Endocrine Disrupting Chemicals

By R. E. Hester, R. M. Harrison

The Royal Society of Chemistry

Copyright © 1999 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-255-5

Contents

Overview of the Endocrine Disrupters Issue Barry Phillips and Paul Harrison, 1,
Environmentally Induced Endocrine Abnormalities in Fish David E. Kime, 27,
Effects of Endocrine Disrupting Chemicals in Invertebrates Michael H. Depledge, Tamara S. Galloway and Zoe Billinghurst, 49,
Endocrine Disruption in Mammals, Birds, Reptiles and Amphibians Catherine Botham, Philip Holmes and Paul Harrison, 61,
Oestrogens, Environmental Oestrogens and Male Reproduction Katie J. Turner, 83,
Human Health Effects of Phytoestrogens Philip HoImes and Barry Phillips, 109,
Endocrine Disrupter Research and Regulation in the United States Anthony F. Maciorowski and Gary E. Timm, 135,
Subject Index, 147,

CHAPTER 1

Overview of the Endocrine Disrupters Issue

BARRY PHILLIPS AND PAUL HARRISON

1 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. 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 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. 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. A study of men exposed in utero showed that 31.5% had abnormalities of the reproductive tract compared with 7.8% of controls. The abnormalities included cryptorchidism and hypospadias. Sperm concentration and quality were also lower, although reduced fertility has not been observed in these men. ° Exposure of mice in utero induced very similar effects to those seen in humans.” 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.’ 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 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 certainty). Some action has already been taken to replace or reduce the use 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.

2 The Expanding Definition of Endocrine Disruption

Originally, the concern over endocrine disruption was based almost entirely on perceived effects on the reproductive system and it was usual to refer to the chemicals concerned as oestrogen mimics or oestrogenic chemicals. Later, chemicals were found that could block oestrogenic responses (anti-oestrogens) or androgenic responses (anti-androgens) and it was soon recognized that chemicals could affect other elements of the endocrine system via interaction with hormone receptors other than those of the sex steroids. The term endocrine disrupter is now preferred because it allows inclusion of health effects thought to result from interference with any part of the endocrine system, including thyroid, thymic and pituitary hormones.

In order to establish consensus on the scope of the endocrine disrupter issue, to facilitate the identification of active chemicals and, ultimately, to underpin any future regulatory control, it is essential to agree a precise definition of an endocrine disrupter (ED). Such a definition was proposed at a major European Workshop on EDs.

‘An endocrine disrupter is an exogenous substance that causes adverse health effects in an intact organism, or its progeny, subsequent to changes in endocrine function.’

It was agreed at the workshop that endocrine disrupting activity could only be adequately defined in terms of effects in intact animals, be they juvenile or adult, or in the offspring of exposed parents. For many chemicals, evidence of endocrine disrupting activity has been obtained only by the use of in vitro models, such as hormone binding assays. It was accepted, therefore, that chemicals active in such models should be considered only as ‘potential’ EDs and should be distinguished from those established as active in vivo. For such chemicals, an alternative definition was recommended:

‘A potential endocrine disrupter is a substance that possesses properties that might be expected to lead to endocrine disruption in an intact organism.’

However, several different definitions are also in current use:

• The US Environmental Protection Agency (EPA) Risk Assessment Forum: ‘An endocrine disrupter is an exogenous agent that interferes with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for the maintenance of homeostasis, reproduction, development and/or behaviour.’

• The International Programme on Chemical Safety (IPCS): ‘An endocrine disrupter is an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations.’ and ‘A potential endocrine disrupter is an exogenous substance or mixture that possesses properties that might be expected to lead to endocrine disruption in an intact organism, or its progeny, or (sub)populations.’

• The working definition used in the final report of the US EPA’s Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC): ‘An endocrine disruptor is an exogenous chemical substance or mixture that alters the structure or function(s) of the endocrine system and causes adverse effects at the level of the organism, its progeny, populations, or subpopulations of organisms, based on scientijic principles, data, weight-of-evidence, and the precautionary principle.’

A major difficulty which has been encountered with these definitions (identified as a particular problem by EDSTAC) is the definition of the term ‘adverse’. For a chemical to bejudged an ED, it is important to show that the response seen has an adverse effect on the health or reproductive capacity of affected organisms or populations and is not just a change which falls within the normal range of physiological variation.

A second problem concerns delimiting the mechanisms of action which should be included in the definition, to exclude effects which are a secondary consequence of overt toxicity in other body systems. For example, disruption to the endocrine system caused by general metabolic disturbance, such as in severe liver damage, should not be grounds for calling a chemical an ED.

3 Human Health and Endocrine Disrupters

Effects in humans for which links with exposure to endocrine disrupters have been suggested include the following.

Temporal Reductions in Sperm Counts and Quality

A study of sperm counts conducted worldwide suggested that an annual fall of 0.8% had occurred between 1938 and 1990. Since then, falling sperm count and quality have been reported in a number of countries and a recent study of testicular morphology in Finland suggested a reduction in spermatogenesis between 1981 and 1991. In contrast, no evidence for a decline in sperm counts or quality has been found at a number of locations within the USA, although considerable geographical variations in sperm counts were noted. Despite uncertainties, there is general consensus that, in some countries at least, semen quality (sperm count, sperm morphology and/or sperm physiology) has declined. It is now apparent that determining trends in sperm counts and quality is extremely difficult, owing to geographical and cyclic variation and the influence of bias in the selection of subjects for study. There are also considerable concerns and uncertainties about the consistency and reliability of baseline data and measurement methodologies.

While considerable attention is given to the question of male fertility, the incidence of infertility or sub-fertility in the population is difficult to measure and it is not known to what extent measures of semen quality, for example, are indicators of male fertility as such.

Increased Incidence of Testicular and Prostate Cancer

The incidence of testicular cancer has increased quite dramatically in many countries with cancer registries, including Scandinavia, the countries around the Baltic Sea, Germany, the UK, the USA and New Zealand. It is interesting that although the incidences of testicular cancer in Denmark and Finland are rising, rates in Finland are several times lower than in Denmark; further study of this apparent geographical gradient may give important clues on aetiology.

The incidence of prostate cancer also appears to have risen in many countries.

Increused Incidence of Cryptorchidism and Hypospadias

The incidence of congenital malformations such as cryptorchidism (undescended testes) and hypospadias (malformation of the penis) may have increased, but these trends are difficult to evaluate because of problems with recruiting individuals for analysis and registration of abnormalities at birth.

Altered Sex Ratios

There have been suggestions of alterations in sex ratios following accidental environmental exposure to dioxin in Seveso, Italy, in 1976. Between 1977 and 1984, 74 births occurred in the most heavily contaminated zone which showed an excess of females (26 males and 48 females born). Preliminary evidence suggests that the excess was associated with high dioxin exposure in both parents. Over a later period, between 1985 and 1994, the ratio declined (60 males and 64 females) and was no longer statistically significant.

Increased Incidence of Female Breast Cancer

In women, the incidence of breast cancer has increased steadily over the past few decades in a number of countries including Finland, Denmark, USA and the UK. In Finland, for example, the incidence rose from 25 per 100000 in 1953 to more than 40 per 100000 in 1980. Although improved detection may be partly responsible, the underlying upward trend is estimated as about 1% per year since 1940. A number of factors that increase breast cancer risk have been identified, including diet, calorie intake and alcohol consumption, but lifetime exposure to oestrogens (age at menarche and menopause, use of contraceptive pill, etc.) is of major importance and environmental oestrogens might contribute to overall exposure and thereby to the rising incidence of the disease.

Neurological Eflects

It is known that the brain is one of the most sensitive sites of action of steroids in utero, and recently there have been suggestions that EDs may affect normal brain development and behaviour. For example, it has been alleged that in utero exposure to polychlorinated biphenyl compounds (PCBs) resulted in adverse effects on neurologic and intellectual function (memory and attention) in young children born to women who had eaten PCB contaminated fish in the USA. It has also been speculated that exposure to environmental pollutants with steroidal activity may be influencing human sexual development and sexually controlled behaviour.

Other Possible Effects

It has also been suggested that endocrine disruption may play a part in an increased incidence of polycystic ovaries and endometriosis in women, cardiovascular disease, thyroid disorders and deficiencies in the immune system.

(Continues…)Excerpted from Endocrine Disrupting Chemicals by R. E. Hester, R. M. Harrison. Copyright © 1999 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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