Reproductive Toxicology and Chemicals

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Toxicology and

Chemicals: a matter

of timing?

A conference hosted by the European

Environment Agency and organized

by ReproSafe, a research programme

supported by the Swedish EPA

Synopsis Copenhagen 2-3 October 2003

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Reproductive Toxicology and

Chemicals: a matter of timing?

Synopsis Copenhagen 2-3 October 2003

A conference hosted by the European Environment Agency and organized by ReproSafe, a research programme supported by the Swedish EPA

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Internet: www.naturvardsverket.se/bokhandeln

Swedish Environmental Protection Agency

Tel 08-698 10 00, fax 08-20 29 25 E-mail: natur@naturvardsverket.se

Postal address: Naturvårdsverket, SE-106 48 Stockholm, Sweden Internet: www.naturvardsverket.se

ISBN 91-620-5435-X.pdf ISSN 0282-7298

Cover photos: IdéoLuck/Åsa Olsson Layout: IdéoLuck AB #41209

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Foreword

Threats to reproductive performance in humans as well as wildlife is an issue that has generated considerable public attention during recent decades: for us humans, the ability to become a parent is a very essential part of life, and for wildlife poor reproductive performance in a species may put biodiversity at risk. This public attention has been matched by considerable political activity, especially within the European Union. For instance, reproductive toxicology has been highlighted in the European Commission’s White Paper on a Strategy for a Future Chemicals Policy as a prioritized area.

Within the field of reproductive toxicology “timing” has a certain meaning that creates true challenges for regulation of chemicals, environmental monitoring as well as for risk assessment. One challenge is the so-called “late effects”. That is, the exposure may occur in utero or before puberty without any overt effect and then the adverse effects on reproductive functions are manifested in adulthood when the individual is supposed to be sexually functioning. Another is “critical or vulner-able windows”, i.e., the reproductive system under development in the foetus and infant is much more sensitive to chemicals than the developed system in the adult. The latter challenge has, for instance, driven the U.S. EPA to apply an extra safety factor in assessing the risk of pesticides to children. An even broader initiative has recently started in the EU.

Experts as well as generalists from organizations within the EU, the chemi-cal industry and NGOs, as well as those in national governmental agencies, were invited to this conference, which focused on:

• Presenting a scientific synopsis of the “timing” issues in reproductive toxicology for environmental chemicals, including recent research results from relevant EU & member states’ research programmes

• Discussing implications of the “timing” issues for management of chemi-cals, particularly exposure monitoring

• Discussing EEA’s role “in diffusion of information on the results of rel-evant environmental research in a form that can best assist policy devel-opment”, with particular regard to reproductive toxicology.

This synopsis is based on contributions from the speakers that were summarised and interpreted by the editors Ulf Magnusson, David Gee and Ingvar Andersson.

The particular findings of relevance are summarised on the ReproSafe website in the abstract book http://www-cru.slu.se/RSTime.pdf. This synopsis is found on http://www-cru.slu.se/RSTsynopsis.pdf

We would like to thank the participants at the conference, who all have contrib-uted to this synopsis.

Ulf Magnusson,

ReproSafe, Uppsala

David Gee

European Environment Agency, Copenhagen

Ingvar Andersson,

European Environment Agency, Copenhagen

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Abstract

Conclusions are based on 14 excellent conference presentations from the cutting edge of reproductive toxicology science and from its interpreters/communicators in the wider society. The conclusions highlight the need for:

• Integrated Thinking • Integrated monitoring

• Integrated toxicology/eco-toxicology testing

• Animal testing is essential and better than human testing –for the present • A European Specimen Bank (Biobank)

• More research on reprotoxicology

• Better overall risk assessments of reprotoxicology • The real costs of adequate information

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General conclusions

These conclusions are based on 14 excellent conference presentations from the cutting edge of reproductive toxicology science and from its interpreters/ communicators in the wider society. The conclusions below are some of the main “meta-issues” that arise from the papers and the discussions.

1. Integrated thinking

Disturbances in reproduction by chemicals are a truly complex “systems science” issues that require multi-disciplinary, integrated approaches within science. This “systems science” involves effect and exposure approaches, such as wildlife field studies, human epidemiology and experimental medicine, as well as several aspects of chemistry and chemical monitoring, respectively. The testicular Dystrophy syn-drome is one promising product of this integrated thinking, as was the endocrine disruption hypothesis formulated at the Wingspread conference in 1992. There are many practical barriers to this approach within the research funding and career structures of science. The bodies responsible for health and development of the relevant sciences must tackle the barriers.

2. Integrated monitoring

There should be more integrated effect and exposure monitoring. Effect monitor-ing is a powerful, but not fully exploited, screenmonitor-ing tool when trackmonitor-ing chemical exposure. The exposure assessments, in turn, should be based on appropriate com-binations of “Macro-Monitoring” (of material flows), “Media-Monitoring” (of air, water, food, soil, other surfaces, and consumer products), and “Micro-Monitoring” (of “surprise sensitive” biological tissues in humans and relevant wildlife), but with more emphasis on micro-monitoring; and focused on relevant windows of sensitiv-ity for potential impacts.

3. Integrated toxicology/eco-toxicology testing

The currently fragmented testing regimes are expensive in animals and their wel-fare. There should be more integrated testing of all important biological

end-points in large-scale studies that maximise the use of the same animals without compromising the validity of the results. This would help to improve the statisti-cal power and value of the studies; to enhance multi- disciplinarity; and to reduce animal welfare costs. Also, data in the open literature generated from studies that do not comply with the currently approved testing-guidelines should be taken more into account in risk assessment of chemicals.

4. Animal testing is essential and better than human testing –for the present

There should be greater efforts to develop and use testing methods that do not involve animals, including the use of “sunset” regulations that mandate the timed phase-out of animal testing, which will increase incentives to develop

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alterna-tives. However, as animal testing is currently essential for several end-points (in e.g. generational, developmental and behavioural studies), and is preferable to human testing, as well as the ongoing full-scale exposure of wildlife, there should be a clearer, better coordinated, and more public defence of such animal testing by relevant scientific and political bodies. This would also help to relieve the unethical and unacceptable pressure on those scientists and NGOs who support animal test-ing in the interests of overall welfare.

5. A European Specimen Bank (Biobank)

Serious consideration should be given to the creation of a European Specimen Bank (for human and ecosystem samples), based on the experience of German and Scandinavian examples. (This is also a recommendation from the EEA in its report on “Chemicals Monitoring In Europe”) The EEA will follow up this conclusion.

6. More research on reprotoxicology

Despite strong public and political concern about the reproductive toxicity of chemicals, this scientific field is in its infancy compared with our understanding of carcinogenic and mutagenic properties. There should be more and well-targeted re-search funds devoted to integrated projects in the field of reproductive toxicology.

7. Better overall risk assessments of reprotoxicology

The quality of the overall risk assessment of the otherwise high quality repro-toxicological science is poor compared with that of the assessments by IPCC of Climate Change science. It should be improved by utilising the kinds of explicit frameworks of evaluation used by IPCC, covering, inter alia, both different levels of proof and the temporal trends in the overall strength of evidence for Endocrine Disruption and related reprotoxicological hypotheses. The EEA paper for the EU Environment and Health Strategy, “A Framework for Evaluating the Scientific Evidence on the Environmental Causes of Diseases” is designed to encourage the WHO/IPCS to update their 2002 “Global Assessment of the State of the Science of Endocrine Disruption”.

8. The real costs of adequate information

Estimates should be made of the very large gap between the current toxicity testing guidelines and those required to adequately assess all risks from all important and relevant impacts on humans, wildlife and eco-systems; from all relevant exposure opportunities; across all relevant time windows; with all relevant dose regimes; supported by all necessary monitoring and modelling of likely exposures; and with sufficient statistical power to detect all unacceptable impacts. The large costs of filling that information gap should then be estimated and widely publicised. Society could then agree on the more cost effective precautionary and proxy measures that are needed to compensate for the absence of adequate information in order to strike a better balance between economic activity and the hazards arising from it.

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12 N AT U R V Å R D S V E R K E T R e p o r t 5 4 3 5 11 N AT U R V Å R D S V E R K E T R e p o r t 5 4 3 5 9. Research dissemination

There should be comprehensive yet clear two-way communication and dialogue between scientists and policymakers about the Reprotox research results, utilising both face-to-face and more remote channels of communication and interaction, as recommended in the EEA Environmental issues series Report 15 on “The dissemi-nation of the results of environmental research”. The content should focus on struc-turing the complex and sometimes conflicting knowledge and data so as to promote the greater use of good science within wiser policymaking.

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Scientific evidence, hypotheses and risk

assessment – summary of presentations

Reproductive toxicology and timing in animals

In most classes of animals increasing amounts of data are indicating that a long exposure time with low dose of chemicals affecting or interacting with the repro-ductive system is more harmful than a short exposure to a high dose of the same chemical. In an environmental context, the low dose-long period of exposure is much more relevant in most cases than the high dose-short time of exposure for the chemical pollutants of concern.

In fish, birds and mammals there seem to be a consensus that the developing re-productive system is more sensitive to chemicals than the developed system in the adult. It is important to note that this physiological system is not fully developed at birth or hatching, but continues to develop till puberty. That is, we have to consider that not only the in ovo or in utero period of life is a vulnerable period (which is widely acknowledged in pharmaceutical and teratological sciences) but also the post-hatching and neonate/pre-pubertal period. This becomes a paradox in the case of suckling mammals. The otherwise nutritionally excellent milk of the dam might accumulate harmful chemicals that are transferred to the offspring!

One peculiarity in fish is that there now are data indicating that the vulner-ability to endocrine disrupting chemicals varies not only by life stage, but also by season. This is likely due to the fact that these fish are seasonal breeders, which is why their hormonal status varies by season, which in turn affects the sensitivity for these chemicals.

Generally, the effect of these chemicals on the developing reproductive system is structural and thus irreversible. For instance, exposure of bird embryos to oestro-genic chemicals creates adults that produce eggs with thinner shells than normal. This irreversible developmental effect might be an explanation of the observations that some birds of prey still lay thin-shelled eggs, despite exposure to oestrogenic pollutants having been reduced for several years.

The other timing issues in reproductive toxicology are the time gap between exposure and overt effects on the reproductive system. This issue has become particularly obvious in birds and mammals when embryos and foetuses or newly hatched or neonates have been exposed without any overt morphological effect. However, when these exposed individuals reach adulthood and are expected to be sexually functional, they aren’t. The sexual dysfunction might be due to malforma-tion of internal organs or tissues, disrupted funcmalforma-tion of physiological pathways or deranged sexual behaviour. The latter phenomenon has attracted increasing scien-tific attention during recent years. Normal sexual behaviour is as important as func-tional physiology for reproductive success, or in other words, it is not good enough that a female and male produce functional ova and sperms, respectively, they also have to interact in an appropriate way. In addition to this, the developing brain in birds as well as in mammals seems to be very sensitive to chemicals when it comes to sexual differentiation. This is an area of research that is largely unexplored.

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The timing issue in human reproductive toxicology

A new concept in the field of human reproductive problems of particular inter-est with regard to a “timing” aspect is the male Tinter-esticular Dysgenesis Syndrome (TDS). This syndrome has been discovered because the constraints inherited in the specialization of today’s medicine have been overcome, i.e., the symptoms of this syndrome (testicular cancer, cryptorchidism, hypospadiasis and low semen quality) are usually analysed by various professional groups such as paediatric endocrinolo-gists, uroloendocrinolo-gists, andrologists and oncologists. In contrast, by applying an inte-grated or comprehensive approach to male reproductive problems it was possible to disclose the concept of TDS. There are epidemiological as well as experimental indications that the origin of TDS should be searched for in the embryo or foetus. The timing aspect of TDS is, thus, that a disruption of the programming or devel-opment, respectively, during these two very sensitive stages may cause the syn-drome. In the context of reproductive toxicology, finally, it should be noted that a chemical endocrine disruptions hypothesis has been proposed.

Exposure monitoring of EDS

Even though the majority of the presentations during the meeting dealt with effects on the reproductive system, there is no doubt that exposure assessment of the chemicals in question is an essential part of risk assessment. However, the research focus has varied between effect and exposure monitoring over the year but it cur-rently becomes increasingly clear that the ideal monitoring should include both as-pects. In this context of integrated monitoring, it is important to highlight archived biological and environmental material, specimens or biobanks. Retrospective studies of such biobanks are invaluable for creating base-line data, for instance, reprotoxic chemicals.

Rodents and other mammals as models for humans in reproductive toxicology

The feasibility of mammalian models for human reproductive toxicology is an area of discussion in the scientific community. The issue becomes very complex since the reproductive system seems to be one of the most diverse physiological systems within the animal kingdom. However, two of the pre-requisites for a good animal model is to have solid knowledge about the physiology of the animal in questions and to have good tools for recording effects on reproductive performance in that species. In these aspects, laboratory rodents are superior to other species. For instance, the current work in knock-out mice of various kinds, combined with observations of mutations in humans causing reproductive dysfunction, has contributed considerably to our understanding of impaired reproductive performance.

Even so, there is a role for alternative animal models. As described above, it is becoming increasingly clear that low dose and long exposure time is

environmentally, as well as toxicologically, relevant for the chemicals of concern and that also the postnatal-prepubertal period is a sensitive period in life for reproductive toxicity. This implies that laboratory rodents are less suitable for such

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types of exposure regime since they have a very short (relative to life-span) birth to puberty period. Therefore, there is a role for species like the rabbit and pig, which have longer birth –to-puberty periods and for which we also have considerable knowledge about the normal physiology and a battery of tools to measure effects on the reproductive system.

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Policy responses

Legislation

The legalisation under which chemicals are regulated in society depends on the intended usage of the chemical. Human and veterinary medicine, cosmetics, pesti-cides and biopesti-cides are examples of chemicals that are approved according to differ-ent legal systems before they differ-enter the market. Industrial chemicals and chemicals used by the public have to be classified and labelled as outlined in the European Commission Directives 67/548/EEC classification and labelling of dangerous sub-stances and preparations and 88/379/EEC for preparations to certify a safe use by the professionals as well as the public. Chemicals used by professionals have to be delivered together with a safety data sheet (SDS). Pesticides and biocides are also classified and labelled according to the criteria in these directives.

Recently, in the framework of the United Nations, a globally harmonized system for classification and labelling of chemicals (GHS) has been adopted. The work is the culmination of more than a decade of work. In 2002, the World Summit on Sustainable Development encouraged countries to implement the new GHS as soon as possible with a view to having the system fully operational by 2008. Thus, this is the starting point for implementation of the GHS in Europe also. The GHS itself does not include requirements for testing substances.

A new strategy for hazard and risk assessment of chemicals has been proposed in the so-called White paper. The responsibility of the chemical industry to gener-ate data and to make risk assessments of new and existing chemicals in the EU is enforced. However, chemicals with CMR (carcinogenic, mutagenic or reproduc-tive toxic) properties will probably be forwarded for authorization by the European Commission after consultation of a central chemicals agency or by national com-petent authorities. The work with classification and labelling will in the future be focused on the chemicals with CMR properties.

The classification of a chemical depends both on the criteria and on the reli-ability of the test methods underpinning the criteria. In the EU the test methods required by part of the regulatory system and performed by the industry are mostly according to the QECDs Guidelines (OECD=Organization for Economic Coop-eration and Development). The Guidelines 414 (prenatal developmental toxicity study) 416 (two-generation reproduction toxicity study) are the most comprehen-sive for testing of the reproductive toxicity of a chemical. The Guideline proposal 426 (developmental neuro-toxicity study) will be a complement to the former ones as it deals with functional and behavioural effects manifested in the adulthood.

Globally harmonized classification and labelling systems will hopefully result in a more uniform outcome of classified substances than today.

…and regulatory test methods for chemicals coping with late effects and vulnerable windows

Reproductive toxicology comprises development toxicity and effects on male or fe-male fertility. Developmental toxicity includes any effects interfering with normal development both before and after birth. These effects may arise due to exposure

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of the parent prior to conception, during prenatal exposure, and during postnatal development up to the time of sexual maturation. The effects may be manifested during any time of the life span of the individual. Effects on male and female fertility includes adverse effects on libido, sexual behaviour, any aspects of sper-matogenesis or oogenesis, or on hormonal activity or physiological response which interferes with the capacity to fertilise, fertilisation itself, or the development of the fertilised ovum up to and including implantation.

The regulatory test methods for reproductive toxicity testing within the OECD Test Guideline Program are:

• TG 414 Prenatal developmental toxicity study • TG 415 One-generation study

• TG 416 Two-generation study

• TG 421/422 Reproduction/Developmental Toxicity Screening Test • Draft TG 426 Developmental Neurotoxicity study.

Of critical concern is the possibility that developmental exposure to neurotoxicants may result in an acceleration of age-related decline in function. Animal studies have demonstrated that developmental exposure to neurotoxicants such as methyl mercury and ethanol may cause few or no neurotoxicity effects in young animals, but marked effects in aging animals.

Another recently emerged concern is the so-called “Barker hypothesis” which is based on epidemiological studies showing that low birth weight or thinness at birth is associated with an increased risk of cardiovascular and metabolic disease as well as neuro-endocrine dysfunction in adult life. These results support the notion that adverse effects in foetal life permanently alter the structure and function of the adult offspring, a phenomenon dubbed ‘foetal programming’. Indications may be observed in the two-generation study if the ‘foetal programming’ also results in effects on growth and survival of the animal, but there are no specific test methods investigating cardiovascular and metabolic diseases.

In conclusion, among the current OECD Test Guidelines for reproductive toxic-ity, all vulnerable periods of development are covered only in the two-generation study design. Late effects are partly covered in young adults, especially in relation to reproductive function and developmental neurotoxicity, but potentially impor-tant late effects are not assessed. Effects becoming manifest during aging are not included in guidelines for reproductive toxicity.

Another perspective – from WWF UK

On the basis of precaution, and because of the greater uncertainty in the risk as-sessment, WWF’s view is that exposure elimination should apply to any substance identified as a developmental neurotoxicant, as it would be difficult if not impossi-ble to determine reliaimpossi-ble safe exposure levels for such chemicals. WWF highlight-ed that the ultimate goal must be to eliminate all animal testing and so there was a need for more resources and commitment to develop non-animal tests. WWF also noted that tests to identify reproductive toxicants should be continually updated to new knowledge. Unfortunately, non-animal test methods that can cover all aspects of the reproductive cycle are not yet available. When designing reproductive

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toxic-18 N AT U R V Å R D S V E R K E T R e p o r t 5 4 3 5 17 N AT U R V Å R D S V E R K E T R e p o r t 5 4 3 5

ity tests many factors need to be taken into consideration. However, our limited knowledge is such that it is currently not possible to fully prescribe the test proto-cols most likely to find effects, and therefore, on occasion, non-harmonised OECD test methods will inform the risk assessment process. Furthermore, the develop-ment of internationally agreed test methods will need to be a well-resourced and iterative process.

Past experience shows that the developing brain can be particularly sensitive to pollutants and yet developmental neurotoxicity is an often-neglected facet of reproductive toxicity testing. Thousands of children worldwide have already suf-fered from IQ deficits due to lead and PCBs, and wildlife is also threatened. This presentation therefore highlights the need to urgently identify chemicals that can act as developmental neurotoxicants. Moreover, argumentation is provided to un-derpin the conclusion that, where possible, exposures to such chemicals should be eliminated on the basis of precaution.

Finally, the need for more research and resources to secure robust non-animal test methods is stressed. For developmental neurotoxicants such methods may, however, be at least 5-10 years away.

...and the perspective of an industrial toxicologist

Industry shares society’s values - to develop, produce and put into the marketplace products that are both beneficial and safe for humans and the environment. Ac-cordingly, science-based evaluations of chemicals are necessary both to determine efficiency and safety for intended uses. Reproductive and developmental toxicity testing are standard elements of safety evaluation programmes for pharmaceuticals, medical devices, biologics, food additives, pesticides and industrial chemicals.

The evaluation of substances for their potential to adversely affect develop-ment and reproduction is founded upon the scientific understanding of ontogenesis, integral to which is the concept of windows of vulnerability both for developmen-tal toxicity and reproductive cells and organs. Windows of vulnerability during fetal development and sexual maturation are not a new concept, as these have been incorporated into research, testing and safety assessments for more than 35 years.

To assess the potential for reproductive and developmental disorders in hu-mans associated with exposures to chemical and physical agents, toxicity testing is generally conducted in laboratory animal models. These models are used because, at the present time, no other approach is considered reliable and predictive of re-productive and developmental effects in humans and more often than not adequate epidemiological human data is lacking.

Practices exist by which policymakers can be assured that studies performed by industry for regulatory purposes meet high standards. The USEPA, OECD (and other competent authorities) subscribe to or administer Good Laboratory Practices (GLP), which specify practices and procedures that must be followed by labs to en-sure the quality and integrity of studies conducted for regulatory agencies (OECD 1988).

In the absence of human data, chemical research and testing with laboratory animals is the most reliable means of detecting toxic properties and for estimating risks to human health and the environment. Reproductive and developmental

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toxic-ity tests are costly and employ significant numbers of laboratory animals and, at the present time, there are no alternative non-animal methods for reproductive and developmental toxicity assessment that have been validated and shown to be both reliable and relevant for human health safety assessment purposes. The chemical industry will continue to use alternatives to animal testing when these alternatives are scientifically valid and predictive.

There is no scientific basis for using a simplified approach based on observa-tions from toxicity tests alone to categorize an agent as “toxic” or “non-toxic”, as “a developmental toxicant” or “not a developmental toxicant”, as “a reproductive toxicant” or “not a reproductive toxicant” because the potential toxicity must be considered in the context of exposure. Therefore, it is critical that the process employed to assess the potential effects of agents on development and reproduction follows a deliberative evaluative framework.

Over the years a number of processes have evolved within governments and industry to evaluate and screen new and existing chemicals for potential reproduc-tive and developmental hazards to human health. Under the US High Production Volume (HPV) Challenge Program, companies have formally committed to gather existing OECD SIDS-level screening data on HPV chemicals (from their files, reports and literature) and make this publicly available

Communication of the results from studies and evaluations of agents for developmental and reproductive toxicity is particularly challenging. The standard toxicity testing protocols all require that the highest dose tested be chosen with the aim to induce some developmental and/ or maternal toxicity but not death or severe suffering. Whereas this approach is precautionary toxicology, because it ensures that there is little chance of “missing” a potential adverse effect, it also has the consequence of complicating communication efforts and precludes use of simple descriptors. Adverse reproductive or developmental effects observed at dose levels that produce parental toxicity may be secondary effects. If studies are conducted under conditions of overt toxicity, such effects may not be indicative of unique or selective developmental or reproductive toxicity. The only way to adequately com-municate potential hazards of exposures is in a risk context. This means that the evaluative process must compare the dose response data generated in the toxicity studies to estimated level of human exposure to derive a margin of exposure. The margin of exposure expresses the magnitude of the difference between a level of anticipated human exposure and the highest level at which there is no significant increase in the frequency of an adverse effect. This is critical information not only for assessing risk and considering risk management options when warranted, but also for communicating potential risks to the public.

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The coordinators of the ReproSafe network organised a meeting to bring together researchers, campaigners and private sector representatives involved in the topic of reproductive toxicology and artificial chemicals.

Objectives of the task were:

• to give a presentation to the meeting on the subject of the effective dissemi-nation of research findings;

• to attend the meeting and to speak to as many of the participants as possible, seeking to identify the potential for communicating research-based knowl-edge effectively to those that might be making decisions relevant to the issues;

• to write a report summarising the findings and making suggestions on action. This report assumes that the task in hand is to disseminate the findings of publicly

funded research, rather than research or other information produced by either

private-sector or non-governmental organisations. Both of these can be expected to pursue their interests via their own forms of communication, and their inclusion in any re-search dissemination exercise is likely to lead to a loss of perceived legitimacy among at least some audiences.

Based in the presentations and discussions during the meeting, one may be able to report a number of findings with a good degree of confidence:

• the field of reproductive toxicology is relatively new, presenting specific challenges to the task of communicating the research findings;

• participants came from a variety of disciplinary approaches, which can pro-vide both benefits and constraints;

• participants in the network feel at best mixed incentives for getting involved in dissemination;

• few individual researchers displayed a predisposition to ‘lead’ public debate on behalf of the research community;

• there currently seem to be few dissemination processes and resources on this topic, although various potential mechanisms were discussed.

Hence, a number of suggestions for action developed as a consequence of the findings, are outlined. Reproductive toxicology seems to have moved far since its inception just over ten years ago. Research perspectives and techniques have been developed across a range of disciplines, and the findings have already made international headlines in the media and have had some impact on policy debates.

However, the field now seems ready to move on to the next stage, which will involve collating, reviewing and disseminating research-based evidence in a more organised fashion than has been possible to date. The findings suggest the need for ac-tion on four main fronts:

• Maintaining and enhancing research funding • Networking researchers and other involved parties • Reviewing the evidence

• Organising dissemination and engagement processes.

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Programme

Reproductive Toxicology and Chemicals:

a matter of timing?

A meeting hosted by European Environment Agency (EEA) and organized by ReproSafe at EEA, Kongens Nytorv 6, in Copenhagen October, 2-3, 2003

October 2

Moderator: Ulf Magnusson, ReproSafe

12.00 Registration

13.00 Welcome

Gordon McInnes, Deputy Director EEA

13.15 Introduction to “Reproductive Toxicology and Timing”

Ulf Magnusson, Centre for Repoductive Biology in Uppsala, Sweden

13.30 Chemicals affecting reproduction - Over view of the classification in the EU and globally

Agneta Ohlsson, National Chemicals Inspectorate, Sweden

14.10 Late effects on reproduction in Fish

Susan Jobling, Brunel University, UK

14.50 Coffee or tea

15.20 Reproduction in birds - late effects and vulnerable windows

Björn Brunström, ReproSafe, Uppsala University, Sweden

16.00 Relevant animal models, vulnerable windows, and late effects in mammalian reproductive toxicology

Rao Veeramachaneni, Colorado State University, USA

16. 40 Short break

17.00 Low dose and late effects: Bisphenol A in mice -17.40 Paola Palanza, Parma University, Italy

19.00 Reception/Dinner, hosted by EEA October 3

Moderator: Bo Jansson, EEA Scientific Committee

8.30 Fertility, subfertility, infertility - comparisons between rodents and humans

Jorma Paranko, University of Turku, Finland

09.10 Late effects and vulnerable windows in human male reproduction

Niels Erik Skakkebaeck, Rigshospitalet, Denmark

09.50 Coffee or tea

10.10 Exposure monitoring of EDS; some implications of the “timing” issue

Monika Herrchen, Fraunhofer Institute, Germany

10.50 How do our current test methods for chemicals cope with late effects and vulnerable windows in reproductive toxicology?

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22 N AT U R V Å R D S V E R K E T R e p o r t 5 4 3 5 23 N AT U R V Å R D S V E R K E T R e p o r t 5 4 3 5 11.30 Short Break

11.40 How do we manage these reproductive risks in the society

Sven Ove Hansson, Royal Technical College, Sweden

12.15 Light Lunch

13.00 Reproductive toxicity testing – Industry’s view

Rick Becker, American Chemistry Council, USA

13.20 Reproductive toxicity testing: An environmental NGO’s perspective

Gwynne Lyons, WWF, UK

13.40 How can EEA communicate scientific results in this area?

Alister Scott, Sussex University, UK

14.15 Final Hearing/Discussion – all speakers

Lead by David Gee, EEA

15.00 Closing

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Speakers and organisers

Andersson, Ingvar, Mr

European Environment Agency Kongens Nytorv 6

DK-1401 Copenhagen, Denmark Email: ingvar.andersson@eea.eu.int Becker, Richard A., Dr.

American Chemistry Council, USA 1300 Wilson Blvd. Arlington, VA 22209, USA

Telephone: +1(703) 741-5210 Fax: +1(703) 741-6056 Email: rick_becker@americanchemistry.com

Brunström, Björn, Professor

Department of Environmental Toxicology Uppsala University

Norbyvägen 18A

SE-752 36 Uppsala, Sweden

Tel. +46 18 4712626 Fax. +46 18 518843 Email: bjorn.brunstrom@ebc.uu.se Gee, David, Mr

DK-1401 Copenhagen, Denmark Email: david.gee@eea.eu.int Hansson, Sven Ove, Professor Philosophy Unit

Royal Institute of Technology Teknikringen 78A 100 44 Stockholm, Sweden Email: soh@infra.kth.se Hass, Ulla, Dr.

Institute of Food Safety and Nutrition Morkhoj Bygade 19

2860 Soborg, Denmark. Telephone: +45 33956000 Email: ulh@fdir.dk

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24 N AT U R V Å R D S V E R K E T R e p o r t 5 4 3 5 25 N AT U R V Å R D S V E R K E T R e p o r t 5 4 3 5 Herrchen, Monika, Dr.

Fraunhofer-Institut fuer Molekularbiologie und Angewandte Oekologie Auf dem Aberg 1,

D-57392 Schmallenberg, Germany

Telephone: +49(0)2972/302-215 Fax: +49(0)2972/302-319 Email: monika.herrchen@ime.fraunhofer.de

Jansson, Bo, Professsor

Institute of Applied Environmental Research

Stockholm University, SE-106 91 Stockholm, Sweden Telephone: +46 - 8674 7220 Fax: +46 - 8758 1360 Email: bo.jansson@itm.su.se

Jobling, Susan, Dr.

Department of Biological Sciences, Brunel University,

Uxbridge, Middlesex, UK

Telephone: +44-1895-27-4000 Fax: +44-1895-27-4348 Email: susan.jobling@brunel.ac.uk

Lyons, Gwynne, Ms

Toxics Science and Policy Advisor WWF UK 17 The Avenues

NR2 3PH, Norwich, UK Telephone: +44-1603-507363 Email: lyonswwf@aol.co Magnusson, Ulf, Professor

Centre for Reproductive Biology in Uppsala, CRU P.O. Box 7039, SLU

SE-75007 Uppsala, Sweden

Telephone: +46-18 672324 Fax: +46-18 673545 E-mail: ulf.magnusson@og.slu.se

Mc Innes, Gordon, Dr

DK-1401 Copenhagen, Denmark Email: gordon.mcinnes@eea.eu.int Ohlsson, Agneta, Dr.

National Chemicals Inspectorate P.O. Box 2

SE - 172 13 Sundbyberg, Sweden

Telephone: +46-8-519 412 41 Fax: +46-8-519 412 41 Email: agneta.ohlsson@kemi.se

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Palanza, Paola, Dr.

Dipartimento di Biologia Evolutiva e Funzionale Universita’ di Parma

Parco Area delle Scienze 11A 43100 Parma, Italy

Telephone: -0521 905628 Fax: -0521 905657 Email: palanza@biol.unipr.it

Paranko, Jorma, Professor Department of Biology

Laboratory of Animal Physiology 20014 University of Turku, Finland Telephone: +358-(0)2-333 5786 Email: paranko@utu.fi

Scott, Alister Mr

SPRU (Science and Technology Policy Research), University of Sussex

and Partner, TheKnowledgeBridge, UK Telephone: +44 1273 678986

Email: alister@theknowledgebridge.com Sakkebaek, Niels Erik, Professor

University Department of Growth and Reproduction, Rigshospitalet,

DK-2100 Copenhagen, Denmark Email: nes@rh.dk

Stanners, David, Dr

DK-1401 Copenhagen, Denmark Email: david.stanners@eea.eu.int Veeramachaneni, D N Rao, Professor

Animal Reproduction and Biotechnology Laboratory Colorado State University

Fort Collins, CO 80523-1683, USA

Telephone: +1(970) 491-1769/1770 Fax: +1(970) 491-3557 Email: rao@colostate.edu

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Participants

Allen, Sandra, Dr

(CEFIC), Syngenta Central Toxicology Laboratory Alderley Park, SK10 3BD Macclesfield, UK

Telephone: +44 (0) 1625 514503 Fax: +44 (0) 1625590249 Email: sandra.allen@syngenta.com

Andersen, Lotte Kau

Danish EPA, Chemicals Division

Strandgade 29, 1401 Copenhagen K, Denmark Telephone: +45 32 66 02 91 Fax: +45 31 66 02 61 Email: lka@mst.dk

Asanji, Soh Raymond, Mr

Land & Water Resources Engineering, kung Tekniska Hogskolan Alhadsvagen 100 - 402, Norsborg, 14559 Stockholm. Sweden Telephone: +46739767659 Fax: +4686243773

Email: asanjis@hotmail.com Assem, Louise, Ms

Biosciences, University of Birmingham Edgbaston, B15 2TT Birmingham, UK Telephone: +44 121 414 5415

Email: FLA258@bham.ac.uk Berg, Cecilia, Assistant Professor

Dept of Environmental Toxicology, Uppsala University Norbyvägen 18A, 752 36 Uppsala, Sweden

Telephone: +46 18 471 2621 Email: cecilia.berg@ebc.uu.se Birkhøj, Mia, Toxicologist

Department of Occupational and Environmental Medicine, Odense University Hospital

Sdr. Boulevard 29, 5000 Odense, Denmark Telephone: 6550 3782

Email: mbirkhoej@health.sdu.dk Bjerselius, Rickard, Dr

Research and Development, Toxicology division Swedish National Food Administration

Box 622, SE-751 22 Uppsala, Sweden

Telephone: +46 18 175793 Fax: +46 18 175500 Email: ribj@slv.se

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Bonefeld-Jorgensen, Eva Cecilie, Associated Professor Unit of Environmental Biotechnology,

Dept. of Environmental and Occupational Medicine University of Aarhus

Vennelyst Boulevard 6, Bouil. 260, 8000 Aarhus, Denmark Telephone: 89426162 Fax: 89426199

Email: ebj@mil.au.dk Borch, Julie, Cand.scient IFTA, Fødevaredirektoratet

Mørkhøj Bygade 19, 2860 Søborg, Denmark Telephone: 33956280

Email: jubo@fdir.dk Bottero, Sergio, Dr.

Dept. of Experimental, Environmental and Applied Biology (DI.BI.S.A.A.) University of Genoa

Viale Benedetto XV, 5, 16132 Genoa, Italy

Telephone: +39 0103538046 Fax: +39 0103538047 Email: bottero@unige.it

Boye, Mette, Environmental policy adviser Danish Consumer Council

Fiolstræde 17, P.O Box 2188, 1701 K. Kbh, DK Telephone: 77417741 Fax: 77417742

Email: mb@fbr.dk

Boye Petersen, Annika, Toxicologist Danish EPA

Strandgade 29, 4101 Copenhagen K, Denmark Telephone: 32660542 Fax: 32660535

Email: aba@mst.dk

Bredhult, Carolina, PhD student

Department of Women’s and Children’s Health, Uppsala University Uppsala University Hospital, SE-751 85 Uppsala, Sweden

Telephone: +46 18 - 611 57 74 Fax: +46 18 - 55 97 75 Email: carolina.bredhult.0180@student.uu.se Bro-Rasmussen, Finn, professor, emer

IPL/LCA, Technical University of Denmark Building 424, DK-2400, Lyngby, Denmark Telephone: +45-45254796 Fax: +45-4525 48031⁄2 Email: fbr@ipl.dtu.dk

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28 N AT U R V Å R D S V E R K E T R e p o r t 5 4 3 5 29 N AT U R V Å R D S V E R K E T R e p o r t 5 4 3 5 Byman, Jan, Dr

Research secretariat, Swedish Environmental Protection Agency SE-106 48 Stockholm, Sweden

Telephone: +4686981570 Fax: +4686981664 Email: jan.byman@naturvardsverket.se Dalgaard, Majken, DVM, Ph.D

Department of Toxicology, Institute of Food Safety and Nutrition Mørkhøj Bygade 19, 2860 Søborg, Denmark

Telephone: +45 33 95 65 60 Fax: +45 33 95 60 00 Email: mac@fdir.dk

Di Lorenzo, Diego, Dr.

Laboratory of Biotechnology, Ospedale Civile di Brescia P.le Spedali Civili 1, 25123 Brescia, Italy

Telephone: 0039 030 3995408 Fax: 0039 030 307251 Email: dilorenz@master.cci.unibs.it

Fisher, Jane, Dr

Centre for Toxicology, The School of Pharmacy, University of London 29-39 Brunswick Square, WC1N 1AX London, UK

Telephone: +44 207 753 5811 Fax: +44 207 753 5908 Email: jane.fisher@ulsop.ac.uk

Gustafsson, Åsa, Fil Mag Biology (Ecotoxikologist)

Division of NBC Defence, FOI, Swedish Defence Research Agency 901 82 Umeå, Sweden

Telephone: +46 90 10 67 25 Fax: +46 90 10 68 09 Email: asa.gustafsson@foi.se

Hanberg, Annika, Dr

Institute of Environmental Medicine, Karolinska Institutet PO Box 210, 171 77 Stockholm, Sweden

Telephone: +46 8 52487526 Fax: +46 8 34 38 49 Email: annika.hanberg@imm.ki.se

Heinzow, Birger G.J., Dr.

Environmental Health, State Agency for Health and Occupational Safety Hamburger Ch. 25, D 24220 Flintbek, Germany

Telephone: +49 4347 704 – 200 Fax: +49 4347 704 - 202 Email: bheinzow@lanu.landsh.de

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Howard, Vyvyan, Dr

Developmental Toxico-Pathology Research Group, Human Anatomy & Cell Biology University of Liverpool Ashton Street, L69 3GE Liverpool, UK

Telephone: +44 151 794 7833 Email: c.v.howard@liv.ac.uk Jacobsen, Helene, DVM, PhD

Danish Veterinary and Food Administration, Inst. of Food Safety and Nutrition, Dept. of Toxicology

Mørkhøj Bygade 19, 2860 Søborg, Denmark Telephone: +45 33 95 62 80

Email: helx@fdir.dk Kirk, Christopher, Dr

Biosciences, University of Birmingham Edgbaston, B15 2TT Birmingham, UK

Telephone: +44 121 414 5414 Fax: +44 121 414 2597 Email: c.j.kirk@bham.ac.uk

Knapp, Mats

Box 7005, 402 31 Göteborg, Sweden Telephone: +46317110152

Email: mats@chemsec.org Kultima, Kim, PhD student

Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University The Biomedical Center, Box 594

SE-75124 Uppsala, Sweden

Telephone: +46184714254 Fax: +46-18-4714253 Email: kim.kultima@farmbio.uu.se

Kusk, K. Ole, Prof.

Environment @ Resources DTU, Technical University of Denmark DTU Building 115, DK-2800 Kgs. Lyngby, Denmark

Telephone: +45 4525 1569 Fax: +45 4593 2850 Email: kok@er.dtu.dk

Larsen, Poul Bo, pharmacist/ toxicologist

Chemicals Division, Danish Environmental Protection Agency Strandgade 29, 1401 K, Copenhagen, Denmark

Telephone: + 45 32 66 01 37 Email: pbl@mst.dk

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30 N AT U R V Å R D S V E R K E T R e p o r t 5 4 3 5 31 N AT U R V Å R D S V E R K E T R e p o r t 5 4 3 5 Leffler, Per, Dr

NBC-Defence, Toxicology, Swedish Defence Research Agency (FOI) Cementvägen 20, SE-901 82 Umeå, Sweden

Telephone: +46-90-106600 Fax: +46-90-106809 Email: per.leffler@foi.se

Ljungvall, Karl, DVM, PhD-student

Dep of Obstetrics and Gynaecology, Swedish University of Agriculture Box 7039, 750 07 Uppsala, Sweden

Telephone: +46 18 67 11 54 Email: karl.ljungvall@og.slu.se Lorenzen, Lene, Toxicologist

Pesticides Division, The Danish Environmental Agency Strandgade 29, 1401 Copenhagen, Denmark

Telephone: 32 66 05 70 Fax: 32 66 05 35 Email: llo@mst.dk

Mandich, Alberta, Dr.

Dept. of Experimental, Environmental and Applied Biology (DI.BI.S.A.A.) University of Genoa

Viale Benedetto XV, 5, 16132 Genoa, Italy

Telephone: +39 0103538046 Fax: +39 0103538047 Email: mandich@unige.it

Nielsen, Pia Juul, M.Sc. (pharm)

Biocides and Chemicals Assessment Division, Danish Environmental Protection Agency Strandgade 29, 1401 Copenhagen K, Denmark Telephone: +45 32660418 Fax: +45 32660369 Email: pjn@mst.dk

Pedersen, Ragnor, Dr

Cluster of Research into Endocrine Disruption in Europé, Centre for Toxicology University of London School of Pharmacy

29/39 Brunswick Square, WC1N 1AX London, United Kingdom Telephone: +44 20 7753 5811 Fax: +44 20 7753 5908

Email: ragnor.pedersen@ulsop.ac.uk Penman, Michael, Mr

Product Stewardship and Regultory Affairs, ExxonMobil Petroleum & Chemical Hermeslaan 2, B-1831 Machelen, Belgium

Telephone: +32 2 722 4416 Fax: +32 2 722 4228 Email: Michael.G.Penman@ExxonMobil.com

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Persson, Bodil, Associate professor

Dept of Occupational and Environmental Medicine, University Hospital SE-581 85 Linköping, Sweden

Telephone: +46-13 221451 Email: bodil.persson@lio.se Pongratz, Ingemar, Dr.

Dept. for Biosciences at Novum, Karolinska Institutet Hälsovägen 7, 141 57 Huddinge, Sweden

Telephone: +46-(0)8-608 9113 Fax: +46-(0)8-774 5538 Email: Ingemar.Pongratz@biosci.ki.se

Salter Green, Elizabeth, Mrs

Toxics Programme Leader, WWF-UK

Panda House, Weyside Park, GU7 1XR, Godalming, UK Telephone: 00 44 1483 412 518 Fax: 00 44 1483 426 409 Email: esaltergreen@wwf.org.uk

Scholz, Birger, PhD student, M.Sc.

Dept of Pharmaceutical Biosciences, div of toxicology, Uppsala university BMC, Uppsala, Box 594, 751 24 Uppsala, Sweden

Telephone: 0046 018 4714265 Fax: Fax 018-471 42 53 Email: Birger.Scholz@farmbio.uu.se

Gabriele Schoning

DK-1401 Copenhagen, Denmark Email: gabriele.schoning @eea.eu.int Selstam, Gunnar, Prof

Dept of Molecular Biology, Univ of Umeå 901 87 Umeå, Umeå, Sweden

Telephone: +46 90 78 50000 ext 53351 Fax: +46 90 77 14 20 Email: gunnar.selstam@molbiol.umu.se

Skaane, Ole, Toxicologist & Lawyer Hydro Polymers AS, Rafnes

N-3966, Stathelle, Norway

Telephone: + 47 95 28 71 81 Fax: + 47 35 00 62 98 Email: ole.skaane@hydro.com

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Spjuth, Linda, Ph D student

Department of Obstetrics and Gyneacology, Faculty of Veterinary Medicine Swedish University of Agricultural Sciences (SLU)

Box 7039, 750 07 Uppsala, Sweden Telephone: +46 18-671154

Email: linda.spjuth@og.slu.se Toneby, Mark, Ph D

MIT miljölab AB

Dal, SE-153 94 Hölö, Sweden

Telephone: +46 8551 59020 Fax: +46 8551 59120 Email: mark.toneby@mitmiljolab.se

Vethaak, Dick, Dr Ecotoxicology, RIKZ

Grenadiersweg. P.O.Box 8039, 4330 EA , Middelburg, Netherlands Telephone: 0031-113-377006 Fax: 0031-113-372855

Email: a.d.vethaak@rikz.rws.minvenw.nl Vinggaard, Anne Marie, Seníor Scientist

Institute of Food Safety and Nutrition, Danish Food Administration Mørkhøj Bygade 19, 2860 Søborg, DK

Telephone: +45 33956549 Email: amv@fdir.dk

Wandall, Birgitte, Ph.d student Filosofienheten, KTH

Teknikringen 78 B, 10044 Stockholm, Sweden Telephone: +46 8 790 95 24

Email: wandall@infra.kth.se Waring, Rosemary, Dr

Biosciences, University of Birmingham Edgbaston, B15 2TT Birmingham, UK Telephone: +44 121 414 5421

Email: r.h.waring@bham.ac.uk Wollenberger, Leah, M.Sc.

Environment & Resources DTU, Technical University of Denmark DTU Building 115, DK-2800 Kgs. Lyngby, Denmark

Telephone: +45 4525 1593 Fax: +45 4593 2850 Email: lew@er.dtu.dk

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Woolford, Justin, Mr

Chemicals and Health Campaign Leader, WWF-UK Panda House, Weyside Park, GU7 1XR, Godalming, UK Telephone: 00 44 1483 412 508 Fax: 00 44 1483 426 409 Email: jwoolford@wwf.org.uk

Yuan, Li, Ph.D., M.D.

Institute of Environmental Medicine, Karolinska Institutet Nobels väg 13, 171 77 Stockholm, Sweden

Telephone: 46 8 7287544 Fax: 46 8 343849 Email: li.yuan@imm.ki.se

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It is well known that chemicals may affect human be-ings as well as wildlife. The reproductive system seems to be particularly sensitive to chemicals. As with most other physiological systems, the reproductive system is especially sensitive during embryonic and foetal develop-ment and in the young individual. However, in contrast to effects on other physiological systems, the effects on the reproductive system are mostly manifested first in adulthood.

These two issues in reproductive toxicology: the sensitive windows for exposure and the late effects of exposure was the topic for a meeting hosted by the Eu-ropean Environment Agency in Copenhagen on October 1 to 3 2003. The meeting, organized by ReproSafe, a research program funded by the Swedish Environmental Protection Agency gathered leading persons from the scientific community, governmental agencies, NGO’s and industry. The biology of the timing issues in reproduc-tive toxicology and it’s impact on regulatory toxicology and environmental monitoring was thoroughly discussed during the meeting.

Toxicology and

Chemicals: a matter

of timing?

A conference hosted by the European

Environment Agency and organized by

ReproSafe, a research programme supported

by the Swedish EPA

Synopsis Copenhagen 2-3 October 2003

ISBN: 91-620-5435-X ISSN: 0282-7298

Reproductive Toxicology and Chemicals

Toxicology and

Chemicals: a matter

of timing?

A conference hosted by the European

Environment Agency and organized

by ReproSafe, a research programme

supported by the Swedish EPA

Synopsis Copenhagen 2-3 October 2003

Reproductive Toxicology and

Chemicals: a matter of timing?

Synopsis Copenhagen 2-3 October 2003

Foreword

Abstract

Table of contents

General conclusions

Scientific evidence, hypotheses and risk

assessment – summary of presentations

Policy responses

Programme

Reproductive Toxicology and Chemicals:

a matter of timing?

Speakers and organisers

Participants

Toxicology and

Chemicals: a matter

of timing?

A conference hosted by the European

Environment Agency and organized by

ReproSafe, a research programme supported

by the Swedish EPA

Synopsis Copenhagen 2-3 October 2003