in fuelling concern was the suspicion that chemicals acting through the medium of hormone receptors might, like the natural hormones, have profound effects at very low concentrations.

The perceived conjunction of a threat to the survival of both human and wildlife populations led to a rapid and vigorous response from governments, international organizations, non-governmental environmental organizations and from the chemical industry. The nature of the response differed between organizations but encompassed the needs both for further research and practical measures to obviate the possible threat. In general, the following requirements were identified:

• Further research was needed to confirm the existence and severity of the reported adverse trends in the reproductive health of both humans and wildlife.

• In cases where an adverse effect was confirmed, a definite, causative link with exposure to an environmental chemical or chemicals needed to be established.

• Reliable methods were required for the detection of chemicals with the potential to cause the adverse effects identified. Existing methods might be sufficient but modifications or entirely new methods might be necessary.

• Known and suspected endocrine disrupting chemicals needed to be ranked in order of priority for possible regulatory action.

• Where appropriate, action should be taken to limit release of certain chemicals into the environment.

The priority given to each of these requirements is of course the most contentious issue. There is considerable disagreement about the standard of scientific proof needed to trigger regulation of a suspected endocrine disrupting chemical, reflecting the various interpretations of the 'Precautionary Principle' (broadly speaking, the concept of taking prudent action in advance of scientific certainty13). Some action has already been taken to replace or reduce the use

13 T. O'Riordan and J. Cameron, Interpreting the Precautionary Principle, Earthscan, London, 1994.

and/or release of particular chemicals where evidence of adverse effects due to endocrine disruption is clear, even in the absence of specific legislation or an agreed testing strategy. This has happened where field studies have suggested effects of particular chemicals on wildlife species, for example the effects of breakdown products of alkylphenol polyethoxylates (used in industrial detergents) on fish in some UK rivers. It should be emphasized that no such action has been based on effects on human health, since there is, at this time, no evidence directly to link such effects with exposure to endocrine disrupting chemicals.3,14

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