COMMISSION OP THE EUROPEAN COMMUNITIES 
C0M(91) 341 final 
Brussels, 30 September 1991 
COMMUNICATION FROM THE COMMISSION TO THE COUNCIL 
on the Community programme of action in the field of 
toxicology for health protection 

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Communication fro» the Connission to the Council on the Community 
programme of action in the field of toxicology for health protection 
(86/C 184/01) (1) 
I SUMMARY 
This Communication summarizes ail the activities carried out as part of 
the toxicology programme for health protection (86/C 184/01) between 1986 
and 1990. The Council and the Representatives of the Governments of the 
Member States meeting within the Council had expressed the political will 
to see a number of measures taken at national and Community level before 
the end of 1990. 
The main purpose of the programme is toxicology aimed at health 
protection through the prevention of diseases which can be caused by 
exposure to toxic substances. 
The objectives defined in the programme have been achieved for the most 
part and a wide variety of work has been carried out. This work has 
brought to light the increasing importance of a targeted approach to 
deteriorations in organs or biological systems as a who!© and will have 
to be taken into account In future work on early effects. This w? ! ! lead 
to improvements in the means of early detection of conditions which are 
conducive to the development of diseases, which will in turn, improve 
prevention and health protection. 
This Programme has paid particular attention to the deterioration of 
early biochemical and physiological parameters in the immune, renal and 
reproductive systems; this is essential for the detection of pathological 
deviations and may be a great help in combating large-scale epidemics. 
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I I INTRODUCTION 
This Communication summarizes all the activities carried out as part of 
the toxicology programme for health protection (86/C 184/01) between 1986 
and 1990. The Council and the Representatives of the Governments of the 
Member States meeting within the Council had expressed the political will 
to see a number of measures taken at national and Community level before 
the end of 1990. 
An interim report (COM88/184 final) was sent to the Council on 11 April 
1988. The Council and the Ministers of Health meeting within the Council 
on 31 May 1988 expressed their interest in the work carried out and 
emphasized the need for the work to be continued with an emphasis notably 
on immunotoxicology, effects on the reproductive and renal systems, and 
in vitro tests. Emphasis was also placed on the need to carry out this 
work in close cooperation with the Member States and international 
organizations. Whenever possible, therefore, the Commission has made a 
point of working together with the institutes and laboratories in the 
Member States and with international organizations (such as the 
specialized bodies of the United Nations), non-governmental organizations 
and worldwide and European associations which bring together competent 
specialists in the various areas. In this way, the Commission has been 
able to broaden the level of expertise for the work in each of these 
areas and to avoid duplication of work. 
I I I MAIN ACHIEVEMENTS 
Immune system 
The findings of an international workshop and an international seminar 
(2-3), which was organized jointly by the Commission and the WHO with the 
very active participation of certain Member States, showed the need for 
advance immunotoxicology tests (histopathology and the immune function), 
in particular in the areas of immunosuppression, hypersensitivity and 
autoimmunity, in view of the impact of immunological disorders on the 
development of morbid conditions. 
Following these recommendations, an international study on immunotoxicity 
tests was carried out under the auspices of the Commission and the WHO; 
the first stage has been completed and the second is under way. A total 
of 17 laboratories from 11 countries, including five Member States of the 
European Community, took part in the first stage in which the most 
sensitive indicators were identified; these are now being examined in 
more detail in the second stage with a view to a possible harmonization 
of methodology. 
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Renal system 
To improve health protection and to prevent renal damage, it is necessary 
to have biological indicators which make it possible to identify renal 
damage at an early stage. To this end, an international workshop was 
organized in cooperation with the WHO (4), during which it emerged that a 
methodological approach to the evaluation of nephrotoxicity was needed. 
A joint Commission/WHO group of experts was formed which drew up tho 
principles and methods to be used for the best possible evaluation of 
nephrotoxic effects, emphasizing the identification of deteriorations at 
the earliest possible stage and the prevention of morbid conditions, by 
means of confirmed biological indicators (5). 
Reproductive system 
A methodological approach for evaluating damage to the reproductive 
system has been established. It takes the form of guidelines drawn up 
jointly by top level experts in this field. It was established that the 
reproductive cycle had to be examined in its entirety (the pre-, peri-
and post-natal effects on offspring, and the possible effects on the 
reproductive capacity of adults). Many parameters have to be taken into 
account in order to achieve a satisfactory evaluation of the potential 
dangers to the reproductive system in experimental and clinical 
toxicology. In 1991 these guidelines will be dealt with in a monograph 
which will also include an evaluation of around 30 compounds, in 
particular those substances which are a potential cause of drug 
addict ion. 
Carcinogenic effects 
In the light of various requests, the scientific evidence of 
carcinogenicity has been reviewed for 85 compounds (6). The 
International Cancer Research Centre contributed to this work. Other 
compounds are currently being analysed. Work is under way on a 
methodology for investigation of the potential involvement of certain 
industrial processes in the appearance or development of carcinogenic 
processes. 
Poison control centres 
The conclusions of a survey of the operation of poison control centres 
carried out in cooperation with the World Health Organization (WHO) (7) 
showed the need for more information on the modes of action and the 
availability of antidotes and for harmonization of the reports on the 
activities of the poison control centres in order to provide comparable 
clinical data. 
The Commission has conducted a survey on the level of knowledge on - and 
the use of - antidotes in the Member States. It showed that little is 
known about their nature and their specific indicators and/or that it is 
difficult to obtain them soon enough to allow for effective treatment of 
poisoning. In addition, the availability of antidotes was examined at an 
international workshop organized in cooperation with the WHO (8). A 
joint Commission/WHO programme on antidotes has been drawn 
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up with the aim of providing a more rapid evaluation of their 
effectiveness and identifying the work which stiii needs to be done. 
Monographs on antidotes are being prepared. 
These studies and surveys were used as the basis for the proposal 
presented by the Commission to the Council and adopted as the Resolution 
of the Council and of the Representatives of the Governments of the 
Member States meeting within the Council of 3 December 1990 on improving 
the prevention and treatment of acute human poisoning (OJ/C 329/03 of 31 
December 1990) (9). This proposal emphasizes the major role of Community 
poison control centres in this area. 
A pilot network of poison control centres has also been set up 
(EUROTOXNET). The poison control centres involved have undertaken to 
cooperate in work on clinical toxicology of interest to the whole 
Community (disséminât ion of information, toxico-vigilance, pooling of 
bibliographical resources and know-how) so that they can deal more 
effectively with the toxicological problems which may arise from the free 
circulation of products in the Community. The members of the network 
also provide training in new technology (toxicology and computer 
science). 
Biological indicators 
Exposure to toxic agents produces concentrations of these agents or their 
metabolites, as well as biochemical effects, in human tissue. Exposure 
to these chemical agents can be evaluated on the basis of these 
biological indicators. Monographs dealing with the usefulness of these 
indicators have been produced for a number of toxic substances and others 
are being prepared (10). There has been considerable demand for these 
documents in the Member States where they have been particularly useful 
to occupational physicians for monitoring workers and taking preventive 
measures. 
In view of the growing concern about genotoxic compounds, an 
international workshop was organized in cooperation with the WHO on the 
indicators which may be used to evaluate exposure and with the biological 
effects of genotoxic chemicals (11). The workshop concluded that it was 
necessary to conduct more basic research before such indicators could be 
used in pract ice. 
The first stage in the study of biochemical and physiological parameters 
in humans and animals and their variability with regard to normal values 
was to draw up a list of reference values of the elements which are 
normally present in minute quantities in the tissue of inhabitants of the 
European Community (12). Pathological variations in the above-mentioned 
parameters could be correlated with the deteriorations observed in 
certain morbid conditions, in particular degenerative diseases, and so 
allow early preventive measures to be considered, as has already been 
done in the case of impairment of the renal function. 
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Experimental toxicology 
Work in this area has focused on the need to minimize the number of 
animals used (in accordance with the 1986 Council Directive (86/609/EEC) 
in the protection of animals used for experimental purposes (13)). To 
this end, the Commission has examined the possibility of replacing in 
Vivo experimental methods by in vitro and/or ex vivo methods, or, 
alternatively, developing existing methods in order to make better use of 
results. Finally, the need to avoid the unnecessary repetition of 
experiments was stressed. 
The toxicological methods in Annex V of the sixth amended version of 
Council Directive 67/548/EEC on the classification, packaging and 
labelling of dangerous substances which are the subject of Commission 
Directive 84/449/EEC (14) required updating in 1989. 14 methods in Annex 
V have been reviewed and two new proposals relating to oral acute 
toxicity have been examined. These will very shortly be covered by a 
corresponding Commission Directive. They were also sent to the OECD so 
that an equivalent approach can be adopted at international level. 
Further steps will have to be taken in this area for all the 
toxicological methods in the Community Directives. 
The Commission carried out two collaborative pilot trials to study the 
possible in vitro and ex vivo replacements for the in vivo methods used 
to evaluate dermal and ocular irritation, which can cause considerable 
suffering to animals (15-16). These pilot trials have produced good 
correlations and should make it possible to replace existing methods by 
in vitro methods (cellular toxicity) or ex vivo methods (on the 
enucleated eye) or tests on the membrane of a hen's egg. 
A compendium of ail the institutes and laboratories which carry out 
toxicological tests has been produced in order to promote more 
coordination of toxicological work and to facilitate more rational use of 
the available facilities in the Member States (17). This compendium, 
which contains details of 129 testing facilities, has been disseminated 
on a large scale in the Member States. The rapid changes in this sphere 
make it necessary to update the compendium periodically by including new 
testing facilities and incorporating any changes in the work of those 
already listed. 
Education and information 
As regards education on toxicology, a study was carried out on the 
university training courses in toxicology in the 12 Member States of the 
European Community (18). The results of this survey, widely distributed 
to universities, students and toxicology laboratories, showed that 
existing training programmes are very varied in many Member States. It 
is important to update the results of the study on a regular basis 
because of the rapid development of this branch of teaching and the 
establishment of new training programmes in this area. 
The Commission has supported the production of course modules in the 
areas of nephrotoxicity, toxicity affecting the reproductive system and 
toxicity by the inhalation pathway. Specific financial aid has been 
given to young toxicologists so that they can complete their training 
with a period of study in well-known laboratories of other Member States. 
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Analytical toxicology 
With a view to promoting the spread of information on clinical toxicology 
in the Member States, the LUX TOX'90 international congress was organized 
by the Commission, the WHO, the World Federation of Associations of 
Clinical Toxicology Centres and Poison Control Centres and the 
international Association of Forensic Toxicologists (19). 
Given the importance of toxicological analyses and the possible effects 
of their results on decision-taking, the Commission is carrying out a 
survey in the 12 Member States at institutions which work in the sphere 
of toxicological analysis. The aim of the survey Is to determine the type 
of tests used, their reliability, the necessary qualifications, the 
respect of good laboratory practices and the capacity of the 
laboratories. To this end, a questionnaire has been drawn up and sent to 
the laboratories. One part concerns the analyses of substances which may 
cause drug addiction. 
The results will improve our knowledge of existing laboratories and their 
opportunities for analysis and will make it easier to locate the 
expertise needed for certain specific toxicological analyses, for example 
the bodies which are able to measure doses of substances, in particular 
in urine, which can lead to drug addiction this being the action taken in 
accordance with the conclusions of the Council and the Ministers of 
Health of the Member States meeting within the Council of 16 May 1989 
concerning the reliability of tests on body fluids to detect the use of 
illicit drugs (OJ C 185 of 22.07.1989, p.2) (20). 
IV CONCLUSIONS 
The study of the biochemical and physiological parameters in humans and 
animals and their variability with regard to "normal" values is the 
essential ground work for the prevention of large-scale epidemics by 
early detection. Indeed, the establishment of ranges of "normal" values 
for such parameters is essential for the detection of pathological 
deviations (which make it possible to identify any aetiological factors 
and/or factors encouraging diseases, in particular those of a 
degenerative nature) and for the study of advance biological 
manifestations of such morbid processes which can be detected in a 
population with a particularly high level of this morbidity. 
The programme has also led to Community-1eve I improvements in the 
prevention of acute poisoning and the in vitro methodology used in 
experimental toxicology. It has also included work on improvements in 
toxicological analyses of drugs. 
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Longer-term work has been started and should be continued. Work on the 
validity of the extrapolation of data from animal experiments to humans 
should be developed, in particular. 
All these conclusions show how important it is to continue the programme 
in the appropriate way, to broaden its aims and especially to lay the 
foundations for the effective prevention of large-scale epidemics so that 
the precious gift of health can be protected In an effective manner. 
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V REFERENCES 
1. Resolution of the Council and the Representatives of the Member 
States meeting within the Council of 29 May 1986 concerning a 
Community programme of action in the field of toxicology for health 
protection (OJ C 184/01 of 23 July 1986) 
2. Immunotoxicology - International Seminar of the Immunological System 
as a Target for Toxic Damage 
Luxembourg, November 1984 - EUR 10041 EN - IPCS Joint Symposia -
Martinus Nyhoff publishers 1987 
3. Immunotoxicity of Metals and Immunotoxicology Proceedings of an 
International Workshop (together with the IPCS (International 
Programme on Chemical Safety) / WH0-IL0-UNEP) and the "International 
Commission on Occupational Health" (ICOH), the Federal German 
Ministry for the Environment, Nature Conservation and Nuclear Safety 
and the Federal German Health Office on "Immunotoxicity of Metals and 
Immunotox i coIogy") 
EUR 12764 (EN) IPCS Joint Symposia, No. 15, published by Plenum 
Press, New York and London 1990 
4. Health Significance and Early Detection of Nephrotoxicity; 
Proceedings of the Joint CEC/IPCS workshop held in Luxembourg on 26-
29 April 1988. 
Toxicology letters vol. 46 Nos. 1-3, March 1989, Elsevier 
5. Principles and Methods for the Assessment of Nephrotoxicity 
associated with Exposure to Chemicals (in press) (EUR 13222) 
6. Carcinogenicity Summary reviews of the Scientific Evidence 
Volume I EUR 12029 EN (1989) 
Volume II EUR 12481 EN (1990) 
7. Survey of Poison Control Centres and related Toxicological Services 
1984-1986 
Journal de toxicologie clinique et expérimentale Septembre/Octobre 
1988 - No. 5 - 8eme année 
8. Availability of antidotes - Oslo 
CEC/V/E/1/LUX/54/89 
9. Resolution of the Council and the Representatives of the Governments 
of the Member States meeting within the Council of 3 December 1990 on 
improving the prevention and treatment of acute human poisoning (0J C 
329/03 of 31 December 1990) 
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10. Biological Indicators for the Assessment of Human Exposure to 
Industrial Chemicals: 
Benzene, Cadmium, Chlorinated Hydrocarbon Solvents, Lead, Manganese, 
Titanium, Toluene - EUR 8476 (1983) 
Aerylonitrile, Aluminium, Chromium, Copper, Styrene, Xylene, Zinc -
EUR 8903 (1984) 
A Iky I Lead Compounds, DimethyIformamide, Mercury, Organophosphorus 
Pesticides - EUR 11135 (1987) 
Aldrin and Dieldrin, Arsenic, Cobalt, Endrin, Vanadium - EUR 11135 
(1987) 
Aromatic amines, aromatic nitro compounds, carbamate pesticides, 
nickel - EUR 11478 EN (1988) 
Beryllium, Carbon Monoxide, Ethyl benzene, Methylstyrene, 
Isopropylbenzene, Inhalation Anaesthetics, Selenium EUR 12174 EN 
(1989) 
11. Indicators for Assessing Exposure and Biological Effects of Genotoxic 
Chem i caI s. 
Consensus report EUR 11659 EN (1988) 
Consensus and technical reports EUR 11642 EN (1988) 
12. Trace Elements reference values in tissues from inhabitants of the 
European Community. 
CEC-Joint Research Centre/Health and Safety Directorate, March 1990 
13. Council Directive of 24 November 1986 (86/609/EEC) on the 
approximation of laws, regulations and administrative provisions of 
the Member States regarding the protection of animals used for 
experimental and other scientific purposes 
(OJ L 358/01 of 18 December 1986) 
14. Commission Directive 84/449/EEC of 25 April 1984 adapting to 
technical progress for the sixth time Council Directive 67/548/EEC on 
the approximation of laws, regulations and administrative provisions 
relating to the classification, packaging and labelling of dangerous 
substances 
(OJ L 251 of 19 September 1984, pp. 94-145) 
15. Collaborative Study on Relationship between "in Vivo" Primary 
Irritation and "in Vitro" Experimental Models CEC/V/E/3/LUX/157/88-
REV.1 
16. Collaborative Study on the Evaluation of Alternative Methods to the 
Eye Irritation Test (to be published) 
17 Compendium of Toxicological testing Facilities in the European 
Commun i t i es 
EUR 11547 EN (1988) 
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18. Survey of Training Programmes in Toxicology in the Member States of 
the European Community - EUR 12386 EN (1989) 
19. a) Proceedings of the International Congress on Clinical Toxicology, 
Poison Control and Analytical Toxicology - LUX TOX'90 of 2-5 May 
1990, Luxembourg: Bulletin de la Société des Sciences Médicales du 
Grand-Duché de Luxembourg, Numéro Spécial 1990 - 127e année 
b) Round table discussion of the Congress of 5 May 1990 
20. Conclusions of the Council and the Ministers for Health of the Member 
States meeting within the Council of 16 May 1989 concerning the 
reliability of tests on body fluids to detect the use of illicit 
drugs (OJ C 185/02 of 22 July 1989) 

ISSN 0254-1475 
COM(91) 341 final 
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