CONCLUSIONS AND PERSPECTIVES

hit progressive loop. The majority of testicular cancer patients are subfertile prior to the time of testicular cancer diagnosis, and the first hit may be the development of infertility. This first hit may occur later in life, and may affect nor- mal individuals who did not develop TDS as a result of genetic mutation or maternal exposure to endocrine disrupter.

Conclusion We have learned a great deal at this confer-

ence about the clinical aspects of hormones and endocrine disrupters. This has been a wonderful learning opportunity although we are still left with many more questions than we have answered.

Concluding remarks: Toxicological aspects Paul Foster Chemical Industry Institute of Toxicology, Re- search Triangle Park, USA

It is difficult to summarise all the toxicological information that has been presented at this meeting in a short space. It is perhaps more rel- evant to make an assessment of future research needs and to consider sources of funding.

Future research needs There is a substantial amount of money avail-

able for toxicological studies, but we must ques- tion if it is being channelled in the right direction. There is certainly a real and desperate need for toxicologists to accumulate better data on hu- man exposure to endocrine disrupters, and to measure the internal dose of such substances fol- lowing the example of Dr John Brock’s study on phthalates. The term “endocrine disrupter” is perhaps too emotive because these substances may not have a disruptive action unless the dose and time of exposure is correct, and a more rel- evant term may be “endocrine active chemical” (E AC) .

It is possible to link human effects to animal studies even although some experiments exam- ine low dose phenomena, whereas other experi- ments look at the effects of heroic doses as de- scribed by Dr Richard Sharpe. There are two ways of linking human and experimental data. Firstly, if we know that humans are exposed to a substance, the effect of different doses of that

S 562

substance can be studied in animals to deter- mine if any effect is produced. Secondly, the re- verse of that situation can be analysed: if a cer- tain effect is noticed in animals exposed to a chemical, we can then look for a similar effect in humans and use epidemiological techniques to determine if the effect is correlated with ex- posure to any particular substances.

Understanding mechanisms In many cases, we only have a very superficial

understanding of the mechanisms involved whereby EACs have their effects. Toxicological experiments may be analogous to looking under the lamp post: we look where the light shines brightest but that may not be the most appro- priate place to find the answers. At this meeting there has been heated discussions about veterin- ary pharmaceuticals, but we have not con- sidered other types of pharmaceuticals either from an environmental point of view, or from a human exposure point of view. Many new drugs are being developed to act on hormone recep- tors, but we do not know the environmental ef- fect they may have once they have been excreted into the environment, and these drugs may be of more significance than any of our industrial chemicals. In fact, it is very surprising that safety assessment experiments on animals are far more intense for a pesticide than for a drug, and it is usually the pesticides rather than the drugs which attract the adverse publicity.

Initially the endocrine action of chemicals was studied in relation to their oestrogenic ac- tivity, but we are finally looking beyond the “oestrogenocentricyy approach. It is sensible to broaden our horizons because oestrogen is not the only hormone in the body. It is encouraging that antiandrogenic effects are now being exam- ined, and at least one paper at this meeting con- sidered thyroid action, which is another incred- ibly important field of endocrinology.

Modijication of standard protocol design This is the more practical aspect of future plan-

ning and toxicologists must invest time into as- sessing our methods of testing EACs. At present, if we suspect that a chemical has endocrine activ- ity, we decide what tests are currently available to confirm such activity and often develop a hybrid assay system. For example, there may be an es- tablished protocol for looking at the effect on re-

CONCLUSIONS AND PERSPECTIVES

production and development and we may assume that such a protocol is appropriate for any sub- stance that we are assessing, but perhaps a differ- ent test may be more relevant. It would be better to think carefully about what kind of effect we are really interested in, and to design a test which addresses that specific aspect. We must try to understand the potential hazards involved, and to generate dose response information over the correct range, which is applicable to human risk assessment. This is basic to the understanding of relevant human exposure data.

Better animal models for human disease Toxicologists strive to develop animal models,

which closely reflect the human situation, but this is not always accurate. The rabbit is often used as a model, but there are no good animal models for many human diseases such as pros- tate cancer. Once better models are available, toxicologists will have greater ability to assess the potential endocrine activity of different chemicals and their effect on disease states, or on their role in the induction of these diseases.

Conclusion There is still much to learn about the physi-

ology of normal hormonal control and normal reproduction and development. It is possible that by gaining better understanding of the ad- verse effects of EACs, we may end up by dis- covering more about normal mechanisms. In other words, the study of toxicology often ad- vances the knowledge of normality. Toxicol- ogists are often the scourge of major pharma- ceutical companies because their results fre- quently condemn promising new drugs. We should now look at the positive contributions that toxicologists make towards generating valuable information about normal repro- duction and development, rather than their negative function of demonstrating only adverse side effects of different compounds.

Concluding remarks: Basic aspects Bernard Jigou GERM-INSERM, UniversitC de Rennes I, Rennes, France

Dr Niels Skakkebak and his colleagues 5 years ago published a curve showing the declining

sperm quality in humans over the last 5 dec- ades, and this provoked a media bombshell. Some scientists would rather not have media coverage of contentious issues and suggest that we should not talk to the media. However, sometimes it is beneficial to communicate im- portant scientific discoveries by way of the me- dia to a wider audience, and this often helps to raise money for research into important issues.

One of the first meetings on endocrine disrup- ters was held in France in 1996 in collaboration with Dr Pierre Jouannet. Those of us who at- tended that meeting have had the privilege of observing the evolution of this topic, and the story continues in this meeting we have just had in Copenhagen.

A scientific publication, which rings alarm bells and suggests, contrary to popular belief, that we are possibly being harmed by practices that were assumed to be safe, results in the authors being accused of science friction. People with vested interests may try to discredit the conclusions in the hope of consigning the paper to scienceJction. In the early days of identifying the endocrine disrupter properties of commer- cial products there was conflict between indus- trial scientists and academic scientists because discovering the truth could have had an adverse effect on businesses. Discussions are now much more open between the different factions and the real risk of collision is between good science and bad science rather than between truth and commerce.

Over the past 5 years, there has been bad news and good news. The bad news is that in the epidemiological study of sperm quality, we omitted to measure and record testicular vol- ume so that we do not have a baseline value to assess changes. The good news is that testicular volume has not been patented, so that we can repeat the experiment and use this as a par- ameter for prospective studies. More bad news lies in the fact that fast screening of testicular volume has turned out to be more difficult than expected, but there is the good news that the complexities are such that the scientists will not be replaced by robots.

What has been the outcome of 5 years of re- search into endocrine disrupters? One positive advance is that we now have a community of different workers and specialists who are work- ing together around the issue of endocrine dis-

S 563